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Query
Query Results Date
RX.TRANS='0/80F51(02)|80F42(030405)|40F61()|01E62()| 636 reactions
1. Query 2023-12-30 09h:33m:37s (UTC)
01E41(06)|01D41(07)|01C41(08)|01B41(*)|*' in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

O HN
2

O O
N N
H H
HO O

Rx-ID: 2071970 View in Reaxys 1/636

Yield Conditions & References
100 % Stage 1: With triethylamine, isobutyl chloroformate in tetrahydrofuran, Time= 0.166667h, T= 0 °C , Inert atmosphere
Stage 2: With ammonia in tetrahydrofuran, Time= 0.5h, T= 20 °C , Inert atmosphere

Simon, Matthieu; Ali, Lamiaa M. A.; El Cheikh, Khaled; Aguesseau, Julie; Gary-Bobo, Magali; Garcia, Marcel;
Morère, Alain; Maillard, Ludovic T.; Chemistry - A European Journal; vol. 24; nb. 44; (2018); p. 11426 - 11432
View in Reaxys

100 % 1.II.2.1 : Step 1 :

To a solution of 5-(Boc-amino)pentanoic acid (1 .0 equiv., 36.8 mmol, 8.0 g) in anhydrous THF at 0°C and under
argon atmosphere were sequentially added IBCF (1 .2 equiv.) and triethylamine (1 .2 equiv.). The white suspension
was stirred for 10 min until complete formation of the mixed anhydride (HPLC monitoring). Then gaseous ammonia
was bubbled for 30 min at r.t. to yield A/-Boc-aminovaleramide I as a white powder. Yield quantitative (8.02 g). 1 H
NMR (400 MHz, DMSO-cfe) d 1 .37 (s, 9H); 1 .42- 1 .46 (m, 4H); 2.01 (t, J = 7.2 Hz, 2H); 2.88 (m, 2H); 6.68 (s, 1 H);
6.76 (t, 1 H, J = 5.4 Hz); 7.21 (s, 1 H).

Stage 1: With triethylamine, isobutyl chloroformate in tetrahydrofuran, Time= 0.166667h, T= 0 °C , Inert atmosphere
Stage 2: With ammonia in tetrahydrofuran, Time= 0.5h, T= 20 °C , Inert atmosphere

PatentUNIVERSITE DE MONTPELLIER;CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE;ECOLE NA‐

TIONALE SUPERIEURE DE CHIMIE DE MONTPELLIER (ENSCM);INSTITUT DE RECHERCHE POUR LE DE‐
VELOPPEMENT;CENTRE HOSPITALIER UNIVERSITAIRE DE MONTPELLIER; INSTITUT DE RECHERCHE
POUR LE DEVELOPPEMENT (IRD); CENTRE HOSPITALIER UNIVERSITAIRE DE MONTPELLIER; UNIVERSITY
OF MONTPELLIER; ECOLE NATIONALE SUPERIEURE DE CHIMIE DE MONTPELLIER; CENTRE NATIONAL
DE LA RECHERCHE SCIENTIFIQUEIRD France; CHU de Montpellier; University of Montpellier; ENSCM; CNRS;
WO2020/64909; (2020); (A1) English
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95 % With ammonia, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride in tetrahydrofuran, methanol,

Time= 2h, T= 20 °C

Mizuhara, Tsukasa; Hioki, Kazuhito; Yamada, Megumi; Sasaki, Hideaki; Morisaki, Daiki; Kunishima, Muneta‐
ka; Chemistry Letters; vol. 37; nb. 12; (2008); p. 1191 - 1192
View in Reaxys

59 % 5.b :Isobutyl chloroformate (1.55 ml, 12 mmol) in tetrahydrofuran (5 ml) was added dropwise over approximately 5
minutes to a vigorously stirred solution of 5-((t- butoxycarbonyl)amino)pentanoic acid (2.61 g., 12 mmol) and N-meth‐
ylmorpholine (1.32 ml., 12 mmol) in tetrahydrofuran (15 ml) at -15°C, while maintaining the reaction temperature be‐
tween - 25°C and -15°C. The reaction mixture was stirred for 12 minutes, and then 10 ml of a solution of ammonia in
methanol (saturated at 0°C) was added dropwise over 30 minutes at approximately - 15°C. The reaction mixture was
stirred an additional 30 minutes in the cold, and then allowed to warm to room temperature and left to stir overnight.
The thick white suspension was diluted with water, concentrated in vacuo to remove organic solvents and then ex‐
tracted with ethyl acetate (150 ml). The ethyl acetate solution was washed with water, 10 % potassium bisulfate, wa‐
ter and brine, dried (anhydrous sodium sulphate), and evaporated to give 1.54 g (59% yield) of white solid product;
m.p. 136-139°C, [M/Z M+l = 217 & 161 (-tBu)].

Stage 1: With 4-methyl-morpholine, isobutyl chloroformate in tetrahydrofuran, Time= 0.283333h, T= -25 - 15 °C

Stage 2: With ammonia in tetrahydrofuran, methanol, T= -15 - 20 °C

PatentNUMEDICUS LIMITED;CAVALLA, David; NUMEDICUS<unknown>; WO2012/143703; (2012); (A1) Eng‐

lish
View in Reaxys

With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, -10 deg C, 20 min., 2.) -10 deg C to
room temp., overnight, Yield given. Multistep reaction

Houssin, Raymond; Bernier, Jean-Luc; Henichart, Jean-Pierre; Synthesis; nb. 3; (1988); p. 259 - 261
View in Reaxys

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 With ammonia, chloroformic acid ethyl ester, triethylamine, 1.) chloroform, 0 deg C, 8 min; 2.) chloroform, RT, 2-4 h,
Yield given. Multistep reaction

Schlewer; Wermuth; Chambon; European Journal of Medicinal Chemistry; vol. 19; nb. 2; (1984); p. 181 - 186
View in Reaxys

Reaction Steps: 2
1: 1,3-dicyclohexylcarbodiimide / propan-2-ol / 3.5 h / 0 - 20 °C
2: 3.5 g / ammonia / propan-2-ol / 0 - 20 °C
With ammonia, dicyclohexyl-carbodiimide in isopropyl alcohol

Song, Yongsheng; Goel, Atul; Basrur, Venkatesha; Roberts, Paula E.A; Mikovits, Judy A; Inman, John K; Tur‐
pin, Jim A; Rice, William G; Appella, Ettore; Bioorganic and Medicinal Chemistry; vol. 10; nb. 5; (2002); p. 1263 -
1273
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780 mg 137.2 : Step 2: Preparation of tert-butyl N-(5-amino-5-oxo-pentyl)carbamate

To a stirred solution of 5-(tert-butoxycarbonylamino)pentanoic acid (1.0 g, 4.6 mmol) and 4-methylmorpholine (0.51
g, 5.06 mmol) in THF (20 mL) was added isobutyl chloro formate (0.69 g, 5.06 mmol) at -20 °C. The resulting mixture
was warmed to 0 °C and stirred for lhr. Then to the resulting mixture was added a solution of N in MeOH (saturated
at 0 °C) drop wise. After being stirred at 0 °C for 0.5 fir and warmed up to rt, The resulting mixture was stirred under
N2for 16 hrs at rt, and then concentrated in vacuo. The residue was diluted with H20 (30 mL) and extracted with EA
(30 mL) for three times. The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2S04,
concentrated in vacuo to give tert-butyl N-(5-amino-5-oxo-pentyl)carbamate (780 mg) as a white solid, which was
used in the next step directly without any further purification.

Stage 1: With 4-methyl-morpholine in tetrahydrofuran, Time= 1h, T= -20 - 0 °C

Stage 2: With ammonia in tetrahydrofuran, methanol, Time= 16.5h, T= 0 - 20 °C , Inert atmosphere

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.;CHENG, Zhanling;HAN, Xingchun;JIANG,

Min;WANG, Jianhua;WANG, Yongguang;YANG, Song; ROCHE HOLDING AGRoche; WO2018/1952; (2018); (A1)
English
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4.5.3 General procedure C for the synthesis of amine hydrochlorides of general structure 17
General procedure: A 20-mL vial was charged with Boc-protected amino acid (specified below; 1 equiv) and tetrahy‐
drofuran (0.15M). 1,1′-Carbonyldiimidazole (1.50 equiv) was added and the resulting mixture was stirred for 1h at
23°C. A solution of ammonia in methanol (7.00M, 5.00 equiv) was added to the reaction mixture, and the resulting
mixture was stirred for 12hat 23°C. The product mixture was concentrated, and the residue obtained was diluted with
ethyl acetate (120mL). The diluted product mixture was transferred to a separatory funnel and sequentially washed
with saturated aqueous ammonium chloride solution (1×50mL), saturated aqueous sodium bicarbonate solution
(1×50mL), and saturated aqueous sodium chloride solution (1×50mL). The organic layer was dried over sodium sul‐
fate. The dried solution was filtered and the filtrate was concentrated. The product thus obtained was transferred to a
20-mL vial. A solution of hydrogen chloride in dioxane (4.00M, 5.00 equiv) was added and the resulting mixture was
stirred at 23°C for 1h. The product mixture was concentrated, providing the amine hydrochloride of general structure
17. The product so obtained was used without further purification.

Stage 1: With 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 1h, T= 23 °C , Inert atmosphere

Stage 2: With ammonia in tetrahydrofuran, methanol, Time= 12h, T= 23 °C , Inert atmosphere

Nikolayevskiy, Herman; Robello, Marco; Scerba, Michael T.; Pasternak, Evan H.; Saha, Mrinmoy; Hartman,
Tracy L.; Buchholz, Caitlin A.; Buckheit, Robert W.; Durell, Stewart R.; Appella, Daniel H.; European Journal of
Medicinal Chemistry; vol. 178; (2019); p. 818 - 837
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Reaction Steps: 2
1: triethylamine / tetrahydrofuran / 0.17 h / 0 °C / Inert atmosphere
2: ammonia / tetrahydrofuran / 0.5 h / 20 °C
With ammonia, triethylamine in tetrahydrofuran

Bonnel, Clément; Legrand, Baptiste; Simon, Matthieu; Clavié, Margaux; Masnou, Agnès; Jumas-Bilak, Es‐
telle; Kang, Young Kee; Licznar-Fajardo, Patricia; Maillard, Ludovic T.; Masurier, Nicolas; Journal of Medicinal
Chemistry; vol. 63; nb. 17; (2020); p. 9168 - 9180

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 View in Reaxys

HO

NH 2

Rx-ID: 254093 View in Reaxys 2/636

Yield Conditions & References
99 % 2.2.1 Synthesis of N-(2-amino-ethyl)-3-{[2-(2-amino-ethylcarbamoyl)ethyl]behenylamino}propionamide 4
To 50 mL of toluene were added 5.5 g (16.17 mmol) of behenic acid. Then, to the resulted dispersion was added
dropwised 10.26 g (80.78 mmol) of oxalyl chloride and the complete mixture was stirred refluxing for 2 h under argon
atmosphere. The solvent and unreacted reagents were both removed under reduced pressure to produce colored oil
which was introduced in 50 mL of THF without further purification. In the next step, 20 mL of 25% NH4OH aqueous
solution was added to the previous clear yellow solution and a white solid started to precipitate which was succes‐
sively filtrated on Buchner, washed with a slight volume of water and THF (mass=5.43 g; yield=99%). The recovered
behenamide powder was dried in a dessicator and remained insoluble in common organic solvents. FT-IR: 3396cm-
1 (NH); 2849-2916cm- 1 (CH ); 1647 and 1526cm-1 (amide). MS: Calcd (M+H+) 339 found 339.23.
2

Stage 1: With oxalyl dichloride in toluene, Time= 2h, Inert atmosphere, Reflux
Stage 2: With ammonium hydroxide in water

Adenier, Guillaume; Delbecq, Frederic; Kawai, Takeshi; Ogue, Yuki; Journal of Molecular Liquids; vol. 303;
(2020)
View in Reaxys

98.7 % 18 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 7h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

With phosphorus pentachloride, T= 160 °C , man versetzt nach Entfernung des POCl3 mit konz.Ammoniak

Fileti; Ponzio; Gazzetta Chimica Italiana; vol. 23 II; (1893); p. 392; Gazzetta Chimica Italiana; vol. 27 II; (1897); p.
298
View in Reaxys

Reaction Steps: 2
1: SOCl2 / Heating
2: ammonia gas / CHCl3

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 With thionyl chloride, ammonia in chloroform

Weissbuch, I.; Majewski, J.; Kjaer, K.; Als-Nielsen, J.; Lahav, M.; Leiserowitz, L.; Journal of Physical Chemistry;
vol. 97; (1993); p. 12848 - 12857
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Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

HO O

O NH 2

Rx-ID: 667448 View in Reaxys 3/636

Yield Conditions & References
98.9 % 14 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 9h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

With ammonia, T= 190 - 210 °C

Ralston; Hoerr; Pool; Journal of Organic Chemistry; vol. 8; (1943); p. 474

View in Reaxys

Reaction Steps: 2
1: phosphorus trichloride
2: ammonia / 0 °C
With ammonia, phosphorus trichloride

Blau; Monatshefte fur Chemie; vol. 26; (1905); p. 107

View in Reaxys

With Diethy phosphocyanidate, ammonia in 1,4-dioxane, N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

With ammonia in poly(ethylene glycol) 400, Time= 72h, T= 20 °C , Enzymatic reaction

Kidwai, Mazaahir; Poddar, Roona; Bhardwaj, Saurav; Biocatalysis and Biotransformation; vol. 29; nb. 4; (2011);
p. 113 - 118
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / toluene / 2 h / 70 °C
2: ammonia / 10 °C
With oxalyl dichloride, ammonia in toluene

PatentACUITAS THERAPEUTICS INC.; ACUITAS THERAPEUTICS INCAcuitas Therapeutics; WO2015/199952;

(2015); (A1) English
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / toluene / 2 h / 70 °C
2: ammonium hydroxide / 10 °C
With ammonium hydroxide, oxalyl dichloride in toluene

PatentTHE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA;ACUITAS THERAPEUTICS INC.;TAM,

Ying;HOPE, Michael, J.; UNIVERSITY OF PENNSYLVANIAUniversity of Pennsylvania; WO2016/176330; (2016);
(A1) English
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / toluene / 2 h / 70 °C
2: ammonium hydroxide / neat (no solvent) / 10 °C
With ammonium hydroxide, oxalyl dichloride in toluene

PatentACUITAS THERAPEUTICS, INC.; ACUITAS THERAPEUTICS INCAcuitas Therapeutics; WO2018/81480;

(2018); (A1) English
View in Reaxys
PatentTHE TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA;ACUITAS THERAPEUTICS, INC.;WEISSMAN,
Drew;PARDI, Norbert; ACUITAS THERAPEUTICS INCAcuitas Therapeutics; WO2018/81638; (2018); (A1) English
View in Reaxys

With Pseudoalteromonas tunicata TamA catalytic adenylation domain, ammonia, ATP, magnesium chloride in di‐
methyl sulfoxide, pH= 9, Enzymatic reaction

Marchetti, Piera M.; Richardson, Shona M.; Kariem, Noor M.; Campopiano, Dominic J.; MedChemComm; vol.
10; nb. 7; (2019); p. 1192 - 1196
View in Reaxys

HO O

O NH 2

Rx-ID: 731771 View in Reaxys 4/636

Yield Conditions & References
98 % 15 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 6/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 7h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

67 % Stage 1: With benzotriazol-1-ol, O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, triethylamine

in dichloromethane, Time= 0.5h
Stage 2: With ammonium chloride in dichloromethane

Ghidini, Andrea; Scalvini, Laura; Palese, Francesca; Lodola, Alessio; Mor, Marco; Piomelli, Daniele; Journal
of Enzyme Inhibition and Medicinal Chemistry; vol. 36; nb. 1; (2021); p. 1411 - 1423
View in Reaxys

25 % (21) General Procedure for Amide Coupling

General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI
(0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After
12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addi‐
tion of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL).
The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide.

Stage 1: With 1,1'-carbonyldiimidazole in dichloromethane, Time= 0.5h, T= 20 °C

Stage 2: With ammonia in dichloromethane, Time= 12h

Johansson, Silje J. R.; Johannessen, Tonje; Ellefsen, Christiane F.; Ristun, Mali S.; Antonsen, Simen; Han‐
sen, Trond V.; Stenstrom, Yngve; Nolsoe, Jens M. J.; Synlett; vol. 30; nb. 2; (2019); p. 213 - 217; Art.No:
ST-2018-D0672-L
View in Reaxys

With ammonia, T= 190 - 210 °C

Ralston; Hoerr; Pool; Journal of Organic Chemistry; vol. 8; (1943); p. 474

View in Reaxys

With pyridine, SULFAMIDE, T= 130 °C

Kirsanow; Solotow; Zhurnal Obshchei Khimii; vol. 19; (1949); p. 2201,2205; Chem.Abstr.; (1950); p. 4446
View in Reaxys

With Diethy phosphocyanidate, ammonia in N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121
View in Reaxys

Reaction Steps: 2
1: thionyl chloride / 0.5 h / Reflux
2: ammonia / water / Cooling with ice
With thionyl chloride, ammonia in water

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Louw, Stefan; Burger, Ben V.; Le Roux, Maritha; Van Wyk, Johannes H.; Journal of Natural Products; vol. 74;
nb. 6; (2011); p. 1364 - 1369
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With ammonia in poly(ethylene glycol) 600, Time= 72h, T= 20 °C , Enzymatic reaction

Kidwai, Mazaahir; Poddar, Roona; Bhardwaj, Saurav; Biocatalysis and Biotransformation; vol. 29; nb. 4; (2011);
p. 113 - 118
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / benzene / 3 h
2: ammonia / dichloromethane
With oxalyl dichloride, ammonia in dichloromethane, benzene

PatentACUITAS THERAPEUTICS INC.; ACUITAS THERAPEUTICS INCAcuitas Therapeutics; WO2015/199952;

(2015); (A1) English
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With ammonia, silica gel, T= 150 - 170 °C

PatentI.G.Farbenind.; I.G. FARBENINDUSTRIE AG (historic)I.G. Farben; DE621963; (1932); (C); Fortschr. Teerfar‐
benfabr. Verw. Industriezweige; vol. 21; p. 191; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 21; p. 191
View in Reaxys

71 % Stage 1: With 1,1'-carbonyldiimidazole in acetonitrile, T= 30 - 70 °C , Inert atmosphere

Stage 2: With potassium tert-butylate, formamide in water, acetonitrile, T= 30 °C , Inert atmosphere

Patel, Manisha A.;Kapdi, Anant R.; Chemistry - An Asian Journal; vol. 18; nb. 22; (2023); Art.No: e202300672
View in Reaxys

HO

NH 2

Rx-ID: 736112 View in Reaxys 5/636

Yield Conditions & References
98.4 % 1 :According to the embodiment of the present invention described above, stearic acid amide, which is a kind of car‐
boxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid injector 250 injects
1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120 ° C. Subsequently,
when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects 10 g of tetraisopropyl
titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater attached to the first
reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the first ammonia injector
281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr. When 500 g of stearic
acid was charged into the first reaction tank 210, the introduction of stearic acid into the first reaction tank 210 was
stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia while maintaining the
reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stearic acid to the first
reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the valve is changed to
be supplied to the second reaction tank 220. When stearic acid is injected into the second reaction tank 220, the
second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the second reaction tank
220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into the second reac‐
tion tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammonia pipe 283 at a
rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of stearic acid to

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 8/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with stearic acid
and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.

With titanium(IV) isopropylate, ammonia, Time= 7h, T= 165 °C , Large scale, Reagent/catalyst, Temperature

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

82 % With ammonium bicarbonate, formamide, Time= 0.15h, Irradiation

Peng, Yanqing; Song, Gonghua; Organic Preparations and Procedures International; vol. 34; nb. 1; (2002); p. 95 -
97
View in Reaxys

23 % (21) General Procedure for Amide Coupling

General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI
(0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After
12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addi‐
tion of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL).
The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide.

Stage 1: With 1,1'-carbonyldiimidazole in dichloromethane, Time= 0.5h, T= 20 °C

Stage 2: With ammonia in dichloromethane, Time= 12h

Johansson, Silje J. R.; Johannessen, Tonje; Ellefsen, Christiane F.; Ristun, Mali S.; Antonsen, Simen; Han‐
sen, Trond V.; Stenstrom, Yngve; Nolsoe, Jens M. J.; Synlett; vol. 30; nb. 2; (2019); p. 213 - 217; Art.No:
ST-2018-D0672-L
View in Reaxys

With ammonia, T= 190 - 210 °C

Ralston; Hoerr; Journal of Organic Chemistry; vol. 8; (1943); p. 474

View in Reaxys

With ammonia, water, T= 300 °C

Seipioni; Zanetti; ; vol. 116; (1958); p. 153,157,159

View in Reaxys

With ammonia, unter Druck

PatentChem.Werke Hansa; Chem.Werke Hansa; DE189477; (1800); (C)

View in Reaxys

With benzoyl chloride, T= 110 - 120 °C , nachfolgende Behandlung des Reaktionsproduktes mit Ammoniak in Ge‐
genwart von Natronlauge

Orton; Journal of the Chemical Society; vol. 79; (1901); p. 1355

View in Reaxys

With ammonium chloride, water, T= 200 °C

Seipioni; Zanetti; ; vol. 116; (1958); p. 153,157,159

View in Reaxys

Reaction Steps: 2
1: benzene; PCl5
2: diethyl ether; NH3
With diethyl ether, phosphorus pentachloride, ammonia, benzene

Sherk; Augur; Soffer; Journal of the American Chemical Society; vol. 67; (1945); p. 2240
View in Reaxys

0.7 g 1 : Preparation of Gelling Agents

(70%) Stearamide (8). The amide was prepared by a common recipe. Thionyl chloride (0.6 g, 6 mmol) was slowly added to
stearic acid (1.0 g, 3.5 mmol) and the mixture was heated at 55° C. for 2 h under a dry atmosphere. Excess thionyl
chloride was removed by distillation and the remaining liquid (stearoyl chloride) was slowly added to 15 mL of an

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 aqueous 30% ammonia solution at 0° C. The precipitate that formed was collected by vacuum filtration and was re‐
crystallized from ethyl acetate to yield 0.7 g (70%) of product, mp 108.6-109.0° C. (lit4 108.4° C.).

With thionyl chloride, ammonia

PatentWeiss, Richard G.;Viswanatha Mallya, Ajaya Mallia; GEORGETOWN UNIVERSITYGeorgetown University;

US2011/251294; (2011); (A1) English
View in Reaxys

Reaction Steps: 2
1: thionyl chloride / 2 h / 55 °C
2: ammonia / water / 0 °C
With thionyl chloride, ammonia in water

PatentGEORGETOWN UNIVERSITY;WEISS, Richard G.;VISWANATHA MALLYA, Ajaya Mallia; GEORGETOWN

UNIVERSITYGeorgetown University; WO2012/47251; (2012); (A1) English
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / benzene / 72 h
2: ammonia / benzene
With oxalyl dichloride, ammonia in benzene

PatentACUITAS THERAPEUTICS INC.; ACUITAS THERAPEUTICS INCAcuitas Therapeutics; WO2015/199952;

(2015); (A1) English
View in Reaxys

A : Amide Intermediate Preparation Example A

General procedure: Into a 1L open reactor was added 500g of carboxylic acid feedstock (chemically pure), stirring
was turned on (600 r/min), ammonia gas was continuously fed to the carboxylic acid feed from the bottom of the
reactor (chemical purity, water content was 5.1wt%, Flow rate is 100g/min). After the reaction was allowed to pro‐
ceed for TC hours at the reaction temperature TA, the ammonia gas flow was stopped. The contents of the reactor
were sampled and nuclear magnetic proton spectra and elemental analysis were performed to characterize the
amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Ta‐
ble A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the obtained amide intermedi‐
ate has an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with
waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest
were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammo‐
nia was 130g/min).

With ammonia, Time= 0.5h, T= 145 °C , Temperature

PatentSinopec Corporation;Sinopec Yangzi Petrochemical Co., Ltd.;Sun Hailong;Wei Yanyu;Gao Yilong;Chen Xin‐
hua;Miao Jun;Li Na;Kan Lin;Bai Jiye;Chen Shaohui;Yang Aiwu;Xu Yuexing; CHINA PETROCHEMICAL CORPORA‐
TIONSinopec Group; CN104557610; (2018); (B) English
View in Reaxys

1 : [Example 1]
According to the flow shown in FIG. 1, fatty acid amide was produced. First, stearic acid (carbon number of alkyl
group: 17) which is heated and melted at about 130 ° C to be liquid is supplied to the reactor 10, and ammonia gas
of about 5 times amount in molar ratio with respect to stearic acid supplied per unit time was fed into the reactor 10.
The supply amount of ammonia gas was 122 m 3 / hr, and the flow rate was 1 m / sec. The inside of the reactor 10
was maintained at a temperature of 130 ° C and a pressure of 608.0 Pa (6 atm) and reaction was performed. The
temperature and pressure inside the reactor 10 can be controlled by a known method. In the present embodiment,
as shown in FIG. 2, the interior of the reactor 10 has a structure including a desulfurization layer 10 A and a catalyst
layer fractionated into three regions (first region 11A, a second region 11B, and a third region 11C), and in the desul‐
furization layer 10 A, an alumina-molybdenum catalyst as a desulfurizing agent is placed, and sulfur compound as
impurities contained in the starting material fatty acid is removed. When the raw material fatty acid from which the
sulfur compound has been removed passes through the first region 11 A, the second region 11 B, and the third re‐
gion 11 C of the catalyst layer, the reaction with the ammonia gas proceeds in the presence of the amidation cata‐
lyst, and fatty acid amide is formed. In this example, as an amidation catalyst, an equal amount mixture of copper
oxide and zinc oxide, which are low temperature type carbon monoxide conversion catalyst, were placed in amounts
of each 500 SV. The reaction was carried out continuously at the above flow rate for 24 hours.The resulting fatty acid
amide in a fluid state was conveyed to a flaker 16 to obtain a solid fatty acid amide having a flake shape. The ob‐

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 tained flaky fatty acid amide was recovered in the silo 18.The recovery amount of fatty acid amide in continuous re‐
action for 24 hours was 99% or more of the theoretical yield with respect to the supply amount of fatty acid. Consid‐
ering the influence of inevitable impurities and the like, the yield was close to 100% of the theoretical yield, and the
yield was very good. In this example, production of fatty acid amide was continuously carried out for 24 hours, but
there was no inconvenience such as a decrease in reactivity between fatty acid and ammonia gas and troubles of
the apparatus.As is clear from this example, the reaction of the fatty acid amide is a simple reaction, and by measur‐
ing the supply amount of the raw material fatty acid and the recovery amount of the fatty acid amide, it can also be
said that the purity can be estimated even without analyzing the obtained fatty acid amide is one of the features of
the production method of the present disclosure.

With ammonia, T= 130 °C , p= 4560.31Torr , Reagent/catalyst

PatentSENSHIN KOGAKU KENKYUSHO K.K.;TAKANO, FUJIO;HAN, WEI; SENNSHIN KOGAKU KEN‐

KYUSHO<unknown>; JP2018/118952; (2018); (A) English
View in Reaxys

With ammonia, silica gel, T= 150 - 170 °C

PatentI.G.Farbenind.; I.G. FARBENINDUSTRIE AG (historic)I.G. Farben; DE621963; (1932); (C); Fortschr. Teerfar‐
benfabr. Verw. Industriezweige; vol. 21; p. 191; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 21; p. 191
View in Reaxys
PatentI.G.Farbenind.; I.G. FARBENINDUSTRIE AG (historic)I.G. Farben; US2013108; (1933); (A); Fortschr. Teer‐
farbenfabr. Verw. Industriezweige; vol. 21; p. 191; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 21; p. 191
View in Reaxys

HO O

O NH 2

Rx-ID: 793298 View in Reaxys 6/636

Yield Conditions & References
98.9 % 12 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 8h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

90 % With silica gel, ammonium chloride, triethylamine, p-toluenesulfonyl chloride, Time= 0.0166667h, T= 20 °C

Khalafi-Nezhad, Ali; Parhami, Abolfath; Soltani Rad, Mohammad Navid; Zarea, Abdolkarim; Tetrahedron Let‐
ters; vol. 46; nb. 40; (2005); p. 6879 - 6882
View in Reaxys

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 11/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 90 % With borane-ammonia complex in 5,5-dimethyl-1,3-cyclohexadiene, Time= 12h, Reflux

Ramachandran, P. Veeraraghavan;Hamann, Henry J.;Choudhary, Shivani; Organic Letters; vol. 22; nb. 21;
(2020); p. 8593 - 8597
View in Reaxys

89 % With 1H-imidazole, urea in octane, Time= 24h, T= 120 °C , Reagent/catalyst

Blacker, A. John; Chhatwal, A. Rosie; Lomax, Helen V.; Marcé, Patricia; Williams, Jonathan M. J.; Chemical
Science; vol. 11; nb. 22; (2020); p. 5808 - 5818
View in Reaxys

85 % With 1H-imidazole, urea, Time= 0.0277778h, microwave irradiation

Khalafi-Nezhad, Ali; Mokhtari, Babak; Rad, Mohammad Navid Soltani; Tetrahedron Letters; vol. 44; nb. 39;
(2003); p. 7325 - 7328
View in Reaxys

61 % With ammonium chloride, triethylamine, Time= 0.0166667h, T= 20 °C

Khalafi-Nezhad, Ali; Zare, Abdolkarim; Parhami, Abolfath; Rad, Mohammad Navid Soltani; Nejabat, Gholam
Reza; Phosphorus, Sulfur and Silicon and the Related Elements; vol. 182; nb. 3; (2007); p. 657 - 666
View in Reaxys

With ammonia, T= 160 - 180 °C

Mitchell; Reid; Journal of the American Chemical Society; vol. 53; (1931); p. 1880,1881
View in Reaxys

With ammonium hydroxide, thionyl chloride, Yield given. Multistep reaction

Boutin, Raymond H.; Loudon, G. Marc; Journal of Organic Chemistry; vol. 49; nb. 22; (1984); p. 4277 - 4284
View in Reaxys

Reaction Steps: 2
1: 2 h / 80 °C / Ionic liquid
2: ammonium acetate; triethylamine / 3 h / 80 °C / Ionic liquid
With ammonium acetate, triethylamine

Lee, Kwan Soo; Kim, Kee D.; Synthetic Communications; vol. 41; nb. 23; (2011); p. 3497 - 3500
View in Reaxys

HO

NH 2

Rx-ID: 18732496 View in Reaxys 7/636

Yield Conditions & References
98 % 7 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 12/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With titanium(IV) isopropylate, ammonia, Time= 7.5h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

Reaction Steps: 2
1: SOCl2
2: NH3
With thionyl chloride, ammonia

Weinbach, Susan P.; Jacquemain, Didier; Leveiller, Franck; Kjaer, Kristian; Als-Nielsen, Jens; Leiserowitz,
Leslie; Journal of the American Chemical Society; vol. 115; nb. 24; (1993); p. 11110 - 11118
View in Reaxys

Reaction Steps: 2
1: SOCl2 / Heating
2: ammonia gas / CHCl3
With thionyl chloride, ammonia in chloroform

Weissbuch, I.; Majewski, J.; Kjaer, K.; Als-Nielsen, J.; Lahav, M.; Leiserowitz, L.; Journal of Physical Chemistry;
vol. 97; (1993); p. 12848 - 12857
View in Reaxys

Reaction Steps: 2
1: thionyl chloride / 0.5 h / Reflux
2: ammonia / water / Cooling with ice
With thionyl chloride, ammonia in water

Louw, Stefan; Burger, Ben V.; Le Roux, Maritha; Van Wyk, Johannes H.; Journal of Natural Products; vol. 74;
nb. 6; (2011); p. 1364 - 1369
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

O NH 2 NH 2

HO O HO
OH O O

O NH 2 O

Rx-ID: 36022474 View in Reaxys 8/636

Yield Conditions & References
15.7 %, 65 5 :Example 5 Efficacy of TiO2 and ZrO2 Supports in Production of Amides [0061] To illustrate the unexpected benefi‐
% cial effects of TiO2 and ZrO2 in the process of the present invention, particularly with regard to the pathway by which
caprolactam is believed to be produced from adipic acid, 20 mg of support and 2.92 mg of Adipic Acid were dis‐
pensed into a 1 mL glass vial contained in a 96-well reactor insert. Next was added 0.2 mL of a solvent mixture con‐
taining 10% v/v aqueous NH4OH (ca. 15M NH3 in H2O) in tert-BuOH or a solvent mixture containing 10% v/v H2O in
tert-BuOH. The vial was covered with a Teflon pinhole sheet, a silicone pinhole mat, and a steel gas diffusion plate.
The reactor insert was placed in a pressure vessel and purged three times with N2. The pressure vessel was then
charged twice with ammonia gas to 10 psig with venting after each pressurization step. The reactor was finally
charged to 10 psig with ammonia gas and placed on a shaker at 500 rpm for 15 minutes at ambient temperature.

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 The reactor was then brought to 825 psig with hydrogen and placed back on the shaker at 800 rpm and heated to
160° C. for the specified time (30 or 120 minutes). [0062] The reactor was cooled to room temperature, vented, and
purged with nitrogen prior to being unsealed. The samples were diluted with water, mixed, and then centrifuged to
separate support particles. Aliquots were removed from the supernatant and diluted further with dilute aqueous HCl
for analysis by HPLC. Product yield was determined using a calibrated HPLC method with Charged Aerosol Detec‐
tion (CAD). The yield of 6-amino-6-oxohexanoic acid and adipamide is listed below in Tables 4 and 5. As illustrated,
titania and zirconia, without added catalytic metal, have a dramatic effect on the production of the intermediates from
which caprolactam is ultimately produced from adipic acid. For comparison, Table 6 illustrates the relative ineffective‐
ness of employing other known support materials.

With ammonium hydroxide, hydrogen in water, tert-butyl alcohol, Time= 0.5h, T= 20 - 160 °C , p= 1277.21 -
43425.9Torr , Inert atmosphere

PatentRennovia, Inc.; ARCHER-DANIELS-MIDLAND COArcher-Daniels-Midland; US2013/225785; (2013); (A1)

English
View in Reaxys

40.5 %, 5 :Example 5 Efficacy of TiO2 and ZrO2 Supports in Production of Amides [0061] To illustrate the unexpected benefi‐
28.6 % cial effects of TiO2 and ZrO2 in the process of the present invention, particularly with regard to the pathway by which
caprolactam is believed to be produced from adipic acid, 20 mg of support and 2.92 mg of Adipic Acid were dis‐
pensed into a 1 mL glass vial contained in a 96-well reactor insert. Next was added 0.2 mL of a solvent mixture con‐
taining 10% v/v aqueous NH4OH (ca. 15M NH3 in H2O) in tert-BuOH or a solvent mixture containing 10% v/v H2O in
tert-BuOH. The vial was covered with a Teflon pinhole sheet, a silicone pinhole mat, and a steel gas diffusion plate.
The reactor insert was placed in a pressure vessel and purged three times with N2. The pressure vessel was then
charged twice with ammonia gas to 10 psig with venting after each pressurization step. The reactor was finally
charged to 10 psig with ammonia gas and placed on a shaker at 500 rpm for 15 minutes at ambient temperature.
The reactor was then brought to 825 psig with hydrogen and placed back on the shaker at 800 rpm and heated to
160° C. for the specified time (30 or 120 minutes). [0062] The reactor was cooled to room temperature, vented, and
purged with nitrogen prior to being unsealed. The samples were diluted with water, mixed, and then centrifuged to
separate support particles. Aliquots were removed from the supernatant and diluted further with dilute aqueous HCl
for analysis by HPLC. Product yield was determined using a calibrated HPLC method with Charged Aerosol Detec‐
tion (CAD). The yield of 6-amino-6-oxohexanoic acid and adipamide is listed below in Tables 4 and 5. As illustrated,
titania and zirconia, without added catalytic metal, have a dramatic effect on the production of the intermediates from
which caprolactam is ultimately produced from adipic acid. For comparison, Table 6 illustrates the relative ineffective‐
ness of employing other known support materials.

With ammonium hydroxide, hydrogen in water, tert-butyl alcohol, Time= 0.5h, T= 20 - 160 °C , p= 1277.21 -
43425.9Torr , Inert atmosphere

PatentRennovia, Inc.; ARCHER-DANIELS-MIDLAND COArcher-Daniels-Midland; US2013/225785; (2013); (A1)

English
View in Reaxys

N NH 2

N
O
O
O
N
NH H
O O

Rx-ID: 54251807 View in Reaxys 9/636

Yield Conditions & References
85% General procedure for the synthesis of (1-3)
General procedure: A solution of1-2ato1-2e(0.175 mmol) and 7N ammonia in methanol (4 mL) in a sealed pressure
vessel was stirred at 90 °C for 12 h. After the completion of the reaction, the mixture was evaporated and purified by
flash column chromatography using DCM/MeOH/Ammonia (90/9/1) as eluent to give the desired final com‐
pound1-3as white solid.

With ammonia in methanol, Time= 12h, T= 90 °C , Sealed tube

Kumar, Kunal; Wang, Peng; Swartz, Ethan A.; Khamrui, Susmita; Secor, Cody; Lazarus, Michael B.; Sanchez,
Roberto; Stewart, Andrew F.; DeVita, Robert J.; Molecules; vol. 25; nb. 8; (2020); Art.No: 1983
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 N
O O
O

N
N H

HN
2

NH
O
O

Rx-ID: 54251808 View in Reaxys 10/636

Yield Conditions & References
94% General procedure for the synthesis of (1-3)
General procedure: A solution of1-2ato1-2e(0.175 mmol) and 7N ammonia in methanol (4 mL) in a sealed pressure
vessel was stirred at 90 °C for 12 h. After the completion of the reaction, the mixture was evaporated and purified by
flash column chromatography using DCM/MeOH/Ammonia (90/9/1) as eluent to give the desired final com‐
pound1-3as white solid.

With ammonia in methanol, Time= 12h, T= 90 °C , Sealed tube

Kumar, Kunal; Wang, Peng; Swartz, Ethan A.; Khamrui, Susmita; Secor, Cody; Lazarus, Michael B.; Sanchez,
Roberto; Stewart, Andrew F.; DeVita, Robert J.; Molecules; vol. 25; nb. 8; (2020); Art.No: 1983
View in Reaxys

S O S NH 2

S S

OH O

Rx-ID: 106258 View in Reaxys 11/636

Yield Conditions & References
34 % Typical procedure:
General procedure: In a screw-capped tube are successively introduced the amine (0.915 mmol, 1 eq), the acid
(0.915 mmol, 1 eq) in a suitable solvent (usually 1,4-dioxane, 2 mL). The 3 Å molecular sieve (50 mg) and the immo‐
bilized CAL-B (50 mg) are finally introduced. The reaction mixture is heated to 50 °C for 3 days. After cooling, the
solvent is evaporated the crude residue is partionned between water and EtOAc. The aqueous layer is extracted with
EtOAc (2 x 2 mL) and the combined organic phases are washed with 3 M HCl (2 x 2 mL) and 10 % aqueous K2CO3
(2 x 2 mL). The solvent is finally evaporated under reduced pressure giving the pure amide (assessed by NMR).
Silica-gel chromatography may be performed in order to obtain analytically pure samples. All the compounds were
characterized by NMR (1H, 13C, mass spectroscopy)..

With ammonium hydroxide, immobilized Candida antarctica Lipase B in 1,4-dioxane, lithium hydroxide monohy‐
drate, Time= 72h, T= 50 °C , Sealed tube, Enzymatic reaction, Reagent/catalyst

Manova, Daniela; Gallier, Florian; Tak-Tak, Lotfi; Yotava, Lyubov; Lubin-Germain, Nadège; Tetrahedron Letters;
vol. 59; nb. 21; (2018); p. 2086 - 2090
View in Reaxys

With tetrahydrofuran, triethylamine, isobutyl chloroformate, Behandeln der Reaktionsloesung mit Ammoniak enthal‐
tendem Tetrahydrofuran

Reed et al.; Journal of Biological Chemistry; vol. 232; (1958); p. 143,144

View in Reaxys

Reaction Steps: 2
1: N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride / dichloromethane / 20 °C / Inert atmos‐
phere
2: ammonium hydroxide / dichloromethane; acetonitrile / 1 h / 20 °C / Inert atmosphere
With ammonium hydroxide, N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride in dichlorome‐
thane, acetonitrile

De La Reberdiere, Arnaud; Lachaud, Fabien; Chuburu, Francoise; Cadiou, Cyril; Lemercier, Gilles; Tetrahe‐
dron Letters; vol. 53; nb. 45; (2012); p. 6115 - 6118,4
View in Reaxys

With ammonium hydroxide, benzotriazol-1-ol, N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride

PatentARTEREZ, INC.; ARTEREZ<unknown>; WO2021/62298; (2021); (A1) English

View in Reaxys

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 3.4 g With ammonium hydroxide, benzotriazol-1-ol, N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride

PatentArterez, Inc.; ARTEREZ<unknown>; US2022/288110; (2022); (A1) English

View in Reaxys

HO Br O Br

O NH 2

Rx-ID: 20986285 View in Reaxys 12/636

Yield Conditions & References
98% Synthesis of 5-bromopentanamide
Synthesis of 5-bromopentanamide
5-bromopentanoic acid (5g, 27.6mmol) was dissolved in methylene chloride (50mL).
To the resulting solution was added N,N-dimethylformamide (DMF).
The resulting mixture was cooled to 0-5°C in an ice-water bath.
To the cooled mixture was slowly and dropwise added oxalyl chloride (10g, 82.8mmoL).
After the completion of the dropwise addition, the mixture was stirred for 2 hours at 40°C to conduct the reaction.
The reaction mixture was concentrated under a reduced pressure to produce a yellow solid.
The resulting solid was dissolved in tetrahydrofuran (THF, 50mL).
The resulting solution was slowly and dropwise added to ammonia-water (10mL).
The resulting mixture was stirred for 2 hours at room temperature, and extracted with methylene chloride.
The organic phase was dried over anhydrous sodium sulfate and concentrated to produce a white solid (4.85g, yield:
98%).

Stage 1: With oxalyl dichloride in dichloromethane, N,N-dimethyl-formamide, Time= 2h, T= 0 - 40 °C

Stage 2: With ammonium hydroxide in tetrahydrofuran, Time= 2h, T= 20 °C

PatentCSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd.; CSPC PHARMACEUTICAL GROUP
LIMITEDCSPC Group; EP3181554; (2017); (A1) English
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Reaction Steps: 2
1: SOCl2 / 4 h / Heating
2: 28percent NH4OH / H2O / 0.75 h / 0 °C
With ammonium hydroxide, thionyl chloride in water

Kohda; Iwai; Watanabe; Arakawa; Fukaya; Yokoyama; Kohama; Mimura; Chemical and Pharmaceutical Bulletin;
vol. 39; nb. 6; (1991); p. 1546 - 1550
View in Reaxys

S NH 2

S S O
N S

O
O
O

Rx-ID: 34227341 View in Reaxys 13/636

Yield Conditions & References
93 % Compound LA-NH2:
The activated ester LA-NHS (707 mg, 2.53 mmol) was dissolved in a chloroform/acetonitrile mixture (1:2, 15 mL).
Then, ammonia (30% in water) was added until the appearance of two phases. The heterogeneous solution was left
under vigorous stirring for one hour. After addition of chloroform (15 mL) the crude product was extracted with water
(2 15 mL) and aqueous solution of KOH (20%). The organic layer was dried under MgSO4. Subsequent evaporation
led to a yellow solid which was ovendried. (485 mg, 93%). 1H NMR (CDCl3) d: 5.53 (broad singlet,2H-NH),
3.63-3.52 (m, 1H), 3.24-3.06 (m, 2H), 2,52-2.40 (m, 1H), 2.24 (t, J = 7.4 Hz, 2H), 1.97-1.84 (m, 1H), 1.77-1.41 (m,
6H). 13C NMR (CDCl3) d: 175.21, 56.52, 40.38, 38.62, 35.69, 34.77, 28.97, 25.27. ESI-MS: m/z = 228.0 (M+Na+).

With ammonium hydroxide in dichloromethane, acetonitrile, Time= 1h, T= 20 °C , Inert atmosphere

De La Reberdiere, Arnaud; Lachaud, Fabien; Chuburu, Francoise; Cadiou, Cyril; Lemercier, Gilles; Tetrahe‐
dron Letters; vol. 53; nb. 45; (2012); p. 6115 - 6118,4
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 O O O O

O O O NH 2

Rx-ID: 41494890 View in Reaxys 14/636

Yield Conditions & References
92 % Amides; General Procedure
General procedure: A 0.2 M solution of the corresponding methyl ester in aq NH4OH (28-30%) was stirred at r.t. for
16 h. The solvent was evaporated to affordthe amide, which was, in some cases, purified by silica gel chromatogra‐
phy. The known amides 3, 33 5a,34 5b, 6c 5h,35 11a,36 11b,37 11c,3611e,38 11h,4 11i,39 11j,39 13,40 14,41
20,42 and 2343 were synthesized following the general procedure described above. Compound 5e was synthesized
following the literature.44

With ammonium hydroxide in water, Time= 16h, T= 20 °C , Inert atmosphere

Keita, Massaba; Vandamme, Mathilde; Paquin, Jean-François; Synthesis; vol. 47; nb. 23; (2015); p. 3758 - 3766;
Art.No: SS-2015-M0394-OP
View in Reaxys

H OH

H OH

HN
2

Rx-ID: 999007 View in Reaxys 15/636

Yield Conditions & References
46% (R,Z)-12-hydroxyoctadec-9-enamide (R-2)
Methyl ester of (R)-RA (1 g, 0.003 mol) was added to a 2%solution of ammonia in dioxane (25 ml) and Novozyme
435(380 mg). The mixture was shaken at 30 °C and 250 rpm for96 h monitoring the progress of the reaction by TLC.
Theenzyme was filtered off and washed by dichloromethane.Evaporation of solvent provided crude solid product
whichwas purified by crystallization in acetone. Pure amide R-2(0.44 g) was white solid of 98% purity (GC) and the
reactionyield was 46%. α23D +2.92 (c 5.2, CHCl3), mp64.8-67.7 °C (acetone), lit. mp 64-65.5 °C (Galstukhova
1960). IR (cm-1, neat): 3353.6, 3184.0, 2922.4, 2850.8,1658.4, 1631.8, 1469.4, 1072.9, 813.1. GC-MS (EI, 70
eV),m/z: 297 (M+, 0), 279 (M+-18, 1), 183 (5), 97 (10), 72 (54),69 (15), 59 (100), 55 (70), 44 (22), 43 (35), 41 (36).
1HNMR (δ ppm): 5.57 (m, 3H; -NH2; -CH=), 5.40 (m, 1H;-CH=), 3.60 (qn J = 6.3 Hz, 1H; -CHOH), 2.21 (m, 4H;-
CHCH2CH=, -CH2CO-), 2.04 (m, 2H), 1.62 (qn J =7.3 Hz, 2H), 1.45 (m, 3H), 1.30 (m, 15H), 0.87 (t J =6.5 Hz; -
CH3). 13C NMR: 176.08 (s; -CO-), 133.10 (d;-CH=), 125.24 (d; -CH=), 71.39 (d; -CHOH-), 36.74 (t),35.82 (t), 35.26
(t), 31.75 (t), 29.43 (t), 29.27 (t), 29.02 (t,2xCH2), 28.94 (t), 27.23 (t), 25.63 (t), 25.38 (t), 22.53 (t),14.01 (q; -CH3).

With ammonia in 1,4-dioxane, Time= 96h, T= 30 °C

Matysiak, Sylwia; Kula, Józef; Błaszczyk, Alina; Medicinal Chemistry Research; vol. 28; nb. 7; (2019); p. 948 -
958
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46 % (R,Z)-12-Hydroxyoctadec-9-Enamide (2-R)
Methyl esters of (R)-RA (1 g, 0.003 mol) were mixed with Novozyme 435 (380 mg) in 2% dioxane solution of NH3 (25
mL) at 30 °C and centrifuged at 250 rpm for 96 hours. The progress of the reaction was monitored by TLC. The
enzyme was filtered off and washed with dichloromethane. Evaporation of the solvent provided a crude solid prod‐
uct, which was purified by crystallization in acetone. Pure amide 2-R (0.44 g) was a white solid of >98% purity (GC);
1H NMR (δ ppm): 5.54 (m, 3H; NH2; CH ), 5.39 (m,1H; CH ), 3.60 (qn J = 6.3 Hz, 1H; CHOH), 2.21 (m,4H;

CHCH2CH ; CH2CO ), 2.04 (m, 2H), 1.62(qn J = 7.3 Hz, 2H), 1.45 (m, 3H), 1.30 (m, 15H), 0.87 (t J = 6.5 Hz; CH3);
13C NMR: 176.08 (s; CO ),133.10 (d; CH ), 125.24 (d; CH ), 71.39 (d;CHOH ), 36.74 (t), 35.82 (t), 35.26 (t), 31.75 (t),

29.43(t), 29.27 (t), 29.02 (t, 2xCH2), 28.94 (t), 27.23 (t), 25.63(t), 25.38 (t), 22.53 (t), 14.01 (q; CH3); IR (cm-1, neat):
3353.6, 3184.0, 2922.4, 2850.8, 1658.4, 1631.8, 1469.4,1072.9, 813.1; and GC MS (EI, 70 eV) m/z (%):297 (0) [M
+], 279 (1) [M+-18], 183 (5), 97 (10), 72 (54),69 (15), 59 (100), 55 (70), 44 (22), 43 (35), 41 (36).

With lipase from Candida antarctica Novozyme 435, ammonia in 1,4-dioxane, Time= 96h, T= 30 °C , Enzymatic re‐
action

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 Matysiak, Sylwia;Zabielska, Julia;Kula, Józef;Kunicka-Styczyńska, Alina; Journal of the American Oil Chemists'
Society; vol. 97; nb. 1; (2020); p. 67 - 79
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With ammonia in methanol

Galstukhova,N.B.; Journal of general chemistry of the USSR; vol. 30; (1960); p. 1418 - 1420; Zhurnal Obshchei
Khimii; vol. 30; (1960); p. 1387 - 1389
View in Reaxys

N N
O O

H H
N O N O
HO HN
O 2
O

O O

Rx-ID: 23158066 View in Reaxys 16/636

Yield Conditions & References
77 % 116.1 : Example 116; [5- { [3- (AMINOMETHYL)-2-ISOBUTYL-4- (4-METHYLPHENYL)-6-] quinolinyl] oxy} pen‐
tanamide
1) A mixture of [5-{[3-{[(TERT-BUTOXYCARBONYL)] amino] methyl}-2- [ISOBUTYL-4- (4-METHYLPHENYL) QUI‐
NOLIN-6-YL] OXY} PENTANOIC] acid (0.8 g, 1.5 mmol), [1-ETHYL-3- (3-] dimethylaminopropyl) carbodiimide hydro‐
chloride (0.38 g, 2.0 mmol), [1-HYDROXY-LH-BENZOTRIAZOLE] ammonium salt (0.24 g, 1.6 mmol) and N, N-dime‐
thylformamide (10 ml) was stirred at room temperature for 15 hrs. Water was added to the reaction mixture and the
mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hy‐
drogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concen‐
trated under reduced pressure. The residue was crystallized from isopropyl ether to give tert-butyl [{ {6- [ (5-AMI‐
NO-5-OXOPENTYL) OXY]-2-] [ISOBUTYL-4- (4-METHYLPHENYL) QUINOLIN-3-YL} METHYL} CARBAMATE] (0.6
g, yield 77%) as crystals. [1H-NMR] [(CDC13)] [G] : 1.02 (6H, d, J = 6. 6 Hz), 1.41 (9H, s), 1. [77-] 1.81 (4H, m),
2.25-2. 38 (3H, m), 2.48 (3H, s), 2.89-2. 96 (2H, m), 3.82 (2H, t, J = 5.1 Hz), 4.26 (2H, d, J = 4.1 Hz), 4.32 [(1H,] s),
5.29 [(1H,] s), 5.40 [(1H,] s), 6.56 [(1H,] d, J = 2.6 Hz), 7.12 (2H, d, [J] = 7.9 Hz), 7.28-7. 34 (3H, m), 7.96 [(1H,] d, [J
=] 9.2 Hz).

With N-hydroxybenzotriazole ammonium salt, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in

DMF (N,N-dimethyl-formamide), Time= 15h, T= 20 °C

PatentTAKEDA CHEMICAL INDUSTRIES, LTD.; TAKEDA PHARMACEUTICAL COMPANY LIMITEDTakeda Phar‐

ma; WO2004/14860; (2004); (A2) English
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77 % tert-Butyl ((6-((5-amino-5-oxopentyl)oxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl)methyl)carbamate (34a)

A mixture of 11d (0.80 g, 1.5 mmol), ammonium salt of 1-hydroxy-1H-benzotriazole (0.25 g, 1.6 mmol), and1-(3-di‐
methylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2.0 mmol) in N,N-dimethylformamide (10mL) was
stirred at room temperature for 17 h. The reaction mixture was partitioned between ethyl acetate and water.The or‐
ganic layer was washed with 1 M HCl, saturated NaHCO3, and brine, dried over MgSO4, and concentrated invacuo.
The residue was crystallized from diisopropyl ether to afford the title compound 34a (0.60 g, 77%) as acolorless pow‐
der.

With N-hydroxybenzotriazole ammonium salt, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in

N,N-dimethyl-formamide, Time= 17h, T= 20 °C

Maezaki, Hironobu; Tawada, Michiko; Yamashita, Tohru; Banno, Yoshihiro; Miyamoto, Yasufumi; Yamamoto,
Yoshio; Ikedo, Koji; Kosaka, Takuo; Tsubotani, Shigetoshi; Tani, Akiyoshi; Asakawa, Tomoko; Suzuki, Nobu‐
hiro; Oi, Satoru; Bioorganic and Medicinal Chemistry Letters; vol. 27; nb. 15; (2017); p. 3565 - 3571
View in Reaxys

HO O

O NH 2

Rx-ID: 3958035 View in Reaxys 17/636

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 Yield Conditions & References
93 % Stage 1: With oxalyl dichloride in dichloromethane, N,N-dimethyl-formamide, Time= 1.5h, T= 0 - 20 °C
Stage 2: With ammonia in dichloromethane, N,N-dimethyl-formamide, T= 0 - 20 °C , Further stages.

Williams, David E.; Craig, Kyle S.; Patrick, Brian; McHardy, Lianne M.; Van Soest, Rob; Roberge, Michel; An‐
dersen, Raymond J.; Journal of Organic Chemistry; vol. 67; nb. 1; (2002); p. 245 - 258
View in Reaxys

89 % With urea

Pirkle, William H.; Liu, Yuelong; Journal of Organic Chemistry; vol. 59; nb. 23; (1994); p. 6911 - 6916
View in Reaxys

63 % With urea, Time= 4h, T= 170 - 180 °C

Cheng, Kai; Landry, Christopher C.; Journal of the American Chemical Society; vol. 129; nb. 31; (2007); p. 9674 -
9685
View in Reaxys

60 % 1 : Synthesis of 10-undecenamide
Urea (15 g, 0.25 mol) and undecylenic acid (23.01 g, 0.125 mol) were taken in a two-necked flask and heated to
170-180 ° C.Heating was stopped after 4 h of reaction.When the temperature drops to 110-120 ° C,The reaction was
stopped by adding a 5% Na2CO3 solution (100-150 ml), and the mixture was placed in an ice water bath, and the
solid was precipitated, filtered, and recrystallized twice with 95% ethanol.Drying in vacuo gave a colorless solid in
60% yield. 1H NMR(400MHzCDCl3)δ5.80(1Hm)5.47(2Hs)2.22(2Ht)2.04(2Hm)1.63(2Hm)1.38-1.29(10Hm)

With urea, Time= 4h, T= 170 - 180 °C

PatentNanjing Tech University;Gao Deqing;Zheng Chaoyue;Chen Naiwu;Zhu Jie;Huang Wei; NANJING TECH UNI‐
VERSITYNanjing Tech University; CN105131027; (2019); (B) English
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Reaction Steps: 2
1: 1,8-diazabicyclo[5.4.0]undec-7-ene / neat (no solvent) / 24 h / 160 °C / Green chemistry
2: ammonia / methanol / 3 h / 20 °C / Green chemistry
With ammonia, 1,8-diazabicyclo[5.4.0]undec-7-ene in methanol

Kreye, Oliver; Meier, Michael A. R.; RSC Advances; vol. 5; nb. 65; (2015); p. 53155 - 53160
View in Reaxys

HO O

O NH 2

Rx-ID: 13468337 View in Reaxys 18/636

Yield Conditions & References
32 % (21) General Procedure for Amide Coupling
General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI
(0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After
12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addi‐
tion of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL).
The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide.

Stage 1: With 1,1'-carbonyldiimidazole in dichloromethane, Time= 0.5h, T= 20 °C

Stage 2: With ammonia in dichloromethane, Time= 12h

Johansson, Silje J. R.; Johannessen, Tonje; Ellefsen, Christiane F.; Ristun, Mali S.; Antonsen, Simen; Han‐
sen, Trond V.; Stenstrom, Yngve; Nolsoe, Jens M. J.; Synlett; vol. 30; nb. 2; (2019); p. 213 - 217; Art.No:
ST-2018-D0672-L

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 View in Reaxys

Reaction Steps: 2
1: (COCl)2 / CH2Cl2 / 20 °C
2: aq. NH3 / 0 °C
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Xu, Ming-Zhe; Lee, Woo Song; Kim, Mi Jeong; Park, Doo-Sang; Yu, Hana; Tian, Guan-Rong; Jeong, Tae-
Sook; Park, Ho-Yong; Bioorganic and Medicinal Chemistry Letters; vol. 14; nb. 16; (2004); p. 4277 - 4280
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Reaction Steps: 2
1: (COCl)2, DMF / benzene / 3 h / Ambient temperature
2: 95 percent / NH3(gas) / CH2Cl2 / 1 h / Ambient temperature
With oxalyl dichloride, ammonia, N,N-dimethyl-formamide in dichloromethane, benzene

Barton; Jaszberenyi; Theodorakis; Tetrahedron; vol. 48; nb. 13; (1992); p. 2613 - 2626
View in Reaxys

Reaction Steps: 2
1: PCl3
2: NH3 / 0 °C
With ammonia, phosphorus trichloride

McCutcheon; Canadian Journal of Research, Section B: Chemical Sciences; vol. 16; (1938); p. 160; Chemisches
Zentralblatt; vol. 110; nb. II; (1939); p. 374
View in Reaxys

OH
OH

NH 2

H OH O

Rx-ID: 33030333 View in Reaxys 19/636

Yield Conditions & References
94 % Ethyl chloroformate (18.0 g, 166 mmol) was added slowly to cooled (< 0°C); dry THF (100 mL) stirred under a nitro‐
gen atmosphere. The mixture was stirred for 20 more min followed by slow addition of HSA (10. 0 g, 33 mmol) and
triethylamine (2.3 g, 33 mmol) in dry THF (50 mL) while maintaining the temperature below 0°C. The contents were
stirred for another 30 min and a stream of anhydrous ammonia gas (prepared from an NH4OH solution (50 mL) in a
hot (ca 60°C) water bath; the gas was passed through a 50 X 2 cm column filled with anhydrous Drierite and ca 20 g
of activated CaO powder (prepared by heating CaCO3 to ca 500°C for 30 min and cooling in a desiccator under a
nitrogen atmosphere) was bubbled rapidly through the solution for 10 min. The mixture was kept for 12 h without
stirring, during which time the temperature slowly rose to room temperature. The solvent was removed by distillation
and the residue, after being dissolved in ethyl acetate (200 mL), was washed successively with 3 N aq HCI (3X15
mL), aqueous 1 M Na2CO3 (3X15 mL), and brine (3X10 mL). During these washings, the amide in the organic phase
formed a gel which was destroyed by warming the outer surface of the separatory funnel. The organic part was col‐
lected, dried with anhydrous sodium sulfate, decanted while hot, and then slowly cooled to 0°C with vigorous stirring.
The precipitate that formed was collected by filtration. This process was repeated once and the solid was dried in
vacuo at 55-60°C for 12 h to yield 9.3 g (94 %), mp 1 13.1-1 13.7°C (lit6 1 1 1-1 12°C).IR (neat): 3412, 3302, 3209
(NH and OH), 2913, 2848 (CH), 1650 (CO) cm"1; 1H-NMR (CDCI3, 300 (MHz): δ 0.92 (t, 3H, CH3, J = 6.1 Hz), 1.3-
1.6 (m, 30 H, CH2), 2.2 (2H, t, CHrCO. J = 7.1 Hz), 3.61 (1 H, m, CH-OH), 5.4 (2H, br, CONH2); elemental analysis;
calcd for C18H37NO2; C, 72.19; H, 12.45; N, 4.68; O, 10.68; found C, 72.55; H, 12.57; N, 4.97.

Stage 1: With chloroformic acid ethyl ester, triethylamine in tetrahydrofuran, Time= 0.5h, T= 0 °C , Inert atmosphere
Stage 2: With ammonia in tetrahydrofuran, Time= 12.17h, T= 0 - 20 °C

PatentGEORGETOWN UNIVERSITY;WEISS, Richard G.;VISWANATHA MALLYA, Ajaya Mallia; GEORGETOWN

UNIVERSITYGeorgetown University; WO2012/47251; (2012); (A1) English
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 O O OH O O
N
N
O O HN
2
O O

Rx-ID: 34701287 View in Reaxys 20/636

Yield Conditions & References
85 % 20 :Synthesis of 5-Nitrooxy-pentanoic acid amide 3; To a solution of compound 2 (1.30 g, 1.0 eq) in dry dichlorome‐
thane (20.0 mL) cooled to 0° C. was added triethylamine (1.30 mL, 1.2 eq) followed by ethyl chloroformate (0.83 mL,
1.1 eq). The reaction mixture was stirred at 0° C. for 45 minutes and 30% aqueous ammonia solution (15.0 mL) was
added. The solution was stirred from 0° C. to RT for 18 hours and sodium sulphate was added to dry the mixture.
The resulting mixture was filtered off and the filtrate was concentrated under vacuum. The residue was adsorbed on
silica gel and purified by flash chromatography [Biotage, dichloromethane/methanol 100/0→98/2 (120V*), 98/2
(6CV)] affording compound 3 as a white solid (1.10 g, yield=85%).The final compound was dried at 60° C. under
reduced pressure for 18 hours. Degradation was observed by 1H NMR. The degraded compound was adsorbed on
silica gel and purified by flash chromatography [Biotage, dichloromethane/methanol 100/0→98/2 (120V), 98/2 (6CV)]
affording compound 3 as a white solid (0.90 g, yield=70%).

Stage 1: With chloroformic acid ethyl ester, triethylamine in dichloromethane, Time= 0.75h, T= 0 °C
Stage 2: With ammonia in dichloromethane, water, Time= 18h, T= 0 - 20 °C

PatentDUVAL STEPHANE;KINDERMANN MAIK; DSM-FIRMENICH AGDSM-Firmenich; US2012/315339; (2012);

(A1) English
View in Reaxys

O NH 2

HO HO
OH O

O O

Rx-ID: 36022475 View in Reaxys 21/636

Yield Conditions & References
36.9 % 5 :Example 5 Efficacy of TiO2 and ZrO2 Supports in Production of Amides [0061] To illustrate the unexpected benefi‐
cial effects of TiO2 and ZrO2 in the process of the present invention, particularly with regard to the pathway by which
caprolactam is believed to be produced from adipic acid, 20 mg of support and 2.92 mg of Adipic Acid were dis‐
pensed into a 1 mL glass vial contained in a 96-well reactor insert. Next was added 0.2 mL of a solvent mixture con‐
taining 10% v/v aqueous NH4OH (ca. 15M NH3 in H2O) in tert-BuOH or a solvent mixture containing 10% v/v H2O in
tert-BuOH. The vial was covered with a Teflon pinhole sheet, a silicone pinhole mat, and a steel gas diffusion plate.
The reactor insert was placed in a pressure vessel and purged three times with N2. The pressure vessel was then
charged twice with ammonia gas to 10 psig with venting after each pressurization step. The reactor was finally
charged to 10 psig with ammonia gas and placed on a shaker at 500 rpm for 15 minutes at ambient temperature.
The reactor was then brought to 825 psig with hydrogen and placed back on the shaker at 800 rpm and heated to
160° C. for the specified time (30 or 120 minutes). [0062] The reactor was cooled to room temperature, vented, and
purged with nitrogen prior to being unsealed. The samples were diluted with water, mixed, and then centrifuged to
separate support particles. Aliquots were removed from the supernatant and diluted further with dilute aqueous HCl
for analysis by HPLC. Product yield was determined using a calibrated HPLC method with Charged Aerosol Detec‐
tion (CAD). The yield of 6-amino-6-oxohexanoic acid and adipamide is listed below in Tables 4 and 5. As illustrated,
titania and zirconia, without added catalytic metal, have a dramatic effect on the production of the intermediates from
which caprolactam is ultimately produced from adipic acid. For comparison, Table 6 illustrates the relative ineffective‐
ness of employing other known support materials.

With ammonium hydroxide, hydrogen in water, tert-butyl alcohol, Time= 2h, T= 20 - 160 °C , p= 1277.21 -
43425.9Torr , Inert atmosphere

PatentRennovia, Inc.; ARCHER-DANIELS-MIDLAND COArcher-Daniels-Midland; US2013/225785; (2013); (A1)

English
View in Reaxys

H
S

O S
O

N
O
NH 2

S O
S

Rx-ID: 40950823 View in Reaxys 22/636

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 21/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
85 % 2 :(R)-Lipoamide. (R)-lipoamide was synthesized as described in Scheme 2 following. A solution of the NHS ester
(2.7 g, 8.9 mmol) in anhydrous CH2Cl2 (50 mL) was cooled in a dry ice acetone bath. Ammonia was condensed into
the reaction mixture over a period of 1-2 hours, then the reaction mixture was allowed to warm to room temperature
overnight and diluted with CH2Cl2 (50 mL). Water (100 mL) was added and the mixture was stirred for 20 minutes.
The phases were separated. The organic phase was washed with saturated aqueous NaCl (100 mL) and dried
(Na2SO4). The drying agent was removed by filtration and the filtrate was concentrated to dryness giving the product
as a yellow microcrystalline sold (1.56 g, 85%).

With ammonia in dichloromethane, T= 20 °C , Cooling with acetone-dry ice

PatentEncore Health, LLC; NOVARTIS AG; Novartis (w/o Sandoz); EH IP, LLCNovartis; Novartis (w/o Sandoz);
&lt;unknown&gt;; US2015/246903; (2015); (A9) English
View in Reaxys

OH

HN

O
N

HN
O

HN 2

Rx-ID: 47427208 View in Reaxys 23/636

Yield Conditions & References
88 % 99.1 : Step 1: tert-butyl 4-(3-(2-(dodecyloxy)-3-(5-(methylamino)-oxopentyloxy) prop ylcarbamo yl) phenvDpi‐
peridine- 1 -carboxylate :
General procedure: To a stirred solution of 5-(3-(3-(l-(tert- butoxycarbonyl) piperidin-4-yl)benzamido)-2-(dodecy‐
loxy)propoxy) pentanoic acid (250 mg, 0.38 mmol) in DMF (5 mL) were added DIPEA (0.656 mL, 3.8 mmol) and
HBTU (230 mg, 0.608 mmol) and stirred for 30 min at room temperature. Then MeNH2.HCl (60 mg, 0.874 mmol)
was added to the reaction mixture and stirring was continued for 18 hours at room temperature. Reaction mixture
was diluted with ethyl acetate and washed with sat. NaHC03 solution, sat. NH4C1 solution, water and brine solution.
The collected organic phase was dried, concentrated and purified by basic silica gel column chromatography gradi‐
ent elution with 5% Methanol in dichloromethane to isolate desired pure product as a yellow liquid (220 mg, 88%).

Stage 1: With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,N-diisopropyl‐

amine in N,N-dimethyl-formamide, Time= 0.5h, T= 20 °C
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 18h, T= 20 °C

PatentNEUROPORE THERAPIES, INC.;WRASIDLO, Wolfgang;NATALA, Srinivasa, Reddy; NEUROPORE THERA‐

PIES&lt;unknown&gt;; WO2018/26866; (2018); (A1) English
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 NH 2

O O O

N
O O

O O
N

HO O O

Rx-ID: 49179749 View in Reaxys 24/636

Yield Conditions & References
100 % 103.1 : Step 1 : Ethyl 9'-(5-amino-5-oxopentyl)-1 0'-methoxv-2'-oxo-2'. 7'-dihyd rospiro[ cyclobutane-1 .6'-pyri‐
do[2. 1-a]isoqu inoline ]-3 '-carboxylate
A mixture of 5-(3'-(ethoxycarbonyl)-1 0'-methoxy-2'-oxo-2',7'-dihydrospiro[cyclobutane-1 ,6'-pyrido[2, 1-a]isoquino‐
lin]-9'-yl)pentanoic acid(45 mg, 0.1mmol), NH4CI (27.4 mg, 0.5 mmol), HBTU (57 mg, 0.15 mmol) and DIPEA (124
ul, 0.7mmol) in DMF (2 ml) was stirred at r.t overnight. The mixture was concentrated and theresidue was purified by
flash chromatography (silica gel, 0-20% MeOH in DCM) to give thetitle compound (45 mg, 100% yield) as a yellow
solid. LCMS (ESI) m/z: 439.4 (M + 1t.

With ammonium chloride, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,N-

diisopropylamine in N,N-dimethyl-formamide, T= 20 °C

PatentGLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED;CATALANO, John G.;DICK‐

SON, Hamilton D.;KAZMIERSKI, Wieslaw Mieczyslaw;LEIVERS, Martin R.;WEATHERHEAD, John Gordon; GLAX‐
OSMITHKLINE PLCGlaxoSmithKline; WO2018/154466; (2018); (A1) English
View in Reaxys

O O

HO HN
2

O O

N N
O O
O O

O O

Rx-ID: 56842073 View in Reaxys 25/636

Yield Conditions & References
98 % 3 : Step 3:
Add ethyl acetate (1 L), compound 2 (260 g, 0.66 mol), di-tert-butyl dicarbonate (172.4 g, 0.79 mol) and pyridine
(62.5 g, 0.79 mol) into a 2 L reaction flask, and react at room temperature After 30 minutes, add ammonium carbo‐
nate (96.1 g, 1.00 mol), stir overnight at room temperature, add 1N hydrochloric acid (1 L), wash the organic phase
with water (1 L), dry with anhydrous sodium sulfate, filter, and concentrate at 50°C to obtain light Yellow viscous liq‐
uid, compound 3 (256.1 g, 065 mol, 98%).

Stage 1: With pyridine, di-tert-butyl dicarbonate in ethyl acetate, Time= 0.5h, T= 20 °C

Stage 2: With ammonium carbonate in ethyl acetate, T= 20 °C

PatentSHANGHAI JIFENG BIOTECHNOLOGY CO LTD; SHANGHAI JIFENG BIOTECHNOLOGY&lt;unknown&gt;;

CN112645833; (2021); (A) English
View in Reaxys

O
O
O

S
N
S O S
S S NH
S
2

Rx-ID: 59956346 View in Reaxys 26/636

Yield Conditions & References
97 % 1 : Production of (R) -lipoamide trisulfide
A 200 mL four-diameter flask was charged with 2.00 g (8.39 mmol) of (R) -lipoic acid trisulfide and 65 mL (32.5 v / w)
of methylene chloride.After confirming that the contents of the flask were dissolved, 2.07 g (10.77 mmol, 1.28 eq) of
1- (3-Dimethylaminopropyl) -3-ethylcarbodimidide Hydrochloride (EDC.HCl) and N-hydroxysuccinimide (NHS). ) 1.42
g (12.33 mmol, 1.47 eq) was added.After replacing the air in the flask with nitrogen, the reaction was carried out at

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 room temperature for about 8 hours.Next, 2.28 mL (33.74 mmol, 4.02 eq) of 28% aqueous ammonia was added
dropwise at room temperature over 5 minutes, and the reaction was carried out overnight.Then, at room tempera‐
ture, 60 mL (30.0 v / w) of water was added to separate the liquids, and then the organic layer was washed 3 times
with 60 mL (30.0 v / w) of a 2.5% aqueous sodium hydrogen carbonate solution. Washed 4 times with 60 mL (30.0
v / w) of water.Then, the washed organic layer was concentrated under reduced pressure at an outside temperature
of 25 ° C., dried with an oil pump, and 1.93 g (8.13 mmol, yield 97%, HPLC purity 99.6%) of (R) -lipoamide trisul‐
fide. , White solid) was obtained.1 1H-NMR: (CDCl3, 400 MHz) δ (ppm) = 5.36 (bs, 2H), 3.33 (m, 1H), 3.13 (m, 2H),
2.22 (m, 3H) ), 1.89 (m, 1H), 1.74-1.42 (m, 6H).HR-ESI-TOF-MS: m / z 236.0238 ([MH]-), calcd for [C8H14NOS3

With ammonium hydroxide in dichloromethane, Time= 0.0833333h, T= 20 °C

PatentKYOWA PHARMA CHEMICAL CO., LTD.; KIRIN HOLDINGS CO LTD; XIEHE PHARMACEUTICAL CHEMI‐
CALKirin Holdings; &lt;unknown&gt;; WO2022/45212; (2022); (A1) Japanese
View in Reaxys

O NH 2

O O

O O

N N

Rx-ID: 23422160 View in Reaxys 27/636

Yield Conditions & References
78 % 1 :4- [1- (2-BENZYLOXYETHYL) piperidin-4-yl] butyramide (4a). Compound 3a (1.30 g, 4.0 mmol) was dissolved in
7 N NH3 in methanol (25 mL) in a sealed tube. The resulting solution was stirred at 50 °C for 3 days. After that the
solvent was removed under vacuum and the residue was purified by FLASH" chromatography (BIOTAGE, Inc) (9.5 :
0.45 : 0.05 DICHLOROMETHANE/METHANOL/CONCENTRATED ammonium hydroxide, v/v) to provide 4a (0.93 g,
78%) as a white SOLID. 1H NMR (300 MHz, CD30D) 8 1.27 (M, 5H), 1.65 (m, 4H), 2.11 (m, 4H), 2.65 (M, 2H), 2.96
(d, 2H), 3.62 (M, 2H), 4.51 (s, 2H), 7.37 (M, 5H). M/Z (ESI): 305 [CL8H28N202+ H].

With ammonia in methanol, Time= 72h, T= 50 °C

PatentPARION SCIENCES, INC.; PARION SCIENCES INCParion; WO2005/16879; (2005); (A2) English
View in Reaxys

O O

O O
N
H O
HN N
H
2

HO

Rx-ID: 24800662 View in Reaxys 28/636

Yield Conditions & References
82 % 4 :l,l'-Carbonyldiimidazole (118 mg, 0.73 mmol) was added to a solution of 3 (200 mg, 0.66 mmol) in tetrahydrofuran
(5 mL) and the mixture stirred at 55. °C for 3 hour. The solution was then cooled to ambient temperature and ammo‐
nia gas passed through the solution for 15 min. The reaction vessel was then sealed and the mixture stirred for 14
hours at room temperature. After this time, the solvent was removed under vacuum and the white residue purified by
column chromatography (silica gel, gradient 99:1 to 90:10 dichloromethane/methanol, v/v) to afford product 10 (163
mg, 82 %) as a white solid: JH NMR (300 MHz, CDC13) 5 1.28 (s, 12H), 1.44 (br, 11H), 1.56-1.66 (m, 2H), 2.20-2.36
(m, 2H), 3.08-3.11 (m,2H).

Stage 1: With 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 3h, T= 55 °C

Stage 2: With ammonia in tetrahydrofuran, Time= 14.25h, T= 20 °C

PatentJOHNSON, Michael, R.; PARION SCIENCES INCParion; WO2006/23573; (2006); (A2) English
View in Reaxys

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 Cl O OH 2
Cl O NH 2
HCl

N
N

H
H

H H
H H
N
N

Rx-ID: 38292787 View in Reaxys 29/636

Yield Conditions & References
82 % 4.1.6 12-N-4-chlorobenzylsophoridinic amide dihydrochloride (8)
To a solution of the mixture 7h (160mg, 0.41mmol) and NH4HCO3 (40mg, 0.49mmol) in acetonitrile (10ml), di-tert-
butyl dicarbonate (115μL, 0.53mmol) and pyridine (20μL, 0.25mmol) were added. Then the reaction solution was
stirred at room temperature till TLC analysis showed completion of the reaction. The reaction mixture was filtered
and the filtrate was evaporated to afford crude compound 8, which was further purified with flash column chromatog‐
raphy and acidized with 3N hydrochloride/ether. Yield: 82%; White solid; mp 127-130°C; 1H NMR (DMSO-d6) δ:
11.54 (s, 1H), 11.05 (s, 1H), 7.95 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 4.38-4.19 (m, 2H), 3.32-3.19 (m, 3H),
3.14-2.76 (m, 5H), 2.70-2.36 (m, 5H), 2.07-1.94 (m, 2H), 1.94-1.59 (m, 7H), 1.56-1.30 (m, 3H), 1.18-1.07 (m, 1H);
13C NMR δ: 179.2, 138.3, 132.2, 130.5 (2), 127.9 (2), 62.7, 59.7, 57.1, 52.4, 50.3, 44.8, 36.0, 35.9, 28.0, 26.4, 23.4,

22.7, 21.7, 17.8; HRMS: calcd for C22H34N3OCl3 [M-2HCl+H]+, 390.2307; found, 390.2306.

Stage 1: With pyridine, di-tert-butyl dicarbonate, ammonium bicarbonate in acetonitrile, T= 20 °C

Stage 2: With hydrogenchloride in diethyl ether

Bi, Chong-Wen; Zhang, Cai-Xia; Li, Ying-Hong; Tang, Sheng; Deng, Hong-Bin; Zhao, Wu-Li; Wang, Zhen;
Shao, Rong-Guang; Song, Dan-Qing; European Journal of Medicinal Chemistry; vol. 81; (2014); p. 95 - 105
View in Reaxys

O NH 2

OH

HO

Rx-ID: 51304540 View in Reaxys 30/636

Yield Conditions & References
52% (R,Z)-12-hydroxyoctadec-9-enamide (R-2)
General procedure: Methyl ester of (R)-RA (1 g, 0.003 mol) was added to a 2%solution of ammonia in dioxane (25
ml) and Novozyme 435(380 mg). The mixture was shaken at 30 °C and 250 rpm for96 h monitoring the progress of
the reaction by TLC. Theenzyme was filtered off and washed by dichloromethane.Evaporation of solvent provided
crude solid product whichwas purified by crystallization in acetone. Pure amide R-2(0.44 g) was white solid of 98%
purity (GC) and the reactionyield was 46%.

With ammonia in 1,4-dioxane, Time= 96h, T= 30 °C

Matysiak, Sylwia; Kula, Józef; Błaszczyk, Alina; Medicinal Chemistry Research; vol. 28; nb. 7; (2019); p. 948 -
958
View in Reaxys

52 % (R,Z)-12-Hydroxyoctadec-9-Enamide (2-R)
General procedure: Methyl esters of (R)-RA (1 g, 0.003 mol) were mixed with Novozyme 435 (380 mg) in 2% diox‐
ane solution of NH3 (25 mL) at 30 °C and centrifuged at 250 rpm for 96 hours. The progress of the reaction was
monitored by TLC. The enzyme was filtered off and washed with dichloromethane. Evaporation of the solvent provi‐
ded a crude solid product, which was purified by crystallization in acetone.

With lipase from Candida antarctica Novozyme 435, ammonia in 1,4-dioxane, Time= 96h, T= 30 °C , Enzymatic re‐
action

Matysiak, Sylwia;Zabielska, Julia;Kula, Józef;Kunicka-Styczyńska, Alina; Journal of the American Oil Chemists'
Society; vol. 97; nb. 1; (2020); p. 67 - 79

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 View in Reaxys

HO O

O NH 2

Rx-ID: 236619 View in Reaxys 31/636

Yield Conditions & References
81 % Stage 1: With thionyl chloride in tetrahydrofuran, Time= 1h, T= 50 °C
Stage 2: With ammonium hydroxide in tetrahydrofuran, Time= 0.0833333h, T= 0 °C

Al-Huniti, Mohammed H.; Rivera-Chávez, José; Colón, Katsuya L.; Stanley, Jarrod L.; Burdette, Joanna E.;
Pearce, Cedric J.; Oberlies, Nicholas H.; Croatt, Mitchell P.; Organic Letters; vol. 20; nb. 19; (2018); p. 6046 -
6050
View in Reaxys

With ammonia, T= 190 - 210 °C

Ralston; Hoerr; Pool; Journal of Organic Chemistry; vol. 8; (1943); p. 474

View in Reaxys

Reaction Steps: 2
1: PCl3 / 60 - 100 °C
2: NH3
With ammonia, phosphorus trichloride

Deffet; Bulletin des Societes Chimiques Belges; vol. 40; (1931); p. 390
View in Reaxys

With Diethy phosphocyanidate, ammonia in 1,4-dioxane, N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121
View in Reaxys

With ammonia in poly(ethylene glycol) 600, Time= 96h, T= 20 °C , Enzymatic reaction

Kidwai, Mazaahir; Poddar, Roona; Bhardwaj, Saurav; Biocatalysis and Biotransformation; vol. 29; nb. 4; (2011);
p. 113 - 118
View in Reaxys

With Pseudoalteromonas tunicata TamA catalytic adenylation domain, ammonia, ATP, magnesium chloride in di‐
methyl sulfoxide, pH= 9, Enzymatic reaction

Marchetti, Piera M.; Richardson, Shona M.; Kariem, Noor M.; Campopiano, Dominic J.; MedChemComm; vol.
10; nb. 7; (2019); p. 1192 - 1196
View in Reaxys

O N

O N O O

HN
2

Rx-ID: 23320834 View in Reaxys 32/636

Yield Conditions & References
70 % 44-1 : Production example 44-1; tert-Butyl 4-(3-carbamoylpropyl)piperidine-1-carboxylate
tert-Butyl 4-(3-ethoxycarbonylpropyl)piperidine-1-carboxylate (0.60 g, 2.0 mmol, the product of Production example
43-1) and formamide (0.27 ml, 6.7 mmol) were dissolved in N,N-dimethylformamide (1.0 ml); sodium ethoxide (0.095
g, 1.4 mmol) was added thereto while stirred and heated at 100 °C; the reaction mixture was stirred for 2 hours un‐
der nitrogen atmosphere. After cooled to room temperature, the reaction mixture was partitioned between water and
ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then the sol‐
vent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent; hex‐
ane-ethyl acetate = 95:5 to 85:15). The title compound was obtained as a colorless oil (0.38 g, 1.4 mmol, 70%). 1H-

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 NMR Spectrum (CDCl3) δ (ppm): 1.03-1.14 (2H, m), 1.26-1.31(2H, m), 1.35-1.45 (1H, m), 1.46 (9H, s), 1.63-1.71
(4H, m), 2.22 (2H, t, J=7.6 Hz), 2.67 (2H, m), 4.07 (2H, brs), 5.30 (1H, brs), 5.39 (1H, brs).

With sodium ethanolate, formamide in DMF (N,N-dimethyl-formamide), Time= 2h, T= 100 °C

PatentEisai Co., Ltd.; EISAI CO LTDEisai; EP1522540; (2005); (A1) English

View in Reaxys

F F F F
F F F F

N N
F F F F
N N

N N

N N N N

N N

O O O O O O

OH NH 2

Rx-ID: 28423646 View in Reaxys 33/636

Yield Conditions & References
74% 4 :Example 4 Synthesis of cis-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-ami‐
no}-2,6-diethyl-piperidine-1-carboxylic acid 4-carbamoyl-butyl ester To a solution of cis-4-{(3,5-bis(trifluorometh‐
yl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2,6-diethylpiperidine-1-carboxylic acid 4-carboxy-butyl
ester (50 mg, 0.0730 mmol), di-tert-butyl dicarbonate (25.5 mg, 0.117 mmol), and pyridine (4.34 uL, 0.0533 mmol) in
acetonitrile (1 mL) is added ammonium hydrogen carbonate (8.65 mg, 0.110 mmol) at room temperature. The mix‐
ture is stirred for 15 hours at room temperature. To the mixture, water is added and the solution is extracted with
dichloromethane. The solvent is removed under reduced pressure, and the obtained residue is purified by silica gel
column chromatography to give cis-4-{(3,5-bis(trifluoromethyl)benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-
amino}-2,6-diethylpiperidine-1-carboxylic acid 4-carbamoyl-butyl ester (37 mg, 74%); ESI-MS m/z: 684 [M+1]+, Re‐
tention time 2.30 min (condition A). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (t, J=7.33 Hz, 6H) 1.41-1.55
(m, 4H) 1.69-1.85 (m, 6H) 2.10-2.21 (m, 2H) 2.29 (t, 2H) 3.95 (s, 3H) 4.10-4.22 (m, 4H) 4.74-4.83 (m, 1H) 4.86 (s,
2H) 5.29 (br. s., 1H) 5.49 (br. s., 1H) 7.54 (s, 1H) 7.66 (s, 1H) 7.71 (s, 2H) 7.75 (s, 1H) 8.43 (s, 2H)

With pyridine, di-tert-butyl dicarbonate, ammonium bicarbonate in acetonitrile, Time= 15h, T= 20 °C

PatentMOGI MUNETO;YAMADA KEN;YASOSHIMA KAYO;KAWANAMI TOSHIO;UMEMURA ICHIRO;IWAKI YU‐

KI;QIN HONGBO;IMASE HIDETOMO; NOVARTIS AG; Novartis (w/o Sandoz)Novartis; Novartis (w/o Sandoz);
US2009/118287; (2009); (A1) English
View in Reaxys

O
N

NH 2

Rx-ID: 40843821 View in Reaxys 34/636

Yield Conditions & References
12 %, 78 Synthesis of nitrile from carboxylic acid, ester, lactone or amide
% General procedure: The solution of aminoalane reagent (prepared from 20 equiv. DIBAL-H in case of ester and lac‐
tonesubstrates or from 40 equiv. in case of carboxylic acid and amide substrates) was added to a solutionof carbox‐
ylic acid (1 eqiuv.) or its derivative (lactone, ester or amide, 1 equiv.) in anhydrous THF atroom temperature. Stirring
was continued for 16 hours at 66 C. After this time, the reaction mixturewas cooled, quenched with aqueous solution
of KHSO4 and the product was extracted with CHCl3.The extract was washed with water, dried over anhydrous so‐
dium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography with hex‐
ane / ethyl acetateelution.

With diisobutylaluminium hydride, ammonium chloride in tetrahydrofuran, Time= 16h, T= 66 °C , Inert atmosphere,
Concentration

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Wojtkielewicz, Agnieszka; Łotowski, Zenon; Morzycki, Jacek W.; Synlett; vol. 26; nb. 16; (2015); p. 2288 - 2292;
Art.No: ST-2015-D0437-L
View in Reaxys

HO

NH 2

Rx-ID: 33443416 View in Reaxys 35/636

Yield Conditions & References
98.8 % 19 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 6h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
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HO

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O
N

NH 2

Rx-ID: 40843818 View in Reaxys 36/636

Yield Conditions & References
67 %, 15 Synthesis of nitrile from carboxylic acid, ester, lactone or amide
% General procedure: The solution of aminoalane reagent (prepared from 20 equiv. DIBAL-H in case of ester and lac‐
tonesubstrates or from 40 equiv. in case of carboxylic acid and amide substrates) was added to a solutionof carbox‐
ylic acid (1 eqiuv.) or its derivative (lactone, ester or amide, 1 equiv.) in anhydrous THF atroom temperature. Stirring
was continued for 16 hours at 66 C. After this time, the reaction mixturewas cooled, quenched with aqueous solution
of KHSO4 and the product was extracted with CHCl3.The extract was washed with water, dried over anhydrous so‐
dium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography with hex‐
ane / ethyl acetateelution.

With diisobutylaluminium hydride, ammonium chloride in tetrahydrofuran, Time= 16h, T= 66 °C , Inert atmosphere

Wojtkielewicz, Agnieszka; Łotowski, Zenon; Morzycki, Jacek W.; Synlett; vol. 26; nb. 16; (2015); p. 2288 - 2292;
Art.No: ST-2015-D0437-L
View in Reaxys

O O O

NH 2

O
O O

N
OH
N

OH

Rx-ID: 52289945 View in Reaxys 37/636

Yield Conditions & References
60 % 68.1 : Step-1
To a stirred solution of (S)-l-((5-((5-methoxy-5-oxopentyl)oxy)-7-((2-methyl- [l,l'-biphenyl]-3-yl)methoxy)-2, 3-dihydro-
lH-inden-4-yl)methyl)piperidine-2- carboxylic acid (103 mg, 0.18 mmol) in MeOH (10 mL) at -35°C in a steel bomb,
ammonia gas was purged for 5 minutes. After sealing the steel bomb, the mixture was heated at 55°C and stirred for
36 h. After completion, excess ammonia was removed by flushing nitrogen gas and concentrated the reaction mix‐
ture. The crude was purified by flash chromatography (silica gel, 4 g cartridge) using 8% MeOH in DCM as eluent to
obtain (S)-l-((5-((5-amino-5-oxopentyl)oxy)-7-((2-methyl-[l,l'-biphenyl]-3- yl)methoxy)-2, 3-dihydro- lH-inden-4-
yl)methyl)piperidine-2-carboxylic acid (Yield: 60 mg, 60%) as off-white solid. LCMS (ES) m/z = 571.45 [M+H]+; NMR
(400 MHz, DMSO-de) d ppm: 1.43-1.74 (m, 5H), 1.74 (m, 4H), 1.95-1.98 (m, 3H), 2.11-2.13 (m, 2H), 2.21 (s, 3H),
2.73 (m, 2H), 2.83 (m, 1H), 3.05 (m, 2H), 3.50 (m, 2H), 3.96-4.03 (m, 4H), 5.19 (s, 2H), 6.67 (s, 1H), 6.75 (bs, 1H),
7.20 (d, 7 = 7.6 Hz, 1H), 7.26-7.39 (m, 5H), 7.44-7.49 (m, 3H).

With ammonia in methanol, Time= 36h, T= -35 - 55 °C

PatentJUBILANT BIOSYS LIMITED; JUBILANT PHARMOVA LTDJubilant Pharmova; WO2019/175897; (2019);

(A1) English
View in Reaxys

O O

O O
N N
HO H O H

O NH 2

Rx-ID: 2072822 View in Reaxys 38/636

Yield Conditions & References
97 % With ammonia, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride in tetrahydrofuran, methanol,
Time= 2h, T= 20 °C

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 Mizuhara, Tsukasa; Hioki, Kazuhito; Yamada, Megumi; Sasaki, Hideaki; Morisaki, Daiki; Kunishima, Muneta‐
ka; Chemistry Letters; vol. 37; nb. 12; (2008); p. 1191 - 1192
View in Reaxys

Multistep reaction

Schoen, Istvan; Szirtes, Tamas; Ueberhardt, Tamas; Csehi, Attila; Journal of Organic Chemistry; vol. 48; nb. 11;
(1983); p. 1916 - 1919
View in Reaxys

With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, -10 deg C, 20 min., 2.) -10 deg C to
room temp., overnight, Yield given. Multistep reaction

Houssin, Raymond; Bernier, Jean-Luc; Henichart, Jean-Pierre; Synthesis; nb. 3; (1988); p. 259 - 261
View in Reaxys

4.5.3 General procedure C for the synthesis of amine hydrochlorides of general structure 17
General procedure: A 20-mL vial was charged with Boc-protected amino acid (specified below; 1 equiv) and tetrahy‐
drofuran (0.15M). 1,1′-Carbonyldiimidazole (1.50 equiv) was added and the resulting mixture was stirred for 1h at
23°C. A solution of ammonia in methanol (7.00M, 5.00 equiv) was added to the reaction mixture, and the resulting
mixture was stirred for 12hat 23°C. The product mixture was concentrated, and the residue obtained was diluted with
ethyl acetate (120mL). The diluted product mixture was transferred to a separatory funnel and sequentially washed
with saturated aqueous ammonium chloride solution (1×50mL), saturated aqueous sodium bicarbonate solution
(1×50mL), and saturated aqueous sodium chloride solution (1×50mL). The organic layer was dried over sodium sul‐
fate. The dried solution was filtered and the filtrate was concentrated. The product thus obtained was transferred to a
20-mL vial. A solution of hydrogen chloride in dioxane (4.00M, 5.00 equiv) was added and the resulting mixture was
stirred at 23°C for 1h. The product mixture was concentrated, providing the amine hydrochloride of general structure
17. The product so obtained was used without further purification.

Stage 1: With 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 1h, T= 23 °C , Inert atmosphere

Stage 2: With ammonia in tetrahydrofuran, methanol, Time= 12h, T= 23 °C , Inert atmosphere

Nikolayevskiy, Herman; Robello, Marco; Scerba, Michael T.; Pasternak, Evan H.; Saha, Mrinmoy; Hartman,
Tracy L.; Buchholz, Caitlin A.; Buckheit, Robert W.; Durell, Stewart R.; Appella, Daniel H.; European Journal of
Medicinal Chemistry; vol. 178; (2019); p. 818 - 837
View in Reaxys

O
O

O HN
N 2

N O
H
H
HO
O

Rx-ID: 24800614 View in Reaxys 39/636

Yield Conditions & References
45 % 7 :A mixture of 12-tert-butoxycarbonylaminododecanoic acid (3) (202 mg, 0.64 mmol) and ljl'-carbonyldiimidazole
(114 mg, 0.70 mmol) in anhydrous THF (6 mL) was stirred at room temperature for 1 hour. -Methanolic ammonia (7
M, 3 mL, 21 mmol) was then added via syringe and the reaction mixture stirred at room temperature for 16 hours.
The solvent was removed by rotary evaporation and the resulting residue was subjected to Biotage silica gel column
chromatography, eluting with 5% to 36% ethyl acetate in hexanes followed by 50 % ethyl acetate in dichlorome‐
thane, to give the desired amide 7 (90.0 mg, 45%) as a white solid: ]HNMR (500 MHz, CDCI3) 6 1.25 (m, 14H), 1.46
(s, 9H), 1.63 (m, 4H), 2.22 (t, 2H), 3.10 (m, 2H), 4.50 (br, 1H), 5.40 (br, 2H). m/z (ESI) 337 [C17H34N2O3 + Na]+.

Stage 1: With 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 1h, T= 20 °C

Stage 2: With ammonia in tetrahydrofuran, methanol, Time= 16h, T= 20 °C

PatentJOHNSON, Michael, R.; PARION SCIENCES INCParion; WO2006/23573; (2006); (A2) English
View in Reaxys

HO

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O
N

NH 2

Rx-ID: 40843817 View in Reaxys 40/636

Yield Conditions & References
60 %, 37 Synthesis of nitrile from carboxylic acid, ester, lactone or amide
% General procedure: The solution of aminoalane reagent (prepared from 20 equiv. DIBAL-H in case of ester and lac‐
tonesubstrates or from 40 equiv. in case of carboxylic acid and amide substrates) was added to a solutionof carbox‐
ylic acid (1 eqiuv.) or its derivative (lactone, ester or amide, 1 equiv.) in anhydrous THF atroom temperature. Stirring
was continued for 16 hours at 66 C. After this time, the reaction mixturewas cooled, quenched with aqueous solution
of KHSO4 and the product was extracted with CHCl3.The extract was washed with water, dried over anhydrous so‐
dium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography with hex‐
ane / ethyl acetateelution.

With diisobutylaluminium hydride, ammonium chloride in tetrahydrofuran, Time= 16h, T= 66 °C , Inert atmosphere,
Reagent/catalyst

Wojtkielewicz, Agnieszka; Łotowski, Zenon; Morzycki, Jacek W.; Synlett; vol. 26; nb. 16; (2015); p. 2288 - 2292;
Art.No: ST-2015-D0437-L
View in Reaxys

O
N

NH 2

Rx-ID: 40843823 View in Reaxys 41/636

Yield Conditions & References
30 %, 63 Synthesis of nitrile from carboxylic acid, ester, lactone or amide
% General procedure: The solution of aminoalane reagent (prepared from 20 equiv. DIBAL-H in case of ester and lac‐
tonesubstrates or from 40 equiv. in case of carboxylic acid and amide substrates) was added to a solutionof carbox‐
ylic acid (1 eqiuv.) or its derivative (lactone, ester or amide, 1 equiv.) in anhydrous THF atroom temperature. Stirring
was continued for 16 hours at 66 C. After this time, the reaction mixturewas cooled, quenched with aqueous solution
of KHSO4 and the product was extracted with CHCl3.The extract was washed with water, dried over anhydrous so‐
dium sulfate, and the solvent was evaporated. The crude product was purified by silica gel chromatography with hex‐
ane / ethyl acetateelution.

With diisobutylaluminium hydride, ammonium chloride in tetrahydrofuran, Time= 16h, T= 66 °C , Inert atmosphere

Wojtkielewicz, Agnieszka; Łotowski, Zenon; Morzycki, Jacek W.; Synlett; vol. 26; nb. 16; (2015); p. 2288 - 2292;
Art.No: ST-2015-D0437-L
View in Reaxys

O O O

O
N O N NH 2

HO

Rx-ID: 46387274 View in Reaxys 42/636

Yield Conditions & References
45 % 14. Tert-butyl N-(5-amino-5-oxo-pentyl)-N-methyl-carbamate (17)
Oxalyl chloride (7.6 g, 60 mmol) was added dropwise at 0 oC to a mixture of 5-[tert-butoxycarbonyl(methyl)ami‐
no]pentanoic acid (16, 11.6 g, 50 mmol) in 240ml of dichloromethane. The mixture was stirred for 1 h at room tem‐
perature,then cooled again to 0 oC. 100 ml of aqueous ammonia was added at thistemperature and the reaction mix‐
ture was stirred for 30 min at roomtemperature. Subsequently the mixture was concentrated under reducedpressure,
the remainder was taken up in water and washed withdichloromethane. The aqueous phase was concentrated under
reduced pressureto obtain tert-butyl N-(5-amino-5-oxo-pentyl)-N-methyl-carbamate (17, 5.2 g,23 mmol, 45 %),

Stage 1: With oxalyl dichloride in dichloromethane, Time= 1h, T= 0 - 20 °C

Stage 2: With ammonia in dichloromethane, water, Time= 0.5h, T= 0 - 20 °C

Sulzer-Mosse, Sarah; Lamberth, Clemens; Kubizna, Peter; Synlett; vol. 28; nb. 17; (2017); p. 2277 - 2280;
Art.No: ST-2017-B0164-L

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 View in Reaxys

O NH 2

HO O

Rx-ID: 50864326 View in Reaxys 43/636

Yield Conditions & References
78 % 2.General procedure for solvent-free reduction of carboxylic acid
Unless otherwise specified, carboxylic acid (0.542 mmol), TCT (0.0400 g, 0.216 mmol) and K2CO3 (0.2247 g, 1.626
mmol) were mixed together and hand ground for one minute using porcelain mortar and pestle. After addition of am‐
monium thiocyanate (0.0495 g, 0.650 mmol), the mixture was ground manually for further five minute. During the
grinding, THF (calculated to be less than 1 L/mg of solids) was added to aid homogeneous mixing. The crude materi‐
al was then purified by short column chromatography (column diameter 1.5 cm, packed with 3-4 g silica gel ) using
40-50% ethyl acetate/hexane as an eluent.

Stage 1: With 1,3,5-trichloro-2,4,6-triazine, potassium carbonate in tetrahydrofuran, Time= 0.0166667h, Milling

Stage 2: With ammonium thiocyanate in tetrahydrofuran, Time= 0.0833333h, Milling

Jaita, Subin; Phakhodee, Wong; Chairungsi, Neeranuch; Pattarawarapan, Mookda; Tetrahedron Letters; vol.
59; nb. 39; (2018); p. 3571 - 3573
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 0 - 20 °C
2: ammonia / methanol; dichloromethane / 2 h / 0 - 20 °C
With oxalyl dichloride, ammonia in methanol, dichloromethane, N,N-dimethyl-formamide

Zhou, Jimei;Jia, Minxian;Song, Menghui;Huang, Zhiliang;Steiner, Alexander;An, Qidong;Ma, Jianwei;Guo,

Zhiyin;Zhang, Qianqian;Sun, Huaming;Robertson, Craig;Bacsa, John;Xiao, Jianliang;Li, Chaoqun; Ange‐
wandte Chemie - International Edition; vol. 61; nb. 30; (2022); Art.No: E202205983; Angew. Chem.; vol. 134; nb. 30;
(2022)
View in Reaxys

NH 2

O
O

H
N O
O O
N
H

HN
O

NH

Rx-ID: 52289943 View in Reaxys 44/636

Yield Conditions & References
51 % 66.1 : Step-1
To a stirred solution of methyl 5-((4-(((2-acetamidoethyl)amino)methyl)-7-((2- methyl-[ l,l'-biphenyl]-3-yl)methoxy)-2,
3-dihydro- lH-inden-5-yl)oxy)pentanoate (60 mg, 0.107 mmol) in MeOH (10 mL) at -60°C in a steel bomb, ammonia
gas was purged for 10 minutes, after sealing the steel bomb the mixture was heated at 60°C and stirred for 16 h.
After completion, excess ammonia was removed by flushing nitrogen gas and concentrated the reaction mixture.
The crude was purified by flash chromatography (silica gel, 4 g cartridge) using 10% MeOH in DCM as eluent to
obtain 5-((4-(((2- acetamidoethyl)amino)methyl)-7-((2-methyl-[l,r-biphenyl]-3-yl)methoxy)-2,3- dihydro-lH-inden-5-
yl)oxy)pentanamide (Yield: 30 mg, 51%) as white solid. LCMS (ES) m/z = 544.42 [M+H]+; NMR (400 MHz, DMSO-
d6) d ppm: 1.67-1.74 (m, 4H), 1.76 (s, 3H), 1.95-1.98 (m, 2H), 2.21 (s, 3H), 2.45 (m, 2H), 2.56 (m, 2H), 2.75 (m, 2H),
2.86 (m, 2H), 3.12 (m, 2H), 3.63 (s, 2H), 3.98 (m, 2H), 5.16 (s, 2H), 6.62 (s, 1H), 6.74 (bs, 1H), 7.19 (d, J= 7.6 Hz,
1H), 7.26-7.39 (m, 5H), 7.44-7.48 (m, 3H), 7.80 (bs, 1H).

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 With ammonia in methanol, Time= 16h, T= -60 - 60 °C

PatentJUBILANT BIOSYS LIMITED; JUBILANT PHARMOVA LTDJubilant Pharmova; WO2019/175897; (2019);

(A1) English
View in Reaxys

HO O

O NH 2

Rx-ID: 998657 View in Reaxys 45/636

Yield Conditions & References
98.6 % 16 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 9h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

95 % With Candida antarctica lipase B, ammonium carbamate in various solvent(s), Time= 96h, T= 35 °C , Substitution

Litjens, Mike J. J.; Straathof, Adrie J. J.; Jongejan, Jaap A.; Heijnen, Joseph J.; Chemical Communications; nb.
13; (1999); p. 1255 - 1256
View in Reaxys

94 % With Candida antarctica lipase B, ammonium carbamate in various solvent(s), Time= 72h, T= 35 °C , Substitution

Litjens, Mike J. J.; Straathof, Adrie J. J.; Jongejan, Jaap A.; Heijnen, Joseph J.; Tetrahedron; vol. 55; nb. 42;
(1999); p. 12411 - 12418
View in Reaxys

90.6 % 2 :In a 100 mL three-necked flask, 5.68 g (0.02 mol) of oleic acid, 2.4 g (0.04 mol) of urea was added, 0. 17g Solid
acid catalyst, Mechanical stirring, heating up to 160 ° C, reaction 2h, cooling to about 100 ° C, adding 10% Potassi‐
um hydroxide methanol solution and 10mL water, adjust the pH value of the solution 8 ~ 9, hot filter, remove the solid
acid catalyst, the filterThe solution was transferred to a 250 mL three-necked flask, 20 mL of absolute ethanol and 1
g of activated carbon were added, heated to reflux for 40 min, filtered while hot,The activated carbon was removed
and the filtrate was transferred to a 250 ml beaker, cooled below 0 ° C and filtered to give the crude product. The
crude product was recrystallized from acetone to give a white powder as a solid, 50 ° (vacuum drying, weighing 5.18,
product yield 90.6%, melting point: 73.4 °C -(75.6 °C).The purity of the oleic acid amide product was 98.6% by

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 HPLC. The acid value of oleic acid amide was 0.3 mgK0H / g and the iodine value was 73.88 g / 100 g according to
the national standard GB1668-81 and GB1676-81.

With urea, Time= 2h, T= 160 °C , Temperature

PatentNantong University;Jiang, guomin;Jiang, Guoqing;Gu, xuefang;Tian, shu;Zhan, wenyi;Yan, rui;Guo, Xiaoqing;

NANTONG UNIVERSITYNantong University; CN104193641; (2016); (B) English
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~ 55 % 4 :Oleic acid (25 g, 74% purity) was charged into a 250 ml round bottom flask and then solid urea beads (22 g) were
charged into the same flask together with tetra-n-butyl titanate (0.25 g). The mixture was stirred for a minute with a
magnetic stirrer in the 900 W microwave oven cavity. The heating program raised the temperature from ambient to
190° C. in 5 minutes and the temperature was maintained at 190° C. for an additional 25 minutes. During the heating
process, urea will melt at temperature above 135° C. and begin to decompose at 150° C. liberating NH3 and CO2.
The acid value of the reaction product was determined to be about 10 and the conversion percentage of oleic acid to
reaction product based on acid value is about 95%.

With urea, titanium(IV) tetraethanolate, Time= 0.5h, T= 20 - 195 °C , Product distribution / selectivity

PatentHOONG SENG S;AHMAD SALMIAH;ABU HASSAN HAZIMAH; MPOB - MALAYSIAN PALM OIL
BOARDMPOB; US2005/283011; (2005); (A1) English
View in Reaxys

~ 54 % 1; 2; 3 :Oleic acid (25 g, 74% purity) was charged into a 250 ml round bottom flask and then solid urea beads (22 g)
were charged into the same flask together with tetra-n-butyl titanate (0.25 g). The mixture was stirred for a minute
with a magnetic stirrer in the 900 W microwave oven cavity. The heating program raised the temperature from ambi‐
ent to 190° C. in 5 minutes and the temperature was maintained at 190° C. for an additional 25 minutes. During the
heating process, urea will melt at temperature above 135° C. and begin to decompose at 150° C. liberating NH3 and
CO2. The acid value of the reaction product was determined to be about 10 and the conversion percentage of oleic
acid to reaction product based on acid value is about 95%.

With urea, tetrabutoxytitanium, Time= 0.5h, T= 20 - 195 °C , Product distribution / selectivity

PatentHOONG SENG S;AHMAD SALMIAH;ABU HASSAN HAZIMAH; MPOB - MALAYSIAN PALM OIL
BOARDMPOB; US2005/283011; (2005); (A1) English
View in Reaxys

~ 52 % 5 :Oleic acid (25 g, 74% purity) was charged into a 250 ml round bottom flask and then solid urea beads (22 g) were
charged into the same flask together with tetra-n-butyl titanate (0.25 g). The mixture was stirred for a minute with a
magnetic stirrer in the 900 W microwave oven cavity. The heating program raised the temperature from ambient to
190° C. in 5 minutes and the temperature was maintained at 190° C. for an additional 25 minutes. During the heating
process, urea will melt at temperature above 135° C. and begin to decompose at 150° C. liberating NH3 and CO2.
The acid value of the reaction product was determined to be about 10 and the conversion percentage of oleic acid to
reaction product based on acid value is about 95%.

With urea, butyltin(IV) chloride dihydroxide, Time= 0.5h, T= 20 - 195 °C , Product distribution / selectivity

PatentHOONG SENG S;AHMAD SALMIAH;ABU HASSAN HAZIMAH; MPOB - MALAYSIAN PALM OIL
BOARDMPOB; US2005/283011; (2005); (A1) English
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40 % Synthesis of Oleamide (Ole)

Synthesis of Oleamide (Ole) (0075) (0076) A solution of oleic acid (447 mg, 1.58 mmol) in dichloromethane in a 10
mL round bottomed flask was cooled to 0 °C before oxalyl chloride was added dropwise (0.4 mL, 4.74 mmol). The
reaction was allowed to heat to 25 °C and left to stir for 4 h. The reaction mixture was concentrated under reduced
pressure and again cooled to 0 °C. The concentrate was treated with saturated aq NH4OH (5 mL) for 5 min. The
mixture was partitioned between ethyl acetate (10 mL) and water (10 mL), before drying the organic layer over mag‐
nesium sulfate. The organic leyer was then concentrated under reduced pressure to yield the crude product. Purifi‐
cation by flash column chromatography (SiO2, 3:2 pentane/ethyl acetate, increasing to 100% ethyl acetate) gave the
title compound oleamide (302 mg, 46%) as a white solid. (0077) Rf = 0.22 (Pentane/EtOAc, 3/1); IR (film) υmax 1675,
1467 cm-1 ; 1H NMR (400 MHz, CDCl3) δ 5.35 (m, 4H), 2.23 (t, J = 7.6 Hz, 2H), 2.01 (q, J = 6.1 Hz, 4H), 1.64 (m,
2H), 1.28 (m, 20H), 0.88 (t, J = 6.7 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 206.80, 130.00, 129.70, 35.90, 31.90,

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 30.90, 29.70, 29.60, 29.50, 29.30, 29.20, 29.10, 27.20, 27.10, 25.50, 22.70, 14.10; HRMS: (ESI-TOF) calculated for
C18H35NO [M - H+] 282.2797, found 294.2803.

Stage 1: With oxalyl dichloride in dichloromethane, Time= 4h, T= 0 - 25 °C

Stage 2: With ammonium hydroxide in water, T= 0 °C

PatentDublin City University;UNIVERSITY COLLEGE DUBLIN;The designation of the inventor has not yet been
filed; NATIONAL UNIVERSITY OF IRELAND; DUBLIN CITY UNIVERSITY; UNIVERSITY OF DUBLINNational Uni‐
versity of Ireland; Dublin City University; Trinity College Dublin; EP3095444; (2016); (A1) English
View in Reaxys

35 % With ammonium hydroxide, ethanol, Time= 6h, T= 160 °C , Autoclave, Green chemistry

Dalu, Francesca; Scorciapino, Mariano A.; Cara, Claudio; Luridiana, Alberto; Musinu, Anna; Casu, Mariano;
Secci, Francesco; Cannas, Carla; Green Chemistry; vol. 20; nb. 2; (2018); p. 375 - 381
View in Reaxys

10 % (21) General Procedure for Amide Coupling

General procedure: To a stirred solution of the fatty acid (1.0 mmol, 1.0 equiv.) inCH2Cl2 (5 mL) was added CDI
(0.178 g, 1.1 mmol, 1.1 equiv.).After 30 min at room temperature, the amine (1.1 mmol, 1.1equiv.) was added. After
12 h, CH2Cl2 (25 mL) was added, followedby saturated aqueous NH4Cl. The mixture was acidified topH 2 by addi‐
tion of HCl, the organic phase was separated, andthe aqueous layer was further extracted with CH2Cl2 (3 × 10mL).
The organic phases were combined, dried over Na2SO4, filtered,and concentrated in vacuo, to give the amide.

Stage 1: With 1,1'-carbonyldiimidazole in dichloromethane, Time= 0.5h, T= 20 °C

Stage 2: With ammonia in dichloromethane, Time= 12h

Johansson, Silje J. R.; Johannessen, Tonje; Ellefsen, Christiane F.; Ristun, Mali S.; Antonsen, Simen; Han‐
sen, Trond V.; Stenstrom, Yngve; Nolsoe, Jens M. J.; Synlett; vol. 30; nb. 2; (2019); p. 213 - 217; Art.No:
ST-2018-D0672-L
View in Reaxys

(i) SOCl2, (ii) NH3, benzene, Multistep reaction

Butenandt,A. et al.; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 333; (1963); p. 114 - 126
View in Reaxys

Reaction Steps: 2
1: phosphorus trichloride
2: ammonia
With ammonia, phosphorus trichloride

Aschan; Chemische Berichte; vol. 31; (1898); p. 2346

View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / 4 h / 0 - 20 °C
2: ammonia / dichloromethane; water / 0.5 h / 0 °C
With oxalyl dichloride, ammonia in dichloromethane, water

Wu, Hui; Kelley, Charles J.; Pino-Figueroa, Alejandro; Vu, Huyen D.; Maher, Timothy J.; Bioorganic and Medici‐
nal Chemistry; vol. 21; nb. 17; (2013); p. 5188 - 5197
View in Reaxys

6 :A solution of 100 g oleic acid and 75 mL of xylenes is heated to reflux with stirring, and NH3 gas is bubbled
through the solution for 25-30 hrs. The xylenes are then removed by heating the solution in vacuo to give the crude

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 oleamide product. The oleamides are recrystallized in hot hexanes, followed by cooling of the mixture to 0° C. Olea‐
mide crystals are collected in a Buchner funnel and washed twice with cold hexanes to provide the purified oleamide
product.

With ammonia in 5,5-dimethyl-1,3-cyclohexadiene, Reflux

PatentBiosynthetic Technologies, LLC;Forest, Jeremy;Bredsguard, Jakob; CALUMET SPECIALTY PRODUCTS

PARTNERS LPCalumet Specialty Products; US9145535; (2015); (B2) English
View in Reaxys

Reaction Steps: 2
1: thionyl chloride / 0.25 h / 60 °C
2: ammonia / Cooling with ice
With thionyl chloride, ammonia

Gupta, Gaurav R.; Joshi, Narendra S.; Phalak, Raju P.; Waghulde, Govinda P.; Oriental Journal of Chemistry;
vol. 37; nb. 5; (2021); p. 1109 - 1116
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 °C
2: ammonium hydroxide / tetrahydrofuran; water / 3 h
With ammonium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide in tetrahydrofuran, dichloromethane, water

Kobayashi, Yasuyuki;Watanabe, Natsumi;Hiura, Reina;Kubota, Mai;Furuta, Kousuke;Sugimoto, Keii‐

chiro;Murota, Kaeko;Nakamura, Eri;Matsuura, Toshiki;Kai, Kenji;Inui, Takashi;Kitakaze, Tomoya;Harada,
Naoki;Yamaji, Ryoichi; Journal of Agricultural and Food Chemistry; vol. 70; nb. 49; (2022); p. 15499 - 15508
View in Reaxys

HO O
Br Br

O NH 2

Rx-ID: 8676728 View in Reaxys 46/636

Yield Conditions & References
93 % With ammonium chloride, N-ethyl-N,N-diisopropylamine, S-(1-oxido-2-pyridyl)-thio-N,N,N',N'-tetramethyluronium
hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.5h, T= 20 °C

Bailen; Chinchilla; Dodsworth; Najera; Tetrahedron Letters; vol. 41; nb. 50; (2000); p. 9809 - 9813
View in Reaxys

87 % With polimer bound N-hydroxy succinimide ammonium salt, N-(3-dimethylaminopropyl)-N-ethylcarbodiimide in

methanol, Time= 24h, Heating

Chinchilla, Rafael; Dodsworth, David J.; Nájera, Carmen; Soriano, José M.; Tetrahedron Letters; vol. 44; nb. 3;
(2003); p. 463 - 466
View in Reaxys

Reaction Steps: 2
1: Et3N / acetone / 0.5 h / -10 °C
2: 25percent aq. NH3 / acetone / 2 h
With ammonium hydroxide, triethylamine in acetone

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

Reaction Steps: 2
1: 2 h / 80 °C / Ionic liquid
2: ammonium acetate; triethylamine / 3 h / 80 °C / Ionic liquid
With ammonium acetate, triethylamine

Lee, Kwan Soo; Kim, Kee D.; Synthetic Communications; vol. 41; nb. 23; (2011); p. 3497 - 3500
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / diethyl ether / 0 - 20 °C

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 2: ammonia / 0.5 h / -10 - 0 °C
With oxalyl dichloride, ammonia in diethyl ether

Deane, Fiona M.; O'Sullivan, Elaine C.; Maguire, Anita R.; Gilbert, Jayne; Sakoff, Jennette A.; McCluskey,
Adam; McCarthy, Florence O.; Organic and Biomolecular Chemistry; vol. 11; nb. 8; (2013); p. 1334 - 1344
View in Reaxys

O O

N Br N Br

O O O O

OH NH 2

N N
H H
O O

Rx-ID: 10468050 View in Reaxys 47/636

Yield Conditions & References
90 % Stage 1: With Rink amide resin after treatment with piperidine in DMF, benzotriazol-1-ol, dacarbazine in N,N-di‐
methyl-formamide, Time= 24h, T= 20 °C
Stage 2: With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 °C

Sun, Li-Ping; Dai, Wei-Min; Angewandte Chemie - International Edition; vol. 45; nb. 43; (2006); p. 7255 - 7258
View in Reaxys

O HN 2

OH O

O O

N N

O O

Rx-ID: 35716017 View in Reaxys 48/636

Yield Conditions & References
97 % 2.1 : 4.2.1 6-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanamide (1e)
A mixture of 6-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanoic acid10 (156.77g, 0.60mol), thionyl chloride (55mL,
0.75mol), and dry benzene (400mL) was refluxed for 2h and evaporated in vacuo; the residue was dissolved in dry
dichloromethane (800mL). Through this solution stirred and cooled at 20°C, a current of dry ammonia was passed to
saturation, followed by washing with water (3×100mL), drying over sodium sulfate, and evaporation to dryness in va‐
cuo to give the analytically pure product (151.48g, 97%) as a colorless crystals; mp 154-155°C; [found: C, 64.49; H,
6.34; N, 11.24. C13H14N2O3 requires C, 64.60; H, 6.20; N, 11.38%]; νmax (KBr) 3387, 3195, 2931, 2852, 1775, 1720,
1649cm-1; δH (DMSO-d6) 7.85 (4H, m, aromatic), 7.21 (1H, br s, NH), 6.67 (1H, br s, NH), 3.56 (2H, m, CH2), 2.03
(2H, m, CH2), 1.59 (2H, m, CH2), 1.50 (2H, m, CH2), 1.25 (2H, m, CH2); δC (DMSO-d6) 175.0 (C=O), 168.4 (C=O),
134.9, 132.0, 123.4, 37.8, 35.4, 28.2, 26.4, 25.1; LCMS: found m/z 261.2, MH+

With thionyl chloride in benzene, Time= 2h, Reflux

Kondratyuk, Kostyantyn M.; Lukashuk, Olena I.; Golovchenko, Aleksandr V.; Komarov, Igor V.; Brovarets,
Volodymyr S.; Kukhar, Valery P.; Tetrahedron; vol. 69; nb. 30; (2013); p. 6251 - 6261
View in Reaxys

O NH 2

Si Si

O O

O O

Rx-ID: 41494898 View in Reaxys 49/636

Yield Conditions & References
23 % Amides; General Procedure
General procedure: A 0.2 M solution of the corresponding methyl ester in aq NH4OH (28-30%) was stirred at r.t. for
16 h. The solvent was evaporated to affordthe amide, which was, in some cases, purified by silica gel chromatogra‐
phy. The known amides 3, 33 5a,34 5b, 6c 5h,35 11a,36 11b,37 11c,3611e,38 11h,4 11i,39 11j,39 13,40 14,41
20,42 and 2343 were synthesized following the general procedure described above. Compound 5e was synthesized
following the literature.44

With ammonium hydroxide in water, Time= 16h, T= 20 °C , Inert atmosphere

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 Keita, Massaba; Vandamme, Mathilde; Paquin, Jean-François; Synthesis; vol. 47; nb. 23; (2015); p. 3758 - 3766;
Art.No: SS-2015-M0394-OP
View in Reaxys

HO

NH 2

Rx-ID: 45392391 View in Reaxys 50/636

Yield Conditions & References
97.7 % 20 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 7h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

O O

O NH 2

Rx-ID: 59844771 View in Reaxys 51/636

Yield Conditions & References
48 % With [2-(di-tert-butylphosphinomethyl)-6-(diethylaminomethyl)pyridine]ruthenium(II) chlorocarbonyl hydride, potassi‐
um-t-butoxide, ammonia, hydrogen in tert-Amyl alcohol, toluene, Time= 36h, T= 120 - 150 °C , p= 5475.55Torr

Ben-David, Yehoshoa; Luo, Jie; Milstein, David; Montag, Michael; Zhou, Quan-Quan; Chemical Science; vol.
13; nb. 13; (2022); p. 3894 - 3901
View in Reaxys

HO O

O NH 2

Rx-ID: 850249 View in Reaxys 52/636

Yield Conditions & References
96% With zirconium(IV) chloride, ammonium carbamate in tetrahydrofuran, Time= 24h, T= 100 °C , Inert atmosphere,
Molecular sieve

Tinnis, Fredrik; Lundberg, Helena; Adolfsson, Hans; Advanced Synthesis and Catalysis; vol. 354; nb. 13; (2012);
p. 2531 - 2536
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 44 % Stage 1: With thionyl chloride in dichloromethane, N,N-dimethyl-formamide, Time= 2h, T= 0 - 20 °C , Inert atmos‐
phere
Stage 2: With ammonium hydroxide in dichloromethane, water, N,N-dimethyl-formamide, Time= 1h, T= 0 - 20 °C ,
Inert atmosphere

Richers, Johannes; Heilmann, Michael; Drees, Markus; Tiefenbacher, Konrad; Organic Letters; vol. 18; nb. 24;
(2016); p. 6472 - 6475
View in Reaxys

With ammonia, T= 180 - 190 °C , unter kontinuierlicher Entfernung des entstehenden Wassers

Mitchell; Reid; Journal of the American Chemical Society; vol. 53; (1931); p. 1880,1881
View in Reaxys

(i) SOCl2, (ii) aq. NH3, Multistep reaction

Chelpanova,L.F.; Mashlyakovskii,L.N.; Journal of Organic Chemistry USSR (English Translation); vol. 2; (1966);
p. 604 - 608; Zhurnal Organicheskoi Khimii; vol. 2; (1966); p. 602 - 607
View in Reaxys

Synthesis of compounds 3a-n; general procedure

General procedure: Ammonium carbonate (0.29 g, 3 mmol) was added to the appropriate aliphatic carboxylic acid (1
mL) and the mixture was stirred at 100 °C for 30 minutes. The appropriate 1-aryl-2-bromoethanone (1 mmol) was
added to the solution. Then the mixture was stirred for 15 minutes. The reaction was extracted with CH2Cl2, and the
combined organic extracts were dried, filtered and concentrated under reduced pressure to give 2-alkyl-4(5)-aryl-1H-
imidazoles.

With ammonium carbonate, Time= 0.5h, T= 100 °C

Liu, Cong; Nie, Yijiao; Yao, Guowei; Dai, Rongji; Deng, Yulin; Journal of Chemical Research; vol. 38; nb. 4;
(2014); p. 208 - 210
View in Reaxys

Reaction Steps: 2
1: triethylamine / tetrahydrofuran / 1.08 h / 0 °C
2: ammonium hydroxide / tetrahydrofuran; water / 0 - 20 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, water

Chen, Dian-Feng; Chu, John C. K.; Rovis, Tomislav; Journal of the American Chemical Society; vol. 139; nb. 42;
(2017); p. 14897 - 14900
View in Reaxys

O NH 2

HO O

Rx-ID: 22085558 View in Reaxys 53/636

Yield Conditions & References
55% H : Method H
Method H 5-Cyclohexylpentylamine Hydrogen Oxalate (126). A solution of cyclohexanepentanoic acid (2 g, 10.9
mmol) in SOCl2 (8 mL) was heated on a steam bath for 3 h. The SOCl2 was removed under vacuum. Chloroform
(2*10 mL) was added and reevaporated to give the crude acid chloride as a yellow liquid. A saturated solution of
ammonia in dry THF (ammonia gas bubbled through 10 mL of THF for 5 min), was slowly added to a solution of the
acid chloride in dry THF (50 mL) while cooling in an ice bath. The reaction mixture was allowed to stir at room tem‐
perature for 3 h and was then concentrated to half of its volume and poured onto water (100 mL). The solid was
removed by filtration, washed with water and dried (MgSO4). Recrystallization from aqueous MeOH gave 5-cyclohex‐
ylvaleramide (1.1 g, 55%); mp 121-122° C. (reported mp 122-123° C.) (Katsellson and Dubinin, Compt. Rend. Acad.
Sci. U.R.S.S. [N.S.] 4:405 (1936); Chem. Abstr. 31:3449 (1937)).

With ammonia in tetrahydrofuran, thionyl chloride, chloroform

PatentUNIV VIRGINIA COMMONWEALTH; VIRGINIA COMMONWEALTH UNIVERSITYVirginia Commonwealth

University; US6057371; (2000); (A) English

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

Reaction Steps: 2
1: thionyl chloride
2: benzene; ammonia
With thionyl chloride, ammonia, benzene

Katznelsson; Dubinin; Doklady Akademii Nauk SSSR; vol. 13; (1936); p. 405,407; Chemisches Zentralblatt; vol.
108; nb. I; (1937); p. 4095
View in Reaxys

HO O HN
2
O

Cl O

OH O OH

H H

H H H H

O O
H H

Rx-ID: 25393669 View in Reaxys 54/636

Yield Conditions & References
94% 81 : Synthesis of 17β-hydroxy-11β-(9-aminocarbonylnonyl)-5α-androstan-3-one
[Example 81] Synthesis of 17β-hydroxy-11β-(9-aminocarbonylnonyl)-5α-androstan-3-one The 17β-hydroxy-11β-(9-
carboxynonyl)-5α-androstan-3-one (16.6 mg) obtained in Example 75 was dissolved in tetrahydrofuran (1 ml) and,
after adding triethylamine (6.0 μl) and ethyl chlorocarbonate (4.0 μl) at -10°C, the mixture was stirred for 10 minutes.
Ammonia gas was blowninto the reaction mixture for 5 minutes and the mixture was stirred for 20 minutes at -10°C.
A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then reverted to
room temperature. After extraction with ethyl acetate, the organic layer was washed with a saturated aqueous solu‐
tion of sodium chloride and dried with magnesium sulfate; after filtering, the solvnt was distilled off at reduced pres‐
sure. The resulting residue was purified by silica gel column chromatography (developing solvents: methanol/chloro‐
form = 1/20) to give the end compound in 15.5 mg (yield, 94%). 1H-NMR(270MHz, CDCl3)δ: 0.85(3H, s),
0.88-1.05(4H, m), 1.15(3H, s), 1.10-1.88(25H, m), 1.97-2.50(10H, m), 3.58(1H, t, J=8.7Hz), 5.34(2H, brs).
Mass(FAB):460(M+1) Rf value (on silica gel plate, developing solvents: methanol/chloroform = 1/10): 0.33

With sodium chloride, ammonium chloride, triethylamine in tetrahydrofuran

PatentCHUGAI SEIYAKU KABUSHIKI KAISHA; Chugai Pharmaceutical (in: Roche); ROCHE HOLDING
AG&lt;unknown&gt;; Roche; EP1219631; (2002); (A1) English
View in Reaxys

O O
Cl O
HO O

O Cl
O NH 2

Rx-ID: 25516492 View in Reaxys 55/636

Yield Conditions & References
89% R.66 : Reference Example 66
Reference Example 66 Oxalyl chloride (0.508 ml) and N,N-dimethylformamide (catalytic amount) were added to a
solution of 6-oxo-6-phenylhexanoic acid (1.00 g) in tetrahydrofuran (15 ml) at room temperature, which was stirred at
room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate (25 ml) and added drop‐
wise to a stirred mixture of 25% aqueous ammonia (20 ml) and ethyl acetate (25 ml) at 0° C. After stirring at room
temperature for 2 hours, water (200 ml) was added and extracted with ethyl acetate. The ethyl acetate layer was
washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining
crystals were recrystallized from ethyl acetate-hexane to obtain 6-oxo-6-phenylhexanamide (885 mg, yield 89%) as
colorless crystals. m.p. 113-114° C.

With ammonium hydroxide, sodium chloride in tetrahydrofuran, water, ethyl acetate, N,N-dimethyl-formamide

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 PatentTakeda Chemical Industries, Ltd.; TAKEDA PHARMACEUTICAL COMPANY LIMITEDTakeda Pharma;
US6251926; (2001); (B1) English
View in Reaxys

H H
N O N NH 2

H H
O O

H H H H
N N

Rx-ID: 33380058 View in Reaxys 56/636

Yield Conditions & References
32 % Synthesis of compound 4
Ammonia (10 mL) was added into a round-bottomed flask (100 ml) containing compound 3b (0.001 mol) dissolved in
methanol (20mL) and calcium chloride (0.001 mol). The solution was stirred at 80° for 18 h. After cooling to room
temperature, the solution was concentrated and the residue was obtained, which was treated with ethanol (30 mL)
and stirred for 0.5 h. The mixture was then filtered and the solvent was evaporated to afford the residue, which was
purified in a reverse-phase silica gel column (distilled water:methanol = 4:1, v/v) to give compound 4.

With ammonia, calcium chloride in methanol, Time= 18h, T= 80 °C

Wang, Lisheng; You, Yejun; Wang, Songqing; Liu, Xu; Liu, Buming; Wang, Jinni; Lin, Xiao; Chen, Min‐
gsheng; Liang, Gang; Yang, Hua; Bioorganic and Medicinal Chemistry Letters; vol. 22; nb. 12; (2012); p. 4100 -
4102
View in Reaxys

Cl Cl Cl Cl

OH NH 2

H H
N N
O O O O

O O
F N N F N N
S S

F O F O
F F

Rx-ID: 41057050 View in Reaxys 57/636

Yield Conditions & References
29 % With ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-
yl-methylene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, T= 25 °C

Zhang, Yue-Mei; Greco, Michael N.; Macielag, Mark J.; Teleha, Christopher A.; Desjarlais, Renee L.; Tang,
Yuting; Ho, George; Hou, Cuifen; Chen, Cailin; Zhao, Shuyuan; Kauffman, Jack; Camacho, Raul; Qi, Jenson;
Murray, William; Demarest, Keith; Leonard, James; Journal of Medicinal Chemistry; vol. 61; nb. 22; (2018); p.
10276 - 10298
View in Reaxys

49 : 5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-8-
yl)oxy)pentanamide
Into a 25-mL round-bottom flask, was placed 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperi‐
din-4-yl]amino]quinolin-8-yl]oxy)pentanoic acid (100 mg, 0.14 mmol, 1.00 equip), NH4Cl (38 mg, 0.71 mmol, 5.00
equip), HATU (80 mg, 0.21 mmol, 1.50 equip), N,N-dimethylformamide (10 mL), and DIEA (0.5 mL).
The resulting solution was stirred overnight at 25° C.
The resulting solution was diluted with water (100 mL).
The solids were collected by filtration.
The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to yield 5-([6-[bis(4-chloro‐
phenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanamide as an off-white sol‐
id.
LCMS (ES, m/z) 709 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.342 (d, J=6.9 Hz, 1H), 7.914 (s, 1H), 7.428 (d,
J=8.4 Hz, 4H), 7.230 (d, J=8.4 Hz, 4H), 7.130 (s, 1H), 6.983 (d, J=6.9 Hz, 1H), 5.767 (s, 1H), 4.121-4.103 (m, 3H),
3.948-3.845 (m, 4H), 3.429-3.345 (m, 2H), 2.188-2.097 (m, 4H), 1.803-1.680 (m, 6H).

With ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-

yl-methylene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, T= 25 °C

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 PatentJANSSEN PHARMACEUTICA NV; JOHNSON & JOHNSON INCJohnson & Johnson; US2015/239844;
(2015); (A1) English
View in Reaxys

49 : Example 49 Compound 538 5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-

yl)amino)quinolin-8-yl)oxy)pentanamide
5-((6-(bis(4-chlorophenyl)methyl)-4-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)quinolin-8-yl)oxy)pentanamide
Into a 25-mL round-bottom flask, was placed 5-([6-[bis(4-chlorophenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperi‐
din-4-yl]amino]quinolin-8-yl]oxy)pentanoic acid (100 mg, 0.14 mmol, 1.00 equip), NH4Cl (38 mg, 0.71 mmol, 5.00
equip), HATU (80 mg, 0.21 mmol, 1.50 equip), N,N-dimethylformamide (10 mL), and DIEA (0.5 mL).
The resulting solution was stirred overnight at 25° C.
The resulting solution was diluted with water (100 mL).
The solids were collected by filtration.
The residue was applied onto a silica gel column with dichloromethane/methanol (10:1) to yield 5-([6-[bis(4-chloro‐
phenyl)methyl]-4-[[1-(trifluoromethane)sulfonylpiperidin-4-yl]amino]quinolin-8-yl]oxy)pentanamide as an off-white sol‐
id.
LCMS (ES, m/z) 709 [M+H]+; 1H-NMR (300 MHz, DMSO-D6) δ: 8.342 (d, J=6.9 Hz, 1H), 7.914 (s, 1H), 7.428 (d,
J=8.4 Hz, 4H), 7.230 (d, J=8.4 Hz, 4H), 7.130 (s, 1H), 6.983 (d, J=6.9 Hz, 1H), 5.767 (s, 1H), 4.121-4.103 (m, 3H),
3.948-3.845 (m, 4H), 3.429-3.345 (m, 2H), 2.188-2.097 (m, 4H), 1.803-1.680 (m, 6H).

With ammonium chloride, N-ethyl-N,N-diisopropylamine, HATU in N,N-dimethyl-formamide, T= 25 °C

PatentJANSSEN PHARMACEUTICA NV; JOHNSON & JOHNSON INCJohnson & Johnson; US2015/239845;
(2015); (A1) English
View in Reaxys

HO

NH 2

Rx-ID: 54232284 View in Reaxys 58/636

Yield Conditions & References
91 % With 1H-imidazole, urea in octane, Time= 24h, T= 120 °C , Reagent/catalyst

Blacker, A. John; Chhatwal, A. Rosie; Lomax, Helen V.; Marcé, Patricia; Williams, Jonathan M. J.; Chemical
Science; vol. 11; nb. 22; (2020); p. 5808 - 5818
View in Reaxys

HO O

O NH 2

Rx-ID: 65885 View in Reaxys 59/636

Yield Conditions & References
79 % With ammonium bicarbonate, formamide, Time= 0.15h, Irradiation

Peng, Yanqing; Song, Gonghua; Organic Preparations and Procedures International; vol. 34; nb. 1; (2002); p. 95 -
97
View in Reaxys

With ammonia, T= 190 - 210 °C

Ralston; Hoerr; Pool; Journal of Organic Chemistry; vol. 8; (1943); p. 474

View in Reaxys

Reaction Steps: 2
1: phosphorus trichloride
2: ammonia
With ammonia, phosphorus trichloride

Caspari; American Chemical Journal; vol. 27; (1902); p. 307

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 With Diethy phosphocyanidate, ammonia in 1,4-dioxane, N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121
View in Reaxys

With ammonia, 3-butyl-1-methyl-1H-imidazol-3-ium hexafluorophosphate, Time= 96h, T= 20 °C , Enzymatic reaction

Kidwai, Mazaahir; Poddar, Roona; Bhardwaj, Saurav; Biocatalysis and Biotransformation; vol. 29; nb. 4; (2011);
p. 113 - 118
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / benzene / 1 h
2: ammonia / dichloromethane
With oxalyl dichloride, ammonia in dichloromethane, benzene

PatentACUITAS THERAPEUTICS INC.; ACUITAS THERAPEUTICS INCAcuitas Therapeutics; WO2015/199952;

(2015); (A1) English
View in Reaxys

A : Amide Intermediate Preparation Example A

General procedure: Into a 1L open reactor was added 500g of carboxylic acid feedstock (chemically pure), stirring
was turned on (600 r/min), ammonia gas was continuously fed to the carboxylic acid feed from the bottom of the
reactor (chemical purity, water content was 5.1wt%, Flow rate is 100g/min). After the reaction was allowed to pro‐
ceed for TC hours at the reaction temperature TA, the ammonia gas flow was stopped. The contents of the reactor
were sampled and nuclear magnetic proton spectra and elemental analysis were performed to characterize the
amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Ta‐
ble A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the obtained amide intermedi‐
ate has an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with
waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest
were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammo‐
nia was 130g/min).

With ammonia, Time= 0.5h, T= 145 °C , Temperature

PatentSinopec Corporation;Sinopec Yangzi Petrochemical Co., Ltd.;Sun Hailong;Wei Yanyu;Gao Yilong;Chen Xin‐
hua;Miao Jun;Li Na;Kan Lin;Bai Jiye;Chen Shaohui;Yang Aiwu;Xu Yuexing; CHINA PETROCHEMICAL CORPORA‐
TIONSinopec Group; CN104557610; (2018); (B) English
View in Reaxys

With Pseudoalteromonas tunicata TamA catalytic adenylation domain, ammonia, ATP, magnesium chloride in di‐
methyl sulfoxide, pH= 9, Enzymatic reaction

Marchetti, Piera M.; Richardson, Shona M.; Kariem, Noor M.; Campopiano, Dominic J.; MedChemComm; vol.
10; nb. 7; (2019); p. 1192 - 1196
View in Reaxys

Reaction Steps: 5
1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 4 h / 0 - 20 °C / Inert atmosphere
2: hydroxylamine hydrochloride; potassium carbonate / water; ethyl acetate / 12 h / 0 - 20 °C / Inert atmosphere
3: dichloromethane / 30 min / 20 °C / Inert atmosphere
4: copper(l) chloride; pyridine / chloroform / 3 h / 80 °C / Inert atmosphere
5: hydrogenchloride / water; 1,4-dioxane / 1 h / 100 °C / Inert atmosphere
With pyridine, hydrogenchloride, oxalyl dichloride, hydroxylamine hydrochloride, potassium carbonate, N,N-dimethyl-
formamide, copper(l) chloride in 1,4-dioxane, dichloromethane, chloroform, water, ethyl acetate

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 Park, Jinhwan;Unnikrishnan Krishnapriya, Anattil;Park, Yeongmi;Kim, Minsuk;Reidl, Tyler W.;Kuniyil, Rosi‐
tha;Son, Jongwoo; Advanced Synthesis and Catalysis; (2023)
View in Reaxys

HO O

O NH 2

Rx-ID: 230957 View in Reaxys 60/636

Yield Conditions & References
98.4 % 13 :General procedure: According to the embodiment of the present invention described above, stearic acid amide,
which is a kind of carboxylic acid amide compound, was prepared in Example 1 as follows. First, the carboxylic acid
injector 250 injects 1000 g of stearic acid into the heater 100, and the heater 100 heats 1000 g of stearic acid to 120
° C. Subsequently, when stearic acid is injected into the first reaction tank 210, the first catalyst injector 261 injects
10 g of tetraisopropyl titanium, which is a metal catalyst, into the first reaction tank 210, Was heated by the heater
attached to the first reaction tank 210. When 150 g of stearic acid was charged into the first reaction tank 210, the
first ammonia injector 281 started to feed the ammonia gas through the ammonia pipe 283 at a rate of 100 L / hr.
When 500 g of stearic acid was charged into the first reaction tank 210, the introduction of stearic acid into the first
reaction tank 210 was stopped. The propeller in the first reaction tank 210 was mixed with stearic acid and ammonia
while maintaining the reaction temperature at 165 ° C in the first reaction tank 210.Next, when the supply of the stea‐
ric acid to the first reaction tank 210 is stopped, the 500 g of stearic acid remaining in the heater 100 through the
valve is changed to be supplied to the second reaction tank 220. When stearic acid is injected into the second reac‐
tion tank 220, the second catalyst injector 262 injects 10 g of tetraisopropyl titanium as a metal catalyst into the sec‐
ond reaction tank 220 and starts heating the second reaction tank 220 . When 150 g of stearic acid was charged into
the second reaction tank 220, the second ammonia feeder 282 started to feed the ammonia gas through the ammo‐
nia pipe 283 at a rate of 100 L / hr. When all 500 g of stearic acid was fed to the second reaction tank, the addition of
stearic acid to the second reaction tank was stopped. The propeller in the second reaction tank 220 was mixed with
stearic acid and ammonia while maintaining the reaction temperature of 165 ° C in the second reaction tank 220.In
Examples 2 to 10, other carboxylic acid amide compounds were prepared in the same manner as in Example 1, ex‐
cept that stearic acid was used instead of stearic acid and other carboxylic acids as shown in the following Table 1
as "acid".

With ammonia, zircornium(IV) n-propoxide, Time= 8h, T= 165 °C , Reagent/catalyst

PatentLee, Chang Ho; Lee, Chang Ho; KR101678461; (2016); (B1) English
View in Reaxys

90 % With Diethy phosphocyanidate, ammonia in N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121
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89 % Stage 1: With niobium pentachloride in dichloromethane

Stage 2: With ammonia in dichloromethane, Time= 0.5h, T= 45 - 50 °C

Nery, Marcelo S.; Ribeiro, Renata P.; Lopes, Claudio C.; Lopes, Rosangela S. C.; Synthesis; nb. 2; (2003); p.
272 - 276
View in Reaxys

11 % Typical procedure:
General procedure: In a screw-capped tube are successively introduced the amine (0.915 mmol, 1 eq), the acid
(0.915 mmol, 1 eq) in a suitable solvent (usually 1,4-dioxane, 2 mL). The 3 Å molecular sieve (50 mg) and the immo‐
bilized CAL-B (50 mg) are finally introduced. The reaction mixture is heated to 50 °C for 3 days. After cooling, the
solvent is evaporated the crude residue is partionned between water and EtOAc. The aqueous layer is extracted with
EtOAc (2 x 2 mL) and the combined organic phases are washed with 3 M HCl (2 x 2 mL) and 10 % aqueous K2CO3
(2 x 2 mL). The solvent is finally evaporated under reduced pressure giving the pure amide (assessed by NMR).
Silica-gel chromatography may be performed in order to obtain analytically pure samples. All the compounds were
characterized by NMR (1H, 13C, mass spectroscopy)..

With ammonium hydroxide, immobilized Candida antarctica Lipase B in 1,4-dioxane, water, Time= 72h, T= 50 °C ,
Sealed tube, Enzymatic reaction

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 Manova, Daniela; Gallier, Florian; Tak-Tak, Lotfi; Yotava, Lyubov; Lubin-Germain, Nadège; Tetrahedron Letters;
vol. 59; nb. 21; (2018); p. 2086 - 2090
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With ammonia, T= 180 °C , unter Abdestillieren des entstandenen Wassers

Mitchell; Reid; Journal of the American Chemical Society; vol. 53; (1931); p. 1880,1881
View in Reaxys

With pyridine, SULFAMIDE

Kirsanow; Solotow; Zhurnal Obshchei Khimii; vol. 19; (1949); p. 2201,2205; Chem.Abstr.; (1950); p. 4446
View in Reaxys

With Candida antarctica lipase B (Novozym 435), ammonia, 1-butyl-3-methylimidazolium Tetrafluoroborate, Time=
96h, T= 40 °C , Product distribution, Kinetics

Madeira Lau; van Rantwijk; Seddon; Sheldon; Organic letters; vol. 2; nb. 26; (2000); p. 4189 - 4191
View in Reaxys

With ammonium hydroxide in acetonitrile, Time= 0.166667h, T= 0 °C

Shimshoni, Jakob Avi; Bialer, Meir; Wlodarczyk, Bogdan; Finnell, Richard H.; Yagen, Boris; Journal of Medici‐
nal Chemistry; vol. 50; nb. 25; (2007); p. 6419 - 6427
View in Reaxys

Reaction Steps: 2
1: phosphorus trichloride
2: ammonia
With ammonia, phosphorus trichloride

Aschan; Chemische Berichte; vol. 31; (1898); p. 2346

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Reaction Steps: 2
1: thionyl chloride / 3 h / Reflux; Inert atmosphere
2: ammonium hydroxide / water / Cooling with ice; Inert atmosphere
With thionyl chloride, ammonium hydroxide in water

Yoshimura, Akira; Middleton, Kyle R.; Luedtke, Matthew W.; Zhu, Chenjie; Zhdankin, Viktor V.; Journal of Or‐
ganic Chemistry; vol. 77; nb. 24; (2012); p. 11399 - 11404
View in Reaxys

Synthesis of compounds 3a-n; general procedure

General procedure: Ammonium carbonate (0.29 g, 3 mmol) was added to the appropriate aliphatic carboxylic acid (1
mL) and the mixture was stirred at 100 °C for 30 minutes. The appropriate 1-aryl-2-bromoethanone (1 mmol) was
added to the solution. Then the mixture was stirred for 15 minutes. The reaction was extracted with CH2Cl2, and the
combined organic extracts were dried, filtered and concentrated under reduced pressure to give 2-alkyl-4(5)-aryl-1H-
imidazoles.

With ammonium carbonate, Time= 0.5h, T= 100 °C

Liu, Cong; Nie, Yijiao; Yao, Guowei; Dai, Rongji; Deng, Yulin; Journal of Chemical Research; vol. 38; nb. 4;
(2014); p. 208 - 210
View in Reaxys

O O

O NH 2

Rx-ID: 1954508 View in Reaxys 61/636

Yield Conditions & References
99 % With magnesium nitride in methanol, Time= 24h, T= 80 °C

Veitch, Gemma E.; Bridgwood, Katy L.; Ley, Steven V.; Organic Letters; vol. 10; nb. 16; (2008); p. 3623 - 3625
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 48 % With ammonia in methanol, Time= 120h

Greenlee, William J.; Thorsett, Eugene D.; Journal of Organic Chemistry; vol. 46; (1981); p. 5351 - 5353
View in Reaxys

O O

HO HN
2

O O
O O O
S S

O Cl

O O
Si Si

O O
Si Si

Rx-ID: 24653938 View in Reaxys 62/636

Yield Conditions & References
84% 95 : Synthesis of (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-diena‐
mide (R1 =Pr, R2 =t BuMe2 Si, R3 =H, R4 =pentyl, W=t BuMe2 SiO, X--Y=CH2 --CH2, Z=CONH2, n=0, --=trans-
CH=CH) STR110
Example 95 Synthesis of (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dien‐
amide (R1 =Pr, R2 =t BuMe2 Si, R3 =H, R4 =pentyl, W=t BuMe2 SiO, X--Y=CH2 --CH2, Z=CONH2, n=0, --=trans-
CH=CH) STR110 A methylene chloride (3 ml) solution of (11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldime‐
thylsiloxy)-7-thiaprosta-8,13-dienoic acid (201 mg) was cooled to -40° C., then isobutyl chloroformate (47 μl) and trie‐
thylamine (63 μl) were added to the solution which was then stirred as is at -40° C. for 30 minutes. Further 1 ml of
30% ammonium hydroxide solution was added and the mixture was stirred overnight while raising the temperature to
room temperature. The reaction solution was diluted by ethyl acetate then was neutralized by dilute hydrochloric
acid. The desired substance was extracted from the mixture by ethyl acetate and extract was successively washed
by saturated sodium hydrogen carbonate and saturated sodium chloride solution. This solution was concentrated un‐
der reduced pressure, then was purified by silica gel column chromatography (45% ethyl acetate/hexane) to obtain
(11R,12S,13E,15S)-9-butyryloxy-11,15-bis(tert-butyldimethylsiloxy)-7-thiaprosta-8,13-dienamide (169 mg, 84%). 1 H-
NMR (270 MHz, δppm, CDCl3) 0.04 (s), 0.05 (s).. .. 12H 0.8-0.9 (m, 3H) 0.88 (s, 9H) 0.89 (s, 9H) 1.00 (t, J=7.4 Hz,
3H) 1.2-1.8 (m, 16H) 2.20 (t, J=7.4 Hz, 2H) 2.4-2.7 (m, 3H) 2.42 (t, J=7.4 Hz, 2H) 2.89 (dd, J=6.9 & 16.2 Hz, 1H)
3.13 (d, J=5.8 Hz, 1H) 4.0-4.2 (m, 2H) 5.43 (dd, J=8.7 & 15.3 Hz, 1H) 5.5-5.7 (m, 2H) 5.62 (dd, J=5.8 & 15.3 Hz, 1H)

With ammonium hydroxide, triethylamine in dichloromethane

PatentTeijin Limited; TEIJIN LIMITEDTeijin; US5731452; (1998); (A) English

View in Reaxys

S
N
Cl
HO
N N

O
N

S
N
Cl
O
N N

NH
N
2

Rx-ID: 55032527 View in Reaxys 63/636

Yield Conditions & References
72 % 1.1 : Step 1:
16-(2-chloro-6-(isopropylthio)-8-methyl-7H-purin-7-yl)hexadecanoic acid (350 mgs,0.70 mmol) was dissolved in DMF
along with NH4CI (80 mgs,1.5 mmol). In another vial (Benzotriazol-l-yloxy)tris(dimethylamino)phosphonium hexa‐
fluorophosphate (467 mg,1.06 mmol) and Benzotriazol-l-ol (143 mg,1.06 mmol) were taken DMF and stirred at 25°C

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 for ~5 minutes. The contents were then added to the first vial and DIPEA (0.49 mL,2.83 mmol)was added dropwise
to reaction. Reaction was mostly complete by 30 mins. The reaction mixture was diluted with EtOAc and the organ‐
ics were washed with water (2 x 20 mL) and brine (l x 20 mL). The EtOAc was removed in vacuo and the crude
material redissolved in DCM. Silica was added and was purified on normal phase column eluting DCM:MeOH (0 -
5%) gradient. Fractions were collected and reduced to obtain 250 mgs (72%) of 16-(2-chloro-6- (isopropylthio)-8-
methyl-7H-purin-7-yl)hexadecanamide as a transparent-whitish solid. LCMS: m/Z 496.05 (M+H) 494.41 (M-H).

Stage 1: With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, ammonium chloride,

benzotriazol-1-ol in N,N-dimethyl-formamide
Stage 2: With N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide

PatentSPEROVIE BIOSCIENCES, INC.; SINO BIOPHARMACEUTICAL LIMITEDSino Biopharmaceutical;

WO2020/181050; (2020); (A1) English
View in Reaxys

NH 2

O
O N
N
O O
HN
N

N
N
H

Rx-ID: 64673130 View in Reaxys 64/636

Yield Conditions & References
59 % General Procedure H:
General procedure: Carboxamides from Methyl Esters. A solution of a methyl ester (0.2 mmol) in 7 N NH3/MeOH (1
mL) was stirred at 70 oC O/N. The solvent was evaporated and then EtOAc (3 mL) and water (1 mL) were added.
The organic layer was dried with Na2SO4 and then the solvent was evaporated. Flash chromatography with an
EtOAc/hexanes gradient provided the purified carboxamide. 1-(4-Carbamoylbutyl)-N-(2-phenylpropan-2-yl)-1H-pyra‐
zole-3-carboxamide (16). The title compound was prepared by the general procedure H to provide 4 mg (59%) of a
colorless gum. 1H NMR (200 MHz, CDCl3) δ 7.45-7.49 (m, 2H, Ar), 7.20-7.40 (m, 5H, Ar & NH), 6.70 (d, J = 6.0 Hz,
1H, Ar), 5.29 (br s, 2H, NH2), 4.13 (t, J = 6.6 Hz, 2H, CH2), 2.24 (t, J = 7.0 Hz, 2H, CH2), 1.60-2.00 (m, 10H, 2Me &
CH2CH2). LC/MS (m/z) 328.8 (M+1), 97% at 4.99 min.

With ammonia in methanol, T= 70 °C

Amato, George;Runyon, Scott;Vasukuttan, Vineetha;Decker, Ann M.;Gay, Elaine A.;Laudermilk, Lucas;Mai‐

tra, Rangan; Bioorganic and Medicinal Chemistry Letters; vol. 93; (2023); Art.No: 129430
View in Reaxys

59 % General Procedure H:
General procedure: Carboxamides from Methyl Esters. A solution of a methyl ester (0.2 mmol) in 7 N NH3/MeOH (1
mL) was stirred at 70 oC O/N. The solvent was evaporated and then EtOAc (3 mL) and water (1 mL) were added.
The organic layer was dried with Na2SO4 and then the solvent was evaporated. Flash chromatography with an
EtOAc/hexanes gradient provided the purified carboxamide. 1-(4-Carbamoylbutyl)-N-(2-phenylpropan-2-yl)-1H-pyra‐
zole-3-carboxamide (16). The title compound was prepared by the general procedure H to provide 4 mg (59%) of a
colorless gum. 1H NMR (200 MHz, CDCl3) δ 7.45-7.49 (m, 2H, Ar), 7.20-7.40 (m, 5H, Ar & NH), 6.70 (d, J = 6.0 Hz,
1H, Ar), 5.29 (br s, 2H, NH2), 4.13 (t, J = 6.6 Hz, 2H, CH2), 2.24 (t, J = 7.0 Hz, 2H, CH2), 1.60-2.00 (m, 10H, 2Me &
CH2CH2). LC/MS (m/z) 328.8 (M+1), 97% at 4.99 min.

With ammonia in methanol, T= 70 °C

Amato, George;Runyon, Scott;Vasukuttan, Vineetha;Decker, Ann M.;Gay, Elaine A.;Laudermilk, Lucas;Mai‐

tra, Rangan; Bioorganic and Medicinal Chemistry Letters; vol. 93; (2023); Art.No: 129430
View in Reaxys

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 O

HO HN
2

OH
OH

O OH

Rx-ID: 25410550 View in Reaxys 65/636

Yield Conditions & References
60% R.3 : Preparation of (1S,5S,6R,7R)-3-(4-carbamoylbutyl)-6-[(3S,5S,1E)-3-hydroxy-5-methyl-1-nonenyl]-7-hy‐
droxybicyclo[3.3.0]-2-octene
[Reference example 3] Preparation of (1S,5S,6R,7R)-3-(4-carbamoylbutyl)-6-[(3S,5S,1E)-3-hydroxy-5-methyl-1-non‐
enyl]-7-hydroxybicyclo[3.3.0]-2-octene 59mg of (1S,5S,6R,7R)-3-(4-methoxycarbonylbutyl)-6-[(3S,5S,1E)-3-hy‐
droxy-5-methyl-1-nonenyl]-7-hydroxybicyclo[3.3.0]-2-octene was taken and dissolved in 3mL acetonitrile, under stir‐
ring, 10mL of 25% ammonium hydroxide in water was added and stirred for 6 days. After concentration, it was sub‐
jected to a silicagel column chromatography, to obtain 34mg of the compound presented in the title(60% yield). 1H-
NMR(270MHz, CDCl3):δ 0.88 (d, 3H, J=6.5Hz), 0.7-1.0 (m, 3H), 1.0-2.5 (m, 25H), 2.9-3.1 (m, 1H), 3.7-3.9 (q, 1H,
J=8.9Hz), 4.0-4.2 (m, 1H), 5.29 (brs, 1H), 5.3-5.6 (m, 2H), 6.0-6.1 (m, 1H), 6.6-6.9 (m, 1H).

With ammonium hydroxide in water, acetonitrile

PatentTEIJIN LIMITED; TEIJIN LIMITEDTeijin; EP1201235; (2002); (A1) English

View in Reaxys

O O

O NH 2

Rx-ID: 41494857 View in Reaxys 66/636

Yield Conditions & References
Amides; General Procedure
General procedure: A 0.2 M solution of the corresponding methyl ester in aq NH4OH (28-30%) was stirred at r.t. for
16 h. The solvent was evaporated to affordthe amide, which was, in some cases, purified by silica gel chromatogra‐
phy. The known amides 3, 33 5a,34 5b, 6c 5h,35 11a,36 11b,37 11c,3611e,38 11h,4 11i,39 11j,39 13,40 14,41
20,42 and 2343 were synthesized following the general procedure described above. Compound 5e was synthesized
following the literature.44

With ammonium hydroxide in water, Time= 16h, T= 20 °C , Inert atmosphere

Keita, Massaba; Vandamme, Mathilde; Paquin, Jean-François; Synthesis; vol. 47; nb. 23; (2015); p. 3758 - 3766;
Art.No: SS-2015-M0394-OP
View in Reaxys

O O O O

N OH N NH 2

H H
O O

H H H H
N N

Rx-ID: 43484444 View in Reaxys 67/636

Yield Conditions & References
Matrinic amide dihydrochloride (13)
To a solution of crude 11 in MeCN (40 mL), Boc2O (8 mmol), ammonium bicarbonate (5 mmol) in 2 mL water and
pyridine (2 mmol) were added and stirred at room temperature for 3-4 h. After the reaction completed, the solvent
was removed under reduced pressure. The residue was dispersed in CH2Cl2 and the solution was washed by water
and saturated brine, then concentrated to produce crude 12, which was dispersed in 2 N HCl/Et2O and stirred for 30
min to produce the target compound 13. A flash column chromatography purification on silica gel with CH2Cl2/
CH3OH as the eluents followed by acidification with 2 N HCl/ether (1 mL) afforded pure compound 13.

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 With pyridine, di-tert-butyl dicarbonate, ammonium bicarbonate in water, acetonitrile, T= 20 °C

Tang, Sheng; Peng, Zong-Gen; Zhang, Xin; Cheng, Xin-Yue; Li, Wen-Jing; Jiang, Jian-Dong; Li, Ying-Hong;
Song, Dan-Qing; Chinese Chemical Letters; vol. 27; nb. 7; (2016); p. 1052 - 1057
View in Reaxys

NH 2

O
O N
N

O HN O

N
N
H

Rx-ID: 64673132 View in Reaxys 68/636

Yield Conditions & References
46 % General Procedure H:
General procedure: Carboxamides from Methyl Esters. A solution of a methyl ester (0.2 mmol) in 7 N NH3/MeOH (1
mL) was stirred at 70 oC O/N. The solvent was evaporated and then EtOAc (3 mL) and water (1 mL) were added.
The organic layer was dried with Na2SO4 and then the solvent was evaporated. Flash chromatography with an
EtOAc/hexanes gradient provided the purified carboxamide.

With ammonia in methanol, T= 70 °C

Amato, George;Runyon, Scott;Vasukuttan, Vineetha;Decker, Ann M.;Gay, Elaine A.;Laudermilk, Lucas;Mai‐

tra, Rangan; Bioorganic and Medicinal Chemistry Letters; vol. 93; (2023); Art.No: 129430
View in Reaxys

O
O

NH 2

N
N
N
N
HN
HN
N
N

OH
OH

Rx-ID: 8648662 View in Reaxys 69/636

Yield Conditions & References
87 % With ammonia in methanol, Time= 72h, T= 100 °C , amidation

Bookser, Brett C.; Kasibhatla, Srinivas Rao; Appleman, James R.; Erion, Mark D.; Journal of Medicinal Chemis‐
try; vol. 43; nb. 8; (2000); p. 1495 - 1507
View in Reaxys

Cl O HO O

O O NH 2

Rx-ID: 24420086 View in Reaxys 70/636

Yield Conditions & References
62% 2.A : A.
A. Pentanamide Valeric acid (10.86 mL, 100 mmol, 1.0 eq) was dissolved in chloroform (100 mL, 0.1 M) and cooled
to -20° C. Ethyl chloroformate (9.52 mL, 100 mmol, 1 eq) was added. Triethylamine (14.0 mL, 100 mmol, 1.0 eq)
was then added dropwise over 5 minutes. The mixture was stirred at -20° C. for 30 minutes. Ammonia was bubbled
through the mixture 10 minutes at -20° C. and 20 minutes at 0° C. The mixture was then allowed to warm to room
temperature and stirred for 90 minutes. Chloroform (100 mL) and 1 N hydrochloric acid (50 mL) were added. The
layers were separated and the organic layer was washed with saturated sodium bicarbonate solution, dried (magne‐
sium sulfate), filtered and freed of solvent in vacuo. Trituration with isopropyl ether gave the title compound (6.315 g,
62%) as a white solid.

With hydrogenchloride, ammonia, triethylamine in chloroform

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 PatentE. R. Squibb & Sons, Inc.; BRISTOL-MYERS SQUIBB CO; ZULU TXBristol-Myers Squibb; &lt;unknown&gt;;
US5177097; (1993); (A) English
View in Reaxys

O O

HO O HN
2
O

Rx-ID: 63657527 View in Reaxys 71/636

Yield Conditions & References
299 mg 22 : Example 22: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanamide (Compound 32)
1-Hydroxybenzotriazole monohydrate (168 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideto
a solution of 379 mg of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanoic acid (i.e. intermediate 2) in 5 mL
of acetonitrile , the mixture was stirred at room temperature for 15 minutes. Then add 0.5 mL of 28% aqueous am‐
monia.was added to the mixture, and the mixture was stirred at room temperature for 18 hours. At ice-cooling tem‐
perature, sodium bicarbonate solutionwas added to the mixture, and the precipitate was collected by filtration and
dried under reduced pressure to give 299 mg of the title compound.all.

Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in acetonitrile, T=

20 °C
Stage 2: With ammonia in water, acetonitrile, T= 20 °C

PatentTAIHO PHARMACEUTICAL CO LTD; OTSUKA HOLDINGS CO LTDOtsuka Holdings; KR2023/43923;

(2023); (A) Korean
View in Reaxys

299 mg 22 : Example 22: Synthesis of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanamide (Compound 32)

1-Hydroxybenzotriazole monohydrate (168 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideto
a solution of 379 mg of 15-(2,6,6-trimethyl-3-oxocyclohex-1-en-1-yl)pentadecanoic acid (i.e. intermediate 2) in 5 mL
of acetonitrile , the mixture was stirred at room temperature for 15 minutes. Then add 0.5 mL of 28% aqueous am‐
monia.was added to the mixture, and the mixture was stirred at room temperature for 18 hours. At ice-cooling tem‐
perature, sodium bicarbonate solutionwas added to the mixture, and the precipitate was collected by filtration and
dried under reduced pressure to give 299 mg of the title compound.all.

Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in acetonitrile, T=

20 °C
Stage 2: With ammonia in water, acetonitrile, T= 20 °C

PatentTAIHO PHARMACEUTICAL CO LTD; OTSUKA HOLDINGS CO LTDOtsuka Holdings; KR2023/43923;

(2023); (A) Korean
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 O

NH 2

O
HO

Rx-ID: 63657641 View in Reaxys 72/636

Yield Conditions & References
146 mg 42 : Example 42: Synthesis of 15-(2,5,5-trimethyl-3-oxocyclopent-1-en-1-yl)pentadecanamide (Compound 74)
1-Hydroxybenzotriazole monohydrate (115 mg) and 158 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro‐
chloride were mixed with 250 mg 15-(2,5,5-trimethyl)-3-oxocyclopent-1-en-1-yl)pentadecanoic acid (ie intermediate
22) was added to a solution of 3.44 mL of acetonitrile and the mixture was stirred at room temperature for 16 mi‐
nutes. 343 μL of 28% aqueous ammonia was then added to the reaction mixture, which was then stirred at room
temperature for 17 hours. 170 μL of 28% aqueous ammonia was then added thereto, followed by stirring at room
temperature for 4 hours. Additionally, 343 μL of 28% aqueous ammonia was added, followed by stirring at room tem‐
perature for 20 hours. At ice-cooling temperature, saturated sodium hydrogen carbonate solution was added to the
reaction mixture, and the solvent was evaporated under reduced pressure. Thereafter, ethyl acetate and water were
added thereto, the mixture was extracted, heptane was added to the organic layer, and the mixture was washed with
10% sodium chloride solution and dried over anhydrous sodium sulfate. After filtration of the drying agent and evapo‐
ration under reduced pressure, the obtained residue was purified by silica gel column chromatography (methanol/
chloroform) to obtain 146 mg of the title compound.

Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in acetonitrile, T=

20 °C
Stage 2: With ammonia in water, acetonitrile, T= 20 °C

PatentTAIHO PHARMACEUTICAL CO LTD; OTSUKA HOLDINGS CO LTDOtsuka Holdings; KR2023/43923;

(2023); (A) Korean
View in Reaxys

146 mg 42 : Example 42: Synthesis of 15-(2,5,5-trimethyl-3-oxocyclopent-1-en-1-yl)pentadecanamide (Compound 74)

1-Hydroxybenzotriazole monohydrate (115 mg) and 158 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydro‐
chloride were mixed with 250 mg 15-(2,5,5-trimethyl)-3-oxocyclopent-1-en-1-yl)pentadecanoic acid (ie intermediate
22) was added to a solution of 3.44 mL of acetonitrile and the mixture was stirred at room temperature for 16 mi‐
nutes. 343 μL of 28% aqueous ammonia was then added to the reaction mixture, which was then stirred at room
temperature for 17 hours. 170 μL of 28% aqueous ammonia was then added thereto, followed by stirring at room
temperature for 4 hours. Additionally, 343 μL of 28% aqueous ammonia was added, followed by stirring at room tem‐
perature for 20 hours. At ice-cooling temperature, saturated sodium hydrogen carbonate solution was added to the
reaction mixture, and the solvent was evaporated under reduced pressure. Thereafter, ethyl acetate and water were
added thereto, the mixture was extracted, heptane was added to the organic layer, and the mixture was washed with
10% sodium chloride solution and dried over anhydrous sodium sulfate. After filtration of the drying agent and evapo‐
ration under reduced pressure, the obtained residue was purified by silica gel column chromatography (methanol/
chloroform) to obtain 146 mg of the title compound.

Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in acetonitrile, T=

20 °C
Stage 2: With ammonia in water, acetonitrile, T= 20 °C

PatentTAIHO PHARMACEUTICAL CO LTD; OTSUKA HOLDINGS CO LTDOtsuka Holdings; KR2023/43923;

(2023); (A) Korean
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 O O

NH 2

O O

O O

N O

O O

Rx-ID: 3621802 View in Reaxys 73/636

Yield Conditions & References
82 % With ammonia in dichloromethane, Time= 2h, T= 20 °C

Kohle; Krohn; Leclercq; Journal of Medicinal Chemistry; vol. 32; nb. 7; (1989); p. 1538 - 1547
View in Reaxys

O HO

HO Cl

Cl HN
2

HO O

Rx-ID: 10560810 View in Reaxys 74/636

Yield Conditions & References
11 :Example 11 6-[4-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide To a solution of 6-hydroxy-6-[4-(4-chlorophen‐
yl)phenyl]hexanoic acid (600 mg) in ethanol (20 ml), aqueous ammonia (5 ml) was added and the mixture was stir‐
red over night at room temperature, then stirred for 5 hours at 70° C. Then gaseous ammonia was blown thereto,
saturated and stirred overnight at room temperature. The reaction mixture was extracted with ethyl acetate. The or‐
ganic layer was washed with 1N hydrochloric acid, water and brine sequentially, dried over anhydrous magnesium
sulfate, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-
hexane:ethyl acetate=1:2) to give the compound in the present invention (160 mg) having the following physical da‐
ta. TLC: Rf 0.20 (ethyl acetate); NMR (DMSO-d6): δ 7.68 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5
Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.19 (br, 1H),6.65 (br, 1H), 5.15 (d, J=4.5 Hz, 1H), 4.54 (m, 1H), 2.01 (t, J=7.5 Hz,
2H), 1.66-1.56 (m, 2H), 1.54-1.44 (m, 2H), 1.40-1.20 (m, 2H).

With ammonia in ethanol, water, T= 20 - 70 °C

PatentNAKA MASAO;TAKAHASHI KANJI; ONO PHARMACEUTICAL CO LTDOno Pharmaceutical;

US2005/119305; (2005); (A1) English
View in Reaxys

O O
O NH 2

O O

N N

Na

O O

N N

Br Br

N N

Cl Cl
Br Br

Rx-ID: 23157315 View in Reaxys 75/636

Yield Conditions & References
84 : EXAMPLE 84
Dissolve 1.0 equivalent of the product of Example 80 . (Compound 70.0-B) in DMF containing 5.0 equivalents of am‐
monium chloride and 1.0 equivalent each of DEC, HOBT and N-methylmorpholine. Stir the mixture at room tempera‐

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 ture for 18 hr, then concentrate in vacuo to a residue and partition between ethyl acetate and water. Wash the organ‐
ic phase with aqueous sodium bicarbonate solution then brine. Dry the organic phase over magnesium sulfate, filter
and concentrate in vacuo to a residue. Chromatograph the residue on silica gel to obtain the product as a white solid
mp =119.2-120°C.

With 4-methyl-morpholine, ammonium chloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide

hydrochloride in DMF (N,N-dimethyl-formamide), Time= 18h, T= 20 °C

PatentSCHERING CORPORATION; MERCK & CO INCMerck & Co; EP942906; (2004); (B1) English
View in Reaxys

O O

O HN
2

O O

N N

Na

O O

N N

Br Br

N N

Cl Br Cl
Br

Rx-ID: 23157316 View in Reaxys 76/636

Yield Conditions & References
82 : EXAMPLE 82
Dissolve 1.0 equivalent of the product of Example 81 (Compound 107.0-B) in DMF containing 5.0 equivalents of am‐
monium chloride and 1.0 equivalent each of DEC, HOBT and N-methylmorpholine. Stir the mixture at room tempera‐
ture for 18 hr, then concentrate in vacuo to a residue and partition between ethyl acetate and water. Wash the organ‐
ic phase with aqueous sodium bicarbonate solution then brine. Dry the organic phase over magnesium sulfate, filter
and concentrate in vacuo to a residue. Chromatograph the residue on silica gel to obtain the product as a white solid
mp = 125.5-126.5°C.

With 4-methyl-morpholine, ammonium chloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide

hydrochloride in DMF (N,N-dimethyl-formamide), Time= 18h, T= 20 °C

PatentSCHERING CORPORATION; MERCK & CO INCMerck & Co; EP942906; (2004); (B1) English
View in Reaxys

HN 2

O O

NH

NH
HN N

HO NH

O O

Rx-ID: 28132868 View in Reaxys 77/636

Yield Conditions & References
325.5 :The acid (ZZ4) (1 eq.) was dissolved in DMF in an ace tube, HATU (2 eq.) and DIPEA (2 eq.) were added and
the mixture was stirred 1 h at RT. A solution of NH3 in dioxane (0.5 N, 5 eq.) was added and after stirring 3 h at RT
solvents were removed under reduced pressure. The crude was used as such in the following reaction.

Stage 1: With N-ethyl-N,N-diisopropylamine, HATU in N,N-dimethyl-formamide, Time= 1h, T= 20 °C

Stage 2: With ammonia in 1,4-dioxane, N,N-dimethyl-formamide, Time= 3h, T= 20 °C

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 53/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 PatentATTENNI BARBARA;FERRIGNO FEDERICA;JONES PHILIP;INGENITO RAFFAELE;KINZEL OLAF;LLAUG‐
ER BUFI LAURA;ONTORIA JESUS MARIA;PESCATORE GIOVANNA;ROWLEY MICHAEL;SCARPELLI RI‐
TA;SCHULTZ CARSTEN; MERCK & CO INCMerck & Co; US2009/48228; (2009); (A1) English
View in Reaxys

HO
OH HO O

NH
O
2

HO
HO

HO
OH

Rx-ID: 32236079 View in Reaxys 78/636

Yield Conditions & References
1 :Example 1 Synthesis of 7- [ (1R, 2R, 3R, 5S) -3 , 5-dihydroxy-2- [ (IE , 3S) -3- hydroxyoct-l-en-l-yl] cyclopentyl]
heptanamide (F02)10 mg (0.028mmol) of 7- [ (2R, 3R, 5S) -3, 5-dihydroxy-2- ( (E) - (S) -3- hydroxyoct-l-en-yl ) -cy‐
clopentyl ] heptanoic acid was dissolved in 2 ml of tetrahydrofuran saturated with ammonia and 9 mg (0.031 mmol)
of DMTM was added. It was stirred overnight at room temperature. The reaction mixture was poured on 10 ml of
water and extracted with 3 x 4ml of ethyl acetate. It was dried with water-free sodium sulphate and evaporated. 15
mg of colourless oil obtained was purified by means of preparative HPLC. After lyophilization 1.5 mg of white solid
was obtained.

With ammonia, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride in tetrahydrofuran, T= 20 °C

Patent"AVIDIN" KUTATÓ, FEJLESZTŐ ÉS KERESKEDELMI KORLÁTOLT FELELŐSSÉGŰ TÁRSASÁG;UBICHEM

KUTATÓ KORLÁTOLT FELELŐSSÉGŰ TÁRSASÁG;PUSKÁS, László;KITAJKA, Klára;ÓZSVÁRI, Béla;NAGY, Lajos
István;FÁBIÁN, Gabriella;RÉPÁSI, József;SZABÓ, András;KERTĖSZ, Máriusz; AVIDIN KUTATO FEJLESZTO ES
KERESKEDELMI KORLATOLT; UBICHEM KUTATO KORLATOLT FELELOSSEGU TARSASAG; AVIDIN KFT;
UBICHEM KFT&lt;unknown&gt;; &lt;unknown&gt;; &lt;unknown&gt;; &lt;unknown&gt;; WO2011/154754; (2011); (A1)
English
View in Reaxys

F F

F F
O O

N N O OH N N O NH 2

N N
N N

N N

Rx-ID: 44247212 View in Reaxys 79/636

Yield Conditions & References
11 mg 64 : Example 64: 5-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phe‐
noxy]pentanamide
Example 64: 5-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phenoxy]penta‐
namide A mixture of methyl 5-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-
yl)phenoxy]pentanoic acid (70 mg, 0.154 mmol) and CDI (37 mg, 0.23 mmol) in DMF (5 mL) was stirred for at rt 2
hrs. Then to the reaction mixture was added NH3 (7 mL, 14 mmol, 2.0 mol/L in isopropyl alcohol). After being stirred
overnight, the resulting mixture was concentrated in vacuo. The residue was diluted with DCM (20 mL) and washed
with water, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by prep-HPLC to give
5-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phenoxy]pentanamide (11
mg) as yellow solid. 1H NMR (400 MHz, Methanol- d4) : 9.05 (d, 2H), 8.88 (s, 1H), 7.67 (s, 1H), 6.48-6.64 (m, 2H),
5.22 (d, 1H), 4.13 (m, 2H), 3.80-3.94 (m, 1H), 3.49-3.62 (m, 1H), 3.10-3.25 (m, 2H), 2.26-2.38 (m, 2H), 1.78-1.90 (m,
4H), 1.42-1.53 (m, 3H); (ESI+) [(M+H)+]: 455.

Stage 1: With 1,1'-carbonyldiimidazole in N,N-dimethyl-formamide, Time= 2h, T= 20 °C

Stage 2: With ammonia in N,N-dimethyl-formamide, isopropyl alcohol

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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 F

F
O

N N O OH

N
N

F
O

N N O NH 2

N
N

Rx-ID: 44247394 View in Reaxys 80/636

Yield Conditions & References
18 mg 87 : Example 87: 7-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phe‐
noxy]heptanamide
Example 87: 7-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phenoxy]hepta‐
namide A mixture of 7-[2,3-difluoro-5-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)phe‐
noxy]heptanoic acid (70 mg, 0.15 mmol) and CDI (28 mg, 0.17 mmol) in DMF (5 mL) was stirred for 3 hrs at rt. Then
to the mixture was added NH3 (0.4 mL, 0.8 mmol, 2.0 M in isopropyl alcohol) and the resulting mixture was stirred for
10 hrs at rt. The mixture was concentrated in vacuo and the residue was purified by prep-HPLC to give 7-[2,3-di‐
fluoro-5- (5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl)phenoxy]heptanamide (18 mg) as a
light yellow solid. 1H NMR (400 MHz, CDCl3) : 9.04 (d, 2H), 8.79 (s, 1H), 7.45 (m, 1H), 6.31-6.46 (m, 2H), 5.53 (br.
s., 2H), 4.97 (m, 1H), 3.97-4.12 (m, 2H), 3.64-3.80 (m, 1H), 3.42-3.59 (m, 1H), 3.16-3.39 (m, 2H), 2.25 (m, 2H),
1.77-1.90 (m, 2H), 1.69 (m, 2H), 1.36-1.59 (m, 7H); MS obsd. (ESI+) [(M+H)+]: 483.

Stage 1: With 1,1'-carbonyldiimidazole in N,N-dimethyl-formamide, Time= 3h, T= 20 °C

Stage 2: With ammonia in N,N-dimethyl-formamide, isopropyl alcohol, Time= 10h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

N O

N N O OH

N
N

N O

N N O NH 2

N
N

Rx-ID: 44248068 View in Reaxys 81/636

Yield Conditions & References
16 mg 156 : Example 156: (-)-7-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl]-4-
pyridyl]oxy]heptanamide
Example 156: (-)-7-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl]-4-pyrid‐
yl]oxy]heptanamide To a solution of (-)-7-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimi‐
din-6-yl]-4-pyridyl]oxy]heptanoic acid (150 mg, 0.322 mol, Example 155) in DMF (10 mL) was added TEA (65.1 mg,
0.64 mmol) and HATU (245 mg, 0.643 mmol). The resulting mixture was stirred for 10 mins at rt. Then to the reaction
mixture was added ammonium chloride (34 mg, 0.643 mmol). After being stirred at rt for10 hrs, the resulting mixture
was poured into water (25 mL) and extracted with EA (50 mL) for three times. The organic layers were combined,
washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a red oil, which was purified by
prep-HPLC to give (-)-7-[[2- fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4- pyrid‐
yl]oxy]heptanamide (16 mg) as a light yellow oil. 1H NMR (400 MHz, Methanol-d4) δ: 8.89-8.99 (m, 2H), 8.74-8.83

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 (m, 1H), 7.51-7.64 (m, 1H), 6.10-6.20 (m, 1H), 5.72-5.81 (m, 1H), 5.53-5.66 (m, 1H), 4.35-4.50 (m, 1H), 3.89-4.08
(m, 2H), 3.31-3.49 (m, 1H), 3.00-3.15 (m, 2H), 2.13 (s, 2H), 1.65-1.77 (m, 2H), 1.49 (d, 9H). MS obsd. (ESI+) [(M+H)
+]: 466. [a] 25 D = -84.00° (0.1 g/100mL, methanol).

Stage 1: With triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylme‐

thanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 10h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

F F

N O N O

N N O OH N N O NH 2

N N
N N

N N

Rx-ID: 44248073 View in Reaxys 82/636

Yield Conditions & References
32 mg 158 : Example 158: (-)-5-[[2-fluoro-6-[methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-
pyridyl]oxy]pentanamide
Example 158: (-)-5-[[2-fluoro-6-[methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-pyrid‐
yl]oxy]pentanamide To a solution (-)-5-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimi‐
din-6-yl]-4-pyridyl]oxy]pentanoic acid (175 mg, 0.4 mol, Example 157) in DMF (10 mL) was added TEA (81 mg, 0.8
mmol), HATU (304 mg, 0.8 mmol). The resulting mixture was stirred at rt for 10 mins. To the mixture was added am‐
monium chloride (42 mg, 0.8 mmol). After being stirred at rt for 10 hrs, the resulting mixture was poured into water
(25 mL) and extracted with EA (50 mL) twice. The organic layers were combined, washed with brine, dried over an‐
hydrous Na2SO4 and concentrated in vacuo to give a red oil, which was purified by prep-HPLC to give (-)-5-[[2- fluo‐
ro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4- pyridyl]oxy]pentanamide (32 mg) as a
white solid. 1H NMR (400 MHz, CDCl3): 8.91-8.99 (m, 2H), 8.69-8.78 (m, 1H), 7.31-7.41 (m, 1H), 5.88-5.95 (m, 1H),
5.66-5.76 (m, 1H), 5.52-5.63 (m, 1H), 4.25-4.39 (m, 1H), 3.91-4.02 (m, 2H), 3.35-3.47 (m, 1H), 3.12-3.21 (m, 2H),
2.17-2.32 (m, 2H), 1.71-1.86 (m, 4H), 1.38-1.52 (m, 2H). MS obsd. (ESI+) [(M+H)+]: 438; [a] 25 D = -60.7° (0.1 g/
100mL, methanol).

Stage 1: With triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylme‐

thanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 10h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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N
O N

O N N
HO

N
O N

O N N
HN
2

Rx-ID: 44248139 View in Reaxys 83/636

Yield Conditions & References
37 mg 165 : Example 165: (-)-6-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl]-4-
pyridyl]oxy]hexanamide

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 Example 165: (-)-6-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl]-4-pyrid‐
yl]oxy]hexanamide To a solution of (-)-6-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimi‐
din-6-yl]-4-pyridyl]oxy]hexanoic acid (226 mg, 0.5 mol) in DMF (10 mL) was added TEA (101 mg, 1.0 mmol) and HA‐
TU (380 mg, 1.0 mmol). The resulting mixture was stirred for 10 mins at rt, and then to the resulting mixture was
added ammonium chloride (53 mg, 1.0 mmol). After being stirred for 10 hrs at rt, the resulting reaction mixture was
poured into water (25 mL) and extracted with DCM (50 mL) twice. The organic layers were combined, washed with
brine, dried over anhydrous Na2SO4 and concentrated in vacuo to give a red oil, which was purified by prep-HPLC to
give (-)-6-[[2-fluoro-6-[5-methyl-2-pyrimidin-2-yl-7,8- dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-4-pyridyl]oxy]hexana‐
mide (37 mg) as a white solid. 1H NMR (400 MHz, Methanol-d4) δ: 8.89-8.98 (m, 2H), 8.74-8.83 (m, 1H), 7.50-7.59
(m, 1H), 6.10-6.19 (m, 1H), 5.73-5.81 (m, 1H), 5.58-5.67 (m, 1H), 4.35-4.47 (m, 1H), 3.94-4.04 (m, 2H), 3.35-3.48
(m, 1H), 2.95-3.10 (m, 2H), 2.09-2.20 (m, 2H), 1.66-1.76 (m, 2H), 1.53-1.65 (m, 2H), 1.47-1.51 (m, 3H), 1.37-1.47
(m, 2H). MS obsd. (ESI+) [(M+H)+]: 452. [a] 25 D = -40.3° (0.1 g/100mL, methanol).

Stage 1: With triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylme‐

thanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 10h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

OH
N N O

N O
N

NH 2

N N O

N O
N

Rx-ID: 44248147 View in Reaxys 84/636

Yield Conditions & References
30 mg 169 : Example 169: 8-[[2-fluoro-6-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)-4-
pyridyl]oxy]octanamide
Example 169: 8-[[2-fluoro-6-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)-4-pyridyl]oxy]octa‐
namide To a solution of 8-[[2-fluoro-6-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl)-4-pyrid‐
yl]oxy]octanoic acid (240 mg, 0.5 mol) in DMF (10 mL) was added TEA (101 mg, 1.0 mmol) and HATU (380 mg, 1.0
mmol). The resulting mixture was stirred for 10 mins at rt and then to the reaction mixture was added ammonium
chloride (53 mg, 1.0 mmol). After being stirred for10 hrs at rt, the resulting reaction mixture was poured into water
(25 mL) and extracted with DCM (50 mL) for three times. The combined organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo to give a red oil, which was purified by prep-HPLC to give 8-[[2-
fluoro-6-(5-methyl-2-pyrimidin-2-yl-7,8-dihydro-5H- pyrido[4,3-d]pyrimidin-6-yl)-4-pyridyl]oxy]octanamide (30 mg) as
a light yellow solid. 1H NMR (400 MHz, Methanol-d4) δ: 8.88-8.98 (m, 2H), 8.74-8.81 (m, 1H), 7.47-7.59 (m, 1H),
6.04-6.18 (m, 1H), 5.74-5.81 (m, 1H), 5.58-5.66 (m, 1H), 4.37-4.47 (m, 1H), 3.90-4.00 (m, 2H), 3.35-3.47 (m, 1H),
2.95-3.08 (m, 2H), 2.04-2.17 (m, 2H), 1.65-1.75 (m, 2H), 1.51-1.58 (m, 2H), 1.45-1.51 (m, 3H), 1.37-1.44 (m, 2H),
1.26-1.35 (m, 4H). MS obsd. (ESI+) [(M+H)+]: 480.

Stage 1: With triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylme‐

thanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 10h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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 N

N
O

N N O
OH

N
O

N N O
NH 2

Rx-ID: 44248150 View in Reaxys 85/636

Yield Conditions & References
29 mg 171 : Example 171: 6-[[2-fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-pyrid‐
yl]oxy]hexanamide
Example 171: 6-[[2-fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-pyridyl]oxy]hexana‐
mide To a solution of 6-[[2-fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-pyrid‐
yl]oxy]hexanoic acid (120 mg, 0.266 mol) in DMF (10 mL) was added TEA (53.8 mg, 0.532 mmol) and HATU (202
mg, 0.532 mmol). The resulting mixture was stirred for 10 mins at rt. Then to the reaction mixture was added ammo‐
nium chloride (28.4 mg, 0.532 mmol). After being stirred at rt for 10 hrs, . the resulting mixture was poured into water
(25 mL) and extracted with DCM (50 mL) for three times. The combined organic layer was washed with brine, dried
over anhydrous Na2SO4 and concentrated in vacuo to give a red oil, which was purified by prep-HPLC to give 6-[[2-
fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro- 5H-pyrido[4,3-d]pyrimidin-6-yl]-4-pyridyl]oxy]hexanamide (29 mg) as a
light yellow solid. 1H NMR (400 MHz, Methanol-d4) δ: 8.69-8.77 (m, 1H), 8.60-8.69 (m, 1H), 8.41-8.56 (m, 1H),
7.91-8.08 (m, 1H), 7.46-7.60 (m, 1H), 6.08-6.17 (m, 1H), 5.68-5.79 (m, 1H), 5.50-5.63 (m, 1H), 4.29-4.48 (m, 1H),
3.98 (s, 2H), 3.31-3.47 (m, 1H), 2.91-3.13 (m, 2H), 2.09-2.22 (m, 2H), 1.53- 1.78 (m, 4H), 1.34-1.51 (m, 5H). MS
obsd. (ESI+) [(M+H)+]: 451.

Stage 1: With triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylme‐

thanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.166667h, T= 20 °C
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 10h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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N O

N N O OH

N
N

N O

N N O NH 2

N
N

Rx-ID: 44248212 View in Reaxys 86/636

Yield Conditions & References
30 mg 180 : Example 180: 7-[[2-fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-pyrid‐
yl]oxy]heptanamide tanamide
Example 180: 7-[[2-fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3- d]pyrimidin-6-yl]-4-pyridyl]oxy]hepta‐
namide To a solution of 7-((2-fluoro-6-(5-methyl-2-(pyridin-2-yl)-7,8-dihydropyrido[4,3- d]pyrimidin-6(5H)-yl)pyridin-4-
yl)oxy)heptanoic acid (200 mg, 0.430 mmol) in DMF (3 mL) was added CDI (104 mg, 0.644 mmol). After the mixture
was stirred for 4 hrs at rt, to the mixture was added NH3 (7 mL, ca.4% in isopropyl alcohol, ca.2.0mol/L). The reac‐
tion mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by prep- HPLC to
give 7-[[2-fluoro-6-[5-methyl-2-(2-pyridyl)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6- yl]-4-pyridyl]oxy]heptanamide (30

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 mg) as a light yellow solid.. 1H NMR (400 MHz, Methanol- d4) δ: 8.66-8.74 (m, 1H), 8.56-8.66 (m, 1H), 8.35-8.47 (m,
1H), 7.82-7.93 (m, 1H), 7.37-7.47 (m, 1H), 6.04-6.18 (m, 1H), 5.71-5.84 (m, 1H), 5.45-5.63 (m, 1H), 4.29-4.46 (m,
1H), 3.96 (s, 2H), 3.30-3.45 (m, 1H), 2.88-3.13 (m, 2H), 2.05-2.23 (m, 2H), 1.62-1.79 (m, 2H), 1.51-1.62 (m, 2H),
1.46 (d, 7H). MS obsd. (ESI+) [(M+H)+]: 465.

Stage 1: With 1,1'-carbonyldiimidazole in N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Stage 2: With ammonia in N,N-dimethyl-formamide, isopropyl alcohol, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

O OH O NH 2

14 14

C C

O O

Rx-ID: 48897716 View in Reaxys 87/636

Yield Conditions & References
3.78 g 5-Benzyloxy[carbonyl-14C]pentanoic acid (2,4.55 g) and DMF (3 drops) were dissolved in anhydrous dichlorome‐
thane under argon.After stirring, the temperature was lowered to 0 ° C, and thionyl chloride (8.30 g) was added drop‐
wise.After completion of the dropwise addition, the mixture was stirred at reflux for 1 h, cooled, and then evaporated
and evaporated.The solution was cooled to 10 ° C, and it was added dropwise to stirred ammonia to dry tetrahydro‐
furan (50 mL), and the mixture was stirred and stirred for 30 min;Naturally warm to room temperature and stirred for
12 h.Water was added to the reaction mixture, and the mixture was evaporated to ethyl ether.It was washed with
saturated brine, filtered, and concentrated to give a light yellow solid 5-benzyloxy [carbonyl-14C] pentanamide
(3,3.78g).

Stage 1: With thionyl chloride in dichloromethane, N,N-dimethyl-formamide, Time= 1h, T= 0 °C , Inert atmosphere,
Reflux
Stage 2: With ammonia in tetrahydrofuran, Time= 12.5h, T= 10 - 20 °C

PatentZhejiang University;Wang Wei;Ye Qingfu;Yu Kaixiang; ZHEJIANG UNIVERSITYZhejiang University;

CN108341839; (2018); (A) English
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O O

O N O
HO N O

O NH 2

Rx-ID: 51454040 View in Reaxys 88/636

Yield Conditions & References
1.2 g 141.4; 142.4 : Step 4: Preparation of benzyl N-(5-amino-5-oxo-pentyl)-N-methyl-carbamate
To a solution of 5-[benzyloxycarbonyl(methyl)amino]pentanoic acid (1.5 g, 5.65 mmol) in DMF (20 mL) was added
HATU (4.3 g, 11.31 mmol), NH4Cl(0.91 g, 16.96 mmol) and DIPEA (2.95 mL, 16.96 mmol) at rt. The resulting mixture
was stirred for 3 hrs at rt, then diluted with water (100 mL) and extracted with EA (100 mL) for three times. The com‐
bined organic phase was dried over anhydrous Na2S04and filtered. The filtrate was concentrated in vacuo and the
residue was purified by prep-HPLC to give benzyl N-(5-amino-5-oxo-pentyl)-N-methyl-carbamate (1.2 g) as a light
yellow oil.

With ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-

yl-methylene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 3h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.;CHENG, Zhanling;HAN, Xingchun;JIANG,

Min;WANG, Jianhua;WANG, Yongguang;YANG, Song; ROCHE HOLDING AGRoche; WO2018/1952; (2018); (A1)
English
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 O O

HO N O

O N O

O NH 2

Rx-ID: 51454049 View in Reaxys 89/636

Yield Conditions & References
1.6 g 143.4 : Step 4: Preparation of benzyl N-(5-amino-5-oxo-pentyl)-N-(cyclopropylmethyl)-carbamate
To a solution of 5-[benzyloxycarbonyl-(cyclopropylmethyl)amino]pentanoic acid (2.5 g, 8.19 mmol) in DMF (25 mL)
was added HATU (4.67 g, 12.28 mmol), NH4Cl (1.31 g, 24.56 mmol) and DIPEA (4.28 mL, 24.56 mmol). After being
stirred for 3 hrs at rt, the resulting mixture was diluted with water (100 mL) and extracted with EA (100 mL) for three
times. The combined organic phase was dried over anhydrous Na2S04and filtered. The filtrate was concentrated in
vacuo and the residue was purified by prep-HPLC to give benzyl N-(5-amino-5-oxo-pentyl)-N-(cyclopropylmethyl)-
carbamate (1.6 g) as a light yellow oil.

With ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-

yl-methylene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 3h, T= 20 °C

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.;CHENG, Zhanling;HAN, Xingchun;JIANG,

Min;WANG, Jianhua;WANG, Yongguang;YANG, Song; ROCHE HOLDING AGRoche; WO2018/1952; (2018); (A1)
English
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O O

O HN 2

O O
N N
H H
HO O

Rx-ID: 51953119 View in Reaxys 90/636

Yield Conditions & References
4.5.3 General procedure C for the synthesis of amine hydrochlorides of general structure 17
General procedure: A 20-mL vial was charged with Boc-protected amino acid (specified below; 1 equiv) and tetrahy‐
drofuran (0.15M). 1,1′-Carbonyldiimidazole (1.50 equiv) was added and the resulting mixture was stirred for 1h at
23°C. A solution of ammonia in methanol (7.00M, 5.00 equiv) was added to the reaction mixture, and the resulting
mixture was stirred for 12hat 23°C. The product mixture was concentrated, and the residue obtained was diluted with
ethyl acetate (120mL). The diluted product mixture was transferred to a separatory funnel and sequentially washed
with saturated aqueous ammonium chloride solution (1×50mL), saturated aqueous sodium bicarbonate solution
(1×50mL), and saturated aqueous sodium chloride solution (1×50mL). The organic layer was dried over sodium sul‐
fate. The dried solution was filtered and the filtrate was concentrated. The product thus obtained was transferred to a
20-mL vial. A solution of hydrogen chloride in dioxane (4.00M, 5.00 equiv) was added and the resulting mixture was
stirred at 23°C for 1h. The product mixture was concentrated, providing the amine hydrochloride of general structure
17. The product so obtained was used without further purification.

Stage 1: With 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 1h, T= 23 °C , Inert atmosphere

Stage 2: With ammonia in tetrahydrofuran, methanol, Time= 12h, T= 23 °C , Inert atmosphere

Nikolayevskiy, Herman; Robello, Marco; Scerba, Michael T.; Pasternak, Evan H.; Saha, Mrinmoy; Hartman,
Tracy L.; Buchholz, Caitlin A.; Buckheit, Robert W.; Durell, Stewart R.; Appella, Daniel H.; European Journal of
Medicinal Chemistry; vol. 178; (2019); p. 818 - 837
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H O
2

H
2

H
2
2

H
2

H 2

H
2

H
2

H
2

H 2

H
2

H H
2

H NH 2
2
2

H H
OH 2
2

H
H 2

2 H
H 2

2 H
H 2 2 2 2

H H H 2
2 H H 2

H
2

H H O
2

H 2

H
2

H
2

H
2

Rx-ID: 58281037 View in Reaxys 91/636

Yield Conditions & References
844 mg 1 : Step 1
A stirred solution of nonanoic-d17 acid (1.00 g, 5.70 mmol) in DCM (20 mL) at 0 °C was treated with thionyl chloride
(2.1 mL, 29 mmol) dropwise. The mixture was stirred at 0 °C for 15 min and then at 40 °C for 3 h. The reaction
mixture was concentrated and then co-evaporated with toluene (2x10 mL). The residue was taken up in THF (10

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 mL), cooled to 0 °C and treated with ammonium hydroxide (28% aq., 8.0 mL 57 mmol) dropwise. The reaction mix‐
ture was allowed to warm to RT and stirred for 16 h. The mixture was partially concentrated and extracted with DCM
(3x10 mL). The combined organic extracts were dried (phase separator) and concentrated to afford nonanamide-d17
(844 mg, 4.84 mmol) as a white solid that was used in the next step without further purification. LCMS m/z 175.3 (M
+H)+(ES+).

Stage 1: With thionyl chloride in dichloromethane, Time= 3.25h, T= 0 - 40 °C

Stage 2: With ammonium hydroxide in tetrahydrofuran, water, Time= 16h, T= 0 - 20 °C

PatentSITRYX THERAPEUTICS LIMITED; SITRYX THERAPEUTICS LTD; CYTERA THERAPEUTICS&lt;un‐

known&gt;; &lt;unknown&gt;; WO2021/130492; (2021); (A1) English
View in Reaxys

2 2

H H

O
2
2

H H

NH
HO 2
2

H
2

Rx-ID: 64075943 View in Reaxys 92/636

Yield Conditions & References
60 % 1.1 :To a solution of 14,14,14-D3-tetradecanoic acid (dPEG-A-1) (6 g, 25.9 mmol) in toluene (50 mL) was added ox‐
alyl chloride (38.85 mmol, 4.93 g) at room temperature.After heating the resulting mixture at 70 °C for 2 h, the mix‐
ture was concentrated.The residue was dissolved in toluene and concentrated again.The residual oil was added to
concentrated ammonia solution (20m) via syringe at 10°C.The reaction mixture was filtered and washed with wa‐
ter.The white solid was dried in vacuo.The desired product 14,14,14-D3-tetradecylamide (dPEG-A-3) was obtained
as a white solid (3.58 g, 60%).

Stage 1: With oxalyl dichloride in toluene, T= 70 °C

Stage 2: With ammonium hydroxide in toluene, T= 10 °C

PatentGUANGZHOU ANOVENT PHARMACEUTICAL CO.LTD; GUANGZHOU GUSEN PHARMACEUTICAL;

GUANGZHOU ANOVENT PHARMACEUTICAL&lt;unknown&gt;; &lt;unknown&gt;; WO2023/45377; (2023); (A1)
English
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O H H
N

O H

NH 2

Rx-ID: 23231937 View in Reaxys 93/636

Yield Conditions & References
91 % 27 :Palmitamide Starting Materials Methyl palmitate 0.5 mol (135 g) Ammonia Excess, bubbled through the system.
Sodium methoxide (catalyst) 5 g. Ethylene Glycol 50 g. Operating Conditions Pressure Atmospheric Temperature/
time regime 65° C./8 h. Reaction Progress Monitored by means of the qualitative ferric hydroxamate test for esters.
Work-up The reaction mass was cooled, transfered to a beaker, diluted with 500 mL methanol and 200 mL water,
stirred for 30 minutes and filtered. The filter cake was then washed with water, drained and dried at 70-80° C. over‐
night. 116 g. of white powdery crystals (m.p. 102-103° C.) were obtained (literature m.p. 106-107° C.); the IR spec‐
trum (KBr pellet) shows the “amide I Band” at 1647.42CM-1 and the “C-N Stretch” at 1421.72 CM-1. Yield 91%

With sodium methylate in ethylene glycol, Time= 8h, T= 65 °C , Conversion of starting material

PatentGojon-Zorrilla, Gabriel; REACTIMEX&lt;unknown&gt;; US2005/27120; (2005); (A1) English

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 N
N O
OH

H
N

OH
N
O

HO

H
O OH

HN 2

H OH

Rx-ID: 25401623 View in Reaxys 94/636

Yield Conditions & References
40% R.1 : Preparation of (1S,5S,6R,7R)-3 -(4-carbamoylbutyl)-6-[(4S,1E)-4-hydroxy-4-methyl-1-octenyl]-7-hydroxy‐
bicyclo[3.3.0]-2-octene
[Reference example 1] Preparation of (1S,5S,6R,7R)-3 -(4-carbamoylbutyl)-6-[(4S,1E)-4-hydroxy-4-methyl-1-octen‐
yl]-7-hydroxybicyclo[3.3.0]-2-octene 73mg of (1S,5S,6R,7R)-3-(4-carboxybutyl)-6-[(4S,1E)-4-hydroxy-4-methyl-1-oc‐
tenyl]-7-hydroxybicyclo[3.3.0]-2-octene was taken and dissolved in 2mL ofdimethylformamide. After addition of 49mg
of 1,1'-carbonyldiimidazole, it was stirred at 50°C for 1 hour. It was then cooled to ambient temperature, 5mL of 25%
ammonium hydroxide in water was added, and stirred for 1 hour. An aqueous solution saturated with potassium hy‐
drogen sulfate was added and extracted with ethyl acetate. The organic layer was washed with an aqueous solution
saturated with sodium bicarbonate, then with a saturated saline solution, and dried with anhydrous sodium sulfate.
After filtration and concentration, it was subjected to a silicagel column chromatography, to obtain 29mg of the com‐
pound presented in the title (40% yield). 1H-NMR(270MHz, CDCl3):δ 0.91 (brt, 3H, J=7.1Hz), 1.17 (s, 3H), 1.2-1.7
(m, 15H), 1.8-2.5 (m, 11H), 2.9-3.1 (m, 1H), 3.7-3.9 (m, 1H), 5.30 (brs, 1H), 5.3-5.5 (m, 1H), 5.5-5.7 (m, 1H).

With ammonium hydroxide, potassium hydrogen sulphate in water

PatentTEIJIN LIMITED; TEIJIN LIMITEDTeijin; EP1201235; (2002); (A1) English

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O NH 2

OH

N
H H
S
NH N N

S
H NH
N

N
S

Rx-ID: 34520009 View in Reaxys 95/636

Yield Conditions & References
5.1.29.5-[5-(1,3-Benzothiazol-6-yl)-4-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-2-yl]pentanamide (8d)
To a solution of 7a (282 mg, 0.762 mmol) in THF (10 mL) was added KOH (128 mg, 2.28 mmol) in a mixed solvent of
water (1 mL) and MeOH (1 mL). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture
was neutralized with 4 M HCl in dioxane and concentrated. The residue was dissolved in CHCl3 (10 mL) and n-butyl‐
amine (67 mg, 0.92 mmol), HOBt H2O (103 mg, 0.762 mmol), NEt3 (115 mg, 1.14 mmol) and EDC HCl (218 mg,
1.14 mmol) were added. The reaction mixture was stirred at room temperature for 10 h. The reaction mixture was
diluted with CHCl3 and washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was
dried over MgSO4 and concentrated.

With ethylene dichloride hydrochloride, benzotriazol-1-ol, triethylamine in chloroform, T= 20 °C

Amada, Hideaki; Sekiguchi, Yoshinori; Ono, Naoya; Koami, Takeshi; Takayama, Tetsuo; Yabuuchi, Tetsuya;
Katakai, Hironori; Ikeda, Akiko; Aoki, Mari; Naruse, Takumi; Wada, Reiko; Nozoe, Akiko; Sato, Masakazu; Bio‐
organic and Medicinal Chemistry; vol. 20; nb. 24; (2012); p. 7128 - 7138

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 View in Reaxys

HO O

O NH 2

Rx-ID: 235125 View in Reaxys 96/636

Yield Conditions & References
80% Stage 1: With oxalyl dichloride, N,N-dimethyl-formamide in tetrahydrofuran, Time= 16h, T= 0 - 20 °C
Stage 2: With ammonium hydroxide in tetrahydrofuran, water, Time= 16h, T= 20 °C

Wong, Jeff Y. F.; Tobin, John M.; Vilela, Filipe; Barker, Graeme; Chemistry - A European Journal; vol. 25; nb. 53;
(2019); p. 12439 - 12445
View in Reaxys

With ammonia, T= 200 °C

Turner; Lingafelter; Acta Crystallographica; vol. 8; (1955); p. 549

View in Reaxys

With Pseudoalteromonas tunicata TamA catalytic adenylation domain, ammonia, ATP, magnesium chloride in di‐
methyl sulfoxide, pH= 9, Enzymatic reaction

Marchetti, Piera M.; Richardson, Shona M.; Kariem, Noor M.; Campopiano, Dominic J.; MedChemComm; vol.
10; nb. 7; (2019); p. 1192 - 1196
View in Reaxys

O HN
2

O O

OH OH

Rx-ID: 39969449 View in Reaxys 97/636

Yield Conditions & References
87 % With magnesium nitride in methanol, Time= 25.5h, T= 0 - 80 °C

Nagel, Nadja C.; Masic, Anita; Schurigt, Uta; Boland, Wilhelm; Organic and Biomolecular Chemistry; vol. 13; nb.
18; (2015); p. 5139 - 5146
View in Reaxys

N N
B

F F

N N
B
O
F F

S O
O
N

O
O O
O
HN
NH
O

NH 2

Rx-ID: 54877400 View in Reaxys 98/636

Yield Conditions & References
83 % With ammonia in dimethyl sulfoxide, isopropyl alcohol, Time= 3h, T= 20 °C , Darkness

Gao, Zhan-Guo; Toti, Kiran S.; Campbell, Ryan; Suresh, R. Rama; Yang, Huijun; Jacobson, Kenneth A.; Cells;
vol. 9; nb. 5; (2020); Art.No: 1200
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 HO
NH 2

O H
N

N
H
NH 2

Rx-ID: 55012248 View in Reaxys 99/636

Yield Conditions & References
75 %, 13 Stage 1: With cyclopentyl methyl ether, ammonia, T= 200 °C , p= 4500.45Torr , Sealed tube, Green chemistry
%, 6 % Stage 2: With cyclopentyl methyl ether, ammonia, hydrogen, Time= 6.5h, T= 200 °C , p= 42004.2Torr , Cooling with
ice, Green chemistry

Coeck, Robin; De Vos, Dirk E.; Green Chemistry; vol. 22; nb. 15; (2020); p. 5105 - 5114
View in Reaxys

Rx-ID: 55012254 View in Reaxys 100/636

Yield Conditions & References
76 %, 2 %, Stage 1: With cyclopentyl methyl ether, ammonia, T= 200 °C , p= 4500.45Torr , Sealed tube, Green chemistry
8 %, 4 %, Stage 2: With cyclopentyl methyl ether, ammonia, hydrogen, Time= 6.5h, T= 200 °C , p= 42004.2Torr , Cooling with
5% ice, Green chemistry, Reagent/catalyst

Coeck, Robin; De Vos, Dirk E.; Green Chemistry; vol. 22; nb. 15; (2020); p. 5105 - 5114
View in Reaxys

Rx-ID: 55012255 View in Reaxys 101/636

Yield Conditions & References
76 %, 11 Stage 1: With cyclopentyl methyl ether, ammonia, T= 200 °C , p= 4500.45Torr , Sealed tube, Green chemistry
%, 8 %, 7 Stage 2: With cyclopentyl methyl ether, ammonia, hydrogen, Time= 6.5h, T= 200 °C , p= 42004.2Torr , Cooling with
%, 5 % ice, Green chemistry

Coeck, Robin; De Vos, Dirk E.; Green Chemistry; vol. 22; nb. 15; (2020); p. 5105 - 5114
View in Reaxys

HO OH HO OH

OH HO

HO O O OH

HO HN NH OH

N N

S
O OH

HO OH HO OH

OH HO

HO O O OH

HO HN NH OH

N N

S
O NH 2

Rx-ID: 55797034 View in Reaxys 102/636

Yield Conditions & References
20 % 2.f : Example 2: Synthesis of compound 5 Step f
In a dried round bottom flask, N-methylmorpholine (10 pL. 0.091 mmol) was added to a solution of Compound 4 pre‐
pared as in example 1 (10 mg, 0.0096 mmol) in dry DMF (1 mL). After 30 minutes of stirring under nitrogen flow, a

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 solution of HBTU (13 mg, 0.03 mmol) in DMF (1 mL) was added. After 1 h, a suspension of NFLCl (10 mg, 0.19
mmol) in DMF (1 mL) was added. The mixture was kept under stirring for 2 days, then it was dried under vacuum
and purified on a pre-packed C 18 silica column with a water- acetonitrile gradient. Fractions containing pure product
were combined, concentrated and freeze-dried, obtaining a blue solid (2,56 mg, 20% yield). HPLC purity at 756 nm
97.5%, MS: [M + H]+1043.1.

Stage 1: With 4-methyl-morpholine in N,N-dimethyl-formamide, Time= 0.5h, Inert atmosphere

Stage 2: With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate in N,N-dimethyl-forma‐
mide, Time= 1h
Stage 3: With ammonium chloride in N,N-dimethyl-formamide, Time= 48h

PatentBRACCO IMAGING SPA; BRACCO SPABracco; WO2020/229438; (2020); (A1) English

View in Reaxys

O O

O O NH 2

Rx-ID: 247536 View in Reaxys 103/636

Yield Conditions & References
With ammonia, water

Autenrieth; Chemische Berichte; vol. 34; (1901); p. 177

View in Reaxys

3 : [S-[R*,R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl hexanamide
EXAMPLE 3 STR26 [S-[R*,R*]]-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl hexanamide In a dry 2 L round-bot‐
tomed flask equipped with a magnetic stirrer was added (+)-pseudoephedrine (40.0 g, 242.06 mmol, 1.0 equiv) and
tetrahydrofuran (500 mL), and the mixture was stirred in a 23° C. water bath. Hexanoic anhydride (55.51 g, 259
mmol, 1.07 equiv) was added via cannula over a 10 minute interval, and transfer was quantitated with an additional
portion of tetrahydrofuran (10 mL). After 25 minutes, the reaction was quenched with saturated sodium bicarbonate
(300 mL). Volatile components were removed under reduced pressure, and the residue was extracted from water
(500 mL) with ethyl acetate (3*250 mL). The organic extracts were dried over sodium sulfate, and after removal of
the solvent under reduced pressure, a white solid was obtained, which was recrystallized from 1:1 ether/hexanes
(200 mL) to afford the hexanamide as white crystals (58.2 g, 91% yield): mp 62°-63° C.; 1H NMR (300 MHz, C 6D6)
δ7.0-7.4 (m, 5H), 4.9 (br, 1H), 4.52 (d, 1H, J=6.9 Hz), 4.14 (m, 1H), 3.77 (m, 1H), 2.79 (s, 3H), 2.42 (m, 2H), 2.13 (s,
3H), 1.83 (m, 2H), 1.59 (qn, 2H, J=7.6 Hz), 1.1-1.4 (m, 4H), 0.99 (d, 3H, J=7.0 Hz), 0.86 (t, 3H, J=7.0 Hz), 0.59 (d,
3H, J=6.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ175.2, 174.2, 142.3, 141.6, 128.3, 128.0, 127.8, 127.3, 126.7, 126.2,
76.1, 75.1, 58.2, 57.0, 34.1, 33.4, 32.4, 31.5, 31.3, 26.6, 24.9, 24.5, 22.31, 22.29, 15.2, 14.2, 13.82, 13.79; FTIR
(neat film) cm-1 3378 (br, m), 2956 (m), 2931 (m), 2871 (m), 1618 (s), 1453 (m), 1406 (m), 1051 (m), 701 (m);
HRMS (FAB) Calcd for C16H26N02 (MH+): 264.1965. Found: 264.1966.

With sodium hydrogencarbonate in tetrahydrofuran, pseudoephedrine, ethyl acetate

PatentCalifornia Institute of Technology; CALIFORNIA INSTITUTE OF TECHNOLOGYCaltech; US5488131; (1996);

(A) English
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O O

HO O
N O N O
H H

O NH 2

Rx-ID: 3710573 View in Reaxys 104/636

Yield Conditions & References
98 % With ammonia, 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 0.5h, T= 0 °C

Kondo; Ishibashi; Kobayashi; Tetrahedron; vol. 50; nb. 28; (1994); p. 8355 - 8362
View in Reaxys

HO
N O
H

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 O

O
N O
H

NH 2

Rx-ID: 3710949 View in Reaxys 105/636

Yield Conditions & References
99 % With ammonia, 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 0.5h, T= 0 °C

Kondo; Ishibashi; Kobayashi; Tetrahedron; vol. 50; nb. 28; (1994); p. 8355 - 8362
View in Reaxys

OH NH 2

OH OH

O O

H H

H H H H

O O
H H

Rx-ID: 10482693 View in Reaxys 106/636

Yield Conditions & References
92 % Stage 1: With chloroformic acid ethyl ester, triethylamine in tetrahydrofuran, Time= 0.0833333h, T= 0 °C
Stage 2: With ammonia in tetrahydrofuran, Time= 0.5h

Tachibana, Kazutaka; Imaoka, Ikuhiro; Yoshino, Hitoshi; Emura, Takashi; Kodama, Hirohumi; Furuta, Yosh‐
iyuki; Kato, Nobuaki; Nakamura, Mitsuaki; Ohta, Masateru; Taniguchi, Kenji; Ishikura, Nobuyuki; Nagamuta,
Masahiro; Onuma, Etsuro; Sato, Haruhiko; Bioorganic and Medicinal Chemistry; vol. 15; nb. 1; (2007); p. 174 -
185
View in Reaxys

NH

NH 2

NH

Rx-ID: 23676462 View in Reaxys 107/636

Yield Conditions & References
98 % With ammonia in tetrahydrofuran, water, Time= 40h, T= 20 °C

Patent; Gruenenthal Pharma GmbH & Co. KommanditgesellschaftGruenenthal Pharma; WO2005/110976;

(2005); (A1) English
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98% (4.75 6-(1H-Indol-3-yl)hexanoic acid amide

g) 6-(1H-Indol-3-yl)hexanoic acid amide A solution of 6-(1H-Indol-3-yl)hexanoic acid cyanomethyl ester (5.72 g, 21.16
mmol) in tetrahydrofuran (160 ml) was added to a 25 percent strength ammonia solution (125 ml) and the mixture
was stirred at RT for 40 h. Working up of the mixture was carried out by phase separation and extraction of the
aqueous phase with THF (2*40 ml). The organic extracts were combined and washed with saturated NaCl solution
(50 ml). After drying and concentration of the organic phase, the product was isolated as a colourless solid in a yield
of 98% (4.75 g) with an m.p. of 140-142 C.

With ammonia in tetrahydrofuran

PatentHinze, Claudia;Sundermann, Bernd;Schick, Hans;Henkel, Birgitta; Gruenenthal Pharma GmbH & Co. Kom‐
manditgesellschaftGruenenthal Pharma; US2007/129347; (2007); (A1) English
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 F F

N N

O O
N N

O N NH 2
N

Rx-ID: 24141283 View in Reaxys 108/636

Yield Conditions & References
C.131 : 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyramide
4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyramide A solution of methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazol‐
yl)butyrate (39 g, 120 mmol) in 600 mL of MeOH was saturated with NH3. The solution was periodically treated with
additional NH3 over a 24 h period. The solution was degassed with a stream of nitrogen and the solution was con‐
centrated to leave a yellow solid. The solid was slurried in ether and filtered to leave the title compound: MS (M+H):
325 (base peak).

With ammonia in methanol

PatentG. D. Searle & Company; PFIZER INCPfizer; US6423713; (2002); (B1) English
View in Reaxys

C.131 : 4-[4-(4-pyridyl)-3-(4-fluorophenyl) pyrazolyl]butyramide

4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyramide. A solution of methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyra‐
zolyl)butyrate (39 g, 120 mmol) in 600 mL of MeOH was saturated with NH3. The solution was periodically treated
with additional NH3 over a 24 h period. The solution was degassed with a stream of nitrogen and the solution was
concentrated to leave a yellow solid. The solid was slurried in ether and filtered to leave the title compound: MS (M
+H): 325 (base peak).

With ammonia in methanol

PatentG.D. Searle & Company; PFIZER INCPfizer; US6514977; (2003); (B1) English
View in Reaxys

O O

I I
OH NH 2

Rx-ID: 42526215 View in Reaxys 109/636

Yield Conditions & References
95 % Stage 1: With chloroformic acid ethyl ester, triethylamine in dichloromethane, Time= 0.5h, T= 0 °C , Inert atmos‐
phere
Stage 2: With ammonium hydroxide in dichloromethane, Time= 0.5h, T= 20 °C , Inert atmosphere

Yadav, Jhillu Singh; Suresh, Borra; Srihari, Pabbaraja; European Journal of Organic Chemistry; vol. 2016; nb.
14; (2016); p. 2509 - 2513
View in Reaxys

HN
2

HO

OH

O OH

Rx-ID: 42526255 View in Reaxys 110/636

Yield Conditions & References
97 % Stage 1: With chloroformic acid ethyl ester, triethylamine in dichloromethane, Time= 0.5h, T= 0 °C , Inert atmos‐
phere
Stage 2: With ammonium hydroxide in dichloromethane, Time= 0.25h, T= 20 °C , Inert atmosphere

Yadav, Jhillu Singh; Suresh, Borra; Srihari, Pabbaraja; European Journal of Organic Chemistry; vol. 2016; nb.
14; (2016); p. 2509 - 2513
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 O O

HO HN 2

N N
H H

O O
F F

Rx-ID: 45544763 View in Reaxys 111/636

Yield Conditions & References
53 % Stage 1: With N-ethylmorpholine;, O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate in N,N-
dimethyl-formamide, Time= 2h, T= 20 °C
Stage 2: With trifluoroacetic acid in dichloromethane, Time= 2h, T= 20 °C
Stage 3: in 1,3,5-trimethyl-benzene, Time= 2h, Irradiation

Qvortrup, Katrine; Petersen, Rico G.; Dohn, Asmus O.; Møller, Klaus B.; Nielsen, Thomas E.; Organic Letters;
vol. 19; nb. 12; (2017); p. 3263 - 3266
View in Reaxys

Rx-ID: 55012226 View in Reaxys 112/636

Yield Conditions & References
74 %, 1 %, Stage 1: With cyclopentyl methyl ether, ammonia, T= 200 °C , p= 4500.45Torr , Sealed tube, Green chemistry
3 %, 15 %, Stage 2: With cyclopentyl methyl ether, ammonia, hydrogen, Time= 6.5h, T= 200 °C , p= 42004.2Torr , Cooling with
5% ice, Green chemistry

Coeck, Robin; De Vos, Dirk E.; Green Chemistry; vol. 22; nb. 15; (2020); p. 5105 - 5114
View in Reaxys

N
O O

O HN
2

Rx-ID: 3594994 View in Reaxys 113/636

Yield Conditions & References
87 % With ammonium hydroxide in tetrahydrofuran, Time= 4h, Ambient temperature

Shiraishi; Kato; Terao; Ashida; Terashita; Kito; Journal of Medicinal Chemistry; vol. 32; nb. 9; (1989); p. 2214 -
2221
View in Reaxys

O O

HO O
N O N O
H H

O NH 2

Rx-ID: 3709960 View in Reaxys 114/636

Yield Conditions & References
76 % With ammonia, 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 0.5h, T= 0 °C

Kondo; Ishibashi; Kobayashi; Tetrahedron; vol. 50; nb. 28; (1994); p. 8355 - 8362
View in Reaxys

OH

OH

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 NH 2

OH

Rx-ID: 10287770 View in Reaxys 115/636

Yield Conditions & References
94.0 % With ammonium carbamate, Nowozym 435 in tert-Amyl alcohol, T= 55 °C

Kuo, Tsung Min; Levinson, William E.; Journal of the American Oil Chemists' Society; vol. 83; nb. 8; (2006); p.
671 - 675
View in Reaxys

OH

NH 2

Rx-ID: 10287876 View in Reaxys 116/636

Yield Conditions & References
92.1 % With ammonium carbamate, Nowozym 435 in tert-Amyl alcohol, T= 55 °C

Kuo, Tsung Min; Levinson, William E.; Journal of the American Oil Chemists' Society; vol. 83; nb. 8; (2006); p.
671 - 675
View in Reaxys

O O

O O

Cl O OH OH

O HN
2

OH O

Rx-ID: 24723404 View in Reaxys 117/636

Yield Conditions & References
60 : 5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid amide (+-)
Example 60 5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid amide
(+-) To a 50 mL reaction flask was added 1.2 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)penta‐
noic acid (+-), 2.4 mmol of 4-methylmorpholine, and 10 mL of CH2 Cl2. The reaction was cooled to 0° C. and 2.4
mmol of methyl chloroformate in 3 mL of CH2 Cl2 was added. The reaction was stirred at 0° C. for 2 hours. Ammonia
was bubbled into the vessel for 10-15 minutes and the reaction allowed to stir for 30 minutes at 0° C. The reaction
was poured into ethyl acetate and 1N HCl, the aqueous layer extracted with ethyl acetate, dried over MgSO4, and
concentrated. The crude solid was triturated using CH2 Cl2 to afford 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-
pyran-2-yl)pentanoic acid amide (+-) as a solid (m.p. 173°-174° C.). 1 H NMR (DMSO-d6) δ0.8-1.0 (m, 1H), 1.1-1.3
(m, 1H), 1.3-1.5 (m, 2H), 1.8-2.0 (m, 4H), 2.9 (ABq, 2H), 4.8 (s, 1H), 6.6 (s, 1H), 7.2 (s, 1H), 7.2-7.5 (m, 5H), 11.4 (s,
1H).

With 4-methyl-morpholine in dichloromethane

PatentWarner-Lambert Company; PFIZER INC; PARKE DAVID USPfizer; &lt;unknown&gt;; US5789440; (1998); (A)
English
View in Reaxys

60 : 5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid amide (+-)

EXAMPLE 60 5-(3,6-Dihydro-4-hydroxy-6-oxo-2-phenyl-5-[(2-phenylethyl)thio]-2H-pyran-2-yl)pentanoic acid amide
(+-) To a 50 mL reaction flask was added 1.2 mmol of 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phenyl-2H-pyran-2-yl)penta‐
noic acid (+-), 2.4 mmol of 4-methylmorpholine, and 10 mL of CH2 Cl2. The reaction was cooled to 0° C. and 2.4
mmol of methyl chloroformate in 3 mL of CH2 Cl2 was added. The reaction was stirrred at 0° C. for 2 hours. Ammo‐
nia was bubbled into the vessel for 10-15 minutes and the reaction allowed to stir for 30 minutes at 0° C. The reac‐

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 tion was poured into ethyl acetate and 1N HCl, the aqueous layer extracted with ethyl acetate, dried over MgSO4,
and concentrated. The crude solid was triturated using CH2 Cl2 to afford 5-(3,6-dihydro-4-hydroxy-6-oxo-2-phe‐
nyl-2H-pyran-2-yl)pentanoic acid amide (+-) as a solid (m.p. 173°-174° C.). 1 H NMR (DMSO-d6) δ 0.8-1.0 (m, 1 H),
1.1-1.3 (m, 1 H), 1.3-1.5 (m, 2 H), 1.8-2.0 (m, 4 H), 2.9 (ABq, 2 H), 4.8 (s, 1 H), 6.6 (s, 1 H), 7.2 (s, 1 H), 7.2-7.5 (m,
5 H), 11.4 (s, 1 H).

With 4-methyl-morpholine in dichloromethane

PatentWarner-Lambert Company; PARKE DAVID US; PFIZER INC&lt;unknown&gt;; Pfizer; US5840751; (1998); (A)
English
View in Reaxys

HO HO
Cl O

O
O O

HO N HN
2
N

O O

Rx-ID: 25896221 View in Reaxys 118/636

Yield Conditions & References
3.5 mg 44 : 7-[(R)-2-((E)-3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid amide
(31%) EXAMPLE 44 7-[(R)-2-((E)-3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic acid amide Triethylamine
(9 μL, 0.065 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hep‐
tanoic acid (11.3 mg, 0.030 mmol) in CH2Cl2 (0.3 mL) at rt. After cooling to 0° C., ethyl chloroformate (3.2 μL, 0.033
mmol) was added. After 1 h at 0° C., a solution of ammonia (0.5 M in 1,4-dioxane, 0.3 mL, 0.15 mmol) was added
and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was diluted with EtOAc (10
mL) and washed with aqueous HCl (0.5 M, 3 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried
(Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica
gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 3.5 mg (31%) of the title compound.

With ammonia, triethylamine in 1,4-dioxane, dichloromethane

PatentALLERGAN, INC.; ABBVIE INCAbbVie; US2004/248854; (2004); (A1) English

View in Reaxys

3.5 mg 44 : 7-[(R)-2-((E)-3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic Acid Amide

(31%) EXAMPLE 44 7-[(R)-2-((E)-3-Hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-heptanoic Acid Amide Triethylamine
(9 μL, 0.065 mmol) was added to a solution of 7-[(R)-2-((E)-3-hydroxy-4-phenyl-but-1-enyl)-6-oxo-piperidin-1-yl]-hep‐
tanoic acid (11.3 mg, 0.030 mmol) in CH2Cl2 (0.3 mL) at rt. After cooling to 0° C., ethyl chloroformate (3.2 μL, 0.033
mmol) was added. After 1 h at 0° C., a solution of ammonia (0.5 M in 1,4-dioxane, 0.3 mL, 0.15 mmol) was added
and the reaction mixture was allowed to warm to rt. After 18 h at rt, the reaction mixture was diluted with EtOAc (10
mL) and washed with aqueous HCl (0.5 M, 3 mL), saturated aqueous NaHCO3 (5 mL) and brine (5 mL) then dried
(Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica
gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 3.5 mg (31%) of the title compound.

With ammonia, triethylamine in 1,4-dioxane, dichloromethane

PatentOld, David W.;Dinh, Danny T.;Kedzie, Karen M.;Gil, Daniel W.;Im, Wha Bin; ABBVIE INCAbbVie;
US2005/171062; (2005); (A1) English
View in Reaxys

O O

O NH 2

Rx-ID: 235087 View in Reaxys 119/636

Yield Conditions & References
With ammonia, hydrogen, T= 250 °C , p= 36775.4 - 73550.8Torr

Wojcik; Adkins; Journal of the American Chemical Society; vol. 56; (1934); p. 2419,2422

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 View in Reaxys

HO O

O NH 2

Rx-ID: 4611967 View in Reaxys 120/636

Yield Conditions & References
With thionyl chloride, ammonia, 1.) reflux, 60 min, 2.) H2O, room temperature, Yield given. Multistep reaction

Crisp, Geoffrey T.; Gore, Jeffrey; Tetrahedron; vol. 53; nb. 4; (1997); p. 1505 - 1522
View in Reaxys

Stage 1: With Rink amide resin Fmoc-deprotected, benzotriazol-1-ol, dacarbazine in dichloromethane, N,N-dimeth‐
yl-formamide, Time= 1h, T= 20 °C
Stage 2: With trifluoroacetic acid in dichloromethane, Time= 1h, T= 20 °C

Dai, Wei-Min; Guo, Dian-Shun; Sun, Li-Ping; Huang, Xiang-Hong; Organic Letters; vol. 5; nb. 16; (2003); p. 2919
- 2922
View in Reaxys

Reaction Steps: 2
1: (COCl)2 / Heating
2: aq. NH3
With ammonium hydroxide, oxalyl dichloride

Popova,E.G.; Kraft,M.Ya.; Journal of general chemistry of the USSR; vol. 30; (1960); p. 1771 - 1775; Zhurnal Ob‐
shchei Khimii; vol. 30; (1960); p. 1787 - 1791
View in Reaxys

N
O
O
N N
F F H
HO O
F F

O O
O F HO F
NH 2

O N
HO HN N
O

Rx-ID: 24281549 View in Reaxys 121/636

Yield Conditions & References
115 : N-(5-Carbamoyl-pentyl)-N-isopropyl-3-methyl-5-[2-(pyridin-4ylamino)-ethoxy]-benzamide trifluoroace‐
tate
EXAMPLE 115 N-(5-Carbamoyl-pentyl)-N-isopropyl-3-methyl-5-[2-(pyridin-4ylamino)-ethoxy]-benzamide trifluoroace‐
tate To a solution of 6-[{3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoyl}-(isopropyl)-amino]-hexanoic acid trifluor‐
oacetate (0.022 g) in DMF (1 ml) was added HATU (0.039 g), DIPEA (0.018 ml) and 0.5M ammonia in 1,4-dioxane
solution (0.2 ml). The mixture was stirred overnight. The reaction mixture was evaporated under reduced pressure,
the residue obtained was subjected to preparative hplc to give the title compound as a colourless oil (0.008 g). Hplc
system 1 (λ=254 nm) Rt 5.9 min; Mass spectrum: Found: MH+427.

With ammonia, N-ethyl-N,N-diisopropylamine in 1,4-dioxane, N,N-dimethyl-formamide

PatentGlaxo Group Limited; GLAXOSMITHKLINE PLCGlaxoSmithKline; US6326386; (2001); (B1) English

View in Reaxys

O
NH 2

O
S
O N
O
O
O N
S
O

O
O

Rx-ID: 24286351 View in Reaxys 122/636

Yield Conditions & References
1.e : 5-[Ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentanamide STR20

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 e) A solution of 0.4 g (1 mmol) of methyl 5-[ethylsulfonyl-(2,2,6-trimethyl-chroman-4-yl)amino]pentanoate and 1.5 ml
of liquid ammonia in 10 ml of methanol is allowed to stand at RT for 9 days. After concentrating in vacuo, the residue
is treated with water and extracted with EA. 0.37 g of 5-[ethylsulfonyl-(2,2,6-trimethylchroman-4-yl)amino]pentana‐
mide is obtained; m.p. 127-129° C.

With ammonia in methanol, water

PatentHoechst Marion Roussel Deutschland; SANOFISanofi; US5955607; (1999); (A) English

View in Reaxys

O HN 2

HO O

OH OH

Rx-ID: 24889171 View in Reaxys 123/636

Yield Conditions & References
70 : EXAMPLE 70
EXAMPLE 70 To 10.0 parts of 5-(4-hydroxyphenyl)-5-methyl-hexanoic acid suspended in 75 parts of toluene was
added 10.0 parts thionyl chloride. This mixture was warmed gently to 50° C. until all the suspended acid had passed
into solution, and then set aside overnight at room temperature. The toluene and other volatiles were then removed
at room temperature under reduced pressure, and the residue treated with 75 parts of 0.88 (g/cm3) aqueous ammo‐
nia. The organic phase was extracted with ether, and the ether solution washed with dilute hydrochloric acid followed
by water and evaporated. The residue was taken up in dilute sodium hydroxide, and this solution after treatment with
solid carbon dioxide yielded 5-(4-hydroxyphenyl)-5-methyl-hexanoic acid amide with m.p. 137°-9° C. after crystallisa‐
tion from methanol containing a little ether.

With thionyl chloride in water, toluene

PatentCiba-Geigy AG; BASF SEBASF; US4904815; (1990); (A) English

View in Reaxys

HO HO
O NH 2

N N
HO Cl O Cl

Cl Cl

Rx-ID: 24979402 View in Reaxys 124/636

Yield Conditions & References
10 : 6-{[(5-Chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methylene]-amino}-hexanamide. [X1 =5-Cl, X2
=4-Cl, X3 =H, R=NH2, n=5]
EXAMPLE 10 6-{[(5-Chloro-2-hydroxy-3-methylphenyl)-(4-chlorophenyl)-methylene]-amino}-hexanamide. [X1 =5-Cl,
X2 =4-Cl, X3 =H, R=NH2, n=5] In an Erlenmeyer flask, 17.7 g (0.045 mol) of the acid obtained in Example 9 are intro‐
duced into 200 ml of tetrahydrofuran. 8 g (0.0495 mol) of carbonyldiimidazole are added in small amounts and the
mixture is stirred for four hours at ambient temperature. With cooling, the solution is saturated with ammonia and
stirred for two hours. The mixture is evaporated to dryness, the residue is taken up in a mixture of water and chloro‐
form, and the organic phase is decanted, washed with an aqueous solution of bicarbonate, dried over magnesium
sulphate and evaporated. The compound obtained is recrystallized from a diisopropyl ether/ethyl acetate mixture.
Melting point of the amide product is 160°-161° C.

With ammonia, 1,1'-carbonyldiimidazole in tetrahydrofuran, chloroform, water

PatentSynthelabo; SUNTHELABO; SANOFI&lt;unknown&gt;; Sanofi; US4588748; (1986); (A) English

View in Reaxys

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 OH O

O HN 2

N N
SH SH
N N

N N N N

Rx-ID: 25411656 View in Reaxys 125/636

Yield Conditions & References
14 : 7-D-Mandelamido-3-[1-(5-carbamoylpentyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (XIV)
EXAMPLE 14 7-D-Mandelamido-3-[1-(5-carbamoylpentyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid (XIV)
1-(5-Carboxypentyl)tetrazole-5-thiol (6.0 g., 28 mmol.) was slowly dissolved in 20 ml. of thionyl chloride and the mix‐
ture was stirred at 25° for 1.5 hours. Evaporation of the reaction mixture to dryness gave a residue which was dis‐
solved in 30 ml. of tetrahydrofuran. The tetrahydrofuran solution was added to a cold mixture of 60 ml. of ammonium
hydroxide and 30 ml. of tetrahydrofuran and the resulting mixture was stirred at 25° for two days. The mixture was
extracted with ethyl acetate. The aqueous phase was acidified to pH 1 by addition of 6N hydrochloric acid to precipi‐
tate 1-(5-carbamoylpentyl)tetrazole-5-thiol, m.p. 155°-157°.

With hydrogenchloride, ammonium hydroxide in tetrahydrofuran, thionyl chloride

PatentSmithKline Corporation; GLAXOSMITHKLINE PLCGlaxoSmithKline; US4220644; (1980); (A) English

View in Reaxys

O O

NH NH

N O N O

O O

O NH 2

Rx-ID: 27967398 View in Reaxys 126/636

Yield Conditions & References
65 % With ammonia in methanol, Time= 48h, T= 80 °C

Gasse, Cecile; Douguet, Dominique; Huteau, Valerie; Marchal, Gilles; Munier-Lehmann, Helene; Pochet, Syl‐
vie; Bioorganic and Medicinal Chemistry; vol. 16; nb. 11; (2008); p. 6075 - 6085
View in Reaxys

N N

N O N O
O O O O

HO N HN
2
N
H H

O O

HN HN

Rx-ID: 28263409 View in Reaxys 127/636

Yield Conditions & References
142 :(7S)-7-{[(5-Methoxy-2-methyl-1H-indol-3-yl)acetyl]amino}-7-[5-(2-naphthyl)-1,3,4-oxadiazol-2-yl]heptanoic acid
was obtained as described in Example 141 step 4. Once the coupling was complete, to the reaction mixture were
added HATU (1.3 eq) and after 30 min a solution of NH3 in 1,4-dioxane (10 eq). The mixture was stirred for over‐
night, then the crude was directly purified by preparative RP-HPLC, using H2O (+0.1% TFA) and MeCN (+0.1% TFA)
as eluents (column: C18). The desired fractions were lyophilized to afford Q1 as a white powder.

With ammonia, HATU in 1,4-dioxane

PatentATTENNI BARBARA;FERRIGNO FEDERICA;JONES PHILIP;INGENITO RAFFAELE;KINZEL OLAF;LLAUG‐

ER BUFI LAURA;ONTORIA JESUS MARIA;PESCATORE GIOVANNA;ROWLEY MICHAEL;SCARPELLI RI‐
TA;SCHULTZ CARSTEN; MERCK & CO INCMerck & Co; US2009/48228; (2009); (A1) English

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

HO O HO NH 2

O O O O
O
N N

Rx-ID: 35817413 View in Reaxys 128/636

Yield Conditions & References
90 % With ammonia in methanol, water, Time= 1h, T= 20 °C

Zhu, Bo; Zhang, Wen; Lee, Richmond; Han, Zhiqiang; Yang, Wenguo; Tan, Davin; Huang, Kuo-Wei; Jiang,
Zhiyong; Angewandte Chemie - International Edition; vol. 52; nb. 26; (2013); p. 6666 - 6670; Angew. Chem.; vol.
125; nb. 26; (2013); p. 6919,1
View in Reaxys

Si Si

OH NH 2

O O

Rx-ID: 36229636 View in Reaxys 129/636

Yield Conditions & References
94 % Stage 1: With 4-methyl-morpholine, isobutyl chloroformate in tetrahydrofuran, Time= 0.5h, T= -20 °C , Inert atmos‐
phere
Stage 2: With ammonia in tetrahydrofuran, methanol, T= -20 - 0 °C , Inert atmosphere

Lee, Yun Mi; Lim, Chaemin; Lee, Hun Seok; Shin, Young Kee; Shin, Kyong-Oh; Lee, Yong-Moon; Kim, San‐
ghee; Bioconjugate Chemistry; vol. 24; nb. 8; (2013); p. 1324 - 1331
View in Reaxys

O O

O NH 2

Rx-ID: 40690880 View in Reaxys 130/636

Yield Conditions & References
69 % With ammonia in methanol, Time= 3h, T= 20 °C , Green chemistry

Kreye, Oliver; Meier, Michael A. R.; RSC Advances; vol. 5; nb. 65; (2015); p. 53155 - 53160
View in Reaxys

O
O

HO N
N
O
O

NH
O 2

Rx-ID: 46676667 View in Reaxys 131/636

Yield Conditions & References
166.1 : Step 1: N-(5 -amino-5-oxopentyl)-3 ,5-dimethoxy-4-methyl-N-(3 -phenylpropyl)benzamide
A solution of 5-[(3 ,5-dimethoxy-4-methylbenzoyl)(3-phenylpropyl)amino]pentanoic acid (100 mg, 0.242 mmol, Exam‐
ple 4) in tetrahydrofuran (5 mL) was treated with ((3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)oxy)tri(pyrrolidin- 1 -yl)phos‐
phonium hexafluorophosphate(V) (126 mg, 0.242 mmol) followed by N-ethyl-N-isopropylpropan-2-amine (31.3 mg,
0.242 mmol), and the reaction mixture was stirred for 1 hour. NH4OH (0.49 mL, 3.76 mmol) was added, and the
mixture was stirred for 18 hours. The mixture was concentrated, and the residue was partitioned between ethyl ace‐
tate and 1 N HC1. The organic fraction was washed with 1 N NaOH and brine, dried (Mg504) and concentrated to
the titled compound that was used directly in the next step.

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 Stage 1: With N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methyl‐
ene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofuran, Time= 1h
Stage 2: With ammonium hydroxide in tetrahydrofuran, Time= 18h

PatentABBVIE INC.; ABBVIE INCAbbVie; WO2017/177004; (2017); (A1) English

View in Reaxys

O NH 2

OH O

Rx-ID: 48050699 View in Reaxys 132/636

Yield Conditions & References
A : Amide Intermediate Preparation Example A
General procedure: Into a 1L open reactor was added 500g of carboxylic acid feedstock (chemically pure), stirring
was turned on (600 r/min), ammonia gas was continuously fed to the carboxylic acid feed from the bottom of the
reactor (chemical purity, water content was 5.1wt%, Flow rate is 100g/min). After the reaction was allowed to pro‐
ceed for TC hours at the reaction temperature TA, the ammonia gas flow was stopped. The contents of the reactor
were sampled and nuclear magnetic proton spectra and elemental analysis were performed to characterize the
amide intermediate. Specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Ta‐
ble A-3, Table A-4, Table A-5 and Table A-6. These characterization results show that the obtained amide intermedi‐
ate has an extremely high purity (above 99%).In this embodiment, the ammonia gas can be directly replaced with
waste ammonia gas (from Yangzi Petrochemical Plant, containing approximately50wt% of ammonia gas, the rest
were toluene, oxygen, nitrogen, steam, carbon monoxide, and carbon dioxide, and the flow rate of this waste ammo‐
nia was 130g/min).

With ammonia, Time= 0.5h, T= 165 °C , Temperature

PatentSinopec Corporation;Sinopec Yangzi Petrochemical Co., Ltd.;Sun Hailong;Wei Yanyu;Gao Yilong;Chen Xin‐
hua;Miao Jun;Li Na;Kan Lin;Bai Jiye;Chen Shaohui;Yang Aiwu;Xu Yuexing; CHINA PETROCHEMICAL CORPORA‐
TIONSinopec Group; CN104557610; (2018); (B) English
View in Reaxys

15

O NH 2

O O O

Rx-ID: 49167279 View in Reaxys 133/636

Yield Conditions & References
93 % Stage 1: With triethylamine in dichloromethane, Time= 0.333333h, T= 0 °C , Inert atmosphere
Stage 2: With ammonium-15N hydrochloride in dichloromethane, water, T= 20 °C , Inert atmosphere

Helberg, Julian; Oe, Yohei; Zipse, Hendrik; Chemistry - A European Journal; vol. 24; nb. 54; (2018); p. 14387 -
14391
View in Reaxys

O O O HN
2
O O

O O
HO HO

OH O OH O

Rx-ID: 50172003 View in Reaxys 134/636

Yield Conditions & References
1.1 g 37 : Example 37: Synthesis of baicalein-7-O-butylene carboxamide (Id-13):
Embodiment Same as Example 9, replacing methyl 2-bromoacetate with methyl 5-bromopentanoate,Reaction with
baicalein gave 1.17 g of a yellow solid. Subsequently,The reaction product of the previous step is dissolved in etha‐
nol.Add excess ammonia water (1.5 eq) and stir for more than 14 hours to precipitate.The precipitate was filtered
and recrystallized from ethyl acetate.Obtaining the target product 1.10g,The two-step reaction combined yield:
29.8%.

With ammonium hydroxide in ethanol, Time= 14h

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 PatentThe Chinese People's Liberation Army The Third Ｏ er Hospital;Zhao Yanling;Li Haotian;Zhou Xuelin;Wei Shi‐
chang;Li Jianyu;Li Kun; PLA NO 302 HOSPITAL&lt;unknown&gt;; CN108794442; (2018); (A) English
View in Reaxys

HO O HO O

HO HO

O O O O

O O

O NH 2

Rx-ID: 50172028 View in Reaxys 135/636

Yield Conditions & References
1.02 g 79 : Example 79: Synthesis of baicalein-5-O-butylene carboxamide (Ih-13):
The same as in Example 9, using methyl 5-bromopentanoate instead of ethyl 2-bromoacetate, and reacting with bai‐
caleinTo a yellow solid 1.10 g. Subsequently, the reaction product of the previous step was dissolved in ethanol, and
excess ammonia water (1.5 eq) was added and stirred for 14 hours.Above, the precipitate was precipitated, and the
precipitate was filtered and recrystallized from ethyl acetate to give the object product 1.02 g.Rate: 27.6%.

With ammonium hydroxide in ethanol, Time= 14h

PatentThe Chinese People's Liberation Army The Third Ｏ er Hospital;Zhao Yanling;Li Haotian;Zhou Xuelin;Wei Shi‐
chang;Li Jianyu;Li Kun; PLA NO 302 HOSPITAL&lt;unknown&gt;; CN108794442; (2018); (A) English
View in Reaxys

O N

N O
O N

NH 2

N O

Rx-ID: 54105791 View in Reaxys 136/636

Yield Conditions & References
99 % With ammonia in methanol, Time= 12h, T= 90 °C , Sealed tube

Kumar, Kunal; Wang, Peng; Wilson, Jessica; Zlatanic, Viktor; Berrouet, Cecilia; Khamrui, Susmita; Secor,
Cody; Swartz, Ethan A.; Lazarus, Michael; Sanchez, Roberto; Stewart, Andrew F.; Garcia-Ocana, Adolfo; De‐
vita, Robert J.; Journal of Medicinal Chemistry; vol. 63; nb. 6; (2020); p. 2986 - 3003
View in Reaxys

O O

O NH 2

Rx-ID: 206530 View in Reaxys 137/636

Yield Conditions & References
With ammonia, T= 165 °C

Roe et al.; Journal of the American Oil Chemists' Society; vol. 29; (1952); p. 18
View in Reaxys

With ammonia, T= 165 - 180 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217

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 View in Reaxys

With lithium aluminium tetrahydride, ammonia in tetrahydrofuran

Ghodssi,S.M.A. et al.; Bulletin de la Societe Chimique de France; (1970); p. 1461 - 1466

View in Reaxys

O O

O NH 2

Rx-ID: 236538 View in Reaxys 138/636

Yield Conditions & References
95 % With ammonia, Time= 24h, T= 40 °C , Enzymatic reaction, Temperature, Concentration

Luque, Susana; Álvarez, José R.; Cuperus, F. Petrus; Journal of Molecular Catalysis B: Enzymatic; vol. 107;
(2014); p. 73 - 78
View in Reaxys

With ammonia, water

Felletar; Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften; (1868); p.
624
View in Reaxys

Reaction Steps: 2
1: Candida antarctica lipase B (Novozym 435); 1-butyl-3-methylimidazolium tetrafluoroborate; NH3 / 24 h / 40 °C
2: Candida antarctica lipase B (Novozym 435); 1-butyl-3-methylimidazolium tetrafluoroborate; NH3 / 96 h / 40 °C
With Candida antarctica lipase B (Novozym 435), ammonia, 1-butyl-3-methylimidazolium Tetrafluoroborate

Madeira Lau; van Rantwijk; Seddon; Sheldon; Organic letters; vol. 2; nb. 26; (2000); p. 4189 - 4191
View in Reaxys

O S O S

O NH 2

Rx-ID: 1958269 View in Reaxys 139/636

Yield Conditions & References
74 % With ammonia in methanol, Time= 240h, T= 5 °C

Tolstikov, A. G.; Biktimirova, L. A.; Tolstikova, O. V.; Shmakov, V. S.; Vyrypaev, E. M.; Tolstikov, G. A.; Chemis‐
try of Natural Compounds; vol. 28; nb. 1; (1992); p. 85 - 87; Khimiya Prirodnykh Soedinenii; nb. 1; (1992); p. 102 -
105
View in Reaxys
Biktimirova, L. A.; Likhovskikh, V. V.; Tolstikova, O. V.; Tolstikova, T. G.; Tolstikov, A. G.; Pharmaceutical
Chemistry Journal; vol. 26; nb. 11/12; (1992); p. 843 - 846; Khimiko-Farmatsevticheskii Zhurnal; vol. 26; nb. 11-12;
(1992); p. 45 - 48
View in Reaxys

HO O
Br Br

O NH 2

Rx-ID: 18864594 View in Reaxys 140/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / acetone / 0.5 h / -10 °C
2: 25percent aq. NH3 / acetone / 2 h
With ammonium hydroxide, triethylamine in acetone

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

With ammonium hydroxide, thionyl chloride

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Leys, Jan; Tripathi, Chandra Shekhar Pati; Glorieux, Christ; Zahn, Stefan; Kirchner, Barbara; Longuemart,
Stephane; Lethesh, Kallidanthiyil Chellappan; Nockemann, Peter; Dehaen, Wim; Binnemans, Koen; Physical
Chemistry Chemical Physics; vol. 16; nb. 22; (2014); p. 10548 - 10557
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride; N,N-dimethyl-formamide / tetrahydrofuran / 0 - 20 °C / Inert atmosphere
2: ammonium hydroxide / tetrahydrofuran / 30 min / Cooling with ice; Inert atmosphere
With ammonium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide in tetrahydrofuran

Chen, Xuemeng;Lian, Zhong;Kramer, Søren; Angewandte Chemie - International Edition; vol. 62; nb. 13; (2023);
Art.No: E202217638; Angew. Chem.; vol. 135; nb. 13; (2023)
View in Reaxys

H H
N O N O
Cl O
O NH 2

N O Cl N
HO N O N

Rx-ID: 24716887 View in Reaxys 141/636

Yield Conditions & References
55 : EXAMPLE 55
EXAMPLE 55 To a very fine suspension of 0.4 g of 4-(10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-[1,2-
e]pyrazin-10-yl)butyric acid in 20 ml of chloroform is added, at a temperature in the region of 20° C., 0.13 g of oxalyl
chloride followed by a solution of 0.5 ml of dimethylformamide in 5 ml of chloroform, and the stirring is continued for
3 hours. 2 ml of a 5.6N solution of ammonia in methanol are then added and the stirring is continued for 18 hours.
The reaction mixture is concentrated on a rotary evaporator and the evaporation residue is stirred for 2 hours with 30
ml of distilled water. The solid is filtered off and purified by chromatography on a column of silica (25 g), eluding un‐
der a pressure of 0.5 bar with a mixture of dichloromethane and methanol (9/1 by volume). 0.045 g of 4-(10-meth‐
yl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-10-yl)butyramide is obtained in the form of a light-
beige-coloured solid melting above 260° C. (1 H NMR spectrum: (300 MHz; (CD3)2 SO-d6; δ in ppm): 0.65 (mt, 2H:
CH2); 1.53 (s, 3H: CH3); 1.80 (t, J=7.5 Hz, 2H: CH2 CON); 2.10 and 2.28 (2 mts, 1H each: hetero-CH2); 6.58 and
7.10 (2 broad s, 1H each: CONH2); 7.27 and 7.33 (2 t, J=7.5 Hz, 1H each: H 7 and H 8); 7.42 and 7.92 (2 broad s,
1H each: H of the imidazole); 7.50 and 7.68 (2 broad d, J=7.5 Hz, 1H each: H 6 and H 8)).

With ammonia in N-methyl-acetamide, methanol, dichloromethane, chloroform

PatentRhone-Poulenc Rorer S.A.; SANOFISanofi; US5807859; (1998); (A) English

View in Reaxys

Cl O O

N O

O OH
O
N

N O
O

HN
2

Rx-ID: 24957151 View in Reaxys 142/636

Yield Conditions & References
20 : 6-[2-(1H-Imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanamide
EXAMPLE 20 6-[2-(1H-Imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanamide A stirred solution of
6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]ethoxy]hexanoic acid (Example 1; 10 g, 0.027M) and
triethylamine (3.0 g, 0.030 mol) in dry dichloromethane (100 ml) at -50° C. was treated dropwise with ethyl chlorofor‐
mate (3.2 g, 0.029 mol). The solution was allowed to warm up to 0° C. over 0.5 hours, cooled back to -78° C. and
treated with gaseous ammonia. The solution was allowed to warm up to room temperature over 6 hours and washed
with an aqueous saturated solution of sodium hydrogen carbonate and dried (Na2 CO3). The solvent was evaporated
off under reduced pressure to give a residue which was purified by column chromatography (silica gel, ethyl acetate
to 10% methanol in ethyl acetate) to give 6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl]-ethoxy]hex‐
anamide as a pale yellow oil. 1 H-NMR (δ-CDCl3): 1.15-1.37 (m, 2H), 1.40-1.65 (m, 4H), 2.17 (t, 2H), 3.17-3.65 (m,

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 5H), 3.84 (s, 3H), 3.95-4.15 (m, 2H), 4.51 (ABq, 2H), 5.8 (broad s, 1H), 6.4 (broad s, 1H), 6.93 and 7.27 (ABq, 4H),
6.89 (s, 1H), 7.08 (s, 1H), and 7.53 (s, 1H).

With sodium bicarbonate, ammonia, triethylamine in methanol, dichloromethane, ethyl acetate

PatentG. D. Searle & Co.; PFIZER INCPfizer; US4579862; (1986); (A) English
View in Reaxys

O O O

O HN
2

O O Cl O
N N
H H
HO O

Rx-ID: 25049673 View in Reaxys 143/636

Yield Conditions & References
13.b : (b)
(b) 5-[[(1,1-Dimethylethoxy)carbonyl]amino]pentamide Isobutyl chloroformate (1.55 ml., 12 mmole) in tetrahydrofuran
(5 ml.) is added dropwise over approximately 5 minutes to a vigorously stirred solution of 5-[[(1,1-dimethylethoxy)car‐
bonyl]amino]pentanoic acid (2.61 g., 12 mmole) and N-methylmorpholine (1.32 ml., 12 mmole) in tetrahydrofuran (15
ml.) at -15° while maintaining the reaction temperature between -25° and -15°. The reaction mixture is stirred for 12
minutes, then 10 ml. of a solution of ammonia in methanol (saturated at 0°) is added dropwise over 30 minutes at
approximately -15°. The reaction mixture is stirred an additional 30 minutes in the cold, then allowed to warm to
room temperature and left to stir overnight. The thick white suspension is diluted with water, concentrated in vacuo to
remove organic solvents and then extracted with ethyl acetate (150 ml.). The ethyl acetate solution is washed with
water, 10% potassium bisulfate, water and brine, dried (Na2 SO4), and evaporated to give 1.54 g. of white solid prod‐
uct; m.p. 135°-138.5°. Since the recovery is low, the initial aqueous extract is concentrated to half volume and ex‐
tracted with ethyl acetate (1*75 ml., 3*25 ml.). The ethyl acetate solution is washed with water (2*10 ml.) and brine
(2*10 ml.), dried (Na2 SO4) and concentrated to yield 0.56 g. of white solid, bringing the total yield up to 2.1 g. A
small portion is recrystallized from ethyl acetate to yield an analytically pure sample of 5-[[(1,1-dimethylethoxy)car‐
bonyl]amino]pentamide; m.p. 138°-140°.

With 4-methyl-morpholine, ammonia in tetrahydrofuran, methanol

PatentE. R. Squibb & Sons, Inc.; BRISTOL-MYERS SQUIBB COBristol-Myers Squibb; US4722810; (1988); (A)
English
View in Reaxys

O NH 2

Cl O

HO O OH O O OH
O

O O

Rx-ID: 25108857 View in Reaxys 144/636

Yield Conditions & References
10 : Preparation of 5-(2-formyl-3-hydroxyphenoxy)pentanamide
EXAMPLE 10 Preparation of 5-(2-formyl-3-hydroxyphenoxy)pentanamide 5-(2-Formyl-3-hydroxyphenoxy)pentanoic
acid (595 mg, 0.0025 M) was dissolved in dry tetrahydrofuran (5.5 ml) and immersed in a cooling bath kept at -10°
C. To the stirred solution under nitrogen was added dropwise from a syringe triethylamine (0.35 ml, 0.0025 M). After
5 minutes was then similarly added ethyl chloroformate (0.25 ml, 0.0025 M). After 15 minutes was then added a sol‐
ution of ammonium chloride (0.4 g) in water (1.1 ml) and tetrahydrofuran (1.6 ml) previously cooled to 0° C. The vigo‐
rously stirred mixture was allowed to come to room temperature over 30 minutes, stirred at room temperature (15
minutes), and then diluted with ether/ethyl acetate (1:1) and 1 N hydrochloric acid. The layers were separated and
the organic layer washed with dilute sodium bicarbonate solution and then quickly extracted with 2 N sodium hydrox‐
ide (1*25 ml). The layers were separated and the aqueous phase immediately acidified with dilute hydrochloric acid
and extracted with ethyl acetate. The combined extracts were washed with dilute sodium bicarbonate solution, water,
dried (sodium sulphate) and evaporated to give 5-(2-formyl-3-hydroxyphenoxy)pentanamide, m.p. 94°-95° C. from
ethyl acetate/petrol.

With ammonium chloride, triethylamine in tetrahydrofuran, water

PatentBurroughts Wellcome Co.; GLAXOSMITHKLINE PLCGlaxoSmithKline; US4410537; (1983); (A) English

View in Reaxys

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 HO O

O NH 2

Cl O

O Cl O O

Rx-ID: 25191680 View in Reaxys 145/636

Yield Conditions & References
131.C : 1-Benzyloxy-2-naphthalenepentanamide
PART C 1-Benzyloxy-2-naphthalenepentanamide A mixture of the product of Part B (1.00 g, 3.0 mmole), oxalyl
chloride (1.3 mL, 15.0 mmole) and benzene (10 mL) was stirred at room temperature for 16 hours. The mixture was
concentrated under vacuum to provide a tan, viscous oil which was dissolved in dry tetrahydrofuran (8 mL) and add‐
ed dropwise with stirring to aqueous ammonia (28%, 50 mL) at -12°. The mixture was warmed to room temperature
and stirred for 6 hours, then concentrated under vacuum to remove the ammonia and tetrahydrofuran. The crude
product was isolated by extraction with ethyl acetate as a yellow glass (1.0 g, 100%).

With ammonium hydroxide in tetrahydrofuran, benzene

PatentE. I. Du Pont de Nemours and Company; BRISTOL-MYERS SQUIBB COBristol-Myers Squibb; US4833164;
(1989); (A) English
View in Reaxys

N
Cl Cl

Cl N

N N

NH 2
O

O Cl
N N
O

OH

Rx-ID: 25208055 View in Reaxys 146/636

Yield Conditions & References
11 : EXAMPLE 11
EXAMPLE 11 To a suspension of 1.52 g of 3-(5-carboxypentyl)-5-chloro-1-methyl-2-(3-pyridyl)indole in 50 ml of tol‐
uene under nitrogen is added dropwise at room temperature 0.31 ml of thionyl chloride. The resulting mixture is
heated under reflux for 1 hour. An additional 0.10 ml portion of thionyl chloride is added and the solution is stirred at
room temperature overnight. The resulting suspension is evaporated to dryness to give 3-(5-chlorocarbonylpentyl)-5-
chloro-1-methyl-2-(3-pyridyl)indole. A suspension of the acid chloride in 20 ml of concentrated ammonium hydroxide
is stirred at room temperature overnight. The resulting solid is filtered off to yield 3-(5-carbamoylpentyl)-5-chloro-1-
methyl-2-(3-pyridyl)indole.

With thionyl chloride in toluene

PatentCiba-Geigy Corporation; Novartis (w/o Sandoz); NOVARTIS AGNovartis (w/o Sandoz); Novartis;
US4511573; (1985); (A) English
View in Reaxys

OH NH 2

OH OH

O O
Cl O
H H

H H H H

O O
H H

Rx-ID: 25393672 View in Reaxys 147/636

Yield Conditions & References
114 : Synthesis of 17β-hydroxy-7α-(7-carbamoylheptyl)-5α-androstan-3-one
[Example 114] Synthesis of 17β-hydroxy-7α-(7-carbamoylheptyl)-5α-androstan-3-one The 17β-hydroxy-7α-(7-
carboxyheptyl)-5α-androstan-3-one (12.6 mg) obtained in Example 3 was dissolved in tetrahydrofuran (0.5 ml) and

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 then triethylamine (8.1 μl) and ethyl chloroformate (4.2 μl) were added dropwise at 0°C. After stirring for 5 minutes,
ammonia gas was bubbled for 30 seconds. After stirring for 30 minutes, water was added to the reaction mixture and
extraction with dichloromethane was effected. The organic layer was washed with a saturated aqueous solution of
sodium chloride and dried with magnesium sulfate; after filtering, the solvent was distilled off at reduced pressure.
Purification by silica gel column chromatography (developing solvents: dichloromethane/methanol = 20/1) gave the
end compound in 11.6 mg (92%). 1H-NMR(270MHz, CDCl3)δ: 0.76(3H, s), 1.04(3H, s), 1.00-1.83(27H, m),
1.94-2.16(3H, m), 2.20-2.50(5H, m), 3.65(1H, t, J=8.4Hz), 5.34-5.54(2H, m). Mass(FAB): 432(M+1). Rf value (on sili‐
ca gel plate, developing solvents: dichloromethane/methanol = 20/1): 0.48

With sodium chloride, triethylamine in tetrahydrofuran, water

PatentCHUGAI SEIYAKU KABUSHIKI KAISHA; Chugai Pharmaceutical (in: Roche); ROCHE HOLDING
AG&lt;unknown&gt;; Roche; EP1219631; (2002); (A1) English
View in Reaxys

N
O

NH 2

O N
O
N
O

N O

Rx-ID: 54105796 View in Reaxys 148/636

Yield Conditions & References
80 % With ammonia in methanol, Time= 12h, T= 90 °C , Sealed tube

Kumar, Kunal; Wang, Peng; Wilson, Jessica; Zlatanic, Viktor; Berrouet, Cecilia; Khamrui, Susmita; Secor,
Cody; Swartz, Ethan A.; Lazarus, Michael; Sanchez, Roberto; Stewart, Andrew F.; Garcia-Ocana, Adolfo; De‐
vita, Robert J.; Journal of Medicinal Chemistry; vol. 63; nb. 6; (2020); p. 2986 - 3003
View in Reaxys

O NH 2

H H
N N
HO O

O O

Rx-ID: 3260613 View in Reaxys 149/636

Yield Conditions & References
60 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

Stage 1: With N-ethylmorpholine;, O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate in N,N-

dimethyl-formamide, Time= 2h, T= 20 °C
Stage 2: With trifluoroacetic acid in dichloromethane, Time= 2h, T= 20 °C
Stage 3: in 1,3,5-trimethyl-benzene, Time= 2h, Irradiation

Qvortrup, Katrine; Petersen, Rico G.; Dohn, Asmus O.; Møller, Klaus B.; Nielsen, Thomas E.; Organic Letters;
vol. 19; nb. 12; (2017); p. 3263 - 3266
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 O NH 2

O O

O N

O N

N O

N O

Rx-ID: 4706526 View in Reaxys 150/636

Yield Conditions & References
55 % With ammonium hydroxide, ammonium chloride in ethanol, Time= 20h, T= 100 - 110 °C

Kondo; Ogawa; Nakaya; Tominaga; Yabuuchi; Chemical and Pharmaceutical Bulletin; vol. 44; nb. 4; (1996); p.
725 - 733
View in Reaxys

HO O

O NH 2

Rx-ID: 15382414 View in Reaxys 151/636

Yield Conditions & References
Reaction Steps: 3
1: oxalyl chloride / toluene / 0.5 h / 20 °C
2: aq. NaN3 / acetone / 0.33 h / 0 °C
3: 69 percent / Li; 4,4'-di-tert-butylbiphenyl / tetrahydrofuran / 2 h / 20 °C
With sodium azide, oxalyl dichloride, 4,4'-di-tert-butylbiphenyl, lithium in tetrahydrofuran, acetone, toluene

Yus, Miguel; Radivoy, Gabriel; Alonso, Francisco; Synthesis; nb. 6; (2001); p. 914 - 918
View in Reaxys

Reaction Steps: 2
1.1: Et3N / acetonitrile / 0.5 h / 20 °C
1.2: 78 percent / O-benzotriazolyl-N,N,N',N'-tetramethyluronium BF4 / acetonitrile / 1 h / 20 °C
2.1: 81 percent / Li; 4,4'-di-tert-butylbiphenyl / tetrahydrofuran / 3 h / -78 °C
With 4,4'-di-tert-butylbiphenyl, lithium, triethylamine in tetrahydrofuran, acetonitrile

Yus, Miguel; Radivoy, Gabriel; Alonso, Francisco; Synthesis; nb. 6; (2001); p. 914 - 918
View in Reaxys

Reaction Steps: 2
1.1: Et3N / acetonitrile / 0.5 h / 20 °C
1.2: 67 percent / O-benzotriazolyl-N,N,N',N'-tetramethyluronium BF4 / acetonitrile / 1 h / 20 °C
2.1: 62 percent / Li; 4,4'-di-tert-butylbiphenyl / tetrahydrofuran / 3 h / -78 °C
With 4,4'-di-tert-butylbiphenyl, lithium, triethylamine in tetrahydrofuran, acetonitrile

Yus, Miguel; Radivoy, Gabriel; Alonso, Francisco; Synthesis; nb. 6; (2001); p. 914 - 918
View in Reaxys

Reaction Steps: 2
1.1: Et3N / acetonitrile / 0.5 h / 20 °C
1.2: 85 percent / O-benzotriazolyl-N,N,N',N'-tetramethyluronium BF4 / acetonitrile / 1 h / 20 °C
2.1: 82 percent / Li; 4,4'-di-tert-butylbiphenyl / tetrahydrofuran / 2 h / 20 °C
With 4,4'-di-tert-butylbiphenyl, lithium, triethylamine in tetrahydrofuran, acetonitrile

Yus, Miguel; Radivoy, Gabriel; Alonso, Francisco; Synthesis; nb. 6; (2001); p. 914 - 918
View in Reaxys

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 Reaction Steps: 2
1.1: Et3N / acetonitrile / 0.5 h / 20 °C
1.2: 80 percent / O-benzotriazolyl-N,N,N',N'-tetramethyluronium BF4 / acetonitrile / 1 h / 20 °C
2.1: 70 percent / Li; 4,4'-di-tert-butylbiphenyl / tetrahydrofuran / 3 h / -78 °C
With 4,4'-di-tert-butylbiphenyl, lithium, triethylamine in tetrahydrofuran, acetonitrile

Yus, Miguel; Radivoy, Gabriel; Alonso, Francisco; Synthesis; nb. 6; (2001); p. 914 - 918
View in Reaxys

With Diethy phosphocyanidate, ammonia in 1,4-dioxane, N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121
View in Reaxys

With Pseudoalteromonas tunicata TamA catalytic adenylation domain, ammonia, ATP, magnesium chloride in di‐
methyl sulfoxide, pH= 9, Enzymatic reaction

Marchetti, Piera M.; Richardson, Shona M.; Kariem, Noor M.; Campopiano, Dominic J.; MedChemComm; vol.
10; nb. 7; (2019); p. 1192 - 1196
View in Reaxys

NH

O N

NH
O
HN
2

Rx-ID: 23676458 View in Reaxys 152/636

Yield Conditions & References
68 % With ammonia in tetrahydrofuran, water, Time= 72h, T= 20 °C

Patent; Gruenenthal Pharma GmbH & Co. KommanditgesellschaftGruenenthal Pharma; WO2005/110976;

(2005); (A1) English
View in Reaxys

H H
N O N O

S O S O

HO HN
2

O O

Rx-ID: 34796337 View in Reaxys 153/636

Yield Conditions & References
66 % With 1-hydroxy-pyrrolidine-2,5-dione, dicyclohexyl-carbodiimide in tetrahydrofuran, Time= 1h, T= 0 °C

Berger, Michael L.; Pöhler, Thomas; Schadt, Oliver; Stanger, Maximilian; Rebernik, Patrick; Scholze, Petra;
Noe, Christian R.; ChemMedChem; vol. 8; nb. 1; (2013); p. 82 - 94
View in Reaxys

H
2

H O 2

H
2

H O

OH NH 2

2 2 2 2 2 2 2 2

H H H H H H H H

Rx-ID: 45350399 View in Reaxys 154/636

Yield Conditions & References
65 % Stage 1: With oxalyl dichloride in dichloromethane, N,N-dimethyl-formamide, Time= 1.5h, T= 0 - 25 °C
Stage 2: With ammonia in dichloromethane, N,N-dimethyl-formamide, Time= 0.333333h, T= 0 °C

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 Montes Vidal, Diogo; von Rymon-Lipinski, Anna-Lena; Ravella, Srinivasa; Groenhagen, Ulrike; Herrmann,
Jennifer; Zaburannyi, Nestor; Zarbin, Paulo H. G.; Varadarajan, Adithi R.; Ahrens, Christian H.; Weisskopf,
Laure; Müller, Rolf; Schulz, Stefan; Angewandte Chemie - International Edition; vol. 56; nb. 15; (2017); p. 4342 -
4346; Angew. Chem.; vol. 129; nb. 5; (2017); p. 4406 - 4410
View in Reaxys

NH
O
HN
O
N
O O O
N
H
N
NH OH
O
O

NH
O
HN
O
N
O O O
N
H
N
NH NH 2

O
O

Rx-ID: 61010901 View in Reaxys 155/636

Yield Conditions & References
67 % With 2,6-dimethylpyridine, 1-hydroxy-7-aza-benzotriazole, ammonia hydrochloride, N-[3-(N,N-dimethylamino)-prop‐
yl]-N'-ethyl-carbodiimide hydrochloride in N,N-dimethyl-formamide, Time= 23.5h, T= 0 - 25 °C , Inert atmosphere

Yang, Ming-Hsiu;Russell, Jamie L.;Mifune, Yuto;Wang, Ying;Shi, Hexin;Moresco, Eva Marie Y.;Siegwart, Dan‐
iel J.;Beutler, Bruce;Boger, Dale L.; Journal of Medicinal Chemistry; vol. 65; nb. 13; (2022); p. 9230 - 9252
View in Reaxys

HO O

O NH 2

Rx-ID: 228957 View in Reaxys 156/636

Yield Conditions & References
With ammonia, T= 125 - 180 °C , unter staendiger Entfernung des entstehenden Wassers

Mitchell; Reid; Journal of the American Chemical Society; vol. 53; (1931); p. 1880,1881
View in Reaxys

With ammonia, T= 200 °C

Turner; Lingafelter; Acta Crystallographica; vol. 8; (1955); p. 549

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 OH O

O HN
2

O O

N N

Br Br

N N

Cl Br Cl Br

Rx-ID: 9229168 View in Reaxys 157/636

Yield Conditions & References
With ammonium chloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, 4-meth‐
yl-morpholine in N,N-dimethyl-formamide, T= 20 °C

Njoroge, F. George; Vibulbhan, Bancha; Pinto, Patrick; Strickland, Corey L.; Bishop, W. Robert; Kirschmeir,
Paul; Girijavallabhan; Ganguly, Ashit K.; Bioorganic and Medicinal Chemistry; vol. 11; nb. 1; (2003); p. 139 - 143
View in Reaxys

HO O
O NH 2

O O

N N

Br Br

N N

Cl Br Cl Br

Rx-ID: 9229645 View in Reaxys 158/636

Yield Conditions & References
With ammonium chloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, 4-meth‐
yl-morpholine in N,N-dimethyl-formamide, T= 20 °C

Njoroge, F. George; Vibulbhan, Bancha; Pinto, Patrick; Strickland, Corey L.; Bishop, W. Robert; Kirschmeir,
Paul; Girijavallabhan; Ganguly, Ashit K.; Bioorganic and Medicinal Chemistry; vol. 11; nb. 1; (2003); p. 139 - 143
View in Reaxys

OH O

O HN
2

O O

N N

O O

N N

Br Br

N N

Br Cl Cl
Br

Rx-ID: 9231077 View in Reaxys 159/636

Yield Conditions & References
With ammonium chloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, 4-meth‐
yl-morpholine in N,N-dimethyl-formamide, T= 20 °C

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Njoroge, F. George; Vibulbhan, Bancha; Pinto, Patrick; Strickland, Corey L.; Bishop, W. Robert; Kirschmeir,
Paul; Girijavallabhan; Ganguly, Ashit K.; Bioorganic and Medicinal Chemistry; vol. 11; nb. 1; (2003); p. 139 - 143
View in Reaxys

HO O
O NH 2

O O

N N

O O

N N

Br Br

N N

Cl Cl
Br Br

Rx-ID: 9231136 View in Reaxys 160/636

Yield Conditions & References
With ammonium chloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, 4-meth‐
yl-morpholine in N,N-dimethyl-formamide, T= 20 °C

Njoroge, F. George; Vibulbhan, Bancha; Pinto, Patrick; Strickland, Corey L.; Bishop, W. Robert; Kirschmeir,
Paul; Girijavallabhan; Ganguly, Ashit K.; Bioorganic and Medicinal Chemistry; vol. 11; nb. 1; (2003); p. 139 - 143
View in Reaxys

HO O

N N
O NH 2

Rx-ID: 35394665 View in Reaxys 161/636

Yield Conditions & References
48 % Stage 1: With triethylamine, isobutyl chloroformate in tetrahydrofuran
Stage 2: With ammonium hydroxide in tetrahydrofuran

Rossi, Steven A.; Shimkin, Kirk W.; Xu, Qun; Mori-Quiroz, Luis M.; Watson, Donald A.; Organic Letters; vol.
15; nb. 9; (2013); p. 2314 - 2317
View in Reaxys

HO O

OH NH 4

O NH 2

Rx-ID: 40122829 View in Reaxys 162/636

Yield Conditions & References
67 % Stage 1: With 7,7-dichlorocyclohepta-1,3,5-triene, triethylamine in dichloromethane, Time= 0.416667h, T= 20 °C
Stage 2: in dichloromethane, water, T= 20 °C

Nguyen, Thanh V.; Lyons, Demelza J.M.; Chemical Communications; vol. 51; nb. 15; (2015); p. 3131 - 3134
View in Reaxys

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 HN O HN O

O HN
2

OH O

Rx-ID: 3260615 View in Reaxys 163/636

Yield Conditions & References
85 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

O O
O O

S S

NH NH

HO O
Br Br

O NH 2

Rx-ID: 3264714 View in Reaxys 164/636

Yield Conditions & References
90 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

HO O
O NH 2

NH NH

O O
S S

O O

Rx-ID: 3271991 View in Reaxys 165/636

Yield Conditions & References
90 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O NH 2

O O

N O

N O

Rx-ID: 4705849 View in Reaxys 166/636

Yield Conditions & References
41 % With ammonium hydroxide, ammonium chloride in methanol, Time= 2h, T= 100 °C

Kondo; Ogawa; Nakaya; Tominaga; Yabuuchi; Chemical and Pharmaceutical Bulletin; vol. 44; nb. 4; (1996); p.
725 - 733
View in Reaxys

O OH HN
2
O

N O N O

O O

O O

O O

O O

Rx-ID: 9565699 View in Reaxys 167/636

Yield Conditions & References
Stage 1: With 1,1'-carbonyldiimidazole in dichloromethane, Time= 2h, T= 20 °C
Stage 2: With ammonium hydroxide in dichloromethane, T= 20 °C

Rybczynski, Philip J.; Zeck, Roxanne E.; Dudash Jr., Joseph; Combs, Donald W.; Burris, Thomas P.; Yang,
Maria; Osborne, Melville C.; Chen, Xiaoli; Demarest, Keith T.; Journal of Medicinal Chemistry; vol. 47; nb. 1;
(2004); p. 196 - 209
View in Reaxys

OH O

O NH 2

N O N O

O O

O O

O O

O O

Rx-ID: 9566339 View in Reaxys 168/636

Yield Conditions & References
Stage 1: With 1,1'-carbonyldiimidazole in dichloromethane, Time= 2h, T= 20 °C
Stage 2: With ammonium hydroxide in dichloromethane, T= 20 °C

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Rybczynski, Philip J.; Zeck, Roxanne E.; Dudash Jr., Joseph; Combs, Donald W.; Burris, Thomas P.; Yang,
Maria; Osborne, Melville C.; Chen, Xiaoli; Demarest, Keith T.; Journal of Medicinal Chemistry; vol. 47; nb. 1;
(2004); p. 196 - 209
View in Reaxys

HN
2
O

O O

N O

N O
O

O O

O
O

O O

Rx-ID: 13808933 View in Reaxys 169/636

Yield Conditions & References
Reaction Steps: 2
1.1: H2 / Pd/C / ethanol / 3 h / 20 °C / 2585.74 Torr
2.1: 1,1'-carbonyldiimidazole / CH2Cl2 / 2 h / 20 °C
2.2: aq. NH4OH / CH2Cl2 / 20 °C
With hydrogen, 1,1'-carbonyldiimidazole, palladium on activated charcoal in ethanol, dichloromethane

Rybczynski, Philip J.; Zeck, Roxanne E.; Dudash Jr., Joseph; Combs, Donald W.; Burris, Thomas P.; Yang,
Maria; Osborne, Melville C.; Chen, Xiaoli; Demarest, Keith T.; Journal of Medicinal Chemistry; vol. 47; nb. 1;
(2004); p. 196 - 209
View in Reaxys

NH
O
2

N O

N O
O

O
O

O
O

Rx-ID: 13809629 View in Reaxys 170/636

Yield Conditions & References
Reaction Steps: 2
1.1: H2 / Pd/C / ethanol / 3 h / 20 °C / 2585.74 Torr
2.1: 1,1'-carbonyldiimidazole / CH2Cl2 / 2 h / 20 °C
2.2: aq. NH4OH / CH2Cl2 / 20 °C
With hydrogen, 1,1'-carbonyldiimidazole, palladium on activated charcoal in ethanol, dichloromethane

Rybczynski, Philip J.; Zeck, Roxanne E.; Dudash Jr., Joseph; Combs, Donald W.; Burris, Thomas P.; Yang,
Maria; Osborne, Melville C.; Chen, Xiaoli; Demarest, Keith T.; Journal of Medicinal Chemistry; vol. 47; nb. 1;
(2004); p. 196 - 209
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 O O

N N
O NH 2

N N

N N

Rx-ID: 25136224 View in Reaxys 171/636

Yield Conditions & References
8 : EXAMPLE 8
EXAMPLE 8 A solution of 4 g of 1-(4-methoxycarbonylbutyl)-3-methyl-2-(1-imidazolyl)indole in 40 ml of n-butanol is
saturated with ammonia and heated on a steam bath in a pressure bottle for 3 days. The reaction mixture is evapo‐
rated to dryness and the product is crystallized to yield the 1-[4-carbamoylbutyl]-3-methyl-2-(1-imidazolyl)indole.

in butan-1-ol

PatentCiba-Geigy Corporation; NOVARTIS AG; Novartis (w/o Sandoz)Novartis; Novartis (w/o Sandoz);
US4436746; (1984); (A) English
View in Reaxys
PatentCiba-Geigy Corporation; Novartis (w/o Sandoz); NOVARTIS AGNovartis (w/o Sandoz); Novartis;
US4539410; (1985); (A) English
View in Reaxys

O O

O O

OH

HN
2

OH

Rx-ID: 28891783 View in Reaxys 172/636

Yield Conditions & References
With ammonia in tetrahydrofuran, Time= 0.333333h, T= 0 °C , Inert atmosphere

Hödl, Claudia; Raunegger, Katrin; Strommer, Rainer; Ecker, Gerhard F.; Kunert, Olaf; Sturm, Sonja; Seger,
Christoph; Haslinger, Ernst; Steiner, Rudolf; Strauss, Wolfgang S. L.; Schramm, Hans-Wolfgang; Journal of
Medicinal Chemistry; vol. 52; nb. 5; (2009); p. 1268 - 1274
View in Reaxys

O O

H H
N N
HO HN
2

O O

Rx-ID: 45544751 View in Reaxys 173/636

Yield Conditions & References
Stage 1: With N-ethylmorpholine;, O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate in N,N-
dimethyl-formamide, Time= 2h, T= 20 °C
Stage 2: With trifluoroacetic acid in dichloromethane, Time= 2h, T= 20 °C
Stage 3: in 1,3,5-trimethyl-benzene, Time= 2h, Irradiation

Qvortrup, Katrine; Petersen, Rico G.; Dohn, Asmus O.; Møller, Klaus B.; Nielsen, Thomas E.; Organic Letters;
vol. 19; nb. 12; (2017); p. 3263 - 3266

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

OH O

O NH 2

Rx-ID: 56715375 View in Reaxys 174/636

Yield Conditions & References
48 % With magnesium(II) nitrate hexahydrate, urea in octane, Time= 24h, T= 120 °C

Fawcett, Alexander; Keller, M. Josephine; Herrera, Zachary; Hartwig, John F.; Angewandte Chemie - Interna‐
tional Edition; vol. 60; nb. 15; (2021); p. 8276 - 8283; Angew. Chem.; vol. 133; nb. 15; (2021); p. 8357 - 8364,8
View in Reaxys

NH
O
2

O
O

N
N

O
O
N
N

O N
O N N
N

N
N

Rx-ID: 58364765 View in Reaxys 175/636

Yield Conditions & References
45 % 59.2

With ammonia in methanol, dichloromethane, Time= 6h, T= 20 °C

PatentBETTA PHARMACEUTICALS CO., LTD; BETTA PHARMACEUTICALS CO LTDBetta Pharmaceuticals;

WO2021/203772; (2021); (A1) English
View in Reaxys

O O

O NH 2

Rx-ID: 250002 View in Reaxys 176/636

Yield Conditions & References
68 % With indium(III) chloride, calcium nitride in ethanol, Time= 1.5h, Milling

Gómez-Carpintero, Jorge;Sánchez, J. Domingo;González, J. Francisco;Menéndez, J. Carlos; Journal of Or‐

ganic Chemistry; vol. 86; nb. 20; (2021); p. 14232 - 14237
View in Reaxys

With ammonia

Carlet; Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften; (1859); p.
367
View in Reaxys

HO Br O Br

O NH 2

Rx-ID: 1955378 View in Reaxys 177/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1) acetone, -15 - -10 deg C, 90 min; 60 min,
Yield given. Multistep reaction

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
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 Reaction Steps: 2
1: oxalyl chloride / CH2Cl2; dimethylformamide / 1 h / 0 °C
2: 952 mg / NH4OH / benzene / 0.25 h
With ammonium hydroxide, oxalyl dichloride in dichloromethane, N,N-dimethyl-formamide, benzene

Berube, Marie; Kamal, Fatima; Roy, Jenny; Poirier, Donald; Synthesis; nb. 18; (2006); p. 3085 - 3091
View in Reaxys

Reaction Steps: 2
1: Et3N / acetone / 0.5 h / -10 °C
2: 25percent aq. NH3 / acetone / 2 h
With ammonium hydroxide, triethylamine in acetone

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

Reaction Steps: 2
1: SOCl2
2: NH3 / 0 °C
With thionyl chloride, ammonia

Trunel; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 197; (1933); p. 454; An‐
nales de Chimie (Cachan, France); vol. <11>12; (1939); p. 114
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / 2 h / 20 °C / Inert atmosphere; Cooling with ice
2: ammonia; triethylamine / tetrahydrofuran / 5 h / 20 °C / Inert atmosphere
With oxalyl dichloride, ammonia, triethylamine in tetrahydrofuran, dichloromethane

Thuo, Martin M.; Reus, William F.; Simeone, Felice C.; Kim, Choongik; Schulz, Michael D.; Yoon, Hyo Jae;
Whitesides, George M.; Journal of the American Chemical Society; vol. 134; nb. 26; (2012); p. 10876 - 10884
View in Reaxys

With ammonium hydroxide, thionyl chloride

Leys, Jan; Tripathi, Chandra Shekhar Pati; Glorieux, Christ; Zahn, Stefan; Kirchner, Barbara; Longuemart,
Stephane; Lethesh, Kallidanthiyil Chellappan; Nockemann, Peter; Dehaen, Wim; Binnemans, Koen; Physical
Chemistry Chemical Physics; vol. 16; nb. 22; (2014); p. 10548 - 10557
View in Reaxys

O O

S S

N O N O
H H
HO O

O NH 2

Rx-ID: 2184236 View in Reaxys 178/636

Yield Conditions & References
84 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

O NH 2

O O
HO O

HN
2
O HN
2
O

Rx-ID: 3481595 View in Reaxys 179/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
With urea, Time= 3h, T= 200 °C , Yield given

Freudenreich, Charles; Samama, Jean-Pierre; Biellmann, Jean-Francois; Journal of the American Chemical So‐
ciety; vol. 106; nb. 11; (1984); p. 3344 - 3353
View in Reaxys

H
HO
N

O
O O

Rx-ID: 3923538 View in Reaxys 180/636

Yield Conditions & References
85 % With benzonitrile, iron(II) chloride, Time= 19h, T= 170 °C

Vorob'eva, E. M.; Litvyak, I. G.; Sumarokova, T. N.; Journal of general chemistry of the USSR; vol. 50; nb. 11;
(1980); p. 2043 - 2048; Zhurnal Obshchei Khimii; vol. 50; nb. 11; (1980); p. 2525 - 2531
View in Reaxys

O
O
S
O S
O
N
N

O
O
HN
2

Rx-ID: 9920884 View in Reaxys 181/636

Yield Conditions & References
77 % With ammonia in methanol, Time= 240h

Freitas, Jose M.; Abrantes, Luisa M.; Darbre, Tamis; Helvetica Chimica Acta; vol. 88; nb. 9; (2005); p. 2470 -
2478
View in Reaxys

O O

N Br N Br

O O O O

O NH 2

N N
H H
O O

Rx-ID: 11847358 View in Reaxys 182/636

Yield Conditions & References
Reaction Steps: 2
1.1: 631.8 mg / LiOH / tetrahydrofuran / 0.2 h / 20 °C
2.1: Rink amide resin after treatment with piperidine in DMF; DIC; HOBt / dimethylformamide / 24 h / 20 °C
2.2: 90 percent / CF3CO2H / CH2Cl2 / 1 h / 20 °C
With lithium hydroxide, Rink amide resin after treatment with piperidine in DMF, benzotriazol-1-ol, dacarbazine in
tetrahydrofuran, N,N-dimethyl-formamide

Sun, Li-Ping; Dai, Wei-Min; Angewandte Chemie - International Edition; vol. 45; nb. 43; (2006); p. 7255 - 7258
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 (+)-camphor-β-sulfonic acid

HO

NH 2

Rx-ID: 17794284 View in Reaxys 183/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2 / CH2Cl2 / 4 h / 25 °C
2: aq, NH4OH / 0.08 h / 0 °C
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Cravatt, Benjamin F.; Lerner, Richard A.; Boger, Dale L.; Journal of the American Chemical Society; vol. 118; nb.
3; (1996); p. 580 - 590
View in Reaxys

Si
O

HO

Si
O

HN
2

Rx-ID: 17818372 View in Reaxys 184/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2 / CH2Cl2 / 4 h / 25 °C
2: aq. NH4OH / 0.08 h / 0 °C
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Cravatt, Benjamin F.; Lerner, Richard A.; Boger, Dale L.; Journal of the American Chemical Society; vol. 118; nb.
3; (1996); p. 580 - 590
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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Si
O

Si
O

HN
2

Rx-ID: 17818757 View in Reaxys 185/636

Yield Conditions & References
Reaction Steps: 3
1: 89 percent / aq. LiOH / tetrahydrofuran; methanol / 8 h / 25 °C
2: (COCl)2 / CH2Cl2 / 4 h / 25 °C
3: aq. NH4OH / 0.08 h / 0 °C
With lithium hydroxide, ammonium hydroxide, oxalyl dichloride in tetrahydrofuran, methanol, dichloromethane

Cravatt, Benjamin F.; Lerner, Richard A.; Boger, Dale L.; Journal of the American Chemical Society; vol. 118; nb.
3; (1996); p. 580 - 590
View in Reaxys

O NH 2

O O
O O

HN
2
O HN
2
O

Rx-ID: 19250010 View in Reaxys 186/636

Yield Conditions & References
Reaction Steps: 2
1: 1 N NaOH / methanol / 4 h / Heating
2: urea / 3 h / 200 °C
With sodium hydroxide, urea in methanol

Freudenreich, Charles; Samama, Jean-Pierre; Biellmann, Jean-Francois; Journal of the American Chemical So‐
ciety; vol. 106; nb. 11; (1984); p. 3344 - 3353
View in Reaxys

O NH 2

OH O

Rx-ID: 19328656 View in Reaxys 187/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2, DMF / benzene / 1 h / Ambient temperature
2: NH3(l) / tetrahydrofuran / 0.5 h / -78 °C
With oxalyl dichloride, ammonia, N,N-dimethyl-formamide in tetrahydrofuran, benzene

Lease, Timothy G.; Shea; Journal of the American Chemical Society; vol. 115; nb. 6; (1993); p. 2248 - 2260
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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 OH O

O NH 2

Rx-ID: 19328727 View in Reaxys 188/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2, DMF / benzene / 1 h / Ambient temperature
2: NH3(l) / tetrahydrofuran / 0.5 h / -78 °C
With oxalyl dichloride, ammonia, N,N-dimethyl-formamide in tetrahydrofuran, benzene

Lease, Timothy G.; Shea; Journal of the American Chemical Society; vol. 115; nb. 6; (1993); p. 2248 - 2260
View in Reaxys

H
N
OH

NH 2

H
N
O

Rx-ID: 21953502 View in Reaxys 189/636

Yield Conditions & References
Reaction Steps: 2
1: dicyclohexylcarbodiimide / tetrahydrofuran / 1.) 0 deg C, 1 h, 2.) RT, overnight
2: 25percent aq. NH3 / 18 h
With ammonium hydroxide, dicyclohexyl-carbodiimide in tetrahydrofuran

Popovitz-Biro; Hill; Shavit; Hung; Lahav; Leiserowitz; Sagiv; Hsiung; Meredith; Vanherzeele; Journal of the
American Chemical Society; vol. 112; nb. 7; (1990); p. 2498 - 2506
View in Reaxys

HO

NH 2

Rx-ID: 22177479 View in Reaxys 190/636

Yield Conditions & References
Reaction Steps: 2
1: acetic acid anhydride / 150 °C
2: diethyl ether; ammonia
With diethyl ether, ammonia, acetic anhydride

Albitzki; Emeljanow; Zhurnal Russkago Fiziko-Khimicheskago Obshchestva; vol. 31; (1899); p. 106; Chemisches
Zentralblatt; vol. 70; nb. I; (1899); p. 1070
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

Reaction Steps: 2
1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 0 - 20 °C / Inert atmosphere
2: ammonium hydroxide / tetrahydrofuran / 12 h / 20 °C / Inert atmosphere
With ammonium hydroxide, oxalyl dichloride in tetrahydrofuran, dichloromethane, N,N-dimethyl-formamide

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Hu, Qu-Ping;Liu, Yu-Tao;Liu, Yong-Ze;Pan, Fei; Chemical Communications; vol. 58; nb. 14; (2022); p. 2295 -
2298
View in Reaxys

O
N N
O

O
O

O
N
NH 2

N N

Rx-ID: 22968409 View in Reaxys 191/636

Yield Conditions & References
22 : EXAMPLE 22 ;6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide
EXAMPLE 22 6-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanamide was produced by reaction
of 6-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester with ammonium chlor‐
ide according to general operating instructions 6. MS (EI): 414 (molecular ion peak)

With ammonium chloride

PatentSchering Aktiengesellschaft; BAYER AGBayer; US2003/229085; (2003); (A1) English

View in Reaxys

O O O NH
N N 2

O O
N N N N

Rx-ID: 22972705 View in Reaxys 192/636

Yield Conditions & References
27 : EXAMPLE 27 ;5-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide
EXAMPLE 27 5-[[1-(4-Methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanamide was produced by reac‐
tion of 5-[[1-(4-methylphenyl)-2-(3-pyridinyl)-1H-benzimidazol-6-yl]oxy]pentanoic acid methyl ester with ammonium
chloride according to general operating instructions 6. MS (E1): 400 (molecular ion peak) _

With ammonium chloride

PatentSchering Aktiengesellschaft; BAYER AGBayer; US2003/229085; (2003); (A1) English

View in Reaxys

O N
N

O
O N
N NH 2

HO

Rx-ID: 24663909 View in Reaxys 193/636

Yield Conditions & References
82 : 8-(1,4,5-Triphenylimidazol-2-yloxy)octanamide
EXAMPLE 82 8-(1,4,5-Triphenylimidazol-2-yloxy)octanamide 8-(1,4,5-Triphenylimidazol-2-yloxy)octanoic acid was
treated with thionyl chloride followed by ammonia to give the title compound, m.p. 152.5°-153.5° C., Found: C, 76.6;
H, 7.0; N, 9.1%: C29 H31 N3 O2 requires: C, 76.8; H, 6:9; N, 9.3%

With thionyl chloride, ammonia

PatentSmithKline Beecham Corporation; The Johns Hopkins University; THE JOHNS HOPKINS UNIVERSITY;
GLAXOSMITHKLINE PLCJohns Hopkins University; GlaxoSmithKline; US5648373; (1997); (A) English
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O HN 2

N N

HO O
N N

Rx-ID: 25208805 View in Reaxys 194/636

Yield Conditions & References
27 : EXAMPLE 27
EXAMPLE 27 A solution of 6.0 g of 3-(4-carboxybutyl)-N-(3-pyridyl)indole in 50 g of thionyl chloride is refluxed for 30
minutes, cooled and 50 ml of toluene is added. The solvents are evaporated and the residue is redissolved in 50 ml
of dry methylene chloride at 0°. Gaseous ammonia is bubbled through the solution for 30 minutes. Evaporation of
the solvent yields 3-(4-carbamoylbutyl)-N-(3-pyridyl)indole.

in thionyl chloride, dichloromethane, toluene

PatentCiba-Geigy Corporation; Novartis (w/o Sandoz); NOVARTIS AGNovartis (w/o Sandoz); Novartis;
US4536505; (1985); (A) English
View in Reaxys

HN
2

O O

NH O

H
N O
O

Rx-ID: 25347607 View in Reaxys 195/636

Yield Conditions & References
189 : EXAMPLE 189
EXAMPLE 189 To 2.6 g. of 8-(4'-ethoxycarbonyl)butoxycarbostyril was added 8 ml. of aqueous ammonia, and the
resulting mixture was stirred at room temperature for 1.5 hours to deposit crystals. The deposited crystals were re‐
covered by filtration and then recrystallized from methanol to obtain 2.1 g of 8-(4'-carbamoyl)butoxycarbostyril in the
form of colorless needle-like crystals, m.p. 178° - 180° C.

With ammonium hydroxide

PatentOtsuka Pharmaceutical Co., Ltd.; OTSUKA HOLDINGS CO LTDOtsuka Holdings; US4070470; (1978); (A)
English
View in Reaxys

O
O
H
N Na
H
HO NH 2

N H N
H
O
O

Rx-ID: 36832948 View in Reaxys 196/636

Yield Conditions & References
50 % With chloroformic acid ethyl ester, triethylamine in tetrahydrofuran, methanol, Time= 0.666667h, T= 0 - 20 °C

Cazares Marinero, Jose De Jesus; Lapierre, Marion; Cavailles, Vincent; Saint-Fort, Renette; Vessieres, Anne;
Top, Siden; Jaouen, Gerard; Dalton Transactions; vol. 42; nb. 43; (2013); p. 15489 - 15501
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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 F F
F F F F

O O

O S O S
HCl HCl

N OH N NH 2

H H H H
O O

H H H H
N N

Rx-ID: 40638111 View in Reaxys 197/636

Yield Conditions & References
44 % Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, N-ethyl-N,N-diiso‐
propylamine in dichloromethane, Time= 0.5h, T= 20 °C
Stage 2: With dmap, ammonia in dichloromethane, dimethyl sulfoxide, Time= 12h, T= 20 °C

Li, Yu-Huan; Wang, Sheng-Gang; Kong, Lan-Ying; Li, Ying-Hong; Cheng, Xin-Yue; Su, Feng; Tang, Sheng; Bi,
Chong-Wen; Jiang, Jian-Dong; Song, Dan-Qing; Bioorganic and Medicinal Chemistry Letters; vol. 25; nb. 17;
(2015); p. 3690 - 3693
View in Reaxys

HO O

O NH 2

Rx-ID: 60983044 View in Reaxys 198/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 2 h / 0 - 20 °C
2: ammonia / methanol; dichloromethane / 2 h / 0 - 20 °C
With oxalyl dichloride, ammonia in methanol, dichloromethane, N,N-dimethyl-formamide

Zhou, Jimei;Jia, Minxian;Song, Menghui;Huang, Zhiliang;Steiner, Alexander;An, Qidong;Ma, Jianwei;Guo,

Zhiyin;Zhang, Qianqian;Sun, Huaming;Robertson, Craig;Bacsa, John;Xiao, Jianliang;Li, Chaoqun; Ange‐
wandte Chemie - International Edition; vol. 61; nb. 30; (2022); Art.No: E202205983; Angew. Chem.; vol. 134; nb. 30;
(2022)
View in Reaxys

F F
F F

F F F

F F
O F F
F F
F O
O

HN
2

Rx-ID: 1045357 View in Reaxys 199/636

Yield Conditions & References
With ammonia in methanol, T= 125 °C

Brace,N.O.; Journal of Organic Chemistry; vol. 27; (1962); p. 4491 - 4498

View in Reaxys

O O
O O

S S

NH NH

HO O

O NH 2

Rx-ID: 3266629 View in Reaxys 200/636

Yield Conditions & References
70 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 H
HO
N

O
O O

Rx-ID: 3790143 View in Reaxys 201/636

Yield Conditions & References
80 % With benzonitrile, iron(II) chloride, Time= 20h, T= 170 °C

Vorob'eva, E. M.; Litvyak, I. G.; Sumarokova, T. N.; Journal of general chemistry of the USSR; vol. 50; nb. 11;
(1980); p. 2043 - 2048; Zhurnal Obshchei Khimii; vol. 50; nb. 11; (1980); p. 2525 - 2531
View in Reaxys

HN
2
O
O O

HO
HO OH
OH

Rx-ID: 5351371 View in Reaxys 202/636

Yield Conditions & References
With ammonia in methanol, Time= 120h, T= 20 °C , Substitution

Nakayama, Yuji; Kumar, G. Biju; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 65; nb. 3; (2000); p. 707 -
715
View in Reaxys

O
O
S
O S
O
N
N

O
O
HN
2

Rx-ID: 9916868 View in Reaxys 203/636

Yield Conditions & References
69 % With ammonia in methanol, Time= 240h

Freitas, Jose M.; Abrantes, Luisa M.; Darbre, Tamis; Helvetica Chimica Acta; vol. 88; nb. 9; (2005); p. 2470 -
2478
View in Reaxys

HO O O NH 2

HN
2
OH

N N

Rx-ID: 24978938 View in Reaxys 204/636

Yield Conditions & References
22 : (Compound Id-43)

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 EXAMPLE 22 (Compound Id-43) (E)-7-Phenyl-7-(3-pyridyl)-6-heptenoic acid (0.56 g, 2 mmoles) was dissolved in ox‐
alyl chloride (5 ml), and the solution was heated at 50° C. for an hour. After concentration under reduced pressure,
5% ammonia-methanol (5 ml) was added and the mixture was allowed to stand at room temperature for an hour. The
methanol was removed under reduced pressure and the residue was recrystallized from isopropyl ether to give
(E)-7-phenyl-7-(3-pyridyl)-6-heptenamide (0.48 g).

in oxalyl dichloride

PatentTakeda Chemical Industries, Ltd.; TAKEDA PHARMACEUTICAL COMPANY LIMITEDTakeda Pharma;

US4563446; (1986); (A) English
View in Reaxys

OH O
N
OH NH 4

O NH 2

Rx-ID: 25195043 View in Reaxys 205/636

Yield Conditions & References
11.75 g 59 : Preparation of 3-pyridinehexanamide
(83%) EXAMPLE 59 Preparation of 3-pyridinehexanamide A solution of 14.19 g of 3-pyridinehexanoic acid in 42 ml of thi‐
onyl chloride was stirred at room temperature over night. The reaction mixture was evaporated with two successive
50 ml portions of toluene and the residue was added dropwise to 400 ml of concentrated ammonium hydroxide
maintained between 0°-5° C. The resulting mixture was allowed to warm to room temperature over 4 hours, was dilu‐
ted with water, and was extracted with 3*150 ml of dichloromethane. The combined organic layers were dried over
potassium carbonate and concentrated to yield 11.75 g (83%) of 3-pyridinehexanamide, mp 64°-65° C.

in thionyl chloride

PatentHoffmann-La Roche Inc.; ROCHE HOLDING AG; SPARAMEDICARoche; &lt;unknown&gt;; US4551460;

(1985); (A) English
View in Reaxys

O O

OH O
OH NH 4

N N
H H

O NH 2

Rx-ID: 25400535 View in Reaxys 206/636

Yield Conditions & References
6.A : (A)
(A) 6-[(4-Methyl-2-methylene-1-oxopentyl)amino] hexanamide 6-[(4-Methyl-2-methylene-1-oxopentyl)amino]hexanoic
acid (2.8 g, see Example 4A) is cooled to 5° C. and thionyl chloride is added (5 ml). The reaction mixture is stirred at
35° C. for 3 hours, and concentrated in vacuo at room temperature to remove excess thionyl chloride. The pot resi‐
due is cooled to 5° C. and concentrated ammonium hydroxide (50 ml) is added and stirred for 1 hour. Product is
extracted with ethyl acetate and the ethyl acetate solution is dried over magnesium sulfate, filtered and concentrated
in vacuo. The resulting viscous oil slowly crystallizes, is washed with ether, and recrystallized from ethyl acetate to
yield 0.8 g of the title compound, melting point 76°-82° C.

With thionyl chloride

PatentE. R. Squibb & Sons, Inc.; BRISTOL-MYERS SQUIBB COBristol-Myers Squibb; US4235885; (1980); (A)
English
View in Reaxys

O O

NH HN

N O O N

O NH 2

O O

Rx-ID: 27967392 View in Reaxys 207/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
56 % With ammonium hydroxide, Time= 4h, T= 20 °C

Gasse, Cecile; Douguet, Dominique; Huteau, Valerie; Marchal, Gilles; Munier-Lehmann, Helene; Pochet, Syl‐
vie; Bioorganic and Medicinal Chemistry; vol. 16; nb. 11; (2008); p. 6075 - 6085
View in Reaxys

HO O

O NH 2

Rx-ID: 28151334 View in Reaxys 208/636

Yield Conditions & References
With Diethy phosphocyanidate, ammonia in 1,4-dioxane, N,N-dimethyl-formamide, Time= 4h, T= 20 °C

Georgiades, Savvas N.; Clardy, Jon; Bioorganic and Medicinal Chemistry Letters; vol. 18; nb. 10; (2008); p. 3117 -
3121
View in Reaxys

Reaction Steps: 2
1: thionyl chloride / 0.5 h / Reflux
2: ammonia / water / Cooling with ice
With thionyl chloride, ammonia in water

Louw, Stefan; Burger, Ben V.; Le Roux, Maritha; Van Wyk, Johannes H.; Journal of Natural Products; vol. 74;
nb. 6; (2011); p. 1364 - 1369
View in Reaxys

Na
H
O
N H

OH
N
H

0.5
H O
2

NH 2

N
H

Rx-ID: 36832945 View in Reaxys 209/636

Yield Conditions & References
40 % With chloroformic acid ethyl ester, triethylamine in tetrahydrofuran, methanol, Time= 0.666667h, T= 0 - 20 °C

Cazares Marinero, Jose De Jesus; Lapierre, Marion; Cavailles, Vincent; Saint-Fort, Renette; Vessieres, Anne;
Top, Siden; Jaouen, Gerard; Dalton Transactions; vol. 42; nb. 43; (2013); p. 15489 - 15501
View in Reaxys

O F
F
H H
N N
HO
F

O
Cl

Cl
O

F
O
N N
H H
F
F NH 2

Rx-ID: 48160987 View in Reaxys 210/636

Yield Conditions & References
30 % Stage 1: With 4-methyl-morpholine, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochlor‐
ide in N,N-dimethyl-formamide, Time= 0.5h, T= 20 °C , Inert atmosphere

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 102/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 18h, T= 20 °C , Inert atmosphere

Koolaji, Nooshin; Rawling, Tristan; Bourget, Kirsi; Murray, Michael; ChemMedChem; vol. 13; nb. 10; (2018); p.
1036 - 1043
View in Reaxys

O O

NH

HO HN
2

Rx-ID: 65381304 View in Reaxys 211/636

Yield Conditions & References
Reaction Steps: 3
1.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 1 h / 20 °C
1.2: 16 h / 20 °C
2.1: dichloromethane / 30 min / 20 °C
3.1: copper(I) bromide; (3aR,3a'R,8aS,8a'S)-2,2'-(cyclopentane-1,1-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxa‐
zole) / chlorobenzene / 12 h / 20 °C / Inert atmosphere; Sealed tube
With (3aR,3a'R,8aS,8a'S)-2,2'-(cyclopentane-1,1-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole), 1,1'-carbonyldii‐
midazole, copper(I) bromide in tetrahydrofuran, dichloromethane, chlorobenzene

Kim, Suhyeon;Song, Se Lin;Zhang, Jianbo;Kim, Dongwook;Hong, Sungwoo;Chang, Sukbok; Journal of the

American Chemical Society; vol. 145; nb. 29; (2023); p. 16238 - 16248
View in Reaxys

O O
O O

S S

NH NH

HO O

O NH 2

Rx-ID: 2135912 View in Reaxys 212/636

Yield Conditions & References
60 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

O O

HO O
N N
H H

O NH 2

O O

Rx-ID: 2193038 View in Reaxys 213/636

Yield Conditions & References
60 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 S O S O
HN HN

O O

O HN
2

HO O

Rx-ID: 3268625 View in Reaxys 214/636

Yield Conditions & References
60 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

O NH 2

O O
OH O

O O

Rx-ID: 14034734 View in Reaxys 215/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2; DMF / CH2Cl2
2: aq. NH3 / tetrahydrofuran
With ammonium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide in tetrahydrofuran, dichloromethane

Dai, Yujia; Guo, Yan; Curtin, Michael L.; Li, Junling; Pease, Lori J.; Guo, Jun; Marcotte, Patrick A.; Glaser,
Keith B.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb.
21; (2003); p. 3817 - 3820
View in Reaxys

Reaction Steps: 2
1: SOCl2 / 2 h / Heating
2: 0.086 g / NH3 / CH2Cl2 / -78 °C
With thionyl chloride, ammonia in dichloromethane

Bertolini, Thomas M.; Giorgione, Jennifer; Harvey, Daniel F.; Newton, Alexandra C.; Journal of Organic Chem‐
istry; vol. 68; nb. 13; (2003); p. 5028 - 5036
View in Reaxys

II

Stage 1: With oxalyl dichloride

Stage 2: With ammonium carbonate

PatentARIZONA BOARD OF REGENTS ON BEHALF OF THE UNIVERSITY OF ARIZONA; ARIZONA BOARD OF

REGENTSArizona Board of Regents; WO2021/87077; (2021); (A1) English
View in Reaxys

NH

HN

N O
O N

NH 2

Rx-ID: 27967386 View in Reaxys 216/636

Yield Conditions & References
50 % With ammonia in methanol

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Gasse, Cecile; Douguet, Dominique; Huteau, Valerie; Marchal, Gilles; Munier-Lehmann, Helene; Pochet, Syl‐
vie; Bioorganic and Medicinal Chemistry; vol. 16; nb. 11; (2008); p. 6075 - 6085
View in Reaxys

OH

NH 2

Rx-ID: 205516 View in Reaxys 217/636

Yield Conditions & References
With thionyl chloride, Behandeln des erhaltenen Saeurechlorids mit konz.wss.NH3 in Dioxan

Schmidt; Shirley; Journal of the American Chemical Society; vol. 71; (1949); p. 3806
View in Reaxys
Prout; Cason; Ingersoll; Journal of the American Chemical Society; vol. 70; (1948); p. 304
View in Reaxys

With phosphorus pentachloride, Behandeln des erhaltenen Saeurechlorids mit konz.wss.NH3 in Dioxan

Schmidt; Shirley; Journal of the American Chemical Society; vol. 71; (1949); p. 3806
View in Reaxys
Prout; Cason; Ingersoll; Journal of the American Chemical Society; vol. 70; (1948); p. 304
View in Reaxys

O O

HO O
N N
H H

O NH 2

Rx-ID: 3398013 View in Reaxys 218/636

Yield Conditions & References
51 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

O
O
S
S
O O N O
H NH 2
N O
H
O
O
O O
O

Rx-ID: 4966426 View in Reaxys 219/636

Yield Conditions & References
With ammonia in methanol, dichloromethane, Time= 0.25h, T= -40 °C

Weber, Ingo R.; Neidlein, Richard; Von Der Saal, Wolfgang; Grams, Frank; Leinert, Herbert; Strein, Klaus;
Engh, Richard A.; Kucznierz, Ralf; Bioorganic and Medicinal Chemistry Letters; vol. 8; nb. 13; (1998); p. 1613 -
1618
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O
S O
S
NH O
N O
O H

O O
O
O
O
O NH 2

Rx-ID: 4966637 View in Reaxys 220/636

Yield Conditions & References
With ammonia in methanol, dichloromethane, Time= 0.25h, T= -40 °C

Weber, Ingo R.; Neidlein, Richard; Von Der Saal, Wolfgang; Grams, Frank; Leinert, Herbert; Strein, Klaus;
Engh, Richard A.; Kucznierz, Ralf; Bioorganic and Medicinal Chemistry Letters; vol. 8; nb. 13; (1998); p. 1613 -
1618
View in Reaxys

O
O

O
O

O
O

O
HN
2

O O

Rx-ID: 5079106 View in Reaxys 221/636

Yield Conditions & References
42 mg With ammonium hydroxide in tetrahydrofuran, Time= 0.5h, T= 0 °C , amidation

Fujiwara, Hideyasu; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 54; nb. 3-4; (1998); p. 551 - 564
View in Reaxys

O
O

O
O

O
O

NH 2

Rx-ID: 5079455 View in Reaxys 222/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
15 mg With ammonium hydroxide in tetrahydrofuran, Time= 0.5h, T= 0 °C , amidation

Fujiwara, Hideyasu; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 54; nb. 3-4; (1998); p. 551 - 564
View in Reaxys

O O
O

O O
O

O
O

O
O

NH 2

Rx-ID: 5079464 View in Reaxys 223/636

Yield Conditions & References
49 mg With ammonium hydroxide in tetrahydrofuran, Time= 0.5h, T= 0 °C , amidation

Fujiwara, Hideyasu; Egawa, Sadahiro; Terao, Yoshihiro; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron;
vol. 54; nb. 3-4; (1998); p. 565 - 572
View in Reaxys

O
O O

O O
O

O
O

O O O
HN
2

Rx-ID: 5079484 View in Reaxys 224/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
11 mg With ammonium hydroxide in tetrahydrofuran, Time= 0.5h, T= 0 °C , amidation

Fujiwara, Hideyasu; Egawa, Sadahiro; Terao, Yoshihiro; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron;
vol. 54; nb. 3-4; (1998); p. 565 - 572
View in Reaxys

O
O

O
O

HN
2

Rx-ID: 5079485 View in Reaxys 225/636

Yield Conditions & References
59 mg With ammonium hydroxide in tetrahydrofuran, Time= 0.5h, T= 0 °C , amidation

Fujiwara, Hideyasu; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 54; nb. 3-4; (1998); p. 551 - 564
View in Reaxys

O
O
N HN
2

H
N O
N
O H
O
O
O
O

Rx-ID: 9013861 View in Reaxys 226/636

Yield Conditions & References
3.5 g With ammonia in isopropyl alcohol, T= 0 - 20 °C

Song, Yongsheng; Goel, Atul; Basrur, Venkatesha; Roberts, Paula E.A; Mikovits, Judy A; Inman, John K; Tur‐
pin, Jim A; Rice, William G; Appella, Ettore; Bioorganic and Medicinal Chemistry; vol. 10; nb. 5; (2002); p. 1263 -
1273
View in Reaxys

O O

H H
O O N N O N N

O NH 2

Rx-ID: 9218329 View in Reaxys 227/636

Yield Conditions & References
With ammonia in methanol, dichloromethane, Time= 72h, T= 90 °C

Perron-Sierra, Francoise; Saint Dizier, Dominique; Bertrand, Marc; Genton, Annie; Tucker, Gordon C; Ca‐
sara, Patrick; Bioorganic and medicinal chemistry letters; vol. 12; nb. 22; (2002); p. 3291 - 3296
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O NH 2

HO O
O O

HN HN

H H
N N

O O

Rx-ID: 10177384 View in Reaxys 228/636

Yield Conditions & References
52 % With diphenylphosphoranyl azide, ammonium chloride, triethylamine in N,N-dimethyl-formamide, Time= 72h, cooling

Salzameda, Nicholas T.; Lightner, David A.; Monatshefte fur Chemie; vol. 137; nb. 3; (2006); p. 319 - 337
View in Reaxys

OH
NH 2

H O O

Rx-ID: 22177408 View in Reaxys 229/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl chloride; benzene / Umsetzen des erhaltenes Saeurechlorids mit konz.wss.NH3
With oxalyl dichloride, benzene

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 26 A; nb. 12; (1949); p. 22

View in Reaxys

Reaction Steps: 2
2: PCl5 / Behandeln des erhaltenen Saeurechlorids mit konz.wss.NH3 in Dioxan
With phosphorus pentachloride

Prout; Cason; Ingersoll; Journal of the American Chemical Society; vol. 70; (1948); p. 304
View in Reaxys

NH 2

Rx-ID: 22177602 View in Reaxys 230/636

Yield Conditions & References
Reaction Steps: 2
1: aqueous alcoholic NaOH
2: PCl5 / Behandeln des erhaltenen Saeurechlorids mit konz.wss.NH3 in Dioxan
With sodium hydroxide, phosphorus pentachloride

Schmidt; Shirley; Journal of the American Chemical Society; vol. 71; (1949); p. 3806
View in Reaxys

Reaction Steps: 2
1: alcoholic KOH
2: PCl5 / Behandeln des erhaltenen Saeurechlorids mit konz.wss.NH3 in Dioxan
With potassium hydroxide, phosphorus pentachloride

Prout; Cason; Ingersoll; Journal of the American Chemical Society; vol. 70; (1948); p. 304
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O
NH 2

H
O O

Rx-ID: 22177603 View in Reaxys 231/636

Yield Conditions & References
Reaction Steps: 3
1: aqueous alcoholic KOH
2: oxalyl chloride; benzene / Umsetzen des erhaltenes Saeurechlorids mit konz.wss.NH3
With potassium hydroxide, oxalyl dichloride, benzene

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 26 A; nb. 12; (1949); p. 22

View in Reaxys

Reaction Steps: 3
1: alcoholic KOH
3: PCl5 / Behandeln des erhaltenen Saeurechlorids mit konz.wss.NH3 in Dioxan
With potassium hydroxide, phosphorus pentachloride

Prout; Cason; Ingersoll; Journal of the American Chemical Society; vol. 70; (1948); p. 304
View in Reaxys

O O

O O
O O

O O
O O O O O O
O O
O O
O O
O OH O NH 2

HN HN

O O O O
O O

Rx-ID: 37315792 View in Reaxys 232/636

Yield Conditions & References
8% Stage 1: With N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methyl‐
ene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 14h, T= 20 °C
Stage 2: With triisopropylsilane, trifluoroacetic acid in water, N,N-dimethyl-formamide, Time= 1h

Waldmann, Moritz; Jirmann, Raffael; Hoelscher, Ken; Wienke, Martin; Niemeyer, Felix C.; Rehders, Dirk; Mey‐
er, Bernd; Journal of the American Chemical Society; vol. 136; nb. 2; (2014); p. 783 - 788
View in Reaxys

HO HN
2
O

O NH 2

NH 2

Rx-ID: 736036 View in Reaxys 233/636

Yield Conditions & References
T= 160 °C

MacGregor; Ward; Journal of the Society of Chemical Industry; vol. 66; (1947); p. 345
View in Reaxys

With diammonium phosphate, T= 195 °C

PatentGarbo; Garbo; US2606915; (1947); (A)

View in Reaxys

T= 160 °C

Patentdu Pont de Nemours & Co.; DUPONT DE NEMOURS INCDuPont; US2109941; (1936); (A)

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

T= 205 - 210 °C

PatentResinous Prod. & Chem.Co.; RESINOUS PROD CHEMICAL&lt;unknown&gt;; US1989968; (1934); (A)
View in Reaxys
PatentResinous Prod. & Chem.Co.; RESINOUS PROD CHEMICAL&lt;unknown&gt;; DE641865; (1933); (C);
Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 21; p. 1291; Fortschr. Teerfarbenfabr. Verw. Industriezweige;
vol. 21; p. 1291
View in Reaxys

HN
O 2

O
O

H
H
HN
HN

O S
O S

HN
HN
H
H

Rx-ID: 820801 View in Reaxys 234/636

Yield Conditions & References
With ammonium hydroxide

Wolf et al.; Journal of the American Chemical Society; vol. 73; (1951); p. 4142
View in Reaxys
PatentMerck & Co. Inc.; MERCK & CO INCMerck & Co; US2538139; (1947); (A)
View in Reaxys

NH 2

Rx-ID: 2835481 View in Reaxys 235/636

Yield Conditions & References
86 % in methanol, water

Mayer, Joachim M.; Testa, Bernard; Helvetica Chimica Acta; vol. 65; nb. 6; (1982); p. 1868 - 1884
View in Reaxys

O O

O NH 2

Rx-ID: 2835543 View in Reaxys 236/636

Yield Conditions & References
87 % in methanol, water

Mayer, Joachim M.; Testa, Bernard; Helvetica Chimica Acta; vol. 65; nb. 6; (1982); p. 1868 - 1884
View in Reaxys

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 O O
O O

S S

NH NH

O O
HO O
N N

O O NH 2
O

Rx-ID: 3271528 View in Reaxys 237/636

Yield Conditions & References
40 % With urea, Time= 4h, T= 180 - 200 °C

Pavlidis, V. H.; Chan, E. D.; Pennington, L.; McParland, M.; Whitehead, M.; Synthetic Communications; vol. 18;
nb. 4; (1988); p. 1615 - 1624
View in Reaxys

H OH

NH 2

HO

OH

Rx-ID: 10114280 View in Reaxys 238/636

Yield Conditions & References
With Candida antarctica lipase B, ammonium carbamate in tert-Amyl alcohol, Time= 24h, T= 55 °C

Levinson, William E.; Kuo, Tsung Min; Weisleder, David; Journal of the American Oil Chemists' Society; vol. 82;
nb. 7; (2005); p. 501 - 504
View in Reaxys

O NH 2

OH O

HO HO

Rx-ID: 10117573 View in Reaxys 239/636

Yield Conditions & References
With Candida antarctica lipase B, ammonium carbamate in tert-Amyl alcohol, Time= 24h, T= 55 °C

Levinson, William E.; Kuo, Tsung Min; Weisleder, David; Journal of the American Oil Chemists' Society; vol. 82;
nb. 7; (2005); p. 501 - 504
View in Reaxys

O NH 2

HO O O O

Rx-ID: 18581684 View in Reaxys 240/636

Yield Conditions & References
Reaction Steps: 2
1: CH3SO2Cl / pyridine / 0.25 h / 0 °C
2: NH3 gas / pyridine / 1 h / 0 - 25 °C
With ammonia, methanesulfonyl chloride in pyridine

Gapinski, D. Mark; Roman, Carlos R.; Rinkema, Lynn E.; Fleisch, Jerome H.; Journal of Medicinal Chemistry;
vol. 31; nb. 1; (1988); p. 172 - 175

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

HO O
O O

O NH 2

Rx-ID: 18587869 View in Reaxys 241/636

Yield Conditions & References
Reaction Steps: 2
1: CH3SO2Cl / pyridine / 0.25 h / 0 °C
2: NH3 gas / pyridine / 1 h / 0 - 25 °C
With ammonia, methanesulfonyl chloride in pyridine

Gapinski, D. Mark; Roman, Carlos R.; Rinkema, Lynn E.; Fleisch, Jerome H.; Journal of Medicinal Chemistry;
vol. 31; nb. 1; (1988); p. 172 - 175
View in Reaxys

HO O

O NH 2

O O

O O

Rx-ID: 18836016 View in Reaxys 242/636

Yield Conditions & References
Reaction Steps: 2
1: dicyclohexyl carbodiimide / tetrahydrofuran
2: 82 percent / NH3 (gas) / CH2Cl2 / 2 h / 20 °C
With ammonia, dicyclohexyl-carbodiimide in tetrahydrofuran, dichloromethane

Kohle; Krohn; Leclercq; Journal of Medicinal Chemistry; vol. 32; nb. 7; (1989); p. 1538 - 1547
View in Reaxys

OH OH

O O

OH O
O O

O NH 2

Rx-ID: 20361917 View in Reaxys 243/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl chloride, DMF / CH2Cl2 / 3.5 h
2: 9.2 percent / NH3(g) / CH2Cl2 / 15 h / Ambient temperature
With oxalyl dichloride, ammonia, N,N-dimethyl-formamide in dichloromethane

Herron, David K.; Goodson, Theodore; Bollinger, Nancy G.; Swanson-Bean, Dorothy; Wright, Ian G.; et al.;
Journal of Medicinal Chemistry; vol. 35; nb. 10; (1992); p. 1818 - 1828
View in Reaxys

N
O
N
N

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O

N
HN
2

N
N

Rx-ID: 20366697 View in Reaxys 244/636

Yield Conditions & References
Reaction Steps: 3
1: 40 percent / 1.) 5 N aq. NaOH, 2.) conc. aq. HCl / H2O; methanol / 1.) reflux, 3 h
2: thionyl chloride / Ambient temperature
3: NH4OH
With hydrogenchloride, ammonium hydroxide, sodium hydroxide, thionyl chloride in methanol, water

Harper, Richard W.; Herron, David K.; Bollinger, Nancy G.; Sawyer, J. Scott; Baldwin, Ronald F.; et al.; Journal
of Medicinal Chemistry; vol. 35; nb. 7; (1992); p. 1191 - 1200
View in Reaxys

N N

N N

O HN
2

HO O

Rx-ID: 20970863 View in Reaxys 245/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl chloride, DMF / tetrahydrofuran / 1 h / 0 - 20 °C
2: conc. aq. NH4OH / tetrahydrofuran / 0.33 h
With ammonium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide in tetrahydrofuran

Meanwell, Nicholas A.; Rosenfeld, Michael J.; Wright, J. J. Kim; Brassard, Catherine L.; Buchanan, John O.;
et al.; Journal of Medicinal Chemistry; vol. 35; nb. 2; (1992); p. 389 - 397
View in Reaxys

N N

N N

O HN
2

O O

Rx-ID: 20971483 View in Reaxys 246/636

Yield Conditions & References
Reaction Steps: 3
1: 85 percent / 5 N aq. NaOH / methanol / 0.5 h / Heating
2: oxalyl chloride, DMF / tetrahydrofuran / 1 h / 0 - 20 °C
3: conc. aq. NH4OH / tetrahydrofuran / 0.33 h
With ammonium hydroxide, sodium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide in tetrahydrofuran, metha‐
nol

Meanwell, Nicholas A.; Rosenfeld, Michael J.; Wright, J. J. Kim; Brassard, Catherine L.; Buchanan, John O.;
et al.; Journal of Medicinal Chemistry; vol. 35; nb. 2; (1992); p. 389 - 397
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O NH O
2

O O

O O

Rx-ID: 22657661 View in Reaxys 247/636

Yield Conditions & References
Reaction Steps: 2
1: aq. NaOH / methanol / Heating
2: (i) SOCl2, (ii) aq. NH3, dioxane
With sodium hydroxide in methanol

Kulp,S.S.; Iobst,S.A.; Journal of Medicinal Chemistry; vol. 7; (1964); p. 831

View in Reaxys

H NH H NH
O NH
2 2

HO HO

OH O
O O

Rx-ID: 22772602 View in Reaxys 248/636

Yield Conditions & References
Reaction Steps: 3
1: HCl
2: N2H4*H2O / ethanol
3: Raney-Ni / ethanol / Heating
With hydrogenchloride, hydrazine hydrate, nickel in ethanol

Kimura; Murata; Chemical and pharmaceutical bulletin; vol. 19; nb. 7; (1971); p. 1301 - 1307
View in Reaxys

O
H NH
NH
2

O HO
OH
O
O NH 2
O

Rx-ID: 22773754 View in Reaxys 249/636

Yield Conditions & References
Reaction Steps: 2
1: N2H4*H2O / ethanol
2: Raney-Ni / ethanol / Heating
With hydrazine hydrate, nickel in ethanol

Kimura; Murata; Chemical and pharmaceutical bulletin; vol. 19; nb. 7; (1971); p. 1301 - 1307
View in Reaxys

HO

NH 2

Rx-ID: 33443415 View in Reaxys 250/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / Inert atmosphere
2: ammonium hydroxide
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Divito, Erin B.; Davic, Andrew P.; Johnson, Mitchell E.; Cascio, Michael; Analytical Chemistry; vol. 84; nb. 5;
(2012); p. 2388 - 2394
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O
NH 2
NH 2

O NH 2

Rx-ID: 237638 View in Reaxys 251/636

Yield Conditions & References
With ammonia, water

Marvel et al.; Journal of the American Chemical Society; vol. 68; (1946); p. 1683
View in Reaxys

O NH 2

H H
O N O N
OH O

O O

Rx-ID: 249094 View in Reaxys 252/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit NH3 in Aether

McKay et al.; Journal of the American Chemical Society; vol. 81; (1959); p. 4328,4330,4333
View in Reaxys

O NH 2

H H H H
N N N N
O O

O O

Rx-ID: 252634 View in Reaxys 253/636

Yield Conditions & References
With ammonia, water

Schultz; Journal of the American Chemical Society; vol. 69; (1947); p. 1057
View in Reaxys

HO O O NH 2

Rx-ID: 291619 View in Reaxys 254/636

Yield Conditions & References
With ligroine, phosphorus trichloride, anschliessend Umsetzung mit konz. Ammoniak

Noller; Adams; Journal of the American Chemical Society; vol. 48; (1926); p. 1087
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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 HO O O NH 2

Rx-ID: 293789 View in Reaxys 255/636

Yield Conditions & References
With ligroine, phosphorus trichloride, Umsetzung mit konz. Ammoniak

Noller; Adams; Journal of the American Chemical Society; vol. 48; (1926); p. 1087
View in Reaxys

O NH 2

N N
OH O

Rx-ID: 300338 View in Reaxys 256/636

Yield Conditions & References
With thionyl chloride, Behandeln des Reaktionsprodukts mit konz. wss. NH3

Brody; Bogert; Journal of the American Chemical Society; vol. 65; (1943); p. 1075,1078
View in Reaxys

HO O

O NH 2

Rx-ID: 320057 View in Reaxys 257/636

Yield Conditions & References
With thionyl chloride, Behandeln des Reaktionsprodukts mit wss. NH3

Fieser et al.; Journal of the American Chemical Society; vol. 78; (1956); p. 2825,2830
View in Reaxys

HO O

O NH 2

Rx-ID: 441596 View in Reaxys 258/636

Yield Conditions & References
With phosphorus trichloride, Eintragen des erhaltenen Saeurechlorids in wss. Ammoniak

Hinegardner; Journal of the American Chemical Society; vol. 55; (1933); p. 2831,2833
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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 H H
HO N O O N O

O NH 2

Rx-ID: 2131664 View in Reaxys 259/636

Yield Conditions & References
With ammonia, chloroformic acid ethyl ester, triethylamine, 1.) THF, 20 deg C, 12 h; 2.) THF, 0.5 h, Multistep reac‐
tion

Freudenreich, Charles; Samama, Jean-Pierre; Biellmann, Jean-Francois; Journal of the American Chemical So‐
ciety; vol. 106; nb. 11; (1984); p. 3344 - 3353
View in Reaxys

O
N

O
O
O

N
H

NH 2

H
N
O

Rx-ID: 2239911 View in Reaxys 260/636

Yield Conditions & References
With ammonium hydroxide, Time= 18h

Popovitz-Biro; Hill; Shavit; Hung; Lahav; Leiserowitz; Sagiv; Hsiung; Meredith; Vanherzeele; Journal of the
American Chemical Society; vol. 112; nb. 7; (1990); p. 2498 - 2506
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 2456016 View in Reaxys 261/636

Yield Conditions & References
16.8 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.
Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 2456670 View in Reaxys 262/636

Yield Conditions & References
10.0 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.
Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 2457326 View in Reaxys 263/636

Yield Conditions & References
6.0 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 2457684 View in Reaxys 264/636

Yield Conditions & References
15.2 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.
Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 2458643 View in Reaxys 265/636

Yield Conditions & References
13.0 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.
Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 2459448 View in Reaxys 266/636

Yield Conditions & References
29.0 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.
Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

H H
O N NH 2
HN
2
N O

O NH NH NH 2

Rx-ID: 3476040 View in Reaxys 267/636

Yield Conditions & References
With ammonia, sodium methylate, Yield given

Freudenreich, Charles; Samama, Jean-Pierre; Biellmann, Jean-Francois; Journal of the American Chemical So‐
ciety; vol. 106; nb. 11; (1984); p. 3344 - 3353
View in Reaxys

O NH 2

N N
O O

Rx-ID: 3575391 View in Reaxys 268/636

Yield Conditions & References
78 % in methanol, water

Mayer, Joachim M.; Testa, Bernard; Helvetica Chimica Acta; vol. 65; nb. 6; (1982); p. 1868 - 1884

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

HN
2

O
O
O

HN N
HN N
2
N
2
N
O
O
HN
HN S
S

O
O

Rx-ID: 4193275 View in Reaxys 269/636

Yield Conditions & References
29 % With ammonium hydroxide in methanol, Time= 48h, Ambient temperature

Lewis; Revankar; Fennewald; Huffman; Rando; Journal of Heterocyclic Chemistry; vol. 32; nb. 2; (1995); p. 547 -
556
View in Reaxys

O
O

NH
H
2

N N
O O

O O HN
HN
HN O

O O

O
N

Rx-ID: 8729338 View in Reaxys 270/636

Yield Conditions & References
With ammonia in N,N-dimethyl-formamide, Time= 2h, T= 20 °C , ammonolysis

Wang, Xuebao; Thottathil, John; Tetrahedron Asymmetry; vol. 11; nb. 18; (2000); p. 3665 - 3669
View in Reaxys

O NH 2

HO O
O O

HN HN

H H
N N

Rx-ID: 10176967 View in Reaxys 271/636

Yield Conditions & References
32 % With diphenylphosphoranyl azide, ammonium chloride, triethylamine in N,N-dimethyl-formamide, Time= 72h, cooling

Salzameda, Nicholas T.; Lightner, David A.; Monatshefte fur Chemie; vol. 137; nb. 3; (2006); p. 319 - 337
View in Reaxys

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 HO O

O NH 2

Rx-ID: 17794283 View in Reaxys 272/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2
2: aq. NH4OH
With ammonium hydroxide, oxalyl dichloride

Cravatt, Benjamin F.; Lerner, Richard A.; Boger, Dale L.; Journal of the American Chemical Society; vol. 118; nb.
3; (1996); p. 580 - 590
View in Reaxys

O O

O NH 2

Rx-ID: 17796092 View in Reaxys 273/636

Yield Conditions & References
Reaction Steps: 3
1: 67 percent / aq. LiOH
2: (COCl)2
3: aq. NH4OH
With lithium hydroxide, ammonium hydroxide, oxalyl dichloride

Cravatt, Benjamin F.; Lerner, Richard A.; Boger, Dale L.; Journal of the American Chemical Society; vol. 118; nb.
3; (1996); p. 580 - 590
View in Reaxys

HO O O O

OH
O
O

HO

HO O O O

OH
O
NH 2

HO

Rx-ID: 21725818 View in Reaxys 274/636

Yield Conditions & References
Reaction Steps: 2

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 1: 57 percent / triphenylphosphine, morphiline / tetrakis(triphenylphosphine)-palladium(0) / CH2Cl2 / 5 h / 22 °C
2: 1) N,N'-carbonyldiimidazole, 2) gaseous ammonia / 1) CH2Cl2, 3 h, 2) 0 deg C, 10 min
With morpholine, ammonia, triphenylphosphine, 1,1'-carbonyldiimidazole, tetrakis(triphenylphosphine) palladium(0)
in dichloromethane

Jansen, Rolf; Schummer, Dietmar; Irschik, Herbert; Hoefle, Gerhard; Liebigs Annalen der Chemie; nb. 10;
(1990); p. 975 - 988
View in Reaxys

O
OH

NH 2

O
O

Rx-ID: 22160132 View in Reaxys 275/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride
2: benzene; ammonia
With thionyl chloride, ammonia, benzene

McKay et al.; Journal of the American Chemical Society; vol. 80; (1958); p. 1510,1512,1515
View in Reaxys

HO O

N N
O NH 2

Rx-ID: 22180840 View in Reaxys 276/636

Yield Conditions & References
Reaction Steps: 2
1: benzene; thionyl chloride
2: water; ammonia
With thionyl chloride, ammonia, water, benzene

Rapoport; Baldridge; Journal of the American Chemical Society; vol. 73; (1951); p. 343,345
View in Reaxys

O O NH 2

OH
O

O
OH

O O O

Rx-ID: 22305013 View in Reaxys 277/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: acetone; thionyl chloride; aqueous ammonia
With potassium hydroxide, ammonium hydroxide, thionyl chloride, acetone

Fieser et al.; Journal of the American Chemical Society; vol. 70; (1948); p. 3203
View in Reaxys

HO O
NH 2
NH 2

O NH 2

Rx-ID: 22358177 View in Reaxys 278/636

Yield Conditions & References
Reaction Steps: 2
1: HCl

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 2: water; NH3
With hydrogenchloride, ammonia, water

Marvel et al.; Journal of the American Chemical Society; vol. 68; (1946); p. 1683
View in Reaxys

N N

HO O O NH 2

Rx-ID: 25209258 View in Reaxys 279/636

Yield Conditions & References
64 : Preparation of 4-pyridinevaleramide
EXAMPLE 64 Preparation of 4-pyridinevaleramide 4-Pyridinevaleramide was prepared using the procedures em‐
ployed for 3-pyridinevaleramide. From 9.30 g of 4-pyridinevaleric acid there was obtained 5.3 g (69%), mp 123°-125°
C. The analytical sample was obtained from tetrahydrofuran-hexane, mp 126°-127° C.

PatentHoffmann-La Roche Inc.; ROCHE HOLDING AG; SPARAMEDICARoche; &lt;unknown&gt;; US4551460;

(1985); (A) English
View in Reaxys

HO O O NH 2

N N
SH SH
N N

N N N N

Rx-ID: 25411658 View in Reaxys 280/636

Yield Conditions & References
20 : 7-D-Mandelamido-3-[1-(10-carbamoyldecyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid
EXAMPLE 20 7-D-Mandelamido-3-[1-(10-carbamoyldecyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid 1-(10-
Carbamoyldecyl)tetrazole-5-thiol was prepared from 1-(10-carboxydecyl)tetrazole-5-thiol by the procedure described
in Example 5, m.p. 112°-114°.

PatentSmithKline Corporation; GLAXOSMITHKLINE PLCGlaxoSmithKline; US4220644; (1980); (A) English

View in Reaxys

OH
O

OH
H

HO H

O NH 2

O
O

Rx-ID: 25685067 View in Reaxys 281/636

Yield Conditions & References
3 :Synthesis of compounds. All compounds were synthesized from various intermediates 2a-cprepared using our
published procedure (Singer et al., 1998) and as shown in Schemes 2-7 ofFigures 1-6, starting with the commercially
available 5-cyano-dimethoxyresorcinol 1(Scheme 1, Figure 1). Compounds listed in Table la-c were synthesized
from the acid 7using standard procedures for the preparation of amides. The reverse amides (O-2589, O-2590,

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 O-2619 and O-2620) were synthesized from 5 by conversion to the amine via theazide, followed by condensation
with the appropriate acids using either the acid chloride orthe carbodiimide (EDCI/DMAP) procedures. All the N-alky‐
lated compounds listed in Table2a-c were synthesized from 5 by protection of the phenol as the TBDMS derivative,
whichwas treated with the appropriate amine in the presence of NaH/DMF, to give the targetcompounds. The C-alky‐
lated imidazole derivative (O-2737) was synthesized from 7 byconversion of the acid group to the aldehyde, followed
by condensation with glyoxal/NH3 toform the 2-imidazole derivative (Dhanak et al., 2001). The phenolic esters listed
in Table3a-c were synthesized from 6 using a published procedure (Razdan et al., 1976). The variousacids used in
their preparation were prepared according to literature procedures (Blicke et al.,1941; Cruickshank and Sheehan,
1961; Razdan et al., 1976). The quarternary compoundswere synthesized by the treatment of the amines with CH3I
in ether. The compound listed inTable 4 was synthesized from the amide O-2372 (see Table la) and diisopropylami‐
nobutyricacid.HCl using the EDCI/DMAP procedure and the free base thus obtained was converted toits hydrochlor‐
ide. All compounds showed appropriate .H NMR profiles (Jeol Eclipse 300MHZ; Jeol USA, Inc., Peabody, MA) and
were characterized on the basis of their .H NMRprofiles, TLC, and elemental analyses. Detailed synthesis Schemes
1-6 for the compoundsare given in Figures 1-6, respectively.

PatentVIRGINIA COMMONWEALTH UNIVERSITY; ORGANIX INC.; VIRGINIA COMMONWEALTH UNIVERSI‐

TY&lt;unknown&gt;; Virginia Commonwealth University; WO2006/12176; (2006); (A1) English
View in Reaxys

O O

O O
N O O N O

O O NH 2

Rx-ID: 46582030 View in Reaxys 282/636

Yield Conditions & References
With ammonium hydroxide in tetrahydrofuran, water, T= 0 - 20 °C

Chen, Dian-Feng; Chu, John C. K.; Rovis, Tomislav; Journal of the American Chemical Society; vol. 139; nb. 42;
(2017); p. 14897 - 14900
View in Reaxys

O O O

O O NH 2

Rx-ID: 46582039 View in Reaxys 283/636

Yield Conditions & References
With ammonium hydroxide in tetrahydrofuran, water, T= 0 - 20 °C

Chen, Dian-Feng; Chu, John C. K.; Rovis, Tomislav; Journal of the American Chemical Society; vol. 139; nb. 42;
(2017); p. 14897 - 14900
View in Reaxys

O O

N N

H O H O

O O

H H
H OH H NH 2

O O

O O

Rx-ID: 48321923 View in Reaxys 284/636

Yield Conditions & References
Stage 1: With N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methyl‐
ene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 0.25h, T= 20 °C , Inert at‐
mosphere
Stage 2: With ammonium chloride in N,N-dimethyl-formamide, Time= 2h, T= 20 °C , Inert atmosphere

Soethoudt, Marjolein; Stolze, Sara C.; Westphal, Matthias V.; Van Stralen, Luuk; Martella, Andrea; Van Roo‐
den, Eva J.; Guba, Wolfgang; Varga, Zoltan V.; Deng, Hui; Van Kasteren, Sander I.; Grether, Uwe; Ijzerman,

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Adriaan P.; Pacher, Pal; Carreira, Erick M.; Overkleeft, Herman S.; Ioan-Facsinay, Andreea; Heitman, Laura
H.; Van Der Stelt, Mario; Journal of the American Chemical Society; vol. 140; nb. 19; (2018); p. 6067 - 6075
View in Reaxys

O O

OH HN
2

OH OH

Rx-ID: 50292233 View in Reaxys 285/636

Yield Conditions & References
0.204 Stage 1: With benzotriazol-1-ol, dicyclohexyl-carbodiimide in dichloromethane, Time= 1.5h, T= 0 °C , Inert atmos‐
mmol phere
Stage 2: With ammonium hydroxide in dichloromethane, water, Time= 2h, T= 0 - 20 °C , Inert atmosphere

Li, Jing; Preinfalk, Alexander; Maulide, Nuno; Journal of the American Chemical Society; vol. 141; nb. 1; (2019);
p. 143 - 147
View in Reaxys

O O
O
O HN
2

N
H O
O N
O H
O

Rx-ID: 55503250 View in Reaxys 286/636

Yield Conditions & References
8.02 g With ammonia in tetrahydrofuran, Time= 0.5h, T= 20 °C

Bonnel, Clément; Legrand, Baptiste; Simon, Matthieu; Clavié, Margaux; Masnou, Agnès; Jumas-Bilak, Es‐
telle; Kang, Young Kee; Licznar-Fajardo, Patricia; Maillard, Ludovic T.; Masurier, Nicolas; Journal of Medicinal
Chemistry; vol. 63; nb. 17; (2020); p. 9168 - 9180
View in Reaxys

O O

O NH 2

Rx-ID: 1023679 View in Reaxys 287/636

Yield Conditions & References
With lithium amide in ammonia

Work,S.D.; Hauser,C.R.; Journal of Organic Chemistry; vol. 28; (1963); p. 725 - 730
View in Reaxys

O OH O OH

O NH 2

Rx-ID: 1057775 View in Reaxys 288/636

Yield Conditions & References
With ammonium hydroxide, Time= 192h, T= 25 °C

Mettalia,J.B.; Specht,E.H.; Journal of Organic Chemistry; vol. 32; (1967); p. 3941 - 3947
View in Reaxys

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 O O

H O
2

O N H
15

H 2
N

O O
O 2

O O
N
N O H

Rx-ID: 3006774 View in Reaxys 289/636

Yield Conditions & References
0.13 g With (15N)-ammonium chloride, triethylamine in N,N-dimethyl-formamide, Time= 19h

Manesis, Nick J.; Goodman, Murray; Journal of Organic Chemistry; vol. 52; nb. 24; (1987); p. 5342 - 5349
View in Reaxys

O
O

15

N H N
O
2

O O O

O O O
2

NH H
NH
2

H
O
O O
O

Rx-ID: 3010405 View in Reaxys 290/636

Yield Conditions & References
With (15N)-ammonium chloride, triethylamine in N,N-dimethyl-formamide, Time= 24h, Yield given

Manesis, Nick J.; Goodman, Murray; Journal of Organic Chemistry; vol. 52; nb. 24; (1987); p. 5342 - 5349
View in Reaxys

OH

OH

NH 2

OH

Rx-ID: 4721917 View in Reaxys 291/636

Yield Conditions & References
24 % With ammonium sulfate, disodium hydrogenphosphate, potassium dihydrogenphosphate, Bacillus cereus, iron(II)
sulfate, calcium chloride, yeast extract, Time= 120h, T= 30 °C

Huang; Keudell; Klopfenstein; Wen; Bagby; Vesonder; Norton; Weisleder; Journal of the American Oil Chem‐
ists' Society; vol. 74; nb. 5; (1997); p. 601 - 603
View in Reaxys

petroleum ether

HO

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O

NH 2

Rx-ID: 13041995 View in Reaxys 292/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl chloride
2: ammonia
With oxalyl dichloride, ammonia

De Bank, Paul A.; Kendall, David A.; Alexander, Stephen P.H.; Biochemical Pharmacology; vol. 69; nb. 8; (2005);
p. 1187 - 1193
View in Reaxys

Reaction Steps: 2
1: (COCl)2 / CH2Cl2 / 4 h / 20 °C
2: aq. NH4 / 0.08 h / 0 °C
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Xu, Ming-Zhe; Lee, Woo Song; Kim, Mi Jeong; Park, Doo-Sang; Yu, Hana; Tian, Guan-Rong; Jeong, Tae-
Sook; Park, Ho-Yong; Bioorganic and Medicinal Chemistry Letters; vol. 14; nb. 16; (2004); p. 4277 - 4280
View in Reaxys

O OH HN
2
O

HO HO
OH OH

Rx-ID: 16009597 View in Reaxys 293/636

Yield Conditions & References
Reaction Steps: 2
2: NH3 / methanol / 120 h / 20 °C
With ammonia in methanol, 1: Esterification / 2: Substitution

Nakayama, Yuji; Kumar, G. Biju; Kobayashi, Yuichi; Journal of Organic Chemistry; vol. 65; nb. 3; (2000); p. 707 -
715
View in Reaxys

O NH 2

O O
OH O

O O

Rx-ID: 21157309 View in Reaxys 294/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2 / 72 h / 25 °C
2: NH4OAc / acetone / 3 h / 25 °C
With thionyl chloride, ammonium acetate in acetone

Bradbury; Walker; Journal of Organic Chemistry; vol. 48; nb. 10; (1983); p. 1741 - 1750
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 O O

O NH 2

OH OH

Rx-ID: 3251908 View in Reaxys 295/636

Yield Conditions & References
74 % With methanol, ammonium hydroxide, Time= 1200h, Ambient temperature

Krieg, R.; Schierhorn, M.; Altmann, H.; Deutscher, H.-J.; Journal fur praktische Chemie (Leipzig 1954); vol. 329;
nb. 6; (1987); p. 1123 - 1130
View in Reaxys

HO O

O NH 2

Rx-ID: 17385028 View in Reaxys 296/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl chloride / hexane / 0.5 h / 60 °C
2: conc. NH4OH / diethyl ether
With ammonium hydroxide, oxalyl dichloride in diethyl ether, hexane

Jones; Torres; Snelling; Spande; Journal of Natural Products; vol. 59; nb. 8; (1996); p. 801 - 802
View in Reaxys

HO O
Br Br

O NH 2

Rx-ID: 18864724 View in Reaxys 297/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / acetone / 0.5 h / -10 °C
2: 25percent aq. NH3 / acetone / 2 h
With ammonium hydroxide, triethylamine in acetone

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

Reaction Steps: 2
1: N,N-dimethyl-formamide; thionyl chloride / toluene / 1 h / 80 °C
2: ammonium hydroxide / toluene; water / 0.5 h / 0 °C
With ammonium hydroxide, thionyl chloride, N,N-dimethyl-formamide in water, toluene

Klunda, Tomáš; Hricovíni, Michal; Šesták, Sergej; Kóňa, Juraj; Poláková, Monika; New Journal of Chemistry;
vol. 45; nb. 24; (2021); p. 10940 - 10951
View in Reaxys

O N HN
2

OH O

N N N

Rx-ID: 3213729 View in Reaxys 298/636

Yield Conditions & References
60 %, 30 With ethyl phosphate, ammonia
%
Benson; Li; Snyder; Journal of Organic Chemistry; vol. 57; nb. 20; (1992); p. 5285 - 5287
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

HO O

O NH 2

Rx-ID: 4616028 View in Reaxys 299/636

Yield Conditions & References
With thionyl chloride, ammonia, Multistep reaction

Hamilton, Harriet W.; Tait, Bradley D.; Gajda, Christopher; Hagen, Susan E.; Ferguson, Donna; Lunney, Eliza‐
beth A.; Pavlovsky, Alexander; Tummino, Peter J.; Bioorganic and Medicinal Chemistry Letters; vol. 6; nb. 6;
(1996); p. 719 - 724
View in Reaxys

Reaction Steps: 2
1: SOCl2
2: NH3 / benzene
With thionyl chloride, ammonia in benzene

Eistert,B.; Justus Liebigs Annalen der Chemie; vol. 650; (1961); p. 133 - 156
View in Reaxys

O O

Si Si
O O

O O

O O

O O

O NH 2

HO O

Rx-ID: 4918450 View in Reaxys 300/636

Yield Conditions & References
With potassium hydroxide in 1,4-dioxane, water, Time= 3h, Ambient temperature

Sato, Masaaki; Takeuchi, Shinji; Ishibashi, Masami; Kobayashi, Jun'ichi; Tetrahedron; vol. 54; nb. 19; (1998); p.
4819 - 4826
View in Reaxys

HN
2
NH HN
2
NH
2 2

N N
Br Br

OH NH 2

O O

Rx-ID: 11071177 View in Reaxys 301/636

Yield Conditions & References
Stage 1: With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 1-hydroxybenzotriazol-
hydrate, N-ethyl-N,N-diisopropylamine in 1-methyl-pyrrolidin-2-one, Time= 0.5h
Stage 2: With Fmoc-deprotected Rink Amide MBHA resin in 1-methyl-pyrrolidin-2-one, Time= 22h
Stage 3: With triisopropylsilane, water, trifluoroacetic acid in 1-methyl-pyrrolidin-2-one, Further stages.

Rangarajan, Subhashree; Friedman, Simon H.; Bioorganic and Medicinal Chemistry Letters; vol. 17; nb. 8;
(2007); p. 2267 - 2273
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 HO

NH 2

Rx-ID: 12964069 View in Reaxys 302/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / tetrahydrofuran / 1 h / Heating
2: 62 percent / aq. NH3 / 3 h
With ammonium hydroxide, thionyl chloride in tetrahydrofuran

Howarth, Nicola M.; Lindsell, W. Edward; Murray, Euan; Preston, Peter N.; Tetrahedron; vol. 61; nb. 37; (2005);
p. 8875 - 8887
View in Reaxys

O O

H H
HO N N O N N

O NH 2

Rx-ID: 14492600 View in Reaxys 303/636

Yield Conditions & References
Reaction Steps: 2
1: methanol / 2 h / 80 °C
2: NH3 / methanol; CH2Cl2 / 72 h / 90 °C
With ammonia in methanol, dichloromethane

Perron-Sierra, Francoise; Saint Dizier, Dominique; Bertrand, Marc; Genton, Annie; Tucker, Gordon C; Ca‐
sara, Patrick; Bioorganic and medicinal chemistry letters; vol. 12; nb. 22; (2002); p. 3291 - 3296
View in Reaxys

O O

O O

O O
O O

O HN
2

OH O

Rx-ID: 16593522 View in Reaxys 304/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / tetrahydrofuran / 0.5 h / 0 °C
2: 42 mg / aq. NH4OH / tetrahydrofuran / 0.5 h / 0 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, 1: Acylation / 2: amidation

Fujiwara, Hideyasu; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 54; nb. 3-4; (1998); p. 551 - 564
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

O O
O O

O O

OH O
O HN
2

Rx-ID: 16594239 View in Reaxys 305/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / tetrahydrofuran / 0.5 h / 0 °C
2: 11 mg / aq. NH4OH / tetrahydrofuran / 0.5 h / 0 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, 1: Acylation / 2: amidation

Fujiwara, Hideyasu; Egawa, Sadahiro; Terao, Yoshihiro; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron;
vol. 54; nb. 3-4; (1998); p. 565 - 572
View in Reaxys

O
O

OH

O
O

HN
2

Rx-ID: 16594242 View in Reaxys 306/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / tetrahydrofuran / 0.5 h / 0 °C
2: 59 mg / aq. NH4OH / tetrahydrofuran / 0.5 h / 0 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, 1: Acylation / 2: amidation

Fujiwara, Hideyasu; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 54; nb. 3-4; (1998); p. 551 - 564
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

O O

O O
O O

O NH 2

HO O

Rx-ID: 16594287 View in Reaxys 307/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / tetrahydrofuran / 0.5 h / 0 °C
2: 15 mg / aq. NH4OH / tetrahydrofuran / 0.5 h / 0 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, 1: Acylation / 2: amidation

Fujiwara, Hideyasu; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 54; nb. 3-4; (1998); p. 551 - 564
View in Reaxys

O O

O O
O O

O O

O NH 2

OH O

Rx-ID: 16594322 View in Reaxys 308/636

Yield Conditions & References
Reaction Steps: 2
1: Et3N / tetrahydrofuran / 0.5 h / 0 °C
2: 49 mg / aq. NH4OH / tetrahydrofuran / 0.5 h / 0 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, 1: Acylation / 2: amidation

Fujiwara, Hideyasu; Egawa, Sadahiro; Terao, Yoshihiro; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron;
vol. 54; nb. 3-4; (1998); p. 565 - 572
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O
S S

O N O NH 2
N O
H H
O O

HO O

Rx-ID: 16807719 View in Reaxys 309/636

Yield Conditions & References
Reaction Steps: 2
1: N-methylmorpholine / CH2Cl2
2: NH3 / CH2Cl2; methanol / 0.25 h / -40 °C
With 4-methyl-morpholine, ammonia in methanol, dichloromethane

Weber, Ingo R.; Neidlein, Richard; Von Der Saal, Wolfgang; Grams, Frank; Leinert, Herbert; Strein, Klaus;
Engh, Richard A.; Kucznierz, Ralf; Bioorganic and Medicinal Chemistry Letters; vol. 8; nb. 13; (1998); p. 1613 -
1618
View in Reaxys

O O

S S

N O N O
H H

O O

HO O

O NH 2

Rx-ID: 16808034 View in Reaxys 310/636

Yield Conditions & References
Reaction Steps: 2
1: N-methylmorpholine / CH2Cl2
2: NH3 / CH2Cl2; methanol / 0.25 h / -40 °C
With 4-methyl-morpholine, ammonia in methanol, dichloromethane

Weber, Ingo R.; Neidlein, Richard; Von Der Saal, Wolfgang; Grams, Frank; Leinert, Herbert; Strein, Klaus;
Engh, Richard A.; Kucznierz, Ralf; Bioorganic and Medicinal Chemistry Letters; vol. 8; nb. 13; (1998); p. 1613 -
1618
View in Reaxys

O O
S S

O N O NH 2
N O
H H
O O

O O

Rx-ID: 16809098 View in Reaxys 311/636

Yield Conditions & References
Reaction Steps: 3
1: KOH / ethanol / 2 h / 90 °C
2: N-methylmorpholine / CH2Cl2
3: NH3 / CH2Cl2; methanol / 0.25 h / -40 °C
With 4-methyl-morpholine, potassium hydroxide, ammonia in methanol, ethanol, dichloromethane

Weber, Ingo R.; Neidlein, Richard; Von Der Saal, Wolfgang; Grams, Frank; Leinert, Herbert; Strein, Klaus;
Engh, Richard A.; Kucznierz, Ralf; Bioorganic and Medicinal Chemistry Letters; vol. 8; nb. 13; (1998); p. 1613 -
1618
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

S S

N O N O
H H

O O

O O

O NH 2

Rx-ID: 16809508 View in Reaxys 312/636

Yield Conditions & References
Reaction Steps: 3
1: KOH / ethanol / 2 h / 90 °C
2: N-methylmorpholine / CH2Cl2
3: NH3 / CH2Cl2; methanol / 0.25 h / -40 °C
With 4-methyl-morpholine, potassium hydroxide, ammonia in methanol, ethanol, dichloromethane

Weber, Ingo R.; Neidlein, Richard; Von Der Saal, Wolfgang; Grams, Frank; Leinert, Herbert; Strein, Klaus;
Engh, Richard A.; Kucznierz, Ralf; Bioorganic and Medicinal Chemistry Letters; vol. 8; nb. 13; (1998); p. 1613 -
1618
View in Reaxys

Si O
O
Si
O O

O
O

NH 2

Rx-ID: 16945273 View in Reaxys 313/636

Yield Conditions & References
Reaction Steps: 2
1: 81 percent / 1N KOH / H2O; dioxane / 3 h / Ambient temperature
2: 1.) N,N'-carbonyldiimidazole, 2.) NH3 / 1.) THF, 60 deg C, 1 h, 2.) 0 deg C, 5 min; 30 min
With potassium hydroxide, ammonia, 1,1'-carbonyldiimidazole in 1,4-dioxane, water

Sato, Masaaki; Takeuchi, Shinji; Ishibashi, Masami; Kobayashi, Jun'ichi; Tetrahedron; vol. 54; nb. 19; (1998); p.
4819 - 4826
View in Reaxys

Si O
O
Si
O O

O
O

NH 2

Rx-ID: 16945279 View in Reaxys 314/636

Yield Conditions & References
Reaction Steps: 2
1: 1N KOH / H2O; dioxane / 3 h / Ambient temperature

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 2: 1N KOH / H2O; dioxane / 3 h / Ambient temperature
With potassium hydroxide in 1,4-dioxane, water

Sato, Masaaki; Takeuchi, Shinji; Ishibashi, Masami; Kobayashi, Jun'ichi; Tetrahedron; vol. 54; nb. 19; (1998); p.
4819 - 4826
View in Reaxys

HO S O S

O NH 2

Rx-ID: 18732393 View in Reaxys 315/636

Yield Conditions & References
Reaction Steps: 2
1: 80 percent / p-toluenesulfonic acid / 24 h
2: 74 percent / NH3 / methanol / 240 h / 5 °C
With ammonia, toluene-4-sulfonic acid in methanol

Biktimirova, L. A.; Likhovskikh, V. V.; Tolstikova, O. V.; Tolstikova, T. G.; Tolstikov, A. G.; Pharmaceutical
Chemistry Journal; vol. 26; nb. 11/12; (1992); p. 843 - 846; Khimiko-Farmatsevticheskii Zhurnal; vol. 26; nb. 11-12;
(1992); p. 45 - 48
View in Reaxys

Reaction Steps: 2
1: 80 percent / p-TsOH / 24 h
2: 74 percent / NH3 / methanol / 240 h / 5 °C
With ammonia, toluene-4-sulfonic acid in methanol

Tolstikov, A. G.; Biktimirova, L. A.; Tolstikova, O. V.; Shmakov, V. S.; Vyrypaev, E. M.; Tolstikov, G. A.; Chemis‐
try of Natural Compounds; vol. 28; nb. 1; (1992); p. 85 - 87; Khimiya Prirodnykh Soedinenii; nb. 1; (1992); p. 102 -
105
View in Reaxys

O O

O O

H H

H H H H

O O O O

O OH HN
2
O

Rx-ID: 19174909 View in Reaxys 316/636

Yield Conditions & References
Reaction Steps: 2
1: ClOCCOCl / diethyl ether / 1 h / Ambient temperature
2: NH3 / diethyl ether / 1 h / -50 °C
With oxalyl dichloride, ammonia in diethyl ether

Muhlenbruch; Kirmeier; Roth; Archiv der Pharmazie; vol. 319; nb. 2; (1986); p. 177 - 183
View in Reaxys

NH 2

Rx-ID: 26033981 View in Reaxys 317/636

Yield Conditions & References
With ammonia in diethyl ether, Time= 0.5h

Narasimhan, Balasubramanian; Mourya, Vishnukant; Dhake, Avinash; Bioorganic and Medicinal Chemistry Let‐
ters; vol. 16; nb. 11; (2006); p. 3023 - 3029

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 View in Reaxys

O O

NH NH

N O N O

O NH 2

O O

Rx-ID: 27967390 View in Reaxys 318/636

Yield Conditions & References
With ammonia in methanol

Gasse, Cecile; Douguet, Dominique; Huteau, Valerie; Marchal, Gilles; Munier-Lehmann, Helene; Pochet, Syl‐
vie; Bioorganic and Medicinal Chemistry; vol. 16; nb. 11; (2008); p. 6075 - 6085
View in Reaxys

N N
O O
HN HN

NH NH
O O

HN HN

OH O

O HN
2

Rx-ID: 29045245 View in Reaxys 319/636

Yield Conditions & References
With ammonia, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in N,N-dimethyl-
formamide

Attenni, Barbara; Ontoria, Jesus M.; Cruz, Jonathan C.; Rowley, Michael; Schultz-Fademrecht, Carsten;
Steinkuehler, Christian; Jones, Philip; Bioorganic and Medicinal Chemistry Letters; vol. 19; nb. 11; (2009); p.
3081 - 3084
View in Reaxys

O
O
H
N
HO NH 2

N
H
O
O

Rx-ID: 35480537 View in Reaxys 320/636

Yield Conditions & References
Reaction Steps: 2
1.1: thionyl chloride / dichloromethane / 3 h / Reflux; Inert atmosphere
2.1: ammonium hydroxide; ammonium chloride / water / 8 h / 20 °C
2.2: 1 h / 20 °C
With ammonium hydroxide, thionyl chloride, ammonium chloride in dichloromethane, water

Ginsel, Carsten; Plitzko, Birte; Froriep, Danilo; Stolfa, Diana A.; Jung, Manfred; Kubitza, Christian; Scheidig,
Axel J.; Havemeyer, Antje; Clement, Bernd; Drug Metabolism and Disposition; vol. 46; nb. 10; (2018); p. 1396 -
1402
View in Reaxys

Reaction Steps: 2
1.1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0 - 20 °C
1.2: 20 °C

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 2.1: ammonium hydroxide / dichloromethane; water / 20 °C
With ammonium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide in dichloromethane, water

PatentGLAXOSMITHKLINE LLC;TEMPERO PHARMACEUTICALS, INC.;GHOSH, Shomir;LOBERA, Mer‐

cedes;POHLHAUS, Denise, Teotico;TRUMP, Ryan, Paul;ZHANG, Cunyu;ZUERCHER, William; GLAXOSMITHK‐
LINE PLCGlaxoSmithKline; WO2013/66836; (2013); (A1) English
View in Reaxys

HO

NH 2

Rx-ID: 40752484 View in Reaxys 321/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / tetrahydrofuran / 1 h / Reflux
2: ammonium hydroxide / 3 h / 0 - 20 °C
With ammonium hydroxide, thionyl chloride in tetrahydrofuran

Gasiorowski; Pootrakulchote; Reanprayoon; Jaisabuy; Vanalabhpatana; Sariciftci; Thamyongkit; RSC Ad‐

vances; vol. 5; nb. 89; (2015); p. 72900 - 72906
View in Reaxys

Cl Cl

Cl Cl

H
N
O NH 2

O H
F N N N
S O O

O
F O
F N N
F
S

F O
O O F

Rx-ID: 41057049 View in Reaxys 322/636

Yield Conditions & References
Reaction Steps: 2
1: sodium hydroxide; ethanol / 25 °C
2: ammonium chloride; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-
methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 25 °C
With ethanol, ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-
b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate, sodium hydroxide in N,N-dimethyl-forma‐
mide

PatentJANSSEN PHARMACEUTICA NV; JOHNSON & JOHNSON INCJohnson & Johnson; US2015/239844;
(2015); (A1) English
View in Reaxys

Reaction Steps: 2
1: sodium hydroxide; ethanol / 25 °C
2: ammonium chloride; N-ethyl-N,N-diisopropylamine; HATU / N,N-dimethyl-formamide / 25 °C
With ethanol, ammonium chloride, N-ethyl-N,N-diisopropylamine, HATU, sodium hydroxide in N,N-dimethyl-forma‐
mide

PatentJANSSEN PHARMACEUTICA NV; JOHNSON & JOHNSON INCJohnson & Johnson; US2015/239845;
(2015); (A1) English
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 OH O

O HN 2

HN HN
N N

H OO H OO

O O

HO N N HO N N

O O

O O

N HN N HN

O O

O O

N N N N

O O

O
O
N HN N HN

O HN O HN

O O

Rx-ID: 41827682 View in Reaxys 323/636

Yield Conditions & References
With ammonia, Time= 0.166667h, T= 0 °C

PatentHegmans, Alexander;Fenske, Bruce W.;Trepanier, Dan J.;Abel, Mark D.;Ure, Daren R.;Sugiyama, Shin;
CONTRAVIR PHARMACEUTICALS&lt;unknown&gt;; US9200038; (2015); (B2) English
View in Reaxys

1.12

With ammonia, benzotriazol-1-ol, dicyclohexyl-carbodiimide, Time= 0.166667h, T= 0 °C

PatentCONTRAVIR PHARMACEUTICALS, INC.;FOSTER, Robert Thomas;GALLAY, Philippe;TREPANIER, Daniel

Joseph;URE, Daren Raymond; CONTRAVIR PHARMACEUTICALS&lt;unknown&gt;; WO2018/106928; (2018); (A1)
English
View in Reaxys

O O

H 2
N NH 2
HCl

H H
N
Na O

H H H
N

H H
N

Rx-ID: 43484422 View in Reaxys 324/636

Yield Conditions & References
Reaction Steps: 3
1: methanol / 4 h / 20 °C
2: ammonium bicarbonate; di-tert-butyl dicarbonate; pyridine / water; acetonitrile / 20 °C
3: hydrogenchloride / diethyl ether / 0.5 h
With pyridine, hydrogenchloride, di-tert-butyl dicarbonate, ammonium bicarbonate in methanol, diethyl ether, water,
acetonitrile

Tang, Sheng; Peng, Zong-Gen; Zhang, Xin; Cheng, Xin-Yue; Li, Wen-Jing; Jiang, Jian-Dong; Li, Ying-Hong;
Song, Dan-Qing; Chinese Chemical Letters; vol. 27; nb. 7; (2016); p. 1052 - 1057
View in Reaxys

OH NH 2

H O H O

Rx-ID: 205519 View in Reaxys 325/636

Yield Conditions & References
With phosphorus pentachloride, benzene, Umsetzen des erhaltenes Saeurechlorids mit konz.wss.NH3

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 26 A; nb. 12; (1949); p. 22

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys
Spielman; Journal of Biological Chemistry; vol. 106; (1934); p. 88,93
View in Reaxys

With oxalyl dichloride, benzene, Umsetzen des erhaltenes Saeurechlorids mit konz.wss.NH3

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 26 A; nb. 12; (1949); p. 22

View in Reaxys
Spielman; Journal of Biological Chemistry; vol. 106; (1934); p. 88,93
View in Reaxys

HO

NH 2

Rx-ID: 205521 View in Reaxys 326/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Prout et al.; Journal of Organic Chemistry; vol. 24; (1959); p. 826,828

View in Reaxys
Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

NH 2

Rx-ID: 252312 View in Reaxys 327/636

Yield Conditions & References
With ammonia, water, T= 180 °C

Hofmann,A.W.; Chemische Berichte; vol. 15; (1882); p. 983

View in Reaxys
Carlet; Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften; (1859); p.
367
View in Reaxys

HN
2
O

HO O

O NH 2

Rx-ID: 637566 View in Reaxys 328/636

Yield Conditions & References
T= 230 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217
View in Reaxys

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 T= 160 °C

Granados Jarque et al.; Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica; vol. 54;
(1958); p. 233,234
View in Reaxys
Kaufmann; Skiba; Fette und Seifen; vol. 60; (1958); p. 362
View in Reaxys

T= 200 °C

Granados Jarque et al.; Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica; vol. 54;
(1958); p. 233,234
View in Reaxys
Kaufmann; Skiba; Fette und Seifen; vol. 60; (1958); p. 362
View in Reaxys

T= 230 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217
View in Reaxys

T= 230 °C

PatentResinous Prod. & Chem.Co.; RESINOUS PROD CHEMICAL&lt;unknown&gt;; US1989968; (1934); (A)
View in Reaxys

O O O
Br Br

O O NH 2

Rx-ID: 3116634 View in Reaxys 329/636

Yield Conditions & References
With ammonium hydroxide in acetone, Time= 2h, Yield given

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

S S

O HN
2

OH O

Rx-ID: 3227761 View in Reaxys 330/636

Yield Conditions & References
With ammonia, 1,1'-carbonyldiimidazole, 1.) THF, RT, 1 h, 2.) THF, 2 h, Yield given. Multistep reaction

Labaudiniere, Richard; Hilboll, Gerd; Leon-Lomeli, Alicia; Lautenschlaeger, Hans-Heiner; Parnham, Michael;
et al.; Journal of Medicinal Chemistry; vol. 35; nb. 17; (1992); p. 3156 - 3169
View in Reaxys

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 O O
O O
S S

HO O

O NH 2

N N

Rx-ID: 3578299 View in Reaxys 331/636

Yield Conditions & References
With chloroformic acid ethyl ester, triethylamine in dichloromethane, Yield given

Nomoto, Takashi; Takayama, Hiroaki; Heterocycles; vol. 23; nb. 11; (1985); p. 2913 - 2916
View in Reaxys

O O O
Br Br

O O NH 2

Rx-ID: 3609181 View in Reaxys 332/636

Yield Conditions & References
With ammonium hydroxide in acetone, Time= 2h, Yield given

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

O O O
Br Br

O O NH 2

Rx-ID: 3609863 View in Reaxys 333/636

Yield Conditions & References
With ammonium hydroxide in acetone, Time= 2h, Yield given

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

Br O O O Br

O O NH 2

Rx-ID: 3610304 View in Reaxys 334/636

Yield Conditions & References
With ammonium hydroxide in acetone, Time= 2h, Yield given

Voss, Gundula; Gerlach, Hans; Helvetica Chimica Acta; vol. 66; nb. 7; (1983); p. 2294 - 2307
View in Reaxys

O O

O O

OH OH

O NH 2

HO O

Rx-ID: 4796876 View in Reaxys 335/636

Yield Conditions & References
With 4-methyl-morpholine, ammonia, methyl chloroformate, 1.) CH2Cl2, 0 deg C, 2 h, 2.) CH2Cl2, a) 0 deg C, 30 min,
b) RT, 1.5 h, Multistep reaction

D.tait, Bradley; Journal of Medicinal Chemistry; vol. 40; nb. 23; (1997); p. 3781 - 3792
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

O O

OH OH

O HN 2

OH O

Rx-ID: 4797791 View in Reaxys 336/636

Yield Conditions & References
With 4-methyl-morpholine, ammonia, methyl chloroformate, 1.) CH2Cl2, 0 deg C, 2 h, 2.) CH2Cl2, a) 0 deg C, 30 min,
b) RT, 1.5 h, Multistep reaction

D.tait, Bradley; Journal of Medicinal Chemistry; vol. 40; nb. 23; (1997); p. 3781 - 3792
View in Reaxys

NH 2

O O
O O
O

HN
HN

H
H N
N
O
O

Rx-ID: 12522276 View in Reaxys 337/636

Yield Conditions & References
Reaction Steps: 2
1.1: NaOH / H2O; tetrahydrofuran / 3 h / Heating
1.2: 89 percent / AlCl3 / CH2Cl2 / 1.5 h / 20 °C
2.1: 52 percent / NH4Cl; diphenylphosphoryl azide (DPPA); Et3N / dimethylformamide / 72 h / cooling
With sodium hydroxide, diphenylphosphoranyl azide, ammonium chloride, triethylamine in tetrahydrofuran, water,
N,N-dimethyl-formamide

Salzameda, Nicholas T.; Lightner, David A.; Monatshefte fur Chemie; vol. 137; nb. 3; (2006); p. 319 - 337
View in Reaxys

N N
O NH 2

Cl H
N N
HO S N O S N

Rx-ID: 17869619 View in Reaxys 338/636

Yield Conditions & References
Reaction Steps: 2
1: PCl5 / benzene / 1.5 h / 0 - 20 °C
2: 25percent aq. NH3 / 1.5 h / 0 - 20 °C
With ammonium hydroxide, phosphorus pentachloride in benzene

Kuwahara; Kawano; Kawai; Ashida; Miyake; Chemical and Pharmaceutical Bulletin; vol. 43; nb. 9; (1995); p.
1505 - 1510
View in Reaxys

HO O

NaNO3 Al2O3
O NH 2

Rx-ID: 18467116 View in Reaxys 339/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl chloride / CH2Cl2 / 0 - 20 °C
2: aq. NH4OH / CH2Cl2 / 0 - 20 °C
With ammonium hydroxide, oxalyl dichloride in dichloromethane

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 Fisher; Caroon; Stabler; Lundberg; Zaidi; Sorensen; Sparacino; Muchowski; Canadian Journal of Chemistry;
vol. 72; nb. 1; (1994); p. 142 - 145
View in Reaxys

O O
O O
S S

O O

O NH 2

N N

Rx-ID: 19049880 View in Reaxys 340/636

Yield Conditions & References
Reaction Steps: 2
1: TFA / CH2Cl2 / Ambient temperature
2: ClCO2Et, Et3N / CH2Cl2
With chloroformic acid ethyl ester, triethylamine, trifluoroacetic acid in dichloromethane

Nomoto, Takashi; Takayama, Hiroaki; Heterocycles; vol. 23; nb. 11; (1985); p. 2913 - 2916
View in Reaxys

N
O
N
N

HO

N
HN
2

N
N

Rx-ID: 20366575 View in Reaxys 341/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / Ambient temperature
2: NH4OH
With ammonium hydroxide, thionyl chloride

Harper, Richard W.; Herron, David K.; Bollinger, Nancy G.; Sawyer, J. Scott; Baldwin, Ronald F.; et al.; Journal
of Medicinal Chemistry; vol. 35; nb. 7; (1992); p. 1191 - 1200
View in Reaxys

Rx-ID: 30723527 View in Reaxys 342/636

Yield Conditions & References
0.8 mg, 0.3 With ΔPKS mutant strain Pseudoalteromonas SANK73390 in water, dimethyl sulfoxide, Time= 24h, T= 25 °C
mg, 1.2
mg, 10.7 Murphy, Annabel C.; Fukuda, Daisuke; Song, Zhongshu; Hothersall, Joanne; Cox, Russell J.; Willis, Chris‐
mg, 2.4 mg tine L.; Thomas, Christopher M.; Simpson, Thomas J.; Angewandte Chemie - International Edition; vol. 50; nb.
14; (2011); p. 3271 - 3274
View in Reaxys

HO O

O NH 2

Rx-ID: 183137 View in Reaxys 343/636

Yield Conditions & References
Taylor; Strong; Journal of the American Chemical Society; vol. 72; (1950); p. 4263
View in Reaxys

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 HO O

O NH 2

Rx-ID: 183584 View in Reaxys 344/636

Yield Conditions & References
Taylor; Strong; Journal of the American Chemical Society; vol. 72; (1950); p. 4263
View in Reaxys

HO O

O NH 2

Rx-ID: 183585 View in Reaxys 345/636

Yield Conditions & References
Taylor; Strong; Journal of the American Chemical Society; vol. 72; (1950); p. 4263
View in Reaxys

HO O

O NH 2

Rx-ID: 183912 View in Reaxys 346/636

Yield Conditions & References
Taylor; Strong; Journal of the American Chemical Society; vol. 72; (1950); p. 4263
View in Reaxys

HO

HN
2

Rx-ID: 206369 View in Reaxys 347/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

NH 2

Rx-ID: 206553 View in Reaxys 348/636

Yield Conditions & References
With ammonia, T= 160 °C

Grigor et al.; Journal of the Chemical Society; (1955); p. 1069

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

H OH

NH 2

OH

OH

Rx-ID: 207076 View in Reaxys 349/636

Yield Conditions & References
With ammonia, silica gel, T= 150 - 180 °C

PatentI.G.Farbenind.; I.G. FARBENINDUSTRIE AG (historic)I.G. Farben; US2013108; (1933); (A); Fortschr. Teer‐
farbenfabr. Verw. Industriezweige; vol. 21; p. 191; Fortschr. Teerfarbenfabr. Verw. Industriezweige; vol. 21; p. 191
View in Reaxys

O O

O NH 2

Rx-ID: 239121 View in Reaxys 350/636

Yield Conditions & References
With ammonia, water, T= 120 - 130 °C

Schalfejew; Chemische Berichte; vol. 6; (1873); p. 1252; Zhurnal Russkago Fiziko-Khimicheskago Obshchestva;
vol. 6; (1874); p. 119
View in Reaxys

O O O O

O O O NH 2

Rx-ID: 242931 View in Reaxys 351/636

Yield Conditions & References
With methanol, ammonia, T= 100 °C

Lukes; Kovar; Collection of Czechoslovak Chemical Communications; vol. 21; (1956); p. 1317,1320
View in Reaxys

O O

O NH 2

Rx-ID: 244372 View in Reaxys 352/636

Yield Conditions & References
With ammonia, T= 220 °C

Ehestaedt; Diss.<Freiburg i.Br.1886>,S.13

View in Reaxys

O O

O NH 2

Rx-ID: 247451 View in Reaxys 353/636

Yield Conditions & References
With ammonia, water, T= 250 °C

Reimer; Will; Chemische Berichte; vol. 18; (1885); p. 2016

View in Reaxys

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 N N
O N O N
N N

O NH 2

Rx-ID: 248915 View in Reaxys 354/636

Yield Conditions & References
With ammonia, T= 100 °C

Gryszkiewicz-Trochimowski; Sporzynski; Roczniki Chemii; vol. 16; p. 40; Chemisches Zentralblatt; vol. 107; nb.
II; (1936); p. 1150
View in Reaxys

OH

NH 2

Rx-ID: 250869 View in Reaxys 355/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

OH

NH 2

Rx-ID: 250870 View in Reaxys 356/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

OH

NH 2

Rx-ID: 250871 View in Reaxys 357/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

O OH

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 NH 2

O O

Rx-ID: 251626 View in Reaxys 358/636

Yield Conditions & References
Rabjohn; Cohen; Journal of the American Chemical Society; vol. 76; (1954); p. 1280
View in Reaxys

OH

NH 2

Rx-ID: 251656 View in Reaxys 359/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

OH

NH 2

Rx-ID: 251658 View in Reaxys 360/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

OH

NH 2

Rx-ID: 260384 View in Reaxys 361/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

HO O

O NH 2

Rx-ID: 382989 View in Reaxys 362/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
Pelton; Starnes; Shrader; Journal of the American Chemical Society; vol. 72; (1950); p. 2039
View in Reaxys

H H

O NH 2

HO O
H H

Rx-ID: 438844 View in Reaxys 363/636

Yield Conditions & References
Fieser et al.; Journal of the American Chemical Society; vol. 70; (1948); p. 3177
View in Reaxys

OH O

O HN
2

Rx-ID: 439753 View in Reaxys 364/636

Yield Conditions & References
Fieser et al.; Journal of the American Chemical Society; vol. 70; (1948); p. 3177
View in Reaxys

O O

OH O

O HN
2

Rx-ID: 492848 View in Reaxys 365/636

Yield Conditions & References
Fieser et al.; Journal of the American Chemical Society; vol. 70; (1948); p. 3177
View in Reaxys

H H
O N NH 2
HN 2
N O

Cl H

O NH NH NH 2

Rx-ID: 1344347 View in Reaxys 366/636

Yield Conditions & References
With ammonia in ethanol

Weitzel; Renner; Guglielmi; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 352; nb. 12; (1971); p. 1617
- 1630
View in Reaxys

O
H
N H
O
HN
2
H O
O O N N
2 H H
H
N H O
OH
O
OH

O
H
N H
O
HN 2
H O
O N N
H H
H
N H NH 2

O
OH

Rx-ID: 3496278 View in Reaxys 367/636

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 Yield Conditions & References
With ammonia in methanol, Time= 48h, Ambient temperature

Paruszewski, Ryszard; Gmitrzuk-Zietarska, Elwira; Matusiak, Roza; Gumulka, Stanislaw; Osipiak, Beata;
Krzascik, Pawel; Polish Journal of Chemistry; vol. 60; nb. 4-6; (1986); p. 495 - 504
View in Reaxys

OH

O
H
N H O
O
O HN H N
2

2 H
O N
H
N H O
OH H
O

OH

OH

O
H
N H O
NH 2

HN
2
H N
H
O N
H
N H O
H

OH

Rx-ID: 3496314 View in Reaxys 368/636

Yield Conditions & References
With ammonia in methanol, Time= 48h, Ambient temperature

Paruszewski, Ryszard; Gmitrzuk-Zietarska, Elwira; Matusiak, Roza; Gumulka, Stanislaw; Osipiak, Beata;
Krzascik, Pawel; Polish Journal of Chemistry; vol. 60; nb. 4-6; (1986); p. 495 - 504
View in Reaxys

S
O
H
N H

O
O HN 2
H O
O N N
H H

OH N H O
O H

OH

S
O
H
N H

O
HN 2
H NH 2

O N N
H H

N H O
O H

OH

Rx-ID: 3496346 View in Reaxys 369/636

Yield Conditions & References
With ammonia in methanol, Time= 48h, Ambient temperature

Paruszewski, Ryszard; Gmitrzuk-Zietarska, Elwira; Matusiak, Roza; Gumulka, Stanislaw; Osipiak, Beata;
Krzascik, Pawel; Polish Journal of Chemistry; vol. 60; nb. 4-6; (1986); p. 495 - 504
View in Reaxys

O
H
N H
O
HN 2
H O
O O N N
H H
H
N H HN
OH
O
OH
O O

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 O
H
N H
O
HN
2
H O
O N N
H H
H
N H HN

O
OH
O NH 2

Rx-ID: 3496437 View in Reaxys 370/636

Yield Conditions & References
With ammonia in methanol, Time= 48h, Ambient temperature

Paruszewski, Ryszard; Gmitrzuk-Zietarska, Elwira; Matusiak, Roza; Gumulka, Stanislaw; Osipiak, Beata;
Krzascik, Pawel; Polish Journal of Chemistry; vol. 60; nb. 4-6; (1986); p. 495 - 504
View in Reaxys

OH

O
H
N H O H
N
HN 2
H N
O N H
O
H
N H O
H

OH O

OH

O O

OH

O
H
N H O H
N

HN
2
H N
O N H
H
N H O
H
O

OH

HN 2
O

Rx-ID: 3496456 View in Reaxys 371/636

Yield Conditions & References
With ammonia in methanol, Time= 48h, Ambient temperature

Paruszewski, Ryszard; Gmitrzuk-Zietarska, Elwira; Matusiak, Roza; Gumulka, Stanislaw; Osipiak, Beata;
Krzascik, Pawel; Polish Journal of Chemistry; vol. 60; nb. 4-6; (1986); p. 495 - 504
View in Reaxys

S
O
H
N H
O
O HN 2
H O
O N N
H H
H
OH N H HN

OH
O O

S
O
H
N H
O
HN
2
H O
O N N
H H
H
N H HN

OH
O NH 2

Rx-ID: 3496478 View in Reaxys 372/636

Yield Conditions & References
With ammonia in methanol, Time= 48h, Ambient temperature

Paruszewski, Ryszard; Gmitrzuk-Zietarska, Elwira; Matusiak, Roza; Gumulka, Stanislaw; Osipiak, Beata;
Krzascik, Pawel; Polish Journal of Chemistry; vol. 60; nb. 4-6; (1986); p. 495 - 504

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 View in Reaxys

N
O O

OH OH HN

O O
O

HO O NH 2

HO HO OH O
OH
NH

HN

O S

HN

HN
2

HN

O
NH

HN

O S

HN

HN NH

HO
O H H
OH
H H
HO O N N

O N S
H

O O
HO O OH

OH OH

Rx-ID: 10206235 View in Reaxys 373/636

Yield Conditions & References
2 mg in dimethyl sulfoxide, T= 20 °C

Masud, Mohammad Mehedi; Kuwahara, Masayasu; Ozaki, Hiroaki; Sawai, Hiroaki; Bioorganic and Medicinal
Chemistry; vol. 12; nb. 5; (2004); p. 1111 - 1120
View in Reaxys

HO

NH 2

Rx-ID: 11712084 View in Reaxys 374/636

Yield Conditions & References
Reaction Steps: 2
1: 83 percent / thionyl chloride / petroleum ether / 3 h / Heating

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 2: 82 percent / 25percent aq. ammonia
With ammonium hydroxide, thionyl chloride in Petroleum ether

Budilova, I. Yu.; Kolesnikov, A. M.; Kolotilo, N. V.; Il'chenko, A. Ya.; Journal of Organic Chemistry USSR (English
Translation); vol. 26; nb. 2.1; (1990); p. 264 - 267; Zhurnal Organicheskoi Khimii; vol. 26; nb. 2; (1990); p. 314 - 319
View in Reaxys

O O O O

O O O NH 2

Rx-ID: 15381622 View in Reaxys 375/636

Yield Conditions & References
Reaction Steps: 3
1: 24.3 g / Ba(OH)2 / methanol / 20 h / 20 °C
2: 18.2 g / SOCl2 / benzene / 5 h / Heating
3: 15 g / aq. NH3 / 0 °C
With barium dihydroxide, ammonium hydroxide, thionyl chloride in methanol, benzene

Petrenko; Petukhova; Shakirov; Shul'ts; Tolstikov; Russian Journal of Organic Chemistry; vol. 36; nb. 7; (2000);
p. 982 - 995
View in Reaxys

O OH O O

O O O NH 2

Rx-ID: 15382549 View in Reaxys 376/636

Yield Conditions & References
Reaction Steps: 2
1: 18.2 g / SOCl2 / benzene / 5 h / Heating
2: 15 g / aq. NH3 / 0 °C
With ammonium hydroxide, thionyl chloride in benzene

Petrenko; Petukhova; Shakirov; Shul'ts; Tolstikov; Russian Journal of Organic Chemistry; vol. 36; nb. 7; (2000);
p. 982 - 995
View in Reaxys

O NH 2

O O
OH O

O O

Rx-ID: 15382566 View in Reaxys 377/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2 / benzene / Heating
2: aq. NH3 / 0 °C
With ammonium hydroxide, thionyl chloride in benzene

Petrenko; Petukhova; Shakirov; Shul'ts; Tolstikov; Russian Journal of Organic Chemistry; vol. 36; nb. 7; (2000);
p. 982 - 995
View in Reaxys

O NH 2

O O
O O

O O

Rx-ID: 15382592 View in Reaxys 378/636

Yield Conditions & References
Reaction Steps: 3
1: Ba(OH)2 / methanol / 20 h / 20 °C
2: SOCl2 / benzene / Heating
3: aq. NH3 / 0 °C

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 With barium dihydroxide, ammonium hydroxide, thionyl chloride in methanol, benzene

Petrenko; Petukhova; Shakirov; Shul'ts; Tolstikov; Russian Journal of Organic Chemistry; vol. 36; nb. 7; (2000);
p. 982 - 995
View in Reaxys

OH O

O NH 2

O O

O HN O HN

HN O HN O

N N

O O

Rx-ID: 15576166 View in Reaxys 379/636

Yield Conditions & References
Reaction Steps: 2
1: DCC / acetonitrile; tetrahydrofuran / 16 h / 20 °C
2: NH3 / dimethylformamide / 2 h / 20 °C
With ammonia, dicyclohexyl-carbodiimide in tetrahydrofuran, N,N-dimethyl-formamide, acetonitrile, 1: Esterification /
2: ammonolysis

Wang, Xuebao; Thottathil, John; Tetrahedron Asymmetry; vol. 11; nb. 18; (2000); p. 3665 - 3669
View in Reaxys

NH 2

Rx-ID: 22177606 View in Reaxys 380/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: thionyl chloride / und Behandeln des Reaktionsprodukts mit wss.Ammoniak
With potassium hydroxide, thionyl chloride

Prout et al.; Journal of Organic Chemistry; vol. 24; (1959); p. 826,828

View in Reaxys
Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143
View in Reaxys

O
O

O
NH 2

Rx-ID: 22411409 View in Reaxys 381/636

Yield Conditions & References
Reaction Steps: 2
1: potassium hydroxide / methanol
2: (i) SOCl2, CHCl3, (ii) aq. NH3
With potassium hydroxide in methanol

PatentAmerican Cyanamid Co.; PFIZER INCPfizer; DE2234706; (1973); (A1) German; Chem.Abstr.; vol. 78; nb.
147439; (1973); ; vol. 78; nb. 147439; (1973)

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 View in Reaxys

O O

O NH 2

Rx-ID: 22603088 View in Reaxys 382/636

Yield Conditions & References
Reaction Steps: 2
1: aq. NaOH / ethanol / Heating
2: (i) SOCl2, (ii) aq. NH3
With sodium hydroxide in ethanol

Golmohammadi,R.; Acta Chemica Scandinavica (1947); vol. 20; (1966); p. 479 - 485
View in Reaxys

O O

O O

O NH 2

Rx-ID: 22704112 View in Reaxys 383/636

Yield Conditions & References
Reaction Steps: 4
1: NaNH2 / benzene
2: aq. KOH / Heating
3: SOCl2
4: NH3 / benzene
With potassium hydroxide, thionyl chloride, ammonia, sodium amide in benzene

Eistert,B.; Justus Liebigs Annalen der Chemie; vol. 650; (1961); p. 133 - 156
View in Reaxys

HO O

O NH 2

Rx-ID: 30947791 View in Reaxys 384/636

Yield Conditions & References
Reaction Steps: 2
1: N,N-dimethyl-formamide; thionyl chloride / benzene / 2 h / 80 °C
2: ammonia / dichloromethane / 0.5 h / 0 °C
With thionyl chloride, ammonia, N,N-dimethyl-formamide in dichloromethane, benzene

PatentORCHID RESEARCH LABORATORIES LTD.;RAJAGOPAL, Sridharan;THANGAPAZHAM, Selvaku‐

mar;PAUL-SATYASEELA, Maneesh;BALASUBRAMANIAN, Gopalan;SHAKTI SINGH, Solanki;KUPPUSAMY, Bhara‐
thimohan;KACHHADIA, Virendra;CHENNIAPPAN, Vinoth Kumar;GANESAN, Karthikeyan;NARAYANAN, Shridhar;
ORCHID PHARMA LTD&lt;unknown&gt;; WO2011/58582; (2011); (A1) English
View in Reaxys

NH 2

HO

Rx-ID: 31237922 View in Reaxys 385/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / 0.5 h / Reflux
2: ammonia / water / Cooling with ice

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 With thionyl chloride, ammonia in water

Louw, Stefan; Burger, Ben V.; Le Roux, Maritha; Van Wyk, Johannes H.; Journal of Natural Products; vol. 74;
nb. 6; (2011); p. 1364 - 1369
View in Reaxys

OH NH 2

O O

O O

O O O O

Rx-ID: 31310436 View in Reaxys 386/636

Yield Conditions & References
Reaction Steps: 2
1: triethylamine; dicyclohexyl-carbodiimide / dichloromethane
2: ammonium formate; triethylamine / 1,4-dioxane
With ammonium formate, triethylamine, dicyclohexyl-carbodiimide in 1,4-dioxane, dichloromethane

Sengoku, Tetsuya; Hamamatsu, Tomoya; Inuzuka, Toshiyasu; Takahashi, Masaki; Yoda, Hidemi; Synlett; nb.
12; (2011); p. 1766 - 1768
View in Reaxys

OH NH 2

O O

O O O O

O O

Rx-ID: 31310443 View in Reaxys 387/636

Yield Conditions & References
Reaction Steps: 2
1: triethylamine; dicyclohexyl-carbodiimide / dichloromethane
2: ammonium formate; triethylamine / 1,4-dioxane
With ammonium formate, triethylamine, dicyclohexyl-carbodiimide in 1,4-dioxane, dichloromethane

Sengoku, Tetsuya; Hamamatsu, Tomoya; Inuzuka, Toshiyasu; Takahashi, Masaki; Yoda, Hidemi; Synlett; nb.
12; (2011); p. 1766 - 1768
View in Reaxys

OH NH 2

O O

O O

O O O O

Rx-ID: 31310448 View in Reaxys 388/636

Yield Conditions & References
Reaction Steps: 2
1: triethylamine; dicyclohexyl-carbodiimide / dichloromethane
2: ammonium formate; triethylamine / 1,4-dioxane

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 With ammonium formate, triethylamine, dicyclohexyl-carbodiimide in 1,4-dioxane, dichloromethane

Sengoku, Tetsuya; Hamamatsu, Tomoya; Inuzuka, Toshiyasu; Takahashi, Masaki; Yoda, Hidemi; Synlett; nb.
12; (2011); p. 1766 - 1768
View in Reaxys

O
NH 2

O
N
O
O

O
O

O O
O O

Rx-ID: 31310464 View in Reaxys 389/636

Yield Conditions & References
With ammonium formate, triethylamine in 1,4-dioxane

Sengoku, Tetsuya; Hamamatsu, Tomoya; Inuzuka, Toshiyasu; Takahashi, Masaki; Yoda, Hidemi; Synlett; nb.
12; (2011); p. 1766 - 1768
View in Reaxys

O
NH 2

O
N
O
O

O O
O O

O
O

Rx-ID: 31310470 View in Reaxys 390/636

Yield Conditions & References
With ammonium formate, triethylamine in 1,4-dioxane

Sengoku, Tetsuya; Hamamatsu, Tomoya; Inuzuka, Toshiyasu; Takahashi, Masaki; Yoda, Hidemi; Synlett; nb.
12; (2011); p. 1766 - 1768
View in Reaxys

O
NH 2

O
N
O
O

O
O

O O
O O

Rx-ID: 31310474 View in Reaxys 391/636

Yield Conditions & References
With ammonium formate, triethylamine in 1,4-dioxane

Sengoku, Tetsuya; Hamamatsu, Tomoya; Inuzuka, Toshiyasu; Takahashi, Masaki; Yoda, Hidemi; Synlett; nb.
12; (2011); p. 1766 - 1768
View in Reaxys

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 N N

N N
S S

O NH O NH

O O

O HN 2

O O

Rx-ID: 32734235 View in Reaxys 392/636

Yield Conditions & References
Reaction Steps: 3
1: water; sodium hydroxide / methanol / 1 h / Reflux
2: thionyl chloride / chloroform / 2.5 h / Reflux
3: ammonia / chloroform; water
With thionyl chloride, ammonia, water, sodium hydroxide in methanol, chloroform, water

Amada, Hideaki; Sekiguchi, Yoshinori; Ono, Naoya; Matsunaga, Yuko; Koami, Takeshi; Asanuma, Hajime;
Shiozawa, Fumiyasu; Endo, Mayumi; Ikeda, Akiko; Aoki, Mari; Fujimoto, Natsuko; Wada, Reiko; Sato, Masa‐
kazu; Bioorganic and Medicinal Chemistry Letters; vol. 22; nb. 5; (2012); p. 2024 - 2029
View in Reaxys

H
N
H
N NH 2

H
NH
H
O
H

H H
N

OH

Rx-ID: 33380076 View in Reaxys 393/636

Yield Conditions & References
Reaction Steps: 2
1: methanol / 4.5 h / 0 °C / Reflux
2: ammonia; calcium chloride / methanol / 18 h / 80 °C
With ammonia, calcium chloride in methanol

Wang, Lisheng; You, Yejun; Wang, Songqing; Liu, Xu; Liu, Buming; Wang, Jinni; Lin, Xiao; Chen, Min‐
gsheng; Liang, Gang; Yang, Hua; Bioorganic and Medicinal Chemistry Letters; vol. 22; nb. 12; (2012); p. 4100 -
4102
View in Reaxys

HO O
Br Br

O NH 2

Rx-ID: 33688212 View in Reaxys 394/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / 2 h / 20 °C / Inert atmosphere; Cooling with ice
2: ammonia; triethylamine / tetrahydrofuran / 5 h / 20 °C / Inert atmosphere
With oxalyl dichloride, ammonia, triethylamine in tetrahydrofuran, dichloromethane

Thuo, Martin M.; Reus, William F.; Simeone, Felice C.; Kim, Choongik; Schulz, Michael D.; Yoon, Hyo Jae;
Whitesides, George M.; Journal of the American Chemical Society; vol. 134; nb. 26; (2012); p. 10876 - 10884
View in Reaxys

HO NH 2
O NH 2

Cl H

O NH 2

Rx-ID: 34334220 View in Reaxys 395/636

Yield Conditions & References
Reaction Steps: 3

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 1.1: sodium hydroxide / 1,4-dioxane; water / 18 h
1.2: pH 3
2.1: 4-methyl-morpholine; isobutyl chloroformate / tetrahydrofuran / 0.28 h / -25 - 15 °C
2.2: -15 - 20 °C
3.1: hydrogenchloride / 1,4-dioxane; diethyl ether / 1 h
With 4-methyl-morpholine, hydrogenchloride, sodium hydroxide, isobutyl chloroformate in tetrahydrofuran, 1,4-diox‐
ane, diethyl ether, water

PatentNUMEDICUS LIMITED;CAVALLA, David; NUMEDICUS&lt;unknown&gt;; WO2012/143703; (2012); (A1) Eng‐

lish
View in Reaxys

O NH 2

S
NH N

S
NH
N

N
S

Rx-ID: 34520023 View in Reaxys 396/636

Yield Conditions & References
Reaction Steps: 2
1: potassium hydroxide / methanol; water; tetrahydrofuran / 20 °C
2: benzotriazol-1-ol; ethylene dichloride hydrochloride; triethylamine / chloroform / 20 °C
With ethylene dichloride hydrochloride, benzotriazol-1-ol, triethylamine, potassium hydroxide in tetrahydrofuran,
methanol, chloroform, water

Amada, Hideaki; Sekiguchi, Yoshinori; Ono, Naoya; Koami, Takeshi; Takayama, Tetsuo; Yabuuchi, Tetsuya;
Katakai, Hironori; Ikeda, Akiko; Aoki, Mari; Naruse, Takumi; Wada, Reiko; Nozoe, Akiko; Sato, Masakazu; Bio‐
organic and Medicinal Chemistry; vol. 20; nb. 24; (2012); p. 7128 - 7138
View in Reaxys

HO O

O NH 2

Rx-ID: 34580101 View in Reaxys 397/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / 3 h / Reflux; Inert atmosphere
2: ammonium hydroxide / water / Cooling with ice; Inert atmosphere
With thionyl chloride, ammonium hydroxide in water

Yoshimura, Akira; Middleton, Kyle R.; Luedtke, Matthew W.; Zhu, Chenjie; Zhdankin, Viktor V.; Journal of Or‐
ganic Chemistry; vol. 77; nb. 24; (2012); p. 11399 - 11404
View in Reaxys

H H
N O N O

O O

O O

OH NH 2

Rx-ID: 34796491 View in Reaxys 398/636

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 Yield Conditions & References
Reaction Steps: 2
1: pyridine; oxalyl dichloride / tetrahydrofuran / 1.5 h / 20 °C / Inert atmosphere
2: ammonia / tetrahydrofuran / 1 h / 15 - 20 °C
With pyridine, oxalyl dichloride, ammonia in tetrahydrofuran

Berger, Michael L.; Pöhler, Thomas; Schadt, Oliver; Stanger, Maximilian; Rebernik, Patrick; Scholze, Petra;
Noe, Christian R.; ChemMedChem; vol. 8; nb. 1; (2013); p. 82 - 94
View in Reaxys

H
2

H
2

H
2

H O
HO
2

H
NH 2

O H
2 2 2 2
2

H H H H H

Rx-ID: 35513388 View in Reaxys 399/636

Yield Conditions & References
Reaction Steps: 3
1: water-d2; 10% Pt/activated carbon; [D]-sodium hydroxide / 144 h / 220 °C
2: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 5 h / 50 °C
3: ammonium hydroxide / acetonitrile / 2 h / 0 - 20 °C
With ammonium hydroxide, thionyl chloride, [D]-sodium hydroxide, 10% Pt/activated carbon, water-d2, N,N-dimeth‐
yl-formamide in dichloromethane, acetonitrile

Yepuri, Nageshwar R.; Jamieson, Scott A.; Darwish, Tamim A.; Rawal, Aditya; Hook, James M.; Thordarson,
Pall; Holden, Peter J.; James, Michael; Tetrahedron Letters; vol. 54; nb. 20; (2013); p. 2538 - 2541
View in Reaxys

H 2

H
2

H
2 2

H
2

H
2

H
2

H
2

H O
2
H
H
2

OH H
2

H NH 2

H
2 2 2 2
2

H
2

H
2

H
2

H O
2

H H H H H

Rx-ID: 35513392 View in Reaxys 400/636

Yield Conditions & References
Reaction Steps: 2
1: N,N-dimethyl-formamide; thionyl chloride / dichloromethane / 5 h / 50 °C
2: ammonium hydroxide / acetonitrile / 2 h / 0 - 20 °C
With ammonium hydroxide, thionyl chloride, N,N-dimethyl-formamide in dichloromethane, acetonitrile

Yepuri, Nageshwar R.; Jamieson, Scott A.; Darwish, Tamim A.; Rawal, Aditya; Hook, James M.; Thordarson,
Pall; Holden, Peter J.; James, Michael; Tetrahedron Letters; vol. 54; nb. 20; (2013); p. 2538 - 2541
View in Reaxys

O O O O

H H

N N

O O

OH NH 2

O O

Rx-ID: 36781082 View in Reaxys 401/636

Yield Conditions & References
Reaction Steps: 2
1: N,N-dimethyl-formamide; oxalyl dichloride / dichloromethane / 0.5 h / 20 °C
2: ammonia / methanol; dichloromethane / 2 h / 20 °C
With oxalyl dichloride, ammonia, N,N-dimethyl-formamide in methanol, dichloromethane

PatentPURDUE PHARMA L.P.;TAFESSE, Laykea;PARK, Jae, Hyun;YU, Jianming;ROSEN, David; PURDUE

PHARMA L.P.Purdue Pharma; WO2013/167963; (2013); (A1) English
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 2
Cl O NH 2
HCl
Cl O O

N
N

H
H

H H
H H N
N

Rx-ID: 38292899 View in Reaxys 402/636

Yield Conditions & References
Reaction Steps: 2
1: hydrogenchloride; water / 3 h / Reflux
2: ammonium bicarbonate; di-tert-butyl dicarbonate; pyridine / acetonitrile / 20 °C
With pyridine, hydrogenchloride, di-tert-butyl dicarbonate, water, ammonium bicarbonate in acetonitrile

Bi, Chong-Wen; Zhang, Cai-Xia; Li, Ying-Hong; Tang, Sheng; Deng, Hong-Bin; Zhao, Wu-Li; Wang, Zhen;
Shao, Rong-Guang; Song, Dan-Qing; European Journal of Medicinal Chemistry; vol. 81; (2014); p. 95 - 105
View in Reaxys

F
F
F F

O O O
S
O S
HCl HCl
N
N NH 2

H
H H H
O
O

H H
H H
N O
N

Rx-ID: 40638107 View in Reaxys 403/636

Yield Conditions & References
Reaction Steps: 2
1.1: hydrogenchloride / water / 3 h / Reflux
2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol; N-ethyl-N,N-diisopropyla‐
mine / dichloromethane / 0.5 h / 20 °C
2.2: 12 h / 20 °C
With hydrogenchloride, benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, N-ethyl-
N,N-diisopropylamine in dichloromethane, water

Li, Yu-Huan; Wang, Sheng-Gang; Kong, Lan-Ying; Li, Ying-Hong; Cheng, Xin-Yue; Su, Feng; Tang, Sheng; Bi,
Chong-Wen; Jiang, Jian-Dong; Song, Dan-Qing; Bioorganic and Medicinal Chemistry Letters; vol. 25; nb. 17;
(2015); p. 3690 - 3693
View in Reaxys

F
O

N N O O

N
N

F
O

N N O NH 2

N
N

Rx-ID: 44247211 View in Reaxys 404/636

Yield Conditions & References
Reaction Steps: 2
1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 3 h / 20 °C
2: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 2 h / 20 °C

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 With lithium hydroxide monohydrate, water, 1,1'-carbonyldiimidazole in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

N
N

N N O O

O
F

F
O

N N O NH 2

N
N

Rx-ID: 44247393 View in Reaxys 405/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide; water / methanol; tetrahydrofuran / 10 h / 20 °C
2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 3 h / 20 °C
2.2: 10 h / 20 °C
With water, 1,1'-carbonyldiimidazole, lithium hydroxide in tetrahydrofuran, methanol, N,N-dimethyl-formamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

N O

N N O O

N
N

N O

N N O NH 2

N
N

Rx-ID: 44248067 View in Reaxys 406/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 20 °C
2.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C
2.2: 10 h / 20 °C
With lithium hydroxide monohydrate, water, triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyri‐
din-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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 F

O N

O O N N

N
N

N O

N N O NH 2

N
N

Rx-ID: 44248072 View in Reaxys 407/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 20 °C
2.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C
2.2: 10 h / 20 °C
With lithium hydroxide monohydrate, water, triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyri‐
din-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

N
O N

O N N
O

N
O N

O N N
HN
2

Rx-ID: 44248138 View in Reaxys 408/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 20 °C
2.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C
2.2: 10 h / 20 °C
With lithium hydroxide monohydrate, water, triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyri‐
din-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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 F

O
N N O

N O
N

NH 2

N N O

N O
N

Rx-ID: 44248146 View in Reaxys 409/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 20 °C
2.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C
2.2: 10 h / 20 °C
With lithium hydroxide monohydrate, water, triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyri‐
din-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

N
O

N N O
O

N
O

N N O
NH 2

Rx-ID: 44248149 View in Reaxys 410/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 20 °C
2.1: triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium
hexafluorophosphate / N,N-dimethyl-formamide / 0.17 h / 20 °C
2.2: 10 h / 20 °C
With lithium hydroxide monohydrate, water, triethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyri‐
din-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
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 F

N O

N N O O

N O

N N O NH 2

N
N

Rx-ID: 44248211 View in Reaxys 411/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate; water / methanol; tetrahydrofuran / 20 °C
2.1: 1,1'-carbonyldiimidazole / N,N-dimethyl-formamide / 4 h / 20 °C
2.2: 20 °C
With lithium hydroxide monohydrate, water, 1,1'-carbonyldiimidazole in tetrahydrofuran, methanol, N,N-dimethyl-for‐
mamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.; ROCHE HOLDING AGRoche;

WO2016/177655; (2016); (A1) English
View in Reaxys

O
H
N O

O O

N
O

H
N O
HN
2
O

Rx-ID: 45708749 View in Reaxys 412/636

Yield Conditions & References
Reaction Steps: 2
1: sodium hydroxide / methanol; tetrahydrofuran / 1.5 h / 20 °C
2: N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-di‐
methyl-formamide / 17 h / 20 °C
With N-hydroxybenzotriazole ammonium salt, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, so‐
dium hydroxide in tetrahydrofuran, methanol, N,N-dimethyl-formamide

Maezaki, Hironobu; Tawada, Michiko; Yamashita, Tohru; Banno, Yoshihiro; Miyamoto, Yasufumi; Yamamoto,
Yoshio; Ikedo, Koji; Kosaka, Takuo; Tsubotani, Shigetoshi; Tani, Akiyoshi; Asakawa, Tomoko; Suzuki, Nobu‐
hiro; Oi, Satoru; Bioorganic and Medicinal Chemistry Letters; vol. 27; nb. 15; (2017); p. 3565 - 3571
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 O
O O

O
N O
N

OH NH 2

Rx-ID: 46582099 View in Reaxys 413/636

Yield Conditions & References
Reaction Steps: 2
1: triethylamine / tetrahydrofuran / 1.08 h / 0 °C
2: ammonium hydroxide / tetrahydrofuran; water / 0 - 20 °C
With ammonium hydroxide, triethylamine in tetrahydrofuran, water

Chen, Dian-Feng; Chu, John C. K.; Rovis, Tomislav; Journal of the American Chemical Society; vol. 139; nb. 42;
(2017); p. 14897 - 14900
View in Reaxys

N O
O

O
O N

NH 2

Rx-ID: 46677418 View in Reaxys 414/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide; water / 1,4-dioxane / 1.5 h / 50 °C
2.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-meth‐
ylmethanaminium hexafluorophosphate / tetrahydrofuran / 1 h
2.2: 18 h
With water, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-
N-methylmethanaminium hexafluorophosphate, lithium hydroxide in tetrahydrofuran, 1,4-dioxane

PatentABBVIE INC.; ABBVIE INCAbbVie; WO2017/177004; (2017); (A1) English

View in Reaxys

O
O

HN

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 O

O
N

HN
O

HN
2

Rx-ID: 47427206 View in Reaxys 415/636

Yield Conditions & References
Reaction Steps: 2
1.1: lithium hydroxide monohydrate / methanol / 18 h / 20 °C / Inert atmosphere
2.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine /
N,N-dimethyl-formamide / 0.5 h / 20 °C
2.2: 18 h / 20 °C
With lithium hydroxide monohydrate, O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate,
N-ethyl-N,N-diisopropylamine in methanol, N,N-dimethyl-formamide

PatentNEUROPORE THERAPIES, INC.;WRASIDLO, Wolfgang;NATALA, Srinivasa, Reddy; NEUROPORE THERA‐

PIES&lt;unknown&gt;; WO2018/26866; (2018); (A1) English
View in Reaxys

O O

N N

H O H O

O O

H H
H O H NH 2

O O

O O

Rx-ID: 48321914 View in Reaxys 416/636

Yield Conditions & References
Reaction Steps: 2
1.1: Novozyme 435 on acrylic resin / tetrahydrofuran; aq. phosphate buffer / 3 h / 20 °C / pH 7 / Enzymatic reaction
2.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-meth‐
ylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 20 °C / Inert atmosphere
2.2: 2 h / 20 °C / Inert atmosphere
With N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-
methylmethanaminium hexafluorophosphate in tetrahydrofuran, aq. phosphate buffer, N,N-dimethyl-formamide

Soethoudt, Marjolein; Stolze, Sara C.; Westphal, Matthias V.; Van Stralen, Luuk; Martella, Andrea; Van Roo‐
den, Eva J.; Guba, Wolfgang; Varga, Zoltan V.; Deng, Hui; Van Kasteren, Sander I.; Grether, Uwe; Ijzerman,
Adriaan P.; Pacher, Pal; Carreira, Erick M.; Overkleeft, Herman S.; Ioan-Facsinay, Andreea; Heitman, Laura
H.; Van Der Stelt, Mario; Journal of the American Chemical Society; vol. 140; nb. 19; (2018); p. 6067 - 6075
View in Reaxys

O O

HCl
O NH NH 2
NH

Rx-ID: 50886052 View in Reaxys 417/636

Yield Conditions & References
With ammonium hydroxide, ammonia, Time= 4h, T= 20 °C

Staszewski, Marek; Stasiak, Anna; Karcz, Tadeusz; McNaught Flores, Daniel; Fogel, Wiesława Agnieszka;
Kieć-Kononowicz, Katarzyna; Leurs, Rob; Walczyński, Krzysztof; MedChemComm; vol. 10; nb. 2; (2019); p.
234 - 251

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

NH 2

H OH
O

HO

Rx-ID: 51304533 View in Reaxys 418/636

Yield Conditions & References
Reaction Steps: 2
1: methanesulfonyl chloride
2: ammonia / 1,4-dioxane / 96 h / 30 °C
With ammonia, methanesulfonyl chloride in 1,4-dioxane

Matysiak, Sylwia; Kula, Józef; Błaszczyk, Alina; Medicinal Chemistry Research; vol. 28; nb. 7; (2019); p. 948 -
958
View in Reaxys

O O

O N O
O N O

O NH 2

Rx-ID: 51454036 View in Reaxys 419/636

Yield Conditions & References
Reaction Steps: 2
1: lithium hydroxide; water / tetrahydrofuran / 1 h / 0 - 60 °C
2: N-ethyl-N,N-diisopropylamine; ammonium chloride; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-
methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 20 °C
With water, ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-
b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate, lithium hydroxide in tetrahydrofuran, N,N-
dimethyl-formamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.;CHENG, Zhanling;HAN, Xingchun;JIANG,

Min;WANG, Jianhua;WANG, Yongguang;YANG, Song; ROCHE HOLDING AGRoche; WO2018/1952; (2018); (A1)
English
View in Reaxys

O O

O N O

O N O

O NH 2

Rx-ID: 51454055 View in Reaxys 420/636

Yield Conditions & References
Reaction Steps: 2
1: lithium hydroxide monohydrate / tetrahydrofuran / 1 h / 0 - 60 °C
2: N-ethyl-N,N-diisopropylamine; ammonium chloride; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-
methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 3 h / 20 °C
With lithium hydroxide monohydrate, ammonium chloride, N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-
oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate in tetrahydrofur‐
an, N,N-dimethyl-formamide

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.;CHENG, Zhanling;HAN, Xingchun;JIANG,

Min;WANG, Jianhua;WANG, Yongguang;YANG, Song; ROCHE HOLDING AGRoche; WO2018/1952; (2018); (A1)
English
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 HO NH 2
O NH 2

O NH 2

Rx-ID: 51454340 View in Reaxys 421/636

Yield Conditions & References
Reaction Steps: 3
1.1: sodium hydroxide / water; 1,4-dioxane / 0.5 h / 20 °C
1.2: 16 h / 20 °C
2.1: 4-methyl-morpholine / tetrahydrofuran / 1 h / -20 - 0 °C
2.2: 16.5 h / 0 - 20 °C / Inert atmosphere
3.1: hydrogenchloride / 1,4-dioxane; ethyl acetate / 16 h / 20 °C
With 4-methyl-morpholine, hydrogenchloride, sodium hydroxide in tetrahydrofuran, 1,4-dioxane, water, ethyl acetate

PatentF. HOFFMANN-LA ROCHE AG;HOFFMANN-LA ROCHE INC.;CHENG, Zhanling;HAN, Xingchun;JIANG,

Min;WANG, Jianhua;WANG, Yongguang;YANG, Song; ROCHE HOLDING AGRoche; WO2018/1952; (2018); (A1)
English
View in Reaxys

HO O

O NH 2

Rx-ID: 51958970 View in Reaxys 422/636

Yield Conditions & References
With Pseudoalteromonas tunicata TamA catalytic adenylation domain, ammonia, ATP, magnesium chloride in di‐
methyl sulfoxide, pH= 9, Enzymatic reaction

Marchetti, Piera M.; Richardson, Shona M.; Kariem, Noor M.; Campopiano, Dominic J.; MedChemComm; vol.
10; nb. 7; (2019); p. 1192 - 1196
View in Reaxys

O O O O

N N
O O
N O N O

O N HN
2
N
H H
O O

Rx-ID: 54083221 View in Reaxys 423/636

Yield Conditions & References
With trifluoroacetic acid, Time= 2h, T= 20 °C

Han, Xiao-Ran; Chen, Liqun; Wei, Yuanqi; Yu, Weihua; Chen, Yanke; Zhang, Chunyan; Jiao, Bingyang; Shi,
Tingting; Sun, Lei; Zhang, Chao; Xu, Yang; Lee, Matthew R.; Luo, Ying; Plewe, Michael B.; Wang, Jialiang;
Journal of Medicinal Chemistry; vol. 63; nb. 8; (2020); p. 4069 - 4080
View in Reaxys

N
O

N N
O
Cl
N
S

S
N
Cl
O
N N

NH
N
2

Rx-ID: 55032752 View in Reaxys 424/636

Yield Conditions & References
Reaction Steps: 2
1: lithium hydroxide; water / 2-methyltetrahydrofuran / 4 h / 20 °C
2: benzotriazol-1-ol; ammonium chloride; (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophos‐
phate / N,N-dimethyl-formamide

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 With water, (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, ammonium chloride, ben‐
zotriazol-1-ol, lithium hydroxide in 2-methyltetrahydrofuran, N,N-dimethyl-formamide

PatentSPEROVIE BIOSCIENCES, INC.; SINO BIOPHARMACEUTICAL LIMITEDSino Biopharmaceutical;

WO2020/181050; (2020); (A1) English
View in Reaxys

HO OH HO OH

OH HO

HO O O OH

HO HN NH OH

N N

S
O O

HO OH HO OH

OH HO

HO O O OH

HO HN NH OH

N N

S
O NH 2

Rx-ID: 55797027 View in Reaxys 425/636

Yield Conditions & References
Reaction Steps: 2
1.1: sodium hydroxide; water / 40 h / 20 °C / pH 11
2.1: 4-methyl-morpholine / N,N-dimethyl-formamide / 0.5 h / Inert atmosphere
2.2: 1 h
2.3: 48 h
With 4-methyl-morpholine, water, sodium hydroxide in N,N-dimethyl-formamide

PatentBRACCO IMAGING SPA; BRACCO SPABracco; WO2020/229438; (2020); (A1) English

View in Reaxys

HO N O
N
N
N N

O HN
2 N

Rx-ID: 55917131 View in Reaxys 426/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl dichloride / dichloromethane / 12 h / 0 - 20 °C
2: ammonium hydroxide / 0.17 h / 0 °C
With ammonium hydroxide, oxalyl dichloride in dichloromethane

Hoki, Jason S.; Le, Henry H.; Mellott, Karlie E.; Zhang, Ying K.; Fox, Bennett W.; Rodrigues, Pedro R.; Yu,
Yan; Helf, Maximilian J.; Baccile, Joshua A.; Schroeder, Frank C.; Journal of the American Chemical Society;
vol. 142; nb. 43; (2020); p. 18449 - 18459
View in Reaxys

HO Br O Br

O NH 2

Rx-ID: 57402219 View in Reaxys 427/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
Reaction Steps: 2
1: N,N-dimethyl-formamide; thionyl chloride / toluene / 1 h / 80 °C
2: ammonium hydroxide / toluene; water / 0.5 h / 0 °C
With ammonium hydroxide, thionyl chloride, N,N-dimethyl-formamide in water, toluene

Klunda, Tomáš; Hricovíni, Michal; Šesták, Sergej; Kóňa, Juraj; Poláková, Monika; New Journal of Chemistry;
vol. 45; nb. 24; (2021); p. 10940 - 10951
View in Reaxys

OH
S
S NH
S
2

S
S
S

Rx-ID: 59956362 View in Reaxys 428/636

Yield Conditions & References
Reaction Steps: 2
1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / dichloromethane / 8 h / 20 °C / Inert atmosphere
2: ammonium hydroxide / dichloromethane / 0.08 h / 20 °C
With ammonium hydroxide, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane

PatentKYOWA PHARMA CHEMICAL CO., LTD.; KIRIN HOLDINGS CO LTD; XIEHE PHARMACEUTICAL CHEMI‐
CALKirin Holdings; &lt;unknown&gt;; WO2022/45212; (2022); (A1) Japanese
View in Reaxys

NH
O
HN
O
N
O O O
N
H
N
NH O
O
O

NH
O
HN
O
N
O O O
N
H
N
NH NH 2

O
O

Rx-ID: 61011201 View in Reaxys 429/636

Yield Conditions & References
Reaction Steps: 2
1: lithium hydroxide monohydrate; lithium hydroxide monohydrate / tetrahydrofuran; methanol / 3 h / 0 - 20 °C / Inert
atmosphere
2: ammonia hydrochloride; 1-hydroxy-7-aza-benzotriazole; 2,6-dimethylpyridine; N-[3-(N,N-dimethylamino)-propyl]-
N'-ethyl-carbodiimide hydrochloride / N,N-dimethyl-formamide / 23.5 h / 0 - 25 °C / Inert atmosphere
With 2,6-dimethylpyridine, 1-hydroxy-7-aza-benzotriazole, lithium hydroxide monohydrate, ammonia hydrochloride,
N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride, lithium hydroxide monohydrate in tetrahydro‐
furan, methanol, N,N-dimethyl-formamide

Yang, Ming-Hsiu;Russell, Jamie L.;Mifune, Yuto;Wang, Ying;Shi, Hexin;Moresco, Eva Marie Y.;Siegwart, Dan‐
iel J.;Beutler, Bruce;Boger, Dale L.; Journal of Medicinal Chemistry; vol. 65; nb. 13; (2022); p. 9230 - 9252

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

OH

13

O C

15

NH 2

13

Rx-ID: 61962135 View in Reaxys 430/636

Yield Conditions & References
Reaction Steps: 2
1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 0 °C
2: [15N]-ammonium hydroxide / tetrahydrofuran; water / 3 h
With oxalyl dichloride, [15N]-ammonium hydroxide, N,N-dimethyl-formamide in tetrahydrofuran, dichloromethane,
water

Kobayashi, Yasuyuki;Watanabe, Natsumi;Hiura, Reina;Kubota, Mai;Furuta, Kousuke;Sugimoto, Keii‐

chiro;Murota, Kaeko;Nakamura, Eri;Matsuura, Toshiki;Kai, Kenji;Inui, Takashi;Kitakaze, Tomoya;Harada,
Naoki;Yamaji, Ryoichi; Journal of Agricultural and Food Chemistry; vol. 70; nb. 49; (2022); p. 15499 - 15508
View in Reaxys

HO

NH 2

Rx-ID: 64163389 View in Reaxys 431/636

Yield Conditions & References
Reaction Steps: 3
1: nitric acid; sodium nitrite; cis-nitrous acid / 30 min / 70 °C / Inert atmosphere
2: thionyl chloride / 3 h / 90 °C
3: ammonia / dichloromethane; water / 12 h / 20 °C
With thionyl chloride, ammonia, nitric acid, cis-nitrous acid, sodium nitrite in dichloromethane, water

PatentPEKING UNIVERSITY;INSTITUTE OF GENETICS AND DEVELOPMENTAL BIOLOGY, CHINESE ACADE‐

MY OF SCIENCES; PEKING UNIVERSITY; CHINESE ACADEMY OF SCIENCESPeking University; Chinese Acad‐
emy of Sciences; WO2023/104017; (2023); (A1) English
View in Reaxys

HO

NH 2

Rx-ID: 64163394 View in Reaxys 432/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / 3 h / 90 °C
2: ammonia / dichloromethane; water / 12 h / 20 °C
With thionyl chloride, ammonia in dichloromethane, water

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 PatentPEKING UNIVERSITY;INSTITUTE OF GENETICS AND DEVELOPMENTAL BIOLOGY, CHINESE ACADE‐
MY OF SCIENCES; PEKING UNIVERSITY; CHINESE ACADEMY OF SCIENCESPeking University; Chinese Acad‐
emy of Sciences; WO2023/104017; (2023); (A1) English
View in Reaxys

NH 2

O
HO

Rx-ID: 64163396 View in Reaxys 433/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / 3 h / 90 °C
2: ammonia / dichloromethane; methanol / 12 h / 0 °C
With thionyl chloride, ammonia in methanol, dichloromethane

PatentPEKING UNIVERSITY;INSTITUTE OF GENETICS AND DEVELOPMENTAL BIOLOGY, CHINESE ACADE‐

MY OF SCIENCES; PEKING UNIVERSITY; CHINESE ACADEMY OF SCIENCESPeking University; Chinese Acad‐
emy of Sciences; WO2023/104017; (2023); (A1) English
View in Reaxys

HO HN
2

O O

Rx-ID: 64163399 View in Reaxys 434/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride / 3 h / 90 °C
2: ammonia / dichloromethane; methanol / 12 h / 0 °C
With thionyl chloride, ammonia in methanol, dichloromethane

PatentPEKING UNIVERSITY;INSTITUTE OF GENETICS AND DEVELOPMENTAL BIOLOGY, CHINESE ACADE‐

MY OF SCIENCES; PEKING UNIVERSITY; CHINESE ACADEMY OF SCIENCESPeking University; Chinese Acad‐
emy of Sciences; WO2023/104017; (2023); (A1) English
View in Reaxys

O OH O OH

H NH 2
H NH 2

OH NH 2

O O

Rx-ID: 203797 View in Reaxys 435/636

Yield Conditions & References
With hydrogenchloride, Behandeln des Reaktionsprodukts mit Chlorokohlensaeure-benzylester und wss.NH3 und
Hydrieren des Reaktionsprodukts an Palladium in Essigsaeure

Meister; Journal of Biological Chemistry; vol. 210; (1954); p. 17,21

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 O O

H H

OH NH 2

Rx-ID: 204728 View in Reaxys 436/636

Yield Conditions & References
With thionyl chloride, anschliessend Behandeln mit konz.NH3

Velick; English; Journal of Biological Chemistry; vol. 160; (1945); p. 477

View in Reaxys

HO O

O NH 2

Rx-ID: 236813 View in Reaxys 437/636

Yield Conditions & References
With phosphorus pentachloride, anschliessend mit wss.Ammoniak

Wotiz; Hudak; Journal of Organic Chemistry; vol. 19; (1954); p. 1580,1587

View in Reaxys

HO O

O NH 2

Rx-ID: 238067 View in Reaxys 438/636

Yield Conditions & References
With phosphorus pentachloride, anschliessend mit wss.Ammoniak

Wotiz; Hudak; Journal of Organic Chemistry; vol. 19; (1954); p. 1580,1587

View in Reaxys

HO O

O NH 2

Rx-ID: 238070 View in Reaxys 439/636

Yield Conditions & References
With phosphorus pentachloride, anschliessend mit wss.Ammoniak

Wotiz; Hudak; Journal of Organic Chemistry; vol. 19; (1954); p. 1580,1587

View in Reaxys

F F

HO

F F

NH 2

Rx-ID: 255511 View in Reaxys 440/636

Yield Conditions & References
With thionyl chloride, und Behandeln einer Loesung des erhaltenen Saeurechlorids in Chloroform mit Ammoniak

Gavlin; Maguire; Journal of Organic Chemistry; vol. 21; (1956); p. 1342,1346

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 OH

NH 2

Rx-ID: 256154 View in Reaxys 441/636

Yield Conditions & References
With thionyl chloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Cason; McLeod; Journal of Organic Chemistry; vol. 23; (1958); p. 1497,1499

View in Reaxys

OH

NH 2

Rx-ID: 256165 View in Reaxys 442/636

Yield Conditions & References
With thionyl chloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Cason; McLeod; Journal of Organic Chemistry; vol. 23; (1958); p. 1497,1499

View in Reaxys

OH

NH 2

Rx-ID: 260495 View in Reaxys 443/636

Yield Conditions & References
With thionyl chloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Cason; McLeod; Journal of Organic Chemistry; vol. 23; (1958); p. 1497,1499

View in Reaxys

O
N

Br
O

HN
2

Br
O

Rx-ID: 544804 View in Reaxys 444/636

Yield Conditions & References
With methanol, ammonia

Swain et al.; Journal of Organic Chemistry; vol. 18; (1953); p. 1087,1088

View in Reaxys

HO OH H H O O HO O H H
2 N N

O O H NH 2
NH 2
O NH 2
H

Rx-ID: 2460879 View in Reaxys 445/636

Yield Conditions & References
1.5 % T= 19.9 °C , p= 60004800Torr
Chromat.,

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 18.0 % Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
Chromat. vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

O
H H
HO 2 N
OH
H
O

NH 2 NH 2

H H
O HO N
O O
H
NH 2 O

Rx-ID: 2462535 View in Reaxys 446/636

Yield Conditions & References
3.0 % T= 19.9 °C , p= 60004800Torr
Chromat.,
24.0 % Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
Chromat. vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

O NH 2

O
F
O
O
F
NH HN
O F
F
F O O
O F
O

F
F O F

Rx-ID: 8728324 View in Reaxys 447/636

Yield Conditions & References
With ammonium hydroxide, dicyclohexyl-carbodiimide

Moroni; Koksch; Osipov; Crucianelli; Frigerio; Bravo; Burger; Journal of Organic Chemistry; vol. 66; nb. 1;
(2001); p. 130 - 133
View in Reaxys

F F

NH 2

O
F F
O O
O O
O O
O
O O
F O
NH NH
F

F
F
F F

Rx-ID: 8729214 View in Reaxys 448/636

Yield Conditions & References
With ammonium hydroxide, dicyclohexyl-carbodiimide

Moroni; Koksch; Osipov; Crucianelli; Frigerio; Bravo; Burger; Journal of Organic Chemistry; vol. 66; nb. 1;
(2001); p. 130 - 133
View in Reaxys

HO O
O O

O NH 2

Rx-ID: 12654718 View in Reaxys 449/636

Yield Conditions & References
Reaction Steps: 2
1: (COCl)2; DMF
2: 4.15 g / aq. NH3

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 With ammonium hydroxide, oxalyl dichloride, N,N-dimethyl-formamide

Ligthart; Ohkawa, Haruki; Sijbesma, Rint P.; Meijer; Journal of Organic Chemistry; vol. 71; nb. 1; (2006); p. 375 -
378
View in Reaxys

HO O

O NH 2

O O

HN HN

O O O O
F F

O F O F

Rx-ID: 15659327 View in Reaxys 450/636

Yield Conditions & References
Reaction Steps: 2
1: pyridine
2: NH4OH; DCC
With pyridine, ammonium hydroxide, dicyclohexyl-carbodiimide

Moroni; Koksch; Osipov; Crucianelli; Frigerio; Bravo; Burger; Journal of Organic Chemistry; vol. 66; nb. 1;
(2001); p. 130 - 133
View in Reaxys

O NH 2

HO O

O O O O
O O

O O
NH NH
F F

F F
F F

Rx-ID: 15661739 View in Reaxys 451/636

Yield Conditions & References
Reaction Steps: 2
1: pyridine
2: NH4OH; DCC
With pyridine, ammonium hydroxide, dicyclohexyl-carbodiimide

Moroni; Koksch; Osipov; Crucianelli; Frigerio; Bravo; Burger; Journal of Organic Chemistry; vol. 66; nb. 1;
(2001); p. 130 - 133
View in Reaxys

HO O

O NH 2

Rx-ID: 21996870 View in Reaxys 452/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2
2: NH3
With thionyl chloride, ammonia

Mihina; Herbst; Journal of Organic Chemistry; vol. 15; (1950); p. 1082,1087

View in Reaxys

O O

O NH 2

Rx-ID: 22034315 View in Reaxys 453/636

Yield Conditions & References
Reaction Steps: 2
1: aqueous KOH-solution

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 With potassium hydroxide

Wotiz; Buco; Journal of Organic Chemistry; vol. 20; (1955); p. 210,213

View in Reaxys

F F

F F

NH 2

Rx-ID: 22123254 View in Reaxys 454/636

Yield Conditions & References
Reaction Steps: 2
1: ethanol; NaOH-solution
2: thionyl chloride / und Behandeln einer Loesung des erhaltenen Saeurechlorids in Chloroform mit Ammoniak
With sodium hydroxide, thionyl chloride, ethanol

Gavlin; Maguire; Journal of Organic Chemistry; vol. 21; (1956); p. 1342,1346

View in Reaxys

O O

OH NH 2

H H

Rx-ID: 22175498 View in Reaxys 455/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2
2: water; NH3 / -10 °C
With thionyl chloride, ammonia, water

Levene; Rothen; Marker; Journal of Biological Chemistry; vol. 115; (1936); p. 261
View in Reaxys

HO O
F F

O NH 2

Rx-ID: 22179871 View in Reaxys 456/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride
2: benzene; ammonia
With thionyl chloride, ammonia, benzene

Pattison et al.; Journal of Organic Chemistry; vol. 21; (1956); p. 887; Journal of the American Chemical Society;
vol. 78; (1956); p. 3484,3486
View in Reaxys

HO O
F F

O NH 2

Rx-ID: 22180380 View in Reaxys 457/636

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 Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride
2: benzene; ammonia
With thionyl chloride, ammonia, benzene

Pattison et al.; Journal of Organic Chemistry; vol. 21; (1956); p. 887; Journal of the American Chemical Society;
vol. 78; (1956); p. 3484,3486
View in Reaxys

NH 2

Rx-ID: 22182669 View in Reaxys 458/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: thionyl chloride / und Behandeln des Reaktionsprodukts mit wss.Ammoniak
With potassium hydroxide, thionyl chloride

Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143

View in Reaxys

NH 2

Rx-ID: 22182776 View in Reaxys 459/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: thionyl chloride / und Behandeln des Reaktionsprodukts mit wss.Ammoniak
With potassium hydroxide, thionyl chloride

Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143

View in Reaxys

NH 2

Rx-ID: 22182777 View in Reaxys 460/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: thionyl chloride / und Behandeln des Reaktionsprodukts mit wss.Ammoniak
With potassium hydroxide, thionyl chloride

Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143

View in Reaxys

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 O

NH 2

Rx-ID: 22182778 View in Reaxys 461/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: thionyl chloride / und Behandeln des Reaktionsprodukts mit wss.Ammoniak
With potassium hydroxide, thionyl chloride

Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143

View in Reaxys

NH 2

Rx-ID: 22182905 View in Reaxys 462/636

Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH-solution
2: thionyl chloride / und Behandeln des Reaktionsprodukts mit wss.Ammoniak
With potassium hydroxide, thionyl chloride

Cason; Winans; Journal of Organic Chemistry; vol. 15; (1950); p. 139,143

View in Reaxys

O O

O NH 2

Rx-ID: 228893 View in Reaxys 463/636

Yield Conditions & References
With ammonia, water

Meyer,H.; Monatshefte fur Chemie; vol. 22; (1901); p. 418; Monatshefte fuer Chemie; vol. 27; (1906); p. 43
View in Reaxys

Reaction Steps: 2
1: ammonia
2: sodium / 6 h / 140 °C / Autoclave
With ammonia, sodium

PatentZhejiang University;Qian Chao;Ouyang Bo;Chen Xinzhi; ZHEJIANG UNIVERSITYZhejiang University;

CN106928083; (2017); (A) English
View in Reaxys

O HO O

O O NH 2

Rx-ID: 1948110 View in Reaxys 464/636

Yield Conditions & References
5 % Chro‐ With ammonia in tert-butyl alcohol, Time= 24h, Ambient temperature, Candida antarctica lipase SP435
mat., 95 %
Chromat. Zoete, Marian C. de; Kock-van Dalen, Alida C.; Rantwijk, Fred van; Sheldon, Roger A.; Journal of the Chemical
Society. Chemical communications; nb. 24; (1993); p. 1831 - 1832

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

With ammonia in tert-butyl alcohol, Time= 24h, Ambient temperature, Candida antarctica lipase SP435; other carbox‐
ylic esters, Product distribution

Zoete, Marian C. de; Kock-van Dalen, Alida C.; Rantwijk, Fred van; Sheldon, Roger A.; Journal of the Chemical
Society. Chemical communications; nb. 24; (1993); p. 1831 - 1832
View in Reaxys

With Candida antarctica lipase B (Novozym 435), ammonia, 1-butyl-3-methylimidazolium Tetrafluoroborate, Time=
24h, T= 40 °C , Product distribution, Further Variations: Reaction partners, Reagents, Solvents

Madeira Lau; van Rantwijk; Seddon; Sheldon; Organic letters; vol. 2; nb. 26; (2000); p. 4189 - 4191
View in Reaxys

H HN
HO 2

N
N

O O
O O

Rx-ID: 2937725 View in Reaxys 465/636

Yield Conditions & References
85 % With iron(II) chloride, Time= 20h, T= 170 °C , other temperature; other reaction time, Product distribution

Vorob'eva, E. M.; Litvyak, I. G.; Sumarokova, T. N.; Journal of general chemistry of the USSR; vol. 50; nb. 11;
(1980); p. 2043 - 2048; Zhurnal Obshchei Khimii; vol. 50; nb. 11; (1980); p. 2525 - 2531
View in Reaxys

H HN
HO 2

N
N

O O
O O

Rx-ID: 2937784 View in Reaxys 466/636

Yield Conditions & References
85 % With iron(II) chloride, Time= 19h, T= 170 °C , other temperature; other reaction time, Product distribution

Vorob'eva, E. M.; Litvyak, I. G.; Sumarokova, T. N.; Journal of general chemistry of the USSR; vol. 50; nb. 11;
(1980); p. 2043 - 2048; Zhurnal Obshchei Khimii; vol. 50; nb. 11; (1980); p. 2525 - 2531
View in Reaxys

H
O N O

NH 2

HO

NH 2

Rx-ID: 206023 View in Reaxys 467/636

Yield Conditions & References
T= 230 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217
View in Reaxys

T= 230 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217

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 View in Reaxys

T= 230 °C

PatentResinous Prod. & Chem.Co.; RESINOUS PROD CHEMICAL&lt;unknown&gt;; US1989968; (1934); (A)
View in Reaxys

OH O

O NH 2

Rx-ID: 249316 View in Reaxys 468/636

Yield Conditions & References
With oxalyl dichloride, benzene, anschliessend Behandeln mit konz.NH3

Arosenius et al.; Arkiv foer Kemi; vol. 26 A; nb. 19; (1949); p. 10

View in Reaxys

With thionyl chloride, Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 65,88
View in Reaxys

HO O O NH 2

Rx-ID: 311133 View in Reaxys 469/636

Yield Conditions & References
With diethyl ether, phosphorus trichloride, Behandeln des Reaktionsprodukts mit konz. Ammoniak bei 0grad

Power; Barrowcliff; Journal of the Chemical Society; vol. 87; (1905); p. 895
View in Reaxys

With ammonium hydroxide, phosphorus trichloride

Bokil; Nargund; Proceedings - Indian Academy of Sciences, Section A; vol. <A> 13; (1941); p. 233,235, 237
View in Reaxys

HN
2
O

NH 2

HO O

O NH 2

Rx-ID: 747509 View in Reaxys 470/636

Yield Conditions & References
T= 230 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217
View in Reaxys

T= 230 °C

Roe; Scanlan; Swern; Journal of the American Chemical Society; vol. 71; (1949); p. 2217

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 View in Reaxys

T= 230 °C

PatentResinous Prod. & Chem.Co.; RESINOUS PROD CHEMICAL&lt;unknown&gt;; US1989968; (1934); (A)
View in Reaxys

HO OH

O O

O O

HO O NH 2 OH

Rx-ID: 2481045 View in Reaxys 471/636

Yield Conditions & References
With ammonium hydroxide

Francois; Perilleux; Kempener; Sonveaux; Tetrahedron Letters; vol. 31; nb. 44; (1990); p. 6347 - 6350
View in Reaxys

HO N
HO N
O O
N O O
N

NH
N
NH
HO N
HO
NH
NH

O
O
NH 2

Rx-ID: 3638865 View in Reaxys 472/636

Yield Conditions & References
With ammonium hydroxide

Wang; Bergstrom; Tetrahedron Letters; vol. 34; nb. 42; (1993); p. 6721 - 6724
View in Reaxys

O
O

HO

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 O

O
O

NH 2

Rx-ID: 4284604 View in Reaxys 473/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, 0 deg C, 30 min, 2.) THF, 0 deg C,
30 min, Yield given. Multistep reaction

Noguchi, Hirohide; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 51; nb. 38; (1995); p. 10545 - 10560
View in Reaxys

O
O

HO

O
O

NH 2

Rx-ID: 4284723 View in Reaxys 474/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, 0 deg C, 30 min, 2.) THF, 0 deg C,
30 min, Yield given. Multistep reaction

Noguchi, Hirohide; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 51; nb. 38; (1995); p. 10545 - 10560
View in Reaxys

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 O O

O O

O O O O

O NH 2

O O
HO O

O O

Rx-ID: 4291219 View in Reaxys 475/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30
min, Yield given. Multistep reaction

Noguchi, Hirohide; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 51; nb. 38; (1995); p. 10545 - 10560
View in Reaxys

O O

HO

O O

NH 2

Rx-ID: 4291220 View in Reaxys 476/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30
min, Yield given. Multistep reaction

Noguchi, Hirohide; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 51; nb. 38; (1995); p. 10545 - 10560
View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

O O

O O O O

O NH 2

O O
HO O

O O

Rx-ID: 4291269 View in Reaxys 477/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30
min, Yield given. Multistep reaction

Noguchi, Hirohide; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 51; nb. 38; (1995); p. 10545 - 10560
View in Reaxys

O O

HO

O O

NH 2

Rx-ID: 4291270 View in Reaxys 478/636

Yield Conditions & References
With ammonium hydroxide, chloroformic acid ethyl ester, triethylamine, 1.) THF, 0 deg C, 30 min, 2.) 0 deg C, 30
min, Yield given. Multistep reaction

Noguchi, Hirohide; Aoyama, Toyohiko; Shioiri, Takayuki; Tetrahedron; vol. 51; nb. 38; (1995); p. 10545 - 10560
View in Reaxys

HO O O O

O NH 2

Rx-ID: 4764798 View in Reaxys 479/636

Yield Conditions & References
With oxalyl dichloride, ammonia, Yield given. Multistep reaction

Patt, William C.; Massa, Mark A.; Tetrahedron Letters; vol. 38; nb. 8; (1997); p. 1297 - 1300
View in Reaxys

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 O O

Si Si
O O

O O

O O

O O

O NH 2

HO O

Rx-ID: 4918449 View in Reaxys 480/636

Yield Conditions & References
With ammonia, 1,1'-carbonyldiimidazole, 1.) THF, 60 deg C, 1 h, 2.) 0 deg C, 5 min; 30 min, Yield given. Multistep
reaction

Sato, Masaaki; Takeuchi, Shinji; Ishibashi, Masami; Kobayashi, Jun'ichi; Tetrahedron; vol. 54; nb. 19; (1998); p.
4819 - 4826
View in Reaxys

O NH 2

HO O

O O O O
O O

O O
NH NH
F F

F F
F F

Rx-ID: 5030329 View in Reaxys 481/636

Yield Conditions & References
With pyridine, ammonium hydroxide, 2,3,4,5,6-pentafluorophenol, dicyclohexyl-carbodiimide, 1) CH2Cl2, room tem‐
perature, 2 h; -20 deg C, 1 h, 2), 2) dioxane, H2O, 30 min, Yield given. Multistep reaction

Dal Pozzo, Alma; Muzi, Laura; Moroni, Maurizio; Rondanin, Riccardo; De Castiglione, Roberto; Bravo, Pier‐
francesco; Zanda, Matteo; Tetrahedron; vol. 54; nb. 22; (1998); p. 6019 - 6028
View in Reaxys

O HN 2

OH O

Rx-ID: 16358167 View in Reaxys 482/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2
2: NH4Cl
With thionyl chloride, ammonium chloride

Shinozaki; Sato; Iwakuma; Sato; Kurimoto; Yoshida; Bioorganic and medicinal chemistry letters; vol. 9; nb. 3;
(1999); p. 401 - 406
View in Reaxys

O O NH 2
O

HO N O N
H H

Rx-ID: 21994988 View in Reaxys 483/636

Yield Conditions & References
Reaction Steps: 2
1: hydrogen chloride
2: ammonia
With hydrogenchloride, ammonia

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 Bornwater; Recueil des Travaux Chimiques des Pays-Bas; vol. 36; (1917); p. 281
View in Reaxys

Reaction Steps: 2
1: thionyl chloride / 20 - 35 °C
2: xylene; ammonia
With thionyl chloride, ammonia, xylene

Kanewskaja; Zhurnal Russkago Fiziko-Khimicheskago Obshchestva; vol. 59; (1927); p. 652; Chemisches Zentral‐
blatt; vol. 99; nb. I; (1928); p. 1026
View in Reaxys

HO HN
2

HN HN
N N
O O

H OO H OO

O O

O N N O N N

O O O O

O O

N HN N HN

O O

O O

N N N N

O O

O O
N HN N HN

O HN O HN

O O

Rx-ID: 41827698 View in Reaxys 484/636

Yield Conditions & References
Reaction Steps: 2
1: trifluoroacetic acid
2: ammonia / 0.17 h / 0 °C
With ammonia, trifluoroacetic acid

PatentHegmans, Alexander;Fenske, Bruce W.;Trepanier, Dan J.;Abel, Mark D.;Ure, Daren R.;Sugiyama, Shin;
CONTRAVIR PHARMACEUTICALS&lt;unknown&gt;; US9200038; (2015); (B2) English
View in Reaxys

Reaction Steps: 2
1: thionyl chloride
2: ammonia / 0.17 h / 0 °C
With thionyl chloride, ammonia

PatentCONTRAVIR PHARMACEUTICALS, INC.;FOSTER, Robert Thomas;GALLAY, Philippe;TREPANIER, Daniel

Joseph;URE, Daren Raymond; CONTRAVIR PHARMACEUTICALS&lt;unknown&gt;; WO2018/106928; (2018); (A1)
English
View in Reaxys

O O

OH

O NH 2

Rx-ID: 179711 View in Reaxys 485/636

Yield Conditions & References
With sodium ammonium, ammonia

Chablay; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 156; (1913); p. 1022;
Annales de Chimie (Cachan, France); vol. <9> 8; (1917); p. 217
View in Reaxys

With ammonia, sodium

Chablay; Annales de Chimie (Cachan, France); vol. <9>8; (1917); p. 203,208,215; Comptes Rendus Hebdomad‐
aires des Seances de l'Academie des Sciences; vol. 156; (1913); p. 1021

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 View in Reaxys

HO O

O NH 2

Rx-ID: 206776 View in Reaxys 486/636

Yield Conditions & References
With phosphorus trichloride, Behandeln des Reaktionsprodukts mit Ammoniak

Hopkins; Chisholm; Harris; Canadian Journal of Research, Section B: Chemical Sciences; vol. 27; (1949); p.
38,40
View in Reaxys
Vesely; Chudozilov; Collection of Czechoslovak Chemical Communications; vol. 2; (1930); p. 98,101,102; Chem‐
isches Zentralblatt; vol. 101; nb. I; (1930); p. 2540
View in Reaxys

O NH 2

H H
N N N N
O O

N N N N

NH 2
NH 2

Rx-ID: 490062 View in Reaxys 487/636

Yield Conditions & References
With methanol, ammonia

Sokolowskaja et al.; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 1968,1972;engl.Ausg.S.2030,2033

View in Reaxys

Reaction Steps: 2
1: ethanolic KOH
2: PCl5; acetyl chloride / Behandeln des erhaltenen Saeurechlorids mit wss.NH3
With potassium hydroxide, phosphorus pentachloride, acetyl chloride

Sokolowskaja et al.; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 1968,1972;engl.Ausg.S.2030,2033

View in Reaxys

H H
O N N O N N

O N N NH 2
N N

NH 2
NH 2

Rx-ID: 493027 View in Reaxys 488/636

Yield Conditions & References
Sokolowskaja et al.; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 1968,1972;engl.Ausg.S.2030,2033
View in Reaxys

Reaction Steps: 2
1: ethanolic NaOH
With sodium hydroxide

Sokolowskaja et al.; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 1968,1972;engl.Ausg.S.2030,2033

View in Reaxys

HO
HN
2
O

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 O

NH 2

Rx-ID: 637982 View in Reaxys 489/636

Yield Conditions & References
T= 195 °C

Granados Jarque et al.; Anales de la Real Sociedad Espanola de Fisica y Quimica, Serie B: Quimica; vol. 54;
(1958); p. 233,234
View in Reaxys

T= 180 - 190 °C

Sugasawa; Shigehara; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; vol. 62; (1942); p. 532;
engl. Ref. S. 169; Chem.Abstr.; (1951); p. 2861
View in Reaxys

HO HN
2
O O

O NH 2
NH 2

Rx-ID: 747583 View in Reaxys 490/636

Yield Conditions & References
T= 170 - 180 °C

Guthrie; Rabjohn; Organic Syntheses; vol. 37; (1957); p. 50

View in Reaxys

T= 160 °C

Patentdu Pont de Nemours & Co.; DUPONT DE NEMOURS INCDuPont; US2109941; (1936); (A)
View in Reaxys

O NH 2

HO O

Rx-ID: 1042614 View in Reaxys 491/636

Yield Conditions & References
(i) SOCl2, CCl4, Et2O, (ii) aq. NH3, Multistep reaction

Bolhofer,W.A. et al.; Journal of Medicinal Chemistry; vol. 22; (1979); p. 295 - 301
View in Reaxys

OH NH 2

O O

Rx-ID: 1087572 View in Reaxys 492/636

Yield Conditions & References
(i) (COCl)2, (ii) NH3, Multistep reaction

Kornfeld,E.C. et al.; Journal of Medicinal Chemistry; vol. 8; (1965); p. 342 - 347

View in Reaxys

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 HO H H O
N

O H NH 2

Rx-ID: 2460073 View in Reaxys 493/636

Yield Conditions & References
34 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr
Chromat.
Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

34 % With octanedioic acid ; neutral ammonium salt, T= 19.9 °C , p= 60004800Torr , other ammonium salts of mono- and
Chromat. dibasic, aliphatic and aromatic acids, other pressures, other temp, without matrix, Product distribution

Christotina, N. P.; Zharov, A. A.; Bulletin of the Academy of Sciences of the USSR Division of Chemical Science;
vol. 38; nb. 10; (1989); p. 2103 - 2106; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 10; (1989); p.
2289 - 2292
View in Reaxys

O O
Si Si

O S O HN 2
S O

Si Si

HO O
O O

Rx-ID: 3169317 View in Reaxys 494/636

Yield Conditions & References
With ammonium hydroxide, triethylamine, isobutyl chloroformate, 1.) CH2Cl2, -40 deg C, 30 min; 2.) CH2Cl2, to RT,
18 h, Yield given. Multistep reaction

Tanaka; Okamura; Bannai; Hazato; Sugiura; Manabe; Kamimoto; Kurozumi; Chemical and Pharmaceutical Bul‐
letin; vol. 33; nb. 6; (1985); p. 2359 - 2385
View in Reaxys

HO H H O
N

O H NH 2

Rx-ID: 3616531 View in Reaxys 495/636

Yield Conditions & References
2% in solid, high-pressure extrusion (15-30 kbar)

Bogdanov, A. Yu.; Zharov, A. A.; Zhulin, V. M.; Bulletin of the Academy of Sciences of the USSR Division of
Chemical Science; vol. 35; nb. 1; (1986); p. 233; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; nb. 1;
(1986); p. 250
View in Reaxys

H H
O N NH 2
HN
2
N O
14
14

C C
Cl H Cl H

O NH NH NH 2

Rx-ID: 4371434 View in Reaxys 496/636

Yield Conditions & References
With ammonium hydroxide, Time= 14h

Dischino; Journal of labelled compounds and radiopharmaceuticals; vol. 36; nb. 11; (1995); p. 1097 - 1103
View in Reaxys

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 OH O

O O O NH 2

N N

O O

Rx-ID: 4393274 View in Reaxys 497/636

Yield Conditions & References
(i) SOCl2, (ii) aq. NH3, Multistep reaction

Denny,W.A.; Cain,B.F.; Journal of Medicinal Chemistry; vol. 21; (1978); p. 430 - 437
View in Reaxys

O NH 2

HO O

O O
N N

O O

Rx-ID: 4393281 View in Reaxys 498/636

Yield Conditions & References
(i) SOCl2, (ii) aq. NH3, Multistep reaction

Denny,W.A.; Cain,B.F.; Journal of Medicinal Chemistry; vol. 21; (1978); p. 430 - 437
View in Reaxys

O NH 2

HO O

O O
N N

O O

Rx-ID: 4393746 View in Reaxys 499/636

Yield Conditions & References
(i) SOCl2, (ii) aq. NH3, Multistep reaction

Denny,W.A.; Cain,B.F.; Journal of Medicinal Chemistry; vol. 21; (1978); p. 430 - 437
View in Reaxys

O O NH O
2

O O

HO O

Rx-ID: 4397447 View in Reaxys 500/636

Yield Conditions & References
(i) SOCl2, (ii) aq. NH3, dioxane, Multistep reaction

Kulp,S.S.; Iobst,S.A.; Journal of Medicinal Chemistry; vol. 7; (1964); p. 831

View in Reaxys

N O
N
N N

O O NH 2

O O

Rx-ID: 14022198 View in Reaxys 501/636

Yield Conditions & References
Reaction Steps: 2
1.1: H(1+)
1.2: SOCl2
2.1: NH3

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 With ammonia, hydrogen cation

Oshita, Shinya; Matsumoto, Akikazu; Chemistry Letters; vol. 32; nb. 8; (2003); p. 712 - 713
View in Reaxys

OH O

O HN
2

NH 2
NH 2

O O

Rx-ID: 22182629 View in Reaxys 502/636

Yield Conditions & References
Reaction Steps: 2
1: concentrated KOH
2: SOCl2 / durch folgendes Eintragen in konz. NH3
With potassium hydroxide, thionyl chloride

Franke; Kroupa; Monatshefte fur Chemie; vol. 56; (1930); p. 349

View in Reaxys

OH O

O HN
2

NH 2
NH 2

O O

Rx-ID: 22182901 View in Reaxys 503/636

Yield Conditions & References
Reaction Steps: 2
1: methanolic KOH
2: SOCl2 / beim folgenden Behandlung mit konz. NH3
With potassium hydroxide, thionyl chloride

Franke; Kroupa; Monatshefte fur Chemie; vol. 56; (1930); p. 349

View in Reaxys

HO O O NH 2

O O

OH OH

Rx-ID: 22182952 View in Reaxys 504/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2; NH3
2: alcoholic KOH
With potassium hydroxide, thionyl chloride, ammonia

Franke; Kroupa; Monatshefte fur Chemie; vol. 69; (1936); p. 190

View in Reaxys

S O S NH 2

OH O

Rx-ID: 22240807 View in Reaxys 505/636

Yield Conditions & References
Reaction Steps: 2

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 1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1955); p. 680,684

View in Reaxys
Cagniant; Deluzarche; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 222;
(1946); p. 1301
View in Reaxys

S S

O NH 2

OH O

Rx-ID: 166713 View in Reaxys 506/636

Yield Conditions & References
With pyridine, thionyl chloride, diethyl ether, Behandeln des erhaltenen Saeurechlorids mit wss. Ammoniak

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1953); p. 921

View in Reaxys

S S

O NH 2

OH O

Rx-ID: 166875 View in Reaxys 507/636

Yield Conditions & References
With thionyl chloride, chloroform, Behandeln des erhaltenen Saeurechlorids mit wss. Ammoniak

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1952); p. 629,632

View in Reaxys

H O H O

HO HN 2

Rx-ID: 186445 View in Reaxys 508/636

Yield Conditions & References
With oxalyl dichloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Staellberg; Stenhagen; Arkiv foer Kemi; vol. 2; (1950); p. 95,102

View in Reaxys

H O H O

HO HN
2

Rx-ID: 186528 View in Reaxys 509/636

Yield Conditions & References
With oxalyl dichloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Staellberg; Stenhagen; Arkiv foer Kemi; vol. 2; (1950); p. 95,102

View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 O O

OH NH 2

H H

Rx-ID: 186702 View in Reaxys 510/636

Yield Conditions & References
With oxalyl dichloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 2; (1950); p. 431,435

View in Reaxys

O NH 2

OH O

Rx-ID: 202210 View in Reaxys 511/636

Yield Conditions & References
With thionyl chloride, und Behandeln einer Loesung des Reaktionsprodukts in Dioxan mit wss.Ammoniak

Nunn; Journal of the Chemical Society; (1951); p. 1740,1742

View in Reaxys

H H

HO O

O NH 2

Rx-ID: 204729 View in Reaxys 512/636

Yield Conditions & References
With thionyl chloride, Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 65,88
View in Reaxys

NH 2

Rx-ID: 206823 View in Reaxys 513/636

Yield Conditions & References
With ethanol, ammonia

Grigor et al.; Journal of the Chemical Society; (1955); p. 1069

View in Reaxys

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 H O H O

HO HN 2

Rx-ID: 207226 View in Reaxys 514/636

Yield Conditions & References
With oxalyl dichloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Staellberg; Stenhagen; Arkiv foer Kemi; vol. 2; (1950); p. 95,102

View in Reaxys

HO

NH 2

Rx-ID: 207316 View in Reaxys 515/636

Yield Conditions & References
With phosphorus trichloride, und Behandeln des ausscheidenden Brassidinsaeureanhydrids in aetherisches Loe‐
sung mit Ammoniak, brassidic acid amide

Reimer; Will; Chemische Berichte; vol. 19; (1886); p. 3326

View in Reaxys

O O

NH 2

Rx-ID: 208616 View in Reaxys 516/636

Yield Conditions & References
With diethyl ether, ammonia, erucic acid amide

Reimer; Will; Chemische Berichte; vol. 19; (1886); p. 3326

View in Reaxys

O O

O NH 2

Rx-ID: 228883 View in Reaxys 517/636

Yield Conditions & References
With ammonia, water

Weidel; Ciamician; Chemische Berichte; vol. 13; (1880); p. 66,70

View in Reaxys

O Cl O Cl

O NH 2

Rx-ID: 232848 View in Reaxys 518/636

Yield Conditions & References
With ammonia, water

Chretien; Annales de Chimie (Cachan, France); vol. <13>2; (1957); p. 682,700

View in Reaxys

O O

O NH 2

Rx-ID: 240757 View in Reaxys 519/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
With ethanol, ammonia

Rowney; Justus Liebigs Annalen der Chemie; vol. 79; (1851); p. 236
View in Reaxys

OH O

O NH 2

Rx-ID: 243514 View in Reaxys 520/636

Yield Conditions & References
With oxalyl dichloride, ammonia, benzene

Arosenius et al.; Arkiv foer Kemi; vol. 26 A; nb. 19; (1949); p. 10

View in Reaxys

O NH 2

OH O

Rx-ID: 248712 View in Reaxys 521/636

Yield Conditions & References
With oxalyl dichloride, Behandeln mit konz.NH3

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 22 A; nb. 19; (1946); p. 10

View in Reaxys

HO

NH 2

Rx-ID: 250874 View in Reaxys 522/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys

OH

NH 2

Rx-ID: 251321 View in Reaxys 523/636

Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys

OH

NH 2

Rx-ID: 251618 View in Reaxys 524/636

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Yield Conditions & References
With thionyl chloride, und Behandeln des Reaktionsprodukts mit wss.Ammoniak

Weitzel; Wojahn; Hoppe-Seyler's Zeitschrift fur Physiologische Chemie; vol. 287; (1951); p. 296,304,305
View in Reaxys

HO

NH 2

Rx-ID: 254171 View in Reaxys 525/636

Yield Conditions & References
With oxalyl dichloride, Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Arosenius et al.; Arkiv foer Kemi; vol. 1; (1949); p. 413,417

View in Reaxys

HO

NH 2

Rx-ID: 255475 View in Reaxys 526/636

Yield Conditions & References
With oxalyl dichloride, ammonia, water, benzene

Stenhagen; Arkiv foer Kemi; vol. 1; (1949); p. 100; Chem.Abstr.; (1949); p. 7414
View in Reaxys

H
O N O

O O

H
O N O

O NH 2

Rx-ID: 257417 View in Reaxys 527/636

Yield Conditions & References
With ethanol, ammonia

Nesmejanow et al.; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; (1958); p.

836,839;engl.Ausg.S.815,817
View in Reaxys

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 O O

HO HN
2

Rx-ID: 258820 View in Reaxys 528/636

Yield Conditions & References
With oxalyl dichloride, nachfolgendes Behandeln mit kaltem konz.NH3

Arosenius et al.; Arkiv foer Kemi; vol. 26 A; nb. 19; (1949); p. 10

View in Reaxys

O O

N N

O O O NH 2

OH O

Rx-ID: 294800 View in Reaxys 529/636

Yield Conditions & References
With ammonium hydroxide, phosphorus pentachloride

Ashley; Leeds; Journal of the Chemical Society; (1957); p. 2706,2710

View in Reaxys

HO O O NH 2

Rx-ID: 295520 View in Reaxys 530/636

Yield Conditions & References
With phosphorus trichloride, Behandeln des Reaktionsprodukts mit waessr. Ammoniak

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ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.
 Power; Gornall; Journal of the Chemical Society; vol. 85; (1904); p. 856
View in Reaxys

O O

N O N NH 2

S S

Rx-ID: 311206 View in Reaxys 531/636

Yield Conditions & References
With ammonia

Babitschew; Derkatsch; Ukrainskij Khimicheskij Zhurnal; vol. 22; (1956); p. 208,211; Chem.Abstr.; (1957); p. 373
View in Reaxys

Cl Cl
O NH 2

HO O O O

Cl Cl

Rx-ID: 326477 View in Reaxys 532/636

Yield Conditions & References
With thionyl chloride, Behandeln des Reaktionsprodukts mit wss. Ammoniak

Fawcett et al.; Proceedings of the Royal Society of London. Series B, Biological sciences; vol. 148; (1958); p.
543,547
View in Reaxys

HO O

O O NH 2
O
N N

O O

Rx-ID: 344447 View in Reaxys 533/636

Yield Conditions & References
With ammonium hydroxide, phosphorus pentachloride

Ashley; Leeds; Journal of the Chemical Society; (1957); p. 2706,2710

View in Reaxys

Cl Cl
O NH 2

HO O O O

Cl Cl

Rx-ID: 360345 View in Reaxys 534/636

Yield Conditions & References
With thionyl chloride, benzene, Eintragen des Reaktionsgemisches in wss. NH3

Synerholm; Zimmerman; Contributions from Boyce Thompson Institute; vol. 14; (1947); p. 369,372
View in Reaxys

O O

O O

O NH 2

Rx-ID: 379017 View in Reaxys 535/636

Yield Conditions & References
With ammonium hydroxide

Wallach; Justus Liebigs Annalen der Chemie; vol. 389; (1912); p. 183
View in Reaxys

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 OH O

O HN
2

NH NH

N N

O O

Rx-ID: 407622 View in Reaxys 536/636

Yield Conditions & References
With thionyl chloride, anschliessend mit wss. NH3

Glen; Robinson; Journal of the Chemical Society; (1943); p. 557,558

View in Reaxys

O O O O
O NH 2

OH O

O O O O

Rx-ID: 413729 View in Reaxys 537/636

Yield Conditions & References
With thionyl chloride, Erwaermen des Reaktionsprodukts mit Ammoniumcarbonat in Benzol.

Iguchi; Hisatsune; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; vol. 77; (1957); p. 98,101;
Chem.Abstr.; (1957); p. 8734
View in Reaxys

O NH 2

H H
N N N N
HO O

N N N N

NH 2
NH 2

Rx-ID: 414811 View in Reaxys 538/636

Yield Conditions & References
With phosphorus pentachloride, acetyl chloride, Behandeln des erhaltenen Saeurechlorids mit wss.NH3

Sokolowskaja et al.; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 1968,1972;engl.Ausg.S.2030,2033

View in Reaxys

HO O O NH 2

Rx-ID: 441592 View in Reaxys 539/636

Yield Conditions & References
With phosphorus trichloride, Behandeln des Reaktionsgemisches mit wss. Ammoniak

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 Kariyone; Hasegawa; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; vol. 54; (1934); p.
141,143, 144; engl. Ref. S. 28; Chem.Abstr.; (1936); p. 3264
View in Reaxys

HO O O O

O NH 2

Rx-ID: 468659 View in Reaxys 540/636

Yield Conditions & References
With phosphorus pentachloride, Eingiessen des entstandenen Saeurechlorids in verd. Ammoniak

Blank; Chemische Berichte; vol. 25; (1892); p. 3044

View in Reaxys

HO O

O NH 2

Rx-ID: 470802 View in Reaxys 541/636

Yield Conditions & References
With thionyl chloride, Eintragen des Saeurechlorids in wss. Ammoniak

Ramart-Lucas; Hoch; Bulletin de la Societe Chimique de France; vol. <4> 51; (1932); p. 824,833
View in Reaxys

O O

O O

O NH 2

OH OH

Rx-ID: 484154 View in Reaxys 542/636

Yield Conditions & References
With ammonium hydroxide

v. Braun; Anton; Meyer; Chemische Berichte; vol. 74; (1941); p. 1772,1781

View in Reaxys

O O NH 2
O

O N O N
H H

Rx-ID: 486169 View in Reaxys 543/636

Yield Conditions & References
With ammonia

Bornwater; Recueil des Travaux Chimiques des Pays-Bas; vol. 36; (1917); p. 281
View in Reaxys

O O O O
O NH 2

OH O

O O O O

Rx-ID: 490485 View in Reaxys 544/636

Yield Conditions & References
With thionyl chloride, Erwaermen des Reaktionsprodukts mit Ammoniumcarbonat in Benzol.

Iguchi; Hisatsune; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; vol. 77; (1957); p. 98,101;
Chem.Abstr.; (1957); p. 8734
View in Reaxys

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 Cl Cl

HO O
O O

O Cl NH 2
Cl

Rx-ID: 494984 View in Reaxys 545/636

Yield Conditions & References
With thionyl chloride, benzene, Eintragen des Reaktionsgemisches in wss. NH3

Synerholm; Zimmerman; Contributions from Boyce Thompson Institute; vol. 14; (1947); p. 369,372
View in Reaxys

O O O
NH 2
N
N
H
O N
O
O
N O
H
N
O N
O O O

Rx-ID: 518873 View in Reaxys 546/636

Yield Conditions & References
With methanol, ammonia

Plit; Burmistrow; Ukrainskij Khimicheskij Zhurnal; vol. 24; (1958); p. 73; Chem.Abstr.; (1958); p. 18271
View in Reaxys

HN
2
O HO O

NH 2 O NH 2

Rx-ID: 748467 View in Reaxys 547/636

Yield Conditions & References
T= 120 - 160 °C

Cherbuliez; Landolt; Helvetica Chimica Acta; vol. 29; (1946); p. 1441

View in Reaxys

O O

O O NH 2

Rx-ID: 989348 View in Reaxys 548/636

Yield Conditions & References
With CYANAMID

Kretov,A.E.; Momsenko,A.P.; Journal of general chemistry of the USSR; vol. 33; nb. 10; (1963); p. 3253 - 3255;
Zhurnal Obshchei Khimii; vol. 33; nb. 10; (1963); p. 3325 - 3328
View in Reaxys

O O

O O NH 2

Rx-ID: 1029483 View in Reaxys 549/636

Yield Conditions & References
With CYANAMID

Kretov,A.E.; Momsenko,A.P.; Journal of general chemistry of the USSR; vol. 33; nb. 10; (1963); p. 3253 - 3255;
Zhurnal Obshchei Khimii; vol. 33; nb. 10; (1963); p. 3325 - 3328
View in Reaxys

O O

O O NH 2

Rx-ID: 1186078 View in Reaxys 550/636

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 Yield Conditions & References
With CYANAMID

Kretov,A.E.; Momsenko,A.P.; Journal of general chemistry of the USSR; vol. 33; nb. 10; (1963); p. 3253 - 3255;
Zhurnal Obshchei Khimii; vol. 33; nb. 10; (1963); p. 3325 - 3328
View in Reaxys

HO O O O

OH
O
OH

HO

HO O O O

OH
O
NH 2

HO

Rx-ID: 2469694 View in Reaxys 551/636

Yield Conditions & References
With ammonia, 1,1'-carbonyldiimidazole, 1) CH2Cl2, 3 h, 2) 0 deg C, 10 min, Yield given. Multistep reaction

Jansen, Rolf; Schummer, Dietmar; Irschik, Herbert; Hoefle, Gerhard; Liebigs Annalen der Chemie; nb. 10;
(1990); p. 975 - 988
View in Reaxys

dilithium-<μ-imido-bis-(diamido-hydrido aluminate )>

NH 2

Rx-ID: 6942862 View in Reaxys 552/636

Yield Conditions & References
With diethyl ether

Petit; Poisson; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 247; (1958); p.
1628
View in Reaxys

O O

elaidacidic ammonia
NH 2

Rx-ID: 7075283 View in Reaxys 553/636

Yield Conditions & References
With diethyl ether, ammonia

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 Albitzki; Emeljanow; Zhurnal Russkago Fiziko-Khimicheskago Obshchestva; vol. 31; (1899); p. 106; Chemisches
Zentralblatt; vol. 70; nb. I; (1899); p. 1070
View in Reaxys

2 2
2

H
2

H
2

H H 2

H
2

H
2

H H

2 2

H OH H NH 2

2 2

H H
2 2

H 2

H
2

H O H 2

H
2

H O

Rx-ID: 18071387 View in Reaxys 554/636

Yield Conditions & References
Reaction Steps: 2
1: 89 percent / SOCl2 / 0.5 h / Heating
2: 80 percent / aq. NH4OH / 1 h
With ammonium hydroxide, thionyl chloride

Tsuzuki, Hirohisa; Mukumoto, Mamoru; Mataka, Shuntaro; Yonemitsu, Tadashi; Tashiro, Masashi; Journal of
Chemical Research, Miniprint; nb. 4; (1993); p. 1046 - 1058
View in Reaxys

HO

zinc stearate
O

NH 2

trichloromethyl-chloro formate
Rx-ID: 18881007 View in Reaxys 555/636
Yield Conditions & References
Reaction Steps: 2
1: SOCl2
2: NH3
With thionyl chloride, ammonia

Nakamura, Naotake; Okada, Masao; Okada, Yutaka; Sugita, Kaichiro; Molecular Crystals and Liquid Crystals
(1969-1991); vol. 116; (1984); p. 181 - 186
View in Reaxys

O NH 2

OH O

Rx-ID: 20588471 View in Reaxys 556/636

Yield Conditions & References
Reaction Steps: 2
1: SOCl2
2: 20percent aq. NH3-solution / 0.5 h / 0 °C
With ammonium hydroxide, thionyl chloride

Slopianka, Marion; Gossauer, Albert; Liebigs Annalen der Chemie; nb. 12; (1981); p. 2258 - 2265
View in Reaxys

Cl Cl Cl Cl
O HN 2

Cl Cl

HO O

Rx-ID: 21977759 View in Reaxys 557/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride
2: water; ammonia
With thionyl chloride, ammonia, water

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 Nessmajanow et al.; Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya; (1954); p. 34,38; Chem.Abstr.; nb.
6085; (1955)
View in Reaxys

O O

HO O

O NH 2

OH OH

Rx-ID: 22091525 View in Reaxys 558/636

Yield Conditions & References
Reaction Steps: 2
1: hydrogen chloride; methanol
2: aqueous ammonia
With hydrogenchloride, methanol, ammonium hydroxide

v. Braun; Anton; Meyer; Chemische Berichte; vol. 74; (1941); p. 1772,1781

View in Reaxys

HO

NH 2

Rx-ID: 22177443 View in Reaxys 559/636

Yield Conditions & References
Reaction Steps: 2
1: phosphorus (III)-chloride
2: water; ammonia
With ammonia, water, phosphorus trichloride

Arbusow; Lugowkin; Sb. Statei Obshch. Khim.; (1953); p. 419,423; Chem.Abstr.; (1955); p. 847
View in Reaxys

HO O

O NH 2

Rx-ID: 22177489 View in Reaxys 560/636

Yield Conditions & References
Reaction Steps: 2
1: pyridine; toluene / anschliessenden Erwaermen
2: water; ammonia
With pyridine, ammonia, water, toluene

Kaufmann; Gulinsky; Fette und Seifen; vol. 64; (1962); p. 599

View in Reaxys

HO

NH 2

Rx-ID: 22177490 View in Reaxys 561/636

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 Yield Conditions & References
Reaction Steps: 2
1: pyridine; heptane / anschliessenden Erwaermen
2: water; ammonia
With pyridine, n-heptane, ammonia, water

Kaufmann; Gulinsky; Fette und Seifen; vol. 64; (1962); p. 599

View in Reaxys

O NH 2

H
O H O

Rx-ID: 22177604 View in Reaxys 562/636

Yield Conditions & References
Reaction Steps: 2
1: aqueous alcoholic KOH
2: oxalyl chloride; benzene / Umsetzen des erhaltenes Saeurechlorids mit konz.wss.NH3
With potassium hydroxide, oxalyl dichloride, benzene

Staellberg-Stenhagen; Arkiv foer Kemi; vol. 26 A; nb. 12; (1949); p. 22

View in Reaxys

HO

NH 2

Rx-ID: 22177656 View in Reaxys 563/636

Yield Conditions & References
Reaction Steps: 2
1: diluted nitric acid / bis Schmelzungt erfolgt, und traegt dann Natriumnitrit ein
2: phosphorus trichloride / und Behandeln des ausscheidenden Brassidinsaeureanhydrids in aetherisches Loesung
mit Ammoniak
With nitric acid, phosphorus trichloride

Reimer; Will; Chemische Berichte; vol. 19; (1886); p. 3326

View in Reaxys

HN
2

NH

NH
N

Rx-ID: 22194167 View in Reaxys 564/636

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 Yield Conditions & References
Reaction Steps: 2
1: ethanolic KOH
2: SOCl2 / anschliessend mit wss. NH3
With potassium hydroxide, thionyl chloride

Glen; Robinson; Journal of the Chemical Society; (1943); p. 557,558

View in Reaxys

O O O NH 2

OH O

Rx-ID: 22324467 View in Reaxys 565/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether
2: ammonium carbonate
With ammonium carbonate, thionyl chloride, diethyl ether

Treibs; Heyer; Chemische Berichte; vol. 87; (1954); p. 1197,1200

View in Reaxys

S S

OH O

O HN
2

Rx-ID: 22325487 View in Reaxys 566/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride
With thionyl chloride

Cagniant et al.; Bulletin de la Societe Chimique de France; (1948); p. 1083,1085

View in Reaxys

S O S NH 2

OH O

Rx-ID: 22325927 View in Reaxys 567/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1956); p. 1152,1160

View in Reaxys

O O O NH 2

O O

Rx-ID: 22326588 View in Reaxys 568/636

Yield Conditions & References
Reaction Steps: 3
1: aqueous methanol. NaOH-solution
2: thionyl chloride; diethyl ether
3: ammonium carbonate
With ammonium carbonate, sodium hydroxide, thionyl chloride, diethyl ether

Treibs; Heyer; Chemische Berichte; vol. 87; (1954); p. 1197,1200

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 S O S NH 2

OH O

Rx-ID: 22326699 View in Reaxys 569/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1955); p. 680,684

View in Reaxys

S S

OH O

O HN
2

Rx-ID: 22326808 View in Reaxys 570/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride
With thionyl chloride

Cagniant et al.; Bulletin de la Societe Chimique de France; (1948); p. 1083,1085

View in Reaxys

O S HN 2
S

HO O

Rx-ID: 22327312 View in Reaxys 571/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1956); p. 1152,1160

View in Reaxys

S O S NH 2

OH O

Rx-ID: 22327389 View in Reaxys 572/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1956); p. 1152,1160

View in Reaxys

S S

OH O

O HN
2

Rx-ID: 22327392 View in Reaxys 573/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1956); p. 1152,1160

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 View in Reaxys

HO O O NH 2

Rx-ID: 22332442 View in Reaxys 574/636

Yield Conditions & References
Reaction Steps: 2
2: benzene; ammonia
With ammonia, benzene

Kacnelson; Kondakova; Doklady Akademii Nauk SSSR; vol. 17; (1937); p. 367,368
View in Reaxys

S S
O NH 2

OH O

Rx-ID: 22361836 View in Reaxys 575/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1954); p. 1349,1353

View in Reaxys

S S

O NH 2

OH O

Rx-ID: 22362368 View in Reaxys 576/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
2: aqueous ammonia
With pyridine, ammonium hydroxide, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1954); p. 1349,1353

View in Reaxys

S S

OH O

O HN
2

Rx-ID: 22362577 View in Reaxys 577/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
2: aqueous ammonia
With pyridine, ammonium hydroxide, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1954); p. 1349,1353

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 S S

O NH 2

O O

Rx-ID: 22364458 View in Reaxys 578/636

Yield Conditions & References
Reaction Steps: 3
1: aq.-ethanolic KOH-solution
2: thionyl chloride; diethyl ether; pyridine
With pyridine, potassium hydroxide, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1954); p. 1349,1353

View in Reaxys

S S

O NH 2

OH O

Rx-ID: 22369492 View in Reaxys 579/636

Yield Conditions & References
Reaction Steps: 2
1: thionyl chloride; diethyl ether; pyridine
With pyridine, thionyl chloride, diethyl ether

Cagniant; Cagniant; Bulletin de la Societe Chimique de France; (1954); p. 1349,1353

View in Reaxys

OH O

N O N NH 2

S S

Rx-ID: 22381536 View in Reaxys 580/636

Yield Conditions & References
Reaction Steps: 2
2: methanol. NH3
With ammonia

Babitschew; Derkatsch; Ukrainskij Khimicheskij Zhurnal; vol. 22; (1956); p. 208,211; Chem.Abstr.; (1957); p. 373
View in Reaxys

O O

O NH 2

Rx-ID: 237484 View in Reaxys 581/636

Yield Conditions & References
Wotiz; Buco; Journal of Organic Chemistry; vol. 20; (1955); p. 210,213
View in Reaxys

O O

O NH 2

Rx-ID: 239670 View in Reaxys 582/636

Yield Conditions & References
Wotiz; Buco; Journal of Organic Chemistry; vol. 20; (1955); p. 210,213
View in Reaxys

HO O

O NH 2

Rx-ID: 242270 View in Reaxys 583/636

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 Yield Conditions & References
Wotiz; Buco; Journal of Organic Chemistry; vol. 20; (1955); p. 210,213
View in Reaxys

HO
HN 2
O

NH 2

Rx-ID: 637567 View in Reaxys 584/636

Yield Conditions & References
T= 160 °C

Kaufmann; Skiba; Fette und Seifen; vol. 60; (1958); p. 362

View in Reaxys

HN
2
O

HO O

O NH 2

Rx-ID: 637568 View in Reaxys 585/636

Yield Conditions & References
T= 160 °C

Kaufmann; Skiba; Fette und Seifen; vol. 60; (1958); p. 362

View in Reaxys

HN
2
O

HO O

O NH 2

Rx-ID: 637569 View in Reaxys 586/636

Yield Conditions & References
T= 160 °C

Kaufmann; Skiba; Fette und Seifen; vol. 60; (1958); p. 362

View in Reaxys

HO
HN
2
O

NH 2

Rx-ID: 637989 View in Reaxys 587/636

Yield Conditions & References
T= 180 - 190 °C

Sugasawa; Shigehara; Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan; vol. 62; (1942); p. 532;
engl. Ref. S. 169; Chem.Abstr.; (1951); p. 2861
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 HO O

HN 2
O

O NH 2

Rx-ID: 638066 View in Reaxys 588/636

Yield Conditions & References
T= 230 °C

PatentRoe; Swern; Roe; Swern; US2608562; (1949); (A)

View in Reaxys

H O
HO
HN
2
N

N
O NH 2

NH

Rx-ID: 713633 View in Reaxys 589/636

Yield Conditions & References
T= 210 - 215 °C

Dangjan; Oganisjan; Chemical Abstracts; (1946); p. 3399

View in Reaxys

HO HN
2
O O

O NH 2
NH 2

Rx-ID: 747315 View in Reaxys 590/636

Yield Conditions & References
T= 160 °C

Ragon; Bolle; Memorial des services chimiques de l'Etat; vol. 34; (1948); p. 337,340
View in Reaxys

HO O

O NH 2

Rx-ID: 1023049 View in Reaxys 591/636

Yield Conditions & References
(i) (COCl)2, (ii) NH3, Multistep reaction

Conley,R.T.; Nowak,B.E.; Journal of Organic Chemistry; vol. 27; (1962); p. 3196 - 3201
View in Reaxys

O NH 2

OH O

Rx-ID: 4124979 View in Reaxys 592/636

Yield Conditions & References
(i) SOCl2, (ii) aq. NH3, Multistep reaction

Anderson,A.G. et al.; Journal of Organic Chemistry; vol. 38; nb. 8; (1973); p. 1439 - 1444
View in Reaxys

H H HO O
N

H O NH 2

Rx-ID: 5804718 View in Reaxys 593/636

Yield Conditions & References
T= 160 - 190 °C , unter kontinuierlicher Entfernung des entstandenen Wassers

Mitchell; Reid; Journal of the American Chemical Society; vol. 53; (1931); p. 1880,1881

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 View in Reaxys

NH 2
HO

O O

O
N

NH 2

Rx-ID: 731688 View in Reaxys 594/636

Yield Conditions & References
T= 160 °C

Patentdu Pont de Nemours & Co.; DUPONT DE NEMOURS INCDuPont; US2109941; (1936); (A)
View in Reaxys

H
HO O N

O NH 2

H O
N

NH 2

Rx-ID: 731735 View in Reaxys 595/636

Yield Conditions & References
T= 160 °C

Patentdu Pont de Nemours & Co.; DUPONT DE NEMOURS INCDuPont; US2109941; (1936); (A)
View in Reaxys

H
O N HO

NH 2 O

H
N

NH 2

Rx-ID: 735990 View in Reaxys 596/636

Yield Conditions & References
T= 160 °C

Patentdu Pont de Nemours & Co.; DUPONT DE NEMOURS INCDuPont; US2109941; (1936); (A)
View in Reaxys

Rx-ID: 4248909 View in Reaxys 597/636

Yield Conditions & References
1 % Chro‐ With Bacillus megaterium NRRL B-3437, ammonium chloride in water, Time= 96h, T= 28 °C , Product distribution
mat.
Kaneshiro, T.; Vesonder, R. F.; Peterson, R. E.; Weisleder, D.; Bagby, M. O.; Journal of the American Oil Chem‐
ists' Society; vol. 71; nb. 5; (1994); p. 491 - 494
View in Reaxys

OH O
N N

O NH 2

Rx-ID: 1022987 View in Reaxys 598/636

Yield Conditions & References
(i) SOCl2, THF, (ii) aq. NH3, Multistep reaction

Barbieri,W.; Bernardi,L.; Tetrahedron; vol. 21; (1965); p. 2453 - 2467

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 View in Reaxys

OH NH 2

O O

H H

Rx-ID: 996534 View in Reaxys 599/636

Yield Conditions & References
(i) SOCl2, PE, (ii) aq. NH3, Multistep reaction

Vogler,K.; Chopard-dit-Jean,L.H.; Helvetica Chimica Acta; vol. 43; (1960); p. 279 - 286
View in Reaxys

O O

OH O

O HN
2

Rx-ID: 127247 View in Reaxys 600/636

Yield Conditions & References
Rallings; Smith; Journal of the Chemical Society; (1953); p. 618,619
View in Reaxys

O O
O NH 2

OH O

Rx-ID: 129104 View in Reaxys 601/636

Yield Conditions & References
Rallings; Smith; Journal of the Chemical Society; (1953); p. 618,619
View in Reaxys

O O

OH NH 2

H H

Rx-ID: 205860 View in Reaxys 602/636

Yield Conditions & References
Cavanna; Staellberg-Stenhagen; ; vol. <8>3; nb. 2; (1950); p. 31,37
View in Reaxys

HO O

O NH 2

Rx-ID: 233265 View in Reaxys 603/636

Yield Conditions & References
ueber das Saeurechlorid

Gol'mow; Zhurnal Obshchei Khimii; vol. 23; (1953); p. 1162,1164;engl.Ausg.S.1221,1223

View in Reaxys

O O

OH O

O HN
2

Rx-ID: 269917 View in Reaxys 604/636

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 Yield Conditions & References
Rallings; Smith; Journal of the Chemical Society; (1953); p. 618,619
View in Reaxys

O O

HO O

O NH 2

Rx-ID: 318287 View in Reaxys 605/636

Yield Conditions & References
Chatelus; Annales de Chimie (Cachan, France); vol. <12> 4; (1949); p. 505,526
View in Reaxys

O NH 2

HO O

Rx-ID: 334798 View in Reaxys 606/636

Yield Conditions & References
Behandeln des Saeurechlorids mit wss. Ammoniak

Beyer; Chemische Berichte; vol. 70; (1937); p. 1482,1489

View in Reaxys

H H
HO N N O N N

O N N NH 2
N N

NH 2
NH 2

Rx-ID: 425965 View in Reaxys 607/636

Yield Conditions & References
Sokolowskaja et al.; Zhurnal Obshchei Khimii; vol. 27; (1957); p. 1968,1972;engl.Ausg.S.2030,2033
View in Reaxys

S S

O HN 2

HO O

Rx-ID: 468803 View in Reaxys 608/636

Yield Conditions & References
Cagniant; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 226; (1948); p. 1133
View in Reaxys

O NH 2

OH O

Rx-ID: 530023 View in Reaxys 609/636

Yield Conditions & References
Cagniant; Deluzarche; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 224;
(1947); p. 473
View in Reaxys

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 NH 2

HO
HO
HO H
OH
H OH

HO

HO

Rx-ID: 998883 View in Reaxys 610/636

Yield Conditions & References
(i) ClCO2Et, Et3N, CHCl3, (ii) aq. NH3, Multistep reaction

Subramanian,G.B.V. et al.; Journal of the Chemical Society. Perkin transactions I; (1979); p. 2167 - 2170
View in Reaxys

O
OH

NH 2

O
O

Rx-ID: 1030013 View in Reaxys 611/636

Yield Conditions & References
Garg,S.P. et al.; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 17B; (1979); p. 396
View in Reaxys

O
OH

NH 2

O
O

Rx-ID: 1030314 View in Reaxys 612/636

Yield Conditions & References
Garg,S.P. et al.; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 17B; (1979); p. 396
View in Reaxys

OH O

O NH 2

Rx-ID: 1052788 View in Reaxys 613/636

Yield Conditions & References
(i) SOCl2, (ii) aq. NH3, Multistep reaction

Golmohammadi,R.; Acta Chemica Scandinavica (1947); vol. 20; (1966); p. 479 - 485
View in Reaxys

HO Se Se

O Se Se

NH 2

Rx-ID: 1054089 View in Reaxys 614/636

Yield Conditions & References
(i) (COCl)2, benzene, (ii) aq. NH3, Multistep reaction

Golmohammadi,R.; Acta Chemica Scandinavica (1947); vol. 20; (1966); p. 563 - 571
View in Reaxys

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 HO Se Se

O Se Se

NH 2

Rx-ID: 1054888 View in Reaxys 615/636

Yield Conditions & References
(i) (COCl)2, benzene, (ii) aq. NH3, Multistep reaction

Golmohammadi,R.; Acta Chemica Scandinavica (1947); vol. 20; (1966); p. 563 - 571
View in Reaxys

HO Se Se Se

O Se Se Se

NH 2

Rx-ID: 1055021 View in Reaxys 616/636

Yield Conditions & References
(i) (COCl)2, benzene, (ii) aq. NH3, Multistep reaction

Golmohammadi,R.; Acta Chemica Scandinavica (1947); vol. 20; (1966); p. 563 - 571
View in Reaxys

O NH 2

HO O

Rx-ID: 1063396 View in Reaxys 617/636

Yield Conditions & References
Julia,M.; Chottard,J.-C.; Bulletin de la Societe Chimique de France; (1968); p. 3691 - 3700
View in Reaxys

O NH 2

HO O

Rx-ID: 1081505 View in Reaxys 618/636

Yield Conditions & References
(i) SOCl2, (ii) NH3, Multistep reaction

PatentGlaxo Lab.; GLAXOSMITHKLINE PLCGlaxoSmithKline; FR2327766; (1977); (B1) French; Chem.Abstr.; vol.
87; nb. 102022; (1977); ; vol. 87; nb. 102022; (1977)
View in Reaxys

O
OH

NH 2

O
O

Rx-ID: 1084960 View in Reaxys 619/636

Yield Conditions & References
Garg,S.P. et al.; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 17B; (1979); p. 396
View in Reaxys

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 O
O

OH

O
NH 2

Rx-ID: 1086385 View in Reaxys 620/636

Yield Conditions & References
(i) SOCl2, CHCl3, (ii) aq. NH3, Multistep reaction

PatentAmerican Cyanamid Company; PFIZER INCPfizer; US3981868; (1976); (A) English

View in Reaxys

O NH 2

HO O

Rx-ID: 1127410 View in Reaxys 621/636

Yield Conditions & References
(i) ClCO2Et, Et3N, (ii) NH3, Multistep reaction

Julia,M. et al.; Bulletin de la Societe Chimique de France; (1964); p. 1116 - 1122

View in Reaxys

O
O
HO

O
NH 2

Rx-ID: 1192670 View in Reaxys 622/636

Yield Conditions & References
(i) SOCl2, CHCl3, (ii) aq. NH3, Multistep reaction

PatentAmerican Cyanamid Co.; PFIZER INCPfizer; DE2234706; (1973); (A1) German; Chem.Abstr.; vol. 78; nb.
147439; (1973); ; vol. 78; nb. 147439; (1973)
View in Reaxys

NH 2

OH O

HO
O
OH
OH

O OH

Rx-ID: 1338433 View in Reaxys 623/636

Yield Conditions & References
(i) ClCO2Et, Et3N, CHCl3, (ii) aq. NH3, Multistep reaction

Subramanian,G.B.V. et al.; Journal of the Chemical Society. Perkin transactions I; (1979); p. 2167 - 2170
View in Reaxys

O
O

NH 2

O
O

Rx-ID: 22561957 View in Reaxys 624/636

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 Yield Conditions & References
Reaction Steps: 2
1: (acid hydrolysis)

Garg,S.P. et al.; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 17B; (1979); p. 396
View in Reaxys

O
O

NH 2

O
O

Rx-ID: 22561973 View in Reaxys 625/636

Yield Conditions & References
Reaction Steps: 2
1: (acid hydrolysis)

Garg,S.P. et al.; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 17B; (1979); p. 396
View in Reaxys

O
O

NH 2

O
O

Rx-ID: 22561981 View in Reaxys 626/636

Yield Conditions & References
Reaction Steps: 2
1: (acid hydrolysis)

Garg,S.P. et al.; Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry; vol. 17B; (1979); p. 396
View in Reaxys

O O

Cl O

OH NH 2

H H
O Cl

Rx-ID: 131004 View in Reaxys 627/636

Yield Conditions & References
und beim Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Cavanna; Staellberg-Stenhagen; ; vol. <8>3; nb. 2; (1950); p. 31,37

View in Reaxys

H
Cl O
O

O Cl
HO

HN
2

Rx-ID: 131005 View in Reaxys 628/636

Yield Conditions & References
und beim Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

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 Cavanna; Staellberg-Stenhagen; ; vol. <8>3; nb. 2; (1950); p. 31,35
View in Reaxys

O O

Cl O

OH NH 2

O Cl H H

Rx-ID: 131009 View in Reaxys 629/636

Yield Conditions & References
und beim Behandeln des hergestellten Saeurechlorids mit wss.Ammoniak

Hallgren; Arkiv foer Kemi; vol. 9; (1956); p. 389,393

View in Reaxys

HO O

N S K

O NH 2

Rx-ID: 228935 View in Reaxys 630/636

Yield Conditions & References
Mehlis; Justus Liebigs Annalen der Chemie; vol. 185; (1877); p. 365
View in Reaxys

H H HO O
N

H O NH 2

Rx-ID: 5805576 View in Reaxys 631/636

Yield Conditions & References
T= 190 - 210 °C

Ralston; Hoerr; Pool; Journal of Organic Chemistry; vol. 8; (1943); p. 474

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NH 2
HO HO OH O

N HN 2
2

O O NH
O 2

Rx-ID: 224959 View in Reaxys 632/636

Yield Conditions & References
T= 155 °C , Rate constant

Mukaiyama et al.; Bulletin of the Chemical Society of Japan; vol. 27; (1954); p. 578,580
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NH 2
HO O HO OH

N HN 2
2

O NH O
O 2

Rx-ID: 793229 View in Reaxys 633/636

Yield Conditions & References
T= 155 °C , Rate constant

Mukaiyama et al.; Bulletin of the Chemical Society of Japan; vol. 27; (1954); p. 578,580
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H H HO
N

H O

NH 2

Rx-ID: 6190575 View in Reaxys 634/636

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 Yield Conditions & References
T= 135 - 200 °C , Kinetics

Kita; Sugahara; Kogyo Kagaku zasshi / Journal of the Society of Chemical Industry; vol. 60; (1957); p. 183;
Chem.Abstr.; (1959); p. 7002
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O H H
N
sodium
O H

sodium compound of hexanol-(1)

NH 2

Rx-ID: 7086766 View in Reaxys 635/636

Yield Conditions & References
Chablay; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 154; (1912); p. 365;
Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 156; (1913); p. 1021
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Chablay; Annales de Chimie (Cachan, France); vol. <9>8; (1917); p. 203,208,215; Comptes Rendus Hebdomad‐
aires des Seances de l'Academie des Sciences; vol. 156; (1913); p. 1021
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O H H O
N OH
sodium
O H NH 2

Rx-ID: 7066824 View in Reaxys 636/636

Yield Conditions & References
Chablay; Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 154; (1912); p. 365;
Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences; vol. 156; (1913); p. 1021
View in Reaxys
Chablay; Annales de Chimie (Cachan, France); vol. <9>8; (1917); p. 203,208,215; Comptes Rendus Hebdomad‐
aires des Seances de l'Academie des Sciences; vol. 156; (1913); p. 1021
View in Reaxys

Copyright © 2023 Elsevier Life Sciences IP Limited except certain content provi‐ 221/221 2023-12-30 09:34:21
ded by third parties. Reaxys is a trademark of Elsevier Life Sciences IP Limited.