1-Alkyl-1H-indole-3-carboxylic acid to N-Gstar-1-Alkyl-1H-indole-3-carboxamide [Reaxy

Query Query

Results

Date

63 reactions in Reaxys

2016-04-26 12h:51m:14s (EST)

G* O

O OH

NH

1. Query N ALK

N ALK

Search as: As drawn, No salts, No mixtures

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O Cl

O

Cl

O

OH O O

H 2N

H

Cl

O

N

NH

Cl

Cl

N

Rx-ID: 29853128 View in Reaxys 1/63 Yield

Conditions & References

89.5 %

5 : {2,5-Dichloro-4-[(1-methylindol-3-yl)carboxamido]phenyl}acetic acid ethyl ester Example 5 {2,5-Dichloro-4-[(1-methylindol-3-yl)carboxamido]phenyl}acetic acid ethyl ester A compound represented by formula (I) wherein R1 represents a 1-methylindol-3-yl group (10 g) and toluene (150 mL) were added to a flask, and, at room temperature, (COCl)2 (5.6 mL) was added dropwise to the mixture.

Subsequently, DMF (20 μL) was added to the mixture, and the resultant mixture was stirred for 1 hour at room temperature by means of a mechanical stirrer.

The compound obtained in Example 2 (16.6 g) was added to the reaction mixture, and the resultant mixture was refluxed for 4 hours at an external temperature of 100°C to 120°C. After completion of reaction had been confirmed through HPLC, the reaction mixture was cooled, diisopropyl ether (IPE) (50 mL) was added to the reaction mixture, and the resultant mixture was stirred for a while.

The crystals that precipitated were collected through filtration, washed with IPE, and dried, to thereby yield the title compound represented by formula (22) (20.7 g, 89.5percent).

1H-NMR(CDCl )δ: 1.28(t,J=7.1Hz,3H), 3.72(s,2H), 3.89(s,3H), 4.20(q,J=7.1Hz,2H), 7.32-7.44(m,4H), 7.80(s,1H), 3 8.10- 8.16(m,1H), 8.25(s,1H), 8.81(s,1H) Stage 1: With oxalyl dichloride, N,N-dimethyl-formamide in toluene, Time= 1h, T= 20 °C Stage 2: in toluene, Time= 4h, T= 100 - 120 °C , Heating / reflux Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1698611; (2006); (A1) English View in Reaxys F

O

OH RS F

OH SR

HO O

F

NH 2

F

SR RS NH

N

F

F N

F

F

Rx-ID: 23667019 View in Reaxys 2/63 Yield 71 %

Conditions & References 98 :While stirring (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-[4-(trifluoromethyl)phenyl]propan-1-ol (0.172 g, 0.549 mmol), 1-methylindole-3-carboxylic acid (0.10 g, 0.55 mmol) and 1-hydroxybenzotriazole hydrate (84 mg, 0.55 mmol) in acetonitrile (10 ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.55 mmol) was added and the mixture was stirred overnight at room temperature. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-1/1). Crystallization from diethyl ether-hexane gave the objective substance. white crystal yield 0.183 g, 71percent mp,129-131°C; 1H-NMR (CDCl3, 200MHz) δ 2.91 (1H, dd, J = 9.5 Hz, 13.9 Hz), 3.01 (1H, dd, J = 5.2 Hz, 14.8 Hz), 3.76 (3H, s), 4.58-4.71 (1H, m), 4.73 (1H, br s), 5.10! (1H, br s), 5.89 (1H, d, J = 7.8 Hz), 7.05 (2H, t, J = 8.8 Hz), 7.11-7.19 (1H, m), 7.23-7.30 (4H, m), 7.36-7.51 (6H, m) ; IR (KBr) 3328, 1624, 1545, 1508, 1325, 1229, 1163, 1128, 1067, 747 cm-1; Anal. Calcd for C26H22F4N2O2: C, 66.38; H, 4.71; N, 5.95.

Found: C, 66.27; H, 4.71; N, 5.82.

With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in acetonitrile, T= 20 °C Patent; Takeda Chemical Industries, Ltd.; EP1362846; (2003); (A1) English

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View in Reaxys

O O O

OH

N O

N N

H 2N

N

NH

N

N

Rx-ID: 39792226 View in Reaxys 3/63 Yield

Conditions & References

69 %

3. General procedure for the synthesis of 2–12 General procedure: HATU (0.76 g, 0.002 mol), DIPEA (0.26 g, 0.002 mol), and an equivalent amount of 15 were added to a solution of 14 (0.5 g, 0.002 mol) in CH2Cl2. The reaction was protected by N2 and then stirred at room temperature for 6–10 h. The mixture was washed with water, and the combined organic layer was dried (Na2SO4) and evaporated under a reduced pressure. The crude was purified 2using silica gel chromatography with acetone and petroleum ether as eluents to produce target compounds 2–12 (yield 69percent–81percent).

With N,N- diisopropylethylamine, HATU in dichloromethane, T= 20 °C , Inert atmosphere Huang, Junjun; He, Fei; Huang, Minyi; Liu, Xiawen; Xiong, Yan; Huang, Yajian; Zhu, Liu; Yang, Ya; Xu, Xingjie; Yuan, Mu; European Journal of Medicinal Chemistry; vol. 96; (2015); p. 83 - 91 View in Reaxys

Cl

O OH

N

O

Cl

NH

NH 2

N

Rx-ID: 27845523 View in Reaxys 4/63 Yield 33 %

Conditions & References 5.8 :To a 00C suspension of N-methylindole-3-carboxylic acid (100 mg, 0.57 mmol) in CH2Cl2 (8 ml) was added N, Ndimethyl-4-aminopyridine (DMAP) (131 mg, 1.06 mmol), a solution of 3-chloroaniline (105 mg, 87 μl, 0.83 mmol) in CH2Cl2 (1.6 ml) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCIηC1) (123 mg, 0.65 mmol). The reaction was allowed to warm to 200C, and was stirred at 200C for 16 h. The reaction was diluted with CH2Cl2 (15 ml), and was washed with dilute aqueous NaHCO3 solution (2 x 15 ml). The organic layer was dried (Na2SO4), and concentrated. The crude mixture was purified by column on silica (10 - 50percent ethyl acetate: hexane). The resulting material was purified by column on silica (5percent methanol: CH2Cl2) to give the desired product (53 mg, 33percent) as a white solid.1H NMR (CDCl3) δ ppm 3.89 (s, 3H), 7.10-7.13 (m, IH), 7.31-7.43 (m, 4H), 7.517.52 (m, IH), 7.78 (bs, IH), 7.80-7.82 (m, 2H), 8.03-8.06 (m, IH). HPLC: 100percent at 2.100 minutes; Sunfire Cl 8 4.6 x 50 mm; 10-90percent methanol with 0.1percent TFA: water; Gradient time = 2 min; 3.5 ml/ min; 254 nm. MS = 285 M+H+.

With 4-(N,N-dimethlyamino)pyridine, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 16h, T= 0 - 20 °C Patent; LEXICON PHARMACEUTICALS, INC.; WO2008/89307; (2008); (A2) English View in Reaxys

33 %

6.9 :To a 00C suspension of N-methylindole-3-carboxylic acid (100 mg, 0.57 mmol) in CH2Cl2 (8 ml) was added N, Ndimethyl-4-aminopyridine (DMAP) (131 mg, 1.06 mmol), a solution of 3-chloroaniline (105 mg, 87 μl, 0.83 mmol) in CH2Cl2 (1.6 ml) and N-(3- dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDCIηC1) (123 mg, 0.65 mmol). The reaction was allowed to warm to 200C, and was stirred at 200C for 16 h. The reaction was diluted with CH2Cl2 (15 ml), and was washed with dilute aqueous NaHCO3 solution (2 x 15 ml). The organic layer was dried (Na2SO4), and concentrated. The crude mixture was purified by column on silica (10 - 50percent ethyl acetate: hex-

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ane). The resulting material was purified by column on silica (5percent methanol: CH2Cl2) to give the desired product (53 mg, 33percent) as a white solid.1H NMR (CDCl3) δ ppm 3.89 (s, 3H), 7.10-7.13 (m, IH), 7.31-7.43 (m, 4H), 7.517.52 (m, IH), 7.78 (bs, IH), 7.80-7.82 (m, 2H), 8.03-8.06 (m, IH). HPLC: 100percent at 2.100 minutes; Sunfire Cl 8 4.6 x 50 mm; 10-90percent methanol with 0.1percent TFA: water; Gradient time = 2 min; 3.5 ml/ min; 254 nm. MS = 285 M+H+.

With 4-(N,N-dimethlyamino)pyridine, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 16h, T= 0 - 20 °C Patent; LEXICON PHARMACEUTICALS, INC.; WO2008/89310; (2008); (A2) English View in Reaxys

O

O O trans trans

O Cl

N

O OH

N

O

O trans

O

H 2N

Cl

trans

Cl

transtrans O

N

Cl

O

trans

NH

trans O O

N

Rx-ID: 29853129 View in Reaxys 5/63 Yield

Conditions & References

91 %

14.3.3-1 :1-Methylindole-3-carboxylic acid (400 mg, 2.28 mmol) and toluene (4 mL, 10 v/w) were added to a flask, and the mixture was cooled with ice under nitrogen. Oxalyl chloride (243 μL, 1.2 mole-eq.) was added dropwise to the mixture, a catalytic amount of DMF was added to the resulting mixture, followed by stirring for 1 hour at room temperature. Triethylamine (413 μL, 1.3 mole-eq.) was added to the reaction mixture, and the compound represented by formula (26) (1.13 g, 1.02 mole-eq.) was added to the resulting mixture, followed by stirring for 4 hours at 75°C. After completion of reaction had been confirmed through HPLC, the reaction mixture was cooled, and isopropyl ether (7.2 mL, 18 v/w) was added to the reaction mixture. The resulting mixture was stirred for a while. The crystals that precipitated were collected through filtration, washed with isopropyl ether, and dried under reduced pressure at room temperature, to thereby yield the compound represented by formula (24) (1.3 g, 91percent).

Stage 1: With oxalyl dichloride, N,N-dimethyl-formamide in toluene, Time= 1h, T= 0 - 20 °C Stage 2: With triethylamine in toluene, Time= 4h, T= 75 °C , Product distribution / selectivity Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1698611; (2006); (A1) English View in Reaxys

O O

O OH Cl O

O Cl

O

Cl O

Cl O

NH 2

NH

N

N

Rx-ID: 25397282 View in Reaxys 6/63 Yield 88%

Conditions & References 66.3 : (Step 3) (Step 3) Synthesis of methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate To 1-ethylindole-3-carboxylic acid (160.2 mg, 0.847 mmol) were added methylene chloride (3.5 ml) and oxalyl chloride (108.9 ael, 1.270 mmol) under stirring at 15OEC. The reaction mixture was stirred for 2.5 hours at room temperature.

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The solvent was then distilled off under reduced pressure.

To the residue was added methylene chloride (3.5 ml).

Under stirring at room temperature, a solution of methyl 3-chloro-4-aminophenylacetate (177.5 mg, 0.889 mmol) in methylene chloride (3.5 ml) and triethylamine (0.37 ml, 2.667 mmol) were added and the mixture was heated under reflux for 18 hours.

After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure.

The residue was dissolved in chloroform.

The resulting solution was washed with 1N HCl ad saturated saline, and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to give methyl 3-chloro-4-((1-ethyl-3-indolylcarbonyl)amino)phenylacetate (277.7 mg, 88percent) as a brown amorphous substance.

The resulting compound was provided for the subsequent reaction without further purification.

1H-NMR (CDCl ) δ: 1.54 (3H, t, J=7.6Hz), 3.59 (2H, s), 3.71 (3H, s), 4.23 (2H, m), 7.15-7.49 (5H, m), 7.78 (1H, s), 3 8.14 (1H, m), 8.26 (1H, m), 8.59 (1H, d, J=8.4Hz).

With triethylamine in dichloromethane, chloroform Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

O O

O OH Cl

O

O

Cl

Cl

O O

Cl

O

NH 2

N

NH

N

Rx-ID: 25397286 View in Reaxys 7/63 Yield 91%

Conditions & References 67.3 : (Step 3) (Step 3) Synthesis of methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate To a solution of 1-isopropylindole-3-carboxylic acid (159.6 mg, 0.785 mmol) in methylene chloride (3.5 ml) was added oxalyl chloride (101.0 ael, 1.178 mmol) under stirring at -15OEC. The reaction mixture was stirred for 2.5 hours at room temperature and then distilled under reduced pressure to remove the solvent.

The residue was dissolved in methylene chloride (3.5 ml), followed by the addition of a solution of methyl 3-chloro-4aminophenylacetate (164.6 mg, 0.824 mmol) in methylene chloride (3.5 ml) and triethylamine (0.35 ml, 2.474 mmol) under stirring at room temperature.

The reaction mixture was stirred at room temperature for 18 hours.

The reaction mixture was then distilled under reduced pressure to remove the solvent.

The residue was dissolved in chloroform.

The resulting solution was washed successively with 1N HCl and saturated saline, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent, whereby methyl 3-chloro-4-((1-isopropyl-3-indolylcarbonyl)amino)phenylacetate (275.3 mg, 91percent) was obtained as a brown solid.

The resulting compound was provided for the subsequent reaction without further purification.

1H-NMR (CDCl ) δ: 1.60 (6H, d, J=6.8Hz), 3.60 (2H, s), 3.71 (3H, s), 4.73 (1H, m), 7.15-7.54 (5H, m), 8.00 (1H, s), 3 8.11 (1H, m), 8.28 (1H, m), 8.60 (1H, d, J=8.4Hz).

With triethylamine in dichloromethane, chloroform Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

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OH F

O Cl

O

O

Cl

NH 2

O

O

N

O

F

OH

O

NH

O

O

N

Rx-ID: 25399579 View in Reaxys 8/63 Yield

Conditions & References

71%

76.2 : (Step 2) (Step 2) Synthesis of 2-fluoro-5-methoxy-4-((1-methyl-1H-3-indolylcarbonyl)amino)phenylacetic acid 1-Methyl-1H-indole-3-carboxylic acid (700 mg, 4.0 mmol) was dissolved in methylene chloride (8 ml).

Oxalyl chloride (0.53 ml, 6.1 mmol) was added dropwise to the solution under stirring at 0OEC. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour and distilled under reduced pressure to remove the solvent.

The residue was dissolved in methylene chloride (6 ml).

The resulting solution was added to a solution of triethylamine (0.84 ml, 6.0 mmol) and ethyl 4-amino-2-fluoro-5-methoxyphenylacetate (909 mg, 4.0 mmol) in methylene chloride (3 ml) under stirring at 0OEC. The reaction mixture was heated at reflux for 18 hours.

After cooling to room temperature, the reaction mixture was poured into ice water, followed by extraction with chloroform.

The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent.

The residue was purified by silica gel column chromatography (middle pressure Yamazen, linear gradient of n-hexane/ethyl acetate form 9:1 to 7:3, 12 ml/min, φ 50 mm x 300 mm, charged by dry silica gel method).

The purified ester was added with THF (45 ml) and 0.25M NaOH (18 ml, 4.5 mmol), followed by stirring at room temperature for 4 hours.

The reaction mixture was poured into water and 1M HCl was added to the resulting mixture to make it acidic.

The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 2-fluoro-5-methoxy-4-((1-methyl-1H-3-indolylcarbonyl)amino)phenylacetic acid (1.01 g, 71percent) as a colorless solid.

1H-NMR (CDCl ) δ: 3.60 (s, 2H), 3.90 (s, 6H), 7.05 (d, J=6.8Hz, 1H), 7.22 (t, J=7.5Hz, 1H), 7.30 (t, J=7.5Hz, 1H), 3 7.58 (d, J=7.6Hz, 1H), 7.95 (d, J=11.5Hz, 1H), 8.12 (d, J=7.3Hz, 1H), 8.31 (s, 1H), 8.80 (s, 1H).

MS (ESI) m/z 357 (M+1)+.

With sodium hydroxide, triethylamine in tetrahydrofuran, dichloromethane Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

O OH

O

H 2N

NH

N

N

Rx-ID: 9513109 View in Reaxys 9/63 Yield 68 %

Conditions & References With PS-carbodiimide, benzotriazol-1-ol in 1-methyl-pyrrolidin-2-one, Time= 0.0833333h, T= 100 °C , microwave irradiation Sauer, Daryl R.; Kalvin, Douglas; Phelan, Kathleen M.; Organic Letters; vol. 5; nb. 24; (2003); p. 4721 - 4724 View in Reaxys

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O O

O

O

OH

Cl

O

T-4

T-4 O

N

O

Cl

N T-4 O

H 2N

O

O

O

N

T-4

O

Cl

Cl

NH

N

Rx-ID: 23840204 View in Reaxys 10/63 Yield

Conditions & References

76 %

16 :[Example 16]; trans-4-((2S,4S)-1-{2,5-Dichloro-4-[(1-methylindol-3-yl)carboxamido]phenyl}acetyl-4-methoxypyrrolidin-2-yl)methoxycyclohexane-1-carboxylic acid ethyl ester; [Show Image] [Show Image] While 1-methylindole-3carboxylic acid (150 mg, 0.86 mmol) and 1,2-dichloroethane (3 mL) were stirred under cooling on an ice-water bath, oxalyl chloride (0.095 mL, 1.07 mmol) was added to the mixture, and the resultant mixture was stirred for 1 hour at the same temperature. The reaction mixture was concentrated to dryness under reduced pressure. The thus-obtained crystals were dissolved in 1,2-dichloroethane (3 mL), and the solution was added to trans-4-[(2S,4S)-1-(4amino-2,5-dichlorophenyl)acetyl-4-methoxypyrrolidin-2-yl]methoxycyclohexane-1-carboxylic acid ethyl ester (348 mg, 0.714 mmol) in 1,2-dichloroethane (15 mL) under stirring and under cooling. After completion of addition, the reaction mixture was refluxed for 10 hours under stirring. The reaction mixture was cooled, washed with water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography, to thereby give trans-4-((2S,4S)-1-{2,5-dichloro-4-[(1-methylindol-3-yl)carboxamido]phenyl}acetyl-4-methoxypyrrolidin-2-yl)methoxycyclohexane-1-carboxylic acid ethyl ester (350 mg, 76percent) as a crystalline powder (in a fraction obtained through use of chloroform:ethyl acetate (9:1 to 3:1, v/v)). Spectral data obtained from the thus-produced compound were identical with those of the compound produced through the method described above.

Stage 1: With oxalyl dichloride in 1,2-dichloro-ethane, Time= 1h, T= 0 °C Stage 2: in 1,2-dichloro-ethane, Time= 10h, Heating / reflux, Product distribution / selectivity Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1698621; (2006); (A1) English View in Reaxys

O O

H 2N

OH

H N

N

O

S H N

N

HN RS

O

O

O O

N H

O

N

O O

RS

O O

HN S

HN O

SR

SR N H

O

N

Rx-ID: 25598071 View in Reaxys 11/63 Yield 29 %

Conditions & References B.33 :Following the general procedure of acid-amine coupling as shown in Example 23, Compound 8 (20 mg, 0.03 mmol) was treated with 1-methylindole-3-carboxylic acid (4.6 mg, 0.036 mmol), DIEA (0.013 mL, 0.075 mmol) and the coupling reagent PyAOP (23.5 mg, 0.045 mmol) in acetonitrile (3 mL). After purification by Prep.HPLC column, a white solid was obtained as final 1:1 diastereomers (Compound 19) (7.1 mg, 29percent yield). (Compound 19, 48110-169C): LC-MS (retention time: 1.91 minutes.), MS m/z 695 (MH+).

With N-ethyl-N,N-diisopropylamine, PyAOP in acetonitrile Patent; Hewawasam, Piyasena; Ding, Min; Sun, Li-Qiang; Scola, Paul Michael; US2007/10455; (2007); (A1) English View in Reaxys

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O Cl

O

Cl

O

OH O O

H 2N

Cl

O

O

Cl

O

N

NH

Cl

Cl

N

Rx-ID: 29813403 View in Reaxys 12/63 Yield

Conditions & References 1 :1-methyl-1H-indole-3-carboxylic acid (794 mg, 4.53 mmol) was dissolved inmethylene chloride (25 ml) , and oxalyl chloride (0.79 ml, 9.1 mmol) was added at 0°C with stirring. The reaction mixture was stirred at room temperature for another 1 hour, and the reaction mixture was exsiccated under reduced pressure. The residue was dissolved in methylene chloride (25 ml), and a solution of triethylamine (0.84 ml, 9.0 mmol) and ethyl 4-amino-2,5-dichlorophenylacetate (750 mg, 3.02 mmol) in methylene chloride (5 ml) was added at 0°C with stirring. The reaction mixture was heated under reflux with stirring for 18 hours. After cooling the reaction mixture, water (30 ml) was added and the solution was extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using silica gel (medium pressure HPLC manufactured by Yamazen Corporation; chloroform : methanol, 100:0 to 95:5 (v/v)), and to the resulting ethyl 2,5-dichloro-4-[(1-methyl-1H-indol-3yl)carboxamido]phenyla cetate in ester form with no further purification were added tetrahydrofuran (THF; 45 ml) and 0.25N NaOH (18 ml, 4.5 mmol). The resulting mixture was stirred at room temperature for 4 hours . While cooling the reaction mixture, 1N HCl was gradually added to the reaction mixture to render the pH weakly acidic to thereby collect precipitated crystals. The crystals was washed with water, and dried to give the title compound (807 mg, 71percent) as a crystal powder. MS (ESI); m/z: 378 (M++2). 1H-NMR (DMSO-d6) δ: 3.72 (s, 2H), 3.90 (s, 3H), 7.22 (t, J= 8.1 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H), 7.92 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.31 (s, 1H) , 9.39 (s, 1H).

Stage 1: in dichloromethane, Time= 1h, T= 0 - 20 °C Stage 2: With triethylamine in dichloromethane, Time= 18h, Heating / reflux Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1623975; (2006); (A1) English View in Reaxys

OH

O

HO

OH H

NH 2

HO

N

O NH

OH H

N

Rx-ID: 9582291 View in Reaxys 13/63 Yield 66 %

Conditions & References Stage 1: With benzotriazol-1-ol, dicyclohexyl-carbodiimide in N,N-dimethyl-formamide, Time= 1h, T= 20 °C Stage 2: in N,N-dimethyl-formamide, T= 20 °C Smietana, Michael; Johnson, Robert B.; Wang, Q. May; Kool, Eric T.; Chemistry - A European Journal; vol. 10; nb. 1; (2004); p. 173 - 181 View in Reaxys

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O F

O

F

O

OH

O O

NH 2

O

N

NH

Cl

Cl

N

Rx-ID: 29607273 View in Reaxys 14/63 Yield

Conditions & References

70 %

Stage 1: With oxalyl dichloride in dichloromethane, T= 0 - 20 °C Stage 2: With triethylamine in dichloromethane, Time= 17h, Reflux Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo; Journal of Medicinal Chemistry; vol. 52; nb.

24; (2009); p. 7974 - 7992 View in Reaxys O OH

Cl

O

O Cl

HCl

N

Cl O

O

NH 2

O O Cl O

NH

N

Rx-ID: 25397240 View in Reaxys 15/63 Yield 30%

Conditions & References 147.1 : (Step 1) (Step 1) Synthesis of ethyl (3-Chloro-4-((1-methyl-3-indolylcarbonyl)amino)phenyl)acetate In DMF (20 ml), EDC HCl (1.44 g, 7.49 mmol) was added to 1-methyl-3-indolylcarboxylic acid (1.01 g, 5.71 mmol), ethyl 4-amino-3-chlorophenylacetate (1.22 g, 5.71 mmol), HOBt (0.86 g, 6.34 mmol), and DMAP (0.14 g, 1.15 mmol) and the resulting mixture was stirred at 70OEC for 18 hours.

After cooling to room temperature, the reaction mixture was added with water, followed by extraction with ethyl acetate.

The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent.

The residue was purified by chromatography on a silica gel column, whereby from n-hexane- ethyl acetate (1: 1, v/v) eluate fractions, ethyl (3-chloro-4-((1-methyl-3-indolylcarbonyl)amino)phenyl)acetate (639 mg, 30percent) was obtained as a yellow solid.

1H-NMR (CDCl ) δ: 1.27 (t, J=7.1Hz, 3H), 3.58 (s, 2H), 3.89 (s, 3H), 4.17 (q, J=7.1Hz, 2H), 7.24 (dd, J=8.3,2.0Hz, 3 1H), 7.32-7.43 (m, 4H), 7.81 (s, 1H), 8.16 (m, 1H), 8.28 (broad s, 1H), 8.59 (d, J=8.3Hz, 1H).

MS (ESI) m/z 371 (M++1).

With 4-(N,N-dimethlyamino)pyridine, benzotriazol-1-ol in water, N,N-dimethyl-formamide Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

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N

O OH HO

N

NH

HO

NH 2

HN

N

O

O

OH O

OH

NH

O

Z

Z

O N

Rx-ID: 24880702 View in Reaxys 16/63 Yield

Conditions & References 2 : N-[(1H-Imidazol-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide maleate EXAMPLE 2 N-[(1H-Imidazol-4-yl)methyl]-1-methyl-1H-indole-3-carboxamide maleate Triethylamine (0.27 ml) was added dropwise to a stirred suspension of 1-methyl-1H-indole-3-carboxylic acid (175 mg) and imidazole-4-methanamine (97 mg) in dry dichloromethane at room temperature under nitrogen.

Diphenylphosphoryl azide (0.43 ml) was then added and stirring was continued for 20h.

The reaction mixture was partitioned between hydrochloric acid (1N; 150 ml) and ethyl acetate (2*75 ml) and the aqueous layer was carefully basified (to pH9) with solid potassium carbonate and extracted into ethyl acetate (3*75 ml).

These latter ethyl acetate extracts were combined, dried and evaporated in vacuo to leave a solid (0.15 g) which was dissolved in absolute ethanol (25 ml), and a solution of maleic acid (95 mg) in ethanol (2 ml) was added with stirring.

The resulting solution was diluted with dry ether (ca. 200 ml), precipitating the title compound (110 mg), m.p.

145°-147°.

Analysis. Found: C,57.5; H,4.3; N,14.7; C14 H14 N4 O.1.1C4 H4 O4. 0.046H2 O requires C,57.7; H,4.8; N,14.6percent.

With diphenylphosphoranyl azide, triethylamine in ethanol, dichloromethane Patent; Glaxo Group Limited; US5026722; (1991); (A1) English View in Reaxys

N

O OH

O

NH

N NH 2

N

N

Rx-ID: 36171914 View in Reaxys 17/63 Yield

Conditions & References

75 %

Stage 1: With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 0.5h, T= 25 °C Stage 2: in N,N-dimethyl-formamide, Time= 8h, T= 80 °C Lee, Sang-Hak; Mu, Yu; Kim, Gun-Woo; Kim, Jin-Seok; Park, Seok-Hwi; Jin, Tian; Lee, Kee-Young; Ham, Won-Hun; Heterocycles; vol. 87; nb. 8; (2013); p. 1749 - 1764 View in Reaxys Cl N

N

Cl HN O OH

NH

N

HN

O

NH 2 N

Rx-ID: 10110512 View in Reaxys 18/63

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Yield

Conditions & References

23 %

Stage 1: With 1,1'-carbonyldiimidazole in tetrahydrofuran, Time= 4h, T= 20 °C Stage 2: in tetrahydrofuran, Time= 20h, T= 20 °C Munoz-Ruiz, Pilar; Rubio, Laura; Garcia-Palomero, Esther; Dorronsoro, Isabel; Del Monte-Millan, Maria; Valenzuela, Rita; Usan, Paola; De Austria, Celia; Bartolini, Manuela; Andrisano, Vincenza; Bidon-Chanal, Axel; Orozco, Modesto; Javier Luque; Medina, Miguel; Martinez, Ana; Journal of Medicinal Chemistry; vol. 48; nb. 23; (2005); p. 7223 - 7233 View in Reaxys

O O

OH

Cl

O T-4 O

Cl

O

O

Cl

N Cl

N

H 2N

T-4

O

O

O

O

O

T-4 O

O

N

T-4

O

Cl

NH

Cl

N

Rx-ID: 29813404 View in Reaxys 19/63 Yield

Conditions & References

76 %

6 :Ethyl trans-4-((2S,4S)-1-{2,5-dichloro-4-[(1-methylindol-3-yl)car boxamido]phenyl}acetyl-4-methoxypyrrolidin-2yl)methoxycycl ohexane-1-carboxylate (13) Oxalyl chloride (0.095 ml, 1.07 mmol) was added to 1-methylindol-3-carboxylic acid (19) (150 mg, 0.86 mmol) and 1,2-dichloroethane (3 ml) with cooling in an ice bath and with stirring, and the stirring was continued at the same temperature for 1 hour.

The reaction mixture was exsiccated under reduced pressure, and the resulting crystals were dissolved in 1, 2-dichloroethane (3ml).

This solutionwas addedto a solution of ethyl trans-4-[(2S,4S)-1-(4-amino-2,5-dichlorophenyl)acetyl-4-met hoxypyrrolidin-2-yl]methoxycyclohexane-1-carboxylate (21) (348 mg, 0.714 mmol) in 1,2-dichloroethane (15 ml) at low temperature with stirring.

After completing the addition, the reaction mixture was heated under reflux for 10 hours with stirring.

After cooling the reaction mixture, it was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The resulting residue was purified by column chromatography using silica gel, and from the elude of chloroform: ethyl acetate (9:1 to 3:1, v/v) was obtained the title compound (350 mg, 76percent) as a crystal powder.

The spectral data of the compounds obtained by this method were identified with those obtained by the method as described above.

Stage 1: in 1,2-dichloro-ethane, Time= 1h, T= 0 °C Stage 2:, Time= 10h, Heating / reflux, Product distribution / selectivity Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1623975; (2006); (A1) English View in Reaxys

O OH

N

O

NH

H 2N

N

Rx-ID: 9513111 View in Reaxys 20/63 Yield 98 %

Conditions & References With PS-carbodiimide, benzotriazol-1-ol in 1-methyl-pyrrolidin-2-one, Time= 0.0833333h, T= 100 °C , microwave irradiation, Product distribution, Further Variations: Temperatures, Reagents, Solvents

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Sauer, Daryl R.; Kalvin, Douglas; Phelan, Kathleen M.; Organic Letters; vol. 5; nb. 24; (2003); p. 4721 - 4724 View in Reaxys With PS-carbodiimide, benzotriazol-1-ol in N,N-dimethyl acetamide, Time= 2h, T= 55 °C , Product distribution, Further Variations: Temperatures, Reagents, times Sauer, Daryl R.; Kalvin, Douglas; Phelan, Kathleen M.; Organic Letters; vol. 5; nb. 24; (2003); p. 4721 - 4724 View in Reaxys

O Cl

O

Cl

O

OH O O

H 2N

O

N

Cl

NH

Cl

N

Rx-ID: 23840203 View in Reaxys 21/63 Yield

Conditions & References Stage 1: With oxalyl dichloride in dichloromethane, T= 0 - 20 °C Stage 2: With triethylamine in dichloromethane, Time= 17h, Reflux Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo; Journal of Medicinal Chemistry; vol. 52; nb.

24; (2009); p. 7974 - 7992 View in Reaxys

O O

O OH

O

Cl

O

O

NH

NH 2

N

Cl

N

Rx-ID: 29607380 View in Reaxys 22/63 Yield

Conditions & References Stage 1: With oxalyl dichloride in dichloromethane, T= 0 - 20 °C Stage 2: With triethylamine in dichloromethane, Time= 17h, Reflux Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo; Journal of Medicinal Chemistry; vol. 52; nb.

24; (2009); p. 7974 - 7992 View in Reaxys

O O

O OH O

Cl

Cl

O O

NH 2

N

NH

N

Rx-ID: 29607381 View in Reaxys 23/63

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Yield

Conditions & References Stage 1: With oxalyl dichloride in dichloromethane, T= 0 - 20 °C Stage 2: With triethylamine in dichloromethane, Time= 17h, Reflux Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo; Journal of Medicinal Chemistry; vol. 52; nb.

24; (2009); p. 7974 - 7992 View in Reaxys

O O

O OH O

Cl

Cl O

O

NH 2

NH

N

N

Rx-ID: 29607382 View in Reaxys 24/63 Yield

Conditions & References Stage 1: With oxalyl dichloride in dichloromethane, T= 0 - 20 °C Stage 2: With triethylamine in dichloromethane, Time= 17h, Reflux Muro, Fumihito; Iimura, Shin; Sugimoto, Yuuichi; Yoneda, Yoshiyuki; Chiba, Jun; Watanabe, Toshiyuki; Setoguchi, Masaki; Iigou, Yutaka; Matsumoto, Keiko; Satoh, Atsushi; Takayama, Gensuke; Taira, Tomoe; Yokoyama, Mika; Takashi, Tohru; Nakayama, Atsushi; Machinaga, Nobuo; Journal of Medicinal Chemistry; vol. 52; nb.

24; (2009); p. 7974 - 7992 View in Reaxys O OH N

N

F H 2N

N

O H N O

HN

NH

H N

O

F

O N

N N

Rx-ID: 11179217 View in Reaxys 25/63 Yield 47 %

Conditions & References in dichloromethane, Time= 14h, T= 20 °C , Title compound not separated from byproducts.

Del Pozo, Carlos; Keller, Adam I.; Nagashima, Tadamichi; Curran, Dennis P.; Organic Letters; vol. 9; nb. 21; (2007); p. 4167 - 4170 View in Reaxys

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OH

O

NH O OH

O

NH

N

N

Rx-ID: 14163017 View in Reaxys 26/63 Yield

Conditions & References Reaction Steps: 4 1: HOBt; EDC; NMM / tetrahydrofuran 2: aq. NaOH / methanol 3: i-PrOCOCl; Et3N 4: aq. NH2OH With 4-methyl-morpholine, sodium hydroxide, hydroxylamine, benzotriazol-1-ol, isopropyloxycarbonylchloride, N'-(3dimethylaminopropyl)-N-ethylcarbodiimide, triethylamine in tetrahydrofuran, methanol Dai, Yujia; Guo, Yan; Guo, Jun; Pease, Lori J.; Li, Junling; Marcotte, Patrick A.; Glaser, Keith B.; Tapang, Paul; Albert, Daniel H.; Richardson, Paul L.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 11; (2003); p. 1897 - 1901 View in Reaxys Reaction Steps: 2 1: HOBt; EDC; NMM / dimethylformamide 2: H2 / 10 percent Pd/C / tetrahydrofuran With 4-methyl-morpholine, hydrogen, benzotriazol-1-ol, N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide, palladium on activated charcoal in tetrahydrofuran, N,N-dimethyl-formamide Dai, Yujia; Guo, Yan; Guo, Jun; Pease, Lori J.; Li, Junling; Marcotte, Patrick A.; Glaser, Keith B.; Tapang, Paul; Albert, Daniel H.; Richardson, Paul L.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 11; (2003); p. 1897 - 1901 View in Reaxys

O OH

N

H 2N

N

N

N

O

O

NH

N

N N

N

Rx-ID: 24426412 View in Reaxys 27/63 Yield 2.06 g (76%)

Conditions & References 8 : N-(1-Azabicyclo[3.3.1]non-5-ylmethyl)-1-methyl-1H-indole-3-carboxamide EXAMPLE 8 N-(1-Azabicyclo[3.3.1]non-5-ylmethyl)-1-methyl-1H-indole-3-carboxamide A solution of 1-methyl-1-H-indole-3-carboxylic acid (1.53 g, 8.7 mmol) in anhydrous tetrahydrofuran (8 mL) under nitrogen was treated with 1.49 g (9.2 mmol) of 1,1'-carbonyldiimidazole (CDI) and stirred for 10 minutes.

At this point a thick suspension formed, and anhydrous N,N-dimethylformamide (8 mL) was added.

After an additional 45 minutes the solution was degassed under a stream of nitrogen over 10 minutes, then treated with a solution of 1-azabicyclo[3.3.1]nonane-5-methanamine (1.47 g, 9.5 mmol).

After 18 hours at room temperature and six hours at 55°-60° C., no acid-CDI adduct was detected by TLC (5percent methanol/methylene chloride on alumina), and the mixture was concentrated in vacuo.

The residue was partitioned between 3N sodium hydroxide (50 mL) and toluene (100 mL) containing a little 2-propanol.

The organic layer as separated and the aqueous solution was extracted with toluene (50 mL) containing some 2 propanol.

The combined organic solution was dried (Na2 SO4), concentrated in vacuo, and the residue filtered through alumina (eluted with 20percent methanol/tetrahydrofuran).

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The filtrate was concentrated in vacuo and the residue triturated from ether/petroleum ethers (30°-60°) to give a solid, which was recrystallized from tetrahydrofuran/hexane to afford 2.06 g (76percent) of colorless crystals; mp 145°-147° C. Analysis: Calculated for C19 H25 N3 O: C, 73.28; H, 8.09; N, 13.49. Found: C, 73.28; H, 8.20; N, 13.43. in tetrahydrofuran, N,N-dimethyl-formamide Patent; A. H. Robins Company, Incorporated; US5190953; (1993); (A1) English View in Reaxys HO O OH

H 2N HO

N

N

O HO N

E

OH

N

O N

E

N

O

O HO

NH OH

O

O

N

N

Rx-ID: 24963752 View in Reaxys 28/63 Yield 1.60 g (70%)

Conditions & References 7 : N-(3-Hydroxy-1-azabicyclo[2.2.2]octan-3-ylmethyl)-1-methylindole-3-carboxamide fumarate (1:1) EXAMPLE 7 N-(3-Hydroxy-1-azabicyclo[2.2.2]octan-3-ylmethyl)-1-methylindole-3-carboxamide fumarate (1:1) A solution of 1-methylindole-3-carboxylic acid (1.58 g, 0.009 mole) in anhydrous tetrahydrofuran (5 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.62 g, 0.010 mole), and after a few minutes the bubbling stopped and a precipitate formed.

This was diluted with anhydrous N,N-dimethylformamide (5 ml), stirred for one hour, and degassed for 15 minutes under a stream of nitrogen.

A solution containing 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol in 1:1 tetrahydrofuran-dimethylformamide (10 ml) was added and the mixture stirred for 20 hours at room temperature and for two hours 50° C., then concentrated in vacuo.

The residue was partitioned between 1.0N sodium carbonate (75 ml) and toluene (100 ml) containing some 2-propanol, and the organic layer was separated.

The aqueous solution was extracted with toluene (2*50 ml) containing some 2-propanol, and the combined organic solution was dried (sodium sulfate) and concentrated in vacuo.

The residue was washed with water and dried azetropically with toluene to afford 1.74 g (62percent) of the free base as a colorless gum.

A solution of the free base (1.66 g, 0.0053 mole) in methanol (15 ml) was treated with fumaric acid (1.05 g, 0.009 mole) and warmed until all fumaric acid dissolved.

The mixture was cooled, diluted with ether (30 ml), and a solid soon precipitated.

This was cooled (0° C.) stirred for an hour, filtered, and the solid washed with ether, collected, and recrystallized from methanol (2 crops) to afford 1.60 g (70percent) of the title compound as a colorless solid; mp 213.0°-214.5° C. (foams).

Analysis: Calculated for C18 H23 N3 O2.C4 H4 O4: C, 61.53; H, 6.34; N, 9.78. Found: C, 61.34; H, 6.40; N, 9.58. in tetrahydrofuran, methanol, tetrahydrofuran-dimethylformamide Patent; A. H. Robins Company, Incorporated; US5137895; (1992); (A1) English View in Reaxys

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Cl H N N O

O

OH

HO

N

Cl

N

N H

O

O

HO

O NH

NH 2 NH 2

O

O O

O

O NH H 2N

HN

N

Rx-ID: 4610131 View in Reaxys 29/63 Yield

Conditions & References With triethylamine, diethyl dicarbonate in N,N-dimethyl-formamide, Time= 5h, T= 0 °C Komai, Tomoaki; Higashida, Susumu; Sakurai, Mitsuya; Nitta, Tamayo; Kasuya, Atsushi; Miyamaoto, Shuichi; Yagi, Ryuichi; Ozawa, Yuji; Handa, Hiroshi; Mohri, Hiroshi; Yasuoka, Akira; Oka, Shinichi; Nishigaki, Takashi; Kimura, Satoshi; Shimada, Kaoru; Yabe, Yuichiro; Bioorganic and Medicinal Chemistry; vol. 4; nb. 8; (1996); p. 1365 - 1377 View in Reaxys

O OH

O O

O

OH

NH

N

N

Rx-ID: 13598849 View in Reaxys 30/63 Yield

Conditions & References Reaction Steps: 2 1.1: DCC; HOBT / dimethylformamide / 1 h / 20 °C 1.2: 66 percent / dimethylformamide / 20 °C 2.1: 78 percent / DMAP; DIPEA; pyridine With pyridine, 4-(N,N-dimethlyamino)pyridine, benzotriazol-1-ol, N-ethyl-N,N-diisopropylamine, dicyclohexyl-carbodiimide in N,N-dimethyl-formamide Smietana, Michael; Johnson, Robert B.; Wang, Q. May; Kool, Eric T.; Chemistry - A European Journal; vol. 10; nb. 1; (2004); p. 173 - 181 View in Reaxys

N O OH

O

O O

O

N

NH

O

P N

N

Rx-ID: 13598850 View in Reaxys 31/63 Yield

Conditions & References Reaction Steps: 3 1.1: DCC; HOBT / dimethylformamide / 1 h / 20 °C 1.2: 66 percent / dimethylformamide / 20 °C 2.1: 78 percent / DMAP; DIPEA; pyridine

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3.1: 65 percent / DIPEA / CH2Cl2 / 1.5 h / 20 °C With pyridine, 4-(N,N-dimethlyamino)pyridine, benzotriazol-1-ol, N-ethyl-N,N-diisopropylamine, dicyclohexyl-carbodiimide in dichloromethane, N,N-dimethyl-formamide Smietana, Michael; Johnson, Robert B.; Wang, Q. May; Kool, Eric T.; Chemistry - A European Journal; vol. 10; nb. 1; (2004); p. 173 - 181 View in Reaxys

HO O O

NH

N N

Rx-ID: 36101177 View in Reaxys 32/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / |Inert atmosphere 2: triethylamine / dichloromethane / 14 h / |Inert atmosphere With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael; ACS Chemical Neuroscience; vol. 4; nb. 7; (2013); p. 1081 - 1092 View in Reaxys

HO O

O

NH

N N

Rx-ID: 36101178 View in Reaxys 33/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / |Inert atmosphere 2: triethylamine / dichloromethane / 14 h / |Inert atmosphere With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael; ACS Chemical Neuroscience; vol. 4; nb. 7; (2013); p. 1081 - 1092 View in Reaxys

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HO O O

NH

N N

Rx-ID: 36101179 View in Reaxys 34/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / |Inert atmosphere 2: triethylamine / dichloromethane / 14 h / |Inert atmosphere With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael; ACS Chemical Neuroscience; vol. 4; nb. 7; (2013); p. 1081 - 1092 View in Reaxys

HO O O

NH

N N

Rx-ID: 36101180 View in Reaxys 35/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / |Inert atmosphere 2: triethylamine / dichloromethane / 14 h / |Inert atmosphere With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael; ACS Chemical Neuroscience; vol. 4; nb. 7; (2013); p. 1081 - 1092 View in Reaxys

HO O O

NH

N N

Rx-ID: 36101181 View in Reaxys 36/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 1 h / |Inert atmosphere 2: triethylamine / dichloromethane / 14 h / |Inert atmosphere With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane

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Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael; ACS Chemical Neuroscience; vol. 4; nb. 7; (2013); p. 1081 - 1092 View in Reaxys

O

O

NH 2 S

OH

H 2N

O S

Cl

O

NH

H

O

H 2N

N

O

N

Rx-ID: 42054008 View in Reaxys 37/63 Yield

Conditions & References With 1- hydroxybenzotriazole in dichloromethane, Time= 15.5h, T= 0 - 20 °C Pelz, Nicholas F.; Bian, Zhiguo; Zhao, Bin; Shaw, Subrata; Tarr, James C.; Belmar, Johannes; Gregg, Claire; Camper, DeMarco V.; Goodwin, Craig M.; Arnold, Allison L.; Sensintaffar, John L.; Friberg, Anders; Rossanese, Olivia W.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W.; Journal of Medicinal Chemistry; vol. 59; nb. 5; (2016); p. 2054 - 2066 View in Reaxys O O OH

O NH

N

N

Rx-ID: 13040473 View in Reaxys 38/63 Yield

Conditions & References Reaction Steps: 2 1: N,N-diisopropylethylamine; modified Mukaiyama reagent / tetrahydrofuran / 0.58 h / 23 °C 2: tetrahydrofuran With modified Mukaiyama reagent, N-ethyl-N,N-diisopropylamine in tetrahydrofuran Nagashima, Tadamichi; Lu, Yimin; Petro, Michael J.; Zhang, Wei; Tetrahedron Letters; vol. 46; nb. 38; (2005); p.

6585 - 6588 View in Reaxys

N O OH

O

NH

N

N

Rx-ID: 13040474 View in Reaxys 39/63 Yield

Conditions & References Reaction Steps: 2 1: N,N-diisopropylethylamine; modified Mukaiyama reagent / tetrahydrofuran / 0.58 h / 23 °C 2: tetrahydrofuran With modified Mukaiyama reagent, N-ethyl-N,N-diisopropylamine in tetrahydrofuran Nagashima, Tadamichi; Lu, Yimin; Petro, Michael J.; Zhang, Wei; Tetrahedron Letters; vol. 46; nb. 38; (2005); p.

6585 - 6588 View in Reaxys

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O OH

O

NH

O

N

N

Rx-ID: 13040475 View in Reaxys 40/63 Yield

Conditions & References Reaction Steps: 2 1: N,N-diisopropylethylamine; modified Mukaiyama reagent / tetrahydrofuran / 0.58 h / 23 °C 2: tetrahydrofuran With modified Mukaiyama reagent, N-ethyl-N,N-diisopropylamine in tetrahydrofuran Nagashima, Tadamichi; Lu, Yimin; Petro, Michael J.; Zhang, Wei; Tetrahedron Letters; vol. 46; nb. 38; (2005); p.

6585 - 6588 View in Reaxys O Cl

O OH O

NH

N

N

Rx-ID: 14163015 View in Reaxys 41/63 Yield

Conditions & References Reaction Steps: 3 1: HOBt; EDC; NMM / tetrahydrofuran 2: aq. NaOH / methanol 3: i-PrOCOCl; Et3N With 4-methyl-morpholine, sodium hydroxide, benzotriazol-1-ol, isopropyloxycarbonylchloride, N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide, triethylamine in tetrahydrofuran, methanol Dai, Yujia; Guo, Yan; Guo, Jun; Pease, Lori J.; Li, Junling; Marcotte, Patrick A.; Glaser, Keith B.; Tapang, Paul; Albert, Daniel H.; Richardson, Paul L.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 11; (2003); p. 1897 - 1901 View in Reaxys O OH O OH O

NH

N

N

Rx-ID: 14163016 View in Reaxys 42/63 Yield

Conditions & References Reaction Steps: 2 1: HOBt; EDC; NMM / tetrahydrofuran 2: aq. NaOH / methanol With 4-methyl-morpholine, sodium hydroxide, benzotriazol-1-ol, N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide in tetrahydrofuran, methanol Dai, Yujia; Guo, Yan; Guo, Jun; Pease, Lori J.; Li, Junling; Marcotte, Patrick A.; Glaser, Keith B.; Tapang, Paul; Albert, Daniel H.; Richardson, Paul L.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 11; (2003); p. 1897 - 1901

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View in Reaxys

O OH

O

NH

N

N

Rx-ID: 20708266 View in Reaxys 43/63 Yield

Conditions & References Reaction Steps: 2 1: SOCl2 / 0.5 h / Heating 2: benzene With thionyl chloride in benzene Caramella, P; Corsico, A. Coda; Corsaro, A; Del Monte, D.; Albini, F. Marinone; Tetrahedron; vol. 38; nb. 1; (1982); p. 173 - 182 View in Reaxys

O OH

O NH N

N

Rx-ID: 20708267 View in Reaxys 44/63 Yield

Conditions & References Reaction Steps: 2 1: SOCl2 / 0.5 h / Heating 2: benzene With thionyl chloride in benzene Caramella, P; Corsico, A. Coda; Corsaro, A; Del Monte, D.; Albini, F. Marinone; Tetrahedron; vol. 38; nb. 1; (1982); p. 173 - 182 View in Reaxys

O OH

N

O

O

NH

N

Rx-ID: 31933988 View in Reaxys 45/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 8 h / 0 - 20 °C / Inert atmosphere 2: potassium carbonate / water; ethyl acetate / 8 h / 0 - 20 °C / Inert atmosphere With oxalyl dichloride, potassium carbonate, N,N-dimethyl-formamide in dichloromethane, water, ethyl acetate Li, Bin; Feng, Huiliang; Xu, Shansheng; Wang, Baiquan; Chemistry - A European Journal; vol. 17; nb. 45; (2011); p. 12573 - 12577 View in Reaxys Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C 2: pyridine / dichloromethane / 0 - 20 °C With pyridine, oxalyl dichloride, N,N-dimethyl-formamide in dichloromethane

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Chen, Xuebing; Sun, Peng; Xu, Jinyi; Wu, Xiaoming; Kong, Lingyi; Yao, Hequan; Lin, Aijun; Tetrahedron Letters; vol. 55; nb. 51; (2014); p. 7114 - 7117 View in Reaxys

O O O OH

O

NH 2 O

O

N

NH

N

Rx-ID: 9302912 View in Reaxys 46/63 Yield

Conditions & References With 4-methyl-morpholine, benzotriazol-1-ol, N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide in tetrahydrofuran Dai, Yujia; Guo, Yan; Guo, Jun; Pease, Lori J.; Li, Junling; Marcotte, Patrick A.; Glaser, Keith B.; Tapang, Paul; Albert, Daniel H.; Richardson, Paul L.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 11; (2003); p. 1897 - 1901 View in Reaxys

O

O OH

H N

H 2N

O NH

O

O

N

O NH

N

Rx-ID: 9302913 View in Reaxys 47/63 Yield

Conditions & References With 4-methyl-morpholine, benzotriazol-1-ol, N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide in N,N-dimethyl-formamide Dai, Yujia; Guo, Yan; Guo, Jun; Pease, Lori J.; Li, Junling; Marcotte, Patrick A.; Glaser, Keith B.; Tapang, Paul; Albert, Daniel H.; Richardson, Paul L.; Davidsen, Steven K.; Michaelides, Michael R.; Bioorganic and Medicinal Chemistry Letters; vol. 13; nb. 11; (2003); p. 1897 - 1901 View in Reaxys

O OH

N

O NH

N

Rx-ID: 36171912 View in Reaxys 48/63 Yield

Conditions & References Reaction Steps: 2 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C 1.2: 8 h / 80 °C 2.1: trifluoroacetic acid / dichloromethane / 8 h / 25 °C With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,N-diisopropylamine, trifluoroacetic acid in dichloromethane, N,N-dimethyl-formamide

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Lee, Sang-Hak; Mu, Yu; Kim, Gun-Woo; Kim, Jin-Seok; Park, Seok-Hwi; Jin, Tian; Lee, Kee-Young; Ham, Won-Hun; Heterocycles; vol. 87; nb. 8; (2013); p. 1749 - 1764 View in Reaxys Reaction Steps: 2 1.1: O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C 1.2: 8 h / 80 °C 2.1: trifluoroacetic acid / dichloromethane / 8 h / 25 °C With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N-ethyl-N,N-diisopropylamine, trifluoroacetic acid in dichloromethane, N,N-dimethyl-formamide Lee, Sang-Hak; Mu, Yu; Kim, Gun-Woo; Kim, Jin-Seok; Park, Seok-Hwi; Jin, Tian; Lee, Kee-Young; Ham, Won-Hun; Heterocycles; vol. 87; nb. 8; (2013); p. 1749 - 1764 View in Reaxys

O

H

OH

N

O NH N

N

Rx-ID: 12407416 View in Reaxys 49/63 Yield

Conditions & References Reaction Steps: 2 1: dimethylformamide / 1 h / 20 °C 2: dimethylformamide / 16 h / 20 °C in N,N-dimethyl-formamide Becker, Daniel P.; Flynn, Daniel L.; Moormann, Alan E.; Nosal, Roger; Villamil, Clara I.; Loeffler, Richard; Gullikson, Gary W.; Moummi, Chafiq; Yang, Dai-C.; Journal of Medicinal Chemistry; vol. 49; nb. 3; (2006); p. 1125 1139 View in Reaxys

HO O O

NH

N N

Rx-ID: 31869422 View in Reaxys 50/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / -10 - 20 °C / Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 4 h / 20 °C / Inert atmosphere With oxalyl dichloride, N-ethyl-N,N-diisopropylamine, N,N-dimethyl-formamide in dichloromethane Blaazer, Antoni R.; Lange, Jos H.M.; Van Der Neut, Martina A.W.; Mulder, Arie; Den Boon, Femke S.; Werkman, Taco R.; Kruse, Chris G.; Wadman, Wytse J.; European Journal of Medicinal Chemistry; vol. 46; nb. 10; (2011); p. 5086 - 5098 View in Reaxys

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O OH

N

O

F

NH N

N

N

O

Rx-ID: 32506300 View in Reaxys 51/63 Yield

Conditions & References Reaction Steps: 3 1: sulfuric acid / ethanol / Reflux 2: hydrazine hydrate / ethanol 3: acetic acid / ethanol / Reflux With sulfuric acid, hydrazine hydrate, acetic acid in ethanol Kumar, Dalip; Maruthi Kumar; Ghosh, Soumitra; Shah, Kavita; Bioorganic and Medicinal Chemistry Letters; vol.

22; nb. 1; (2012); p. 212 - 215 View in Reaxys

O OH

N

O

F

NH N

N

N

Cl

Rx-ID: 32506301 View in Reaxys 52/63 Yield

Conditions & References Reaction Steps: 3 1: sulfuric acid / ethanol / Reflux 2: hydrazine hydrate / ethanol 3: acetic acid / ethanol / Reflux With sulfuric acid, hydrazine hydrate, acetic acid in ethanol Kumar, Dalip; Maruthi Kumar; Ghosh, Soumitra; Shah, Kavita; Bioorganic and Medicinal Chemistry Letters; vol.

22; nb. 1; (2012); p. 212 - 215 View in Reaxys

O

O OH

N

O

NH N

N

N

Cl

Rx-ID: 32506302 View in Reaxys 53/63 Yield

Conditions & References Reaction Steps: 3 1: sulfuric acid / ethanol / Reflux 2: hydrazine hydrate / ethanol 3: acetic acid / ethanol / Reflux With sulfuric acid, hydrazine hydrate, acetic acid in ethanol Kumar, Dalip; Maruthi Kumar; Ghosh, Soumitra; Shah, Kavita; Bioorganic and Medicinal Chemistry Letters; vol.

22; nb. 1; (2012); p. 212 - 215 View in Reaxys

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O OH

O

NH 2 NH

N

N

Rx-ID: 32506304 View in Reaxys 54/63 Yield

Conditions & References Reaction Steps: 2 1: sulfuric acid / ethanol / Reflux 2: hydrazine hydrate / ethanol With sulfuric acid, hydrazine hydrate in ethanol Kumar, Dalip; Maruthi Kumar; Ghosh, Soumitra; Shah, Kavita; Bioorganic and Medicinal Chemistry Letters; vol.

22; nb. 1; (2012); p. 212 - 215 View in Reaxys

O OH

OH

O

NH

N

N

Rx-ID: 35329817 View in Reaxys 55/63 Yield

Conditions & References Reaction Steps: 2 1: thionyl chloride / 60 - 80 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethyl acetate; water / 0.08 h / 20 °C With thionyl chloride, hydroxylamine hydrochloride, sodium hydrogencarbonate in water, ethyl acetate Gao, Xi-Ai; Wang, Xian-Xue; Yan, Hao; Li, Jian; Yan, Ru-Long; Huang, Guo-Sheng; Journal of the Indian Chemical Society; vol. 90; nb. 3; (2013); p. 381 - 385 View in Reaxys N

O

N

O

N

OH O

F N N

F F

NH

N N

Rx-ID: 35373252 View in Reaxys 56/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 2 h / 20 °C 2: N-ethyl-N,N-diisopropylamine / dichloromethane / 20 °C With oxalyl dichloride, N-ethyl-N,N-diisopropylamine, N,N-dimethyl-formamide in dichloromethane Patent; GLAXOSMITHKLINE LLC; TEMPERO PHARMACEUTICALS, INC.; GHOSH, Shomir; LOBERA, Mercedes; POHLHAUS, Denise, Teotico; TRUMP, Ryan, Paul; ZHANG, Cunyu; WO2013/66831; (2013); (A1) English View in Reaxys

O OH O

O

NH

N N

Rx-ID: 39026640 View in Reaxys 57/63

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Yield

Conditions & References Reaction Steps: 2 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 20 °C 2: pyridine / dichloromethane / 0 - 20 °C With pyridine, oxalyl dichloride, N,N-dimethyl-formamide in dichloromethane Chen, Xuebing; Sun, Peng; Xu, Jinyi; Wu, Xiaoming; Kong, Lingyi; Yao, Hequan; Lin, Aijun; Tetrahedron Letters; vol. 55; nb. 51; (2014); p. 7114 - 7117 View in Reaxys

O OH

O

NH

N N

Rx-ID: 42016431 View in Reaxys 58/63 Yield

Conditions & References Reaction Steps: 2 1: thionyl chloride 2: sodium hydroxide / tetrahydrofuran; water / 5.5 h / 0 - 20 °C With thionyl chloride, sodium hydroxide in tetrahydrofuran, water Zheng, Jing; Deng, Ziyang; Zhang, Yan; Cui, Sunliang; Advanced Synthesis and Catalysis; vol. 358; nb. 5; (2016); p. 746 - 751 View in Reaxys

O OH

O

NH

N N

Rx-ID: 42016432 View in Reaxys 59/63 Yield

Conditions & References Reaction Steps: 2 1: thionyl chloride 2: sodium hydroxide / tetrahydrofuran; water / 5.5 h / 0 - 20 °C With thionyl chloride, sodium hydroxide in tetrahydrofuran, water Zheng, Jing; Deng, Ziyang; Zhang, Yan; Cui, Sunliang; Advanced Synthesis and Catalysis; vol. 358; nb. 5; (2016); p. 746 - 751 View in Reaxys

O OH

O

NH

N N

Rx-ID: 42016433 View in Reaxys 60/63 Yield

Conditions & References Reaction Steps: 2 1: thionyl chloride 2: sodium hydroxide / tetrahydrofuran; water / 5.5 h / 0 - 20 °C With thionyl chloride, sodium hydroxide in tetrahydrofuran, water

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Zheng, Jing; Deng, Ziyang; Zhang, Yan; Cui, Sunliang; Advanced Synthesis and Catalysis; vol. 358; nb. 5; (2016); p. 746 - 751 View in Reaxys

Cl O

O OH

NH HN O

S

N

O O

HN O

N

Rx-ID: 42054007 View in Reaxys 61/63 Yield

Conditions & References Reaction Steps: 2 1: 1- hydroxybenzotriazole / dichloromethane / 15.5 h / 0 - 20 °C 2: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; dmap / dichloromethane / 15 h / 20 °C With dmap, 1- hydroxybenzotriazole, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane Pelz, Nicholas F.; Bian, Zhiguo; Zhao, Bin; Shaw, Subrata; Tarr, James C.; Belmar, Johannes; Gregg, Claire; Camper, DeMarco V.; Goodwin, Craig M.; Arnold, Allison L.; Sensintaffar, John L.; Friberg, Anders; Rossanese, Olivia W.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W.; Journal of Medicinal Chemistry; vol. 59; nb. 5; (2016); p. 2054 - 2066 View in Reaxys

O

N

N

OH F

F F

F

F

F

F

F

F

F

F

F

F

O

F

F

F

F

F

F

F

F

F

F

F

F

H 2N

N F F

O HN

O

N H

NH F

F F

F

F

F

F

F

F

F

F

F

F

O

F

F

F

F

F

F

F

F

F

F

F

F

F

N

F

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F

F

F F F HN O

F

F F

O

F F

F

O N

F

F

F

F

F

F

F

F N

F

F F

F

F

F

F

F

F

F

F F

F F F

F F

F

F

F

F

F

F F O

N

N

F

F

F

F

F

F F

F F

N

N F

F

F

F

F

F F

F

F F

F

F

F O

F

F F

F

F

F

F

F

F

F

F F

F

Rx-ID: 11179203 View in Reaxys 62/63 Yield

Conditions & References

17 %, 15 %, 36 %, 21 %

in dichloromethane, Time= 3h Del Pozo, Carlos; Keller, Adam I.; Nagashima, Tadamichi; Curran, Dennis P.; Organic Letters; vol. 9; nb. 21; (2007); p. 4167 - 4170 View in Reaxys

N

N

N

O OH HN O

N N H 2N

N

racemate

racemate

Rx-ID: 9869864 View in Reaxys 63/63 Yield

Conditions & References With triethylamine, phosphorochloridic acid diphenyl ester Mazurov, Anatoly; Klucik, Jozef; Miao, Lan; Phillips, Teresa Y.; Seamans, Angela; Schmitt, Jeffrey D.; Hauser, Terry A.; Johnson Jr., Raymond T.; Miller, Craig; Bioorganic and Medicinal Chemistry Letters; vol. 15; nb. 8; (2005); p. 2073 - 2077 View in Reaxys

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