1-'Alkyl'-1H-indazole-3-carboxylic acid to N-'G'star''-1-'Alkyl'-1H-indazole-3-carboxamide [R by Asch

Query Query

Results

Date

63 reactions in Reaxys

2016-04-26 13h:00m:20s (EST)

G* O

O OH

1. Query

N N ALK

Search as: As drawn, No salts, No mixtures

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O O

cis

cis O

cis

OH cis N

N cis NH cis 2

O OH

cis NH cis

N N

Rx-ID: 25678249 View in Reaxys 1/63 Yield

Conditions & References

94 %

2.6 :To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (126 mg, 0.619 mmol), terf-butyl c/s-5-amino-2[(4-hydroxytetrahydro-2/-/-pyran-4-yl)methyl] piperidine-1 -carboxylate (234 mg, 0.743 mmol, step 5 of Example 2), Λ/,Λ/-diisopropylethylamine (96 mg, 0.743 mmol) in Λ/,Λ/-dimethylformamide (3 mL) was added diethyl cyanophosphonate (121 mg, 0.743 mmol) at room temperature, and the mixture was stirred at the same temperature for 18 h. The mixture was concentrated under reduced pressure and the resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ethyl acetate (1 :1) to give 292 mg (94percent) of the title compound as a colorless oil. 1H NMR (CDCI3) δ 8.39 (1 H, d, J = 8.6 Hz), 7.49-7.39 (2 H, m), 7.31-7.26 (1 H, m), 6.87 (1 H, d, J = 8.6 Hz), 4.89 (1 H, septet, J = 6.6 Hz), 4.61 (1 H, br.), 4.38-4.03 (3 H, m), 3.92-3.63 (5 H, m), 2.79 (1 H, t, J = 12.5 Hz), 2.14-1.85 (3 H, m), 1.71-1.58 (10 H, m), 1.47 (9 H, s), 1.45-1.37 (1 H, m). A signal due to OJH was not observed. With diethyl cyanophosphonate, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 18h, T= 18 - 25 °C Patent; PFIZER JAPAN INC.; PFIZER INC.; WO2007/10390; (2007); (A1) English View in Reaxys

O OH

O OHO

N O

N NH 2

N N

Rx-ID: 25678250 View in Reaxys 2/63 Yield 98 %

Conditions & References 7.1 :To a stirred solution of i-isopropyl-IH-indazole-3-carboxylic acid (300 mg, 1.47 mmol) and1-terf-butyl 2-methyl (2S,4S)-4-aminopyrrolidine-1 ,2-dicarboxylate (396 mg, 1.62 mmol, Bioorg. Med. Chem., 2002, 10, 1399-1415) in Λ/,Λ/-dimethylformamide (15 mL) were added diethyl cyanophosphonate (0.27 mL, 1.76 mmol) and Λ/,Λ/-diisopropylethylamine (0.31 mL, 1.76 mmol) at room temperature. The resulting mixture was stirred for 14 h at the same temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate (200 mL), and the solution was washed with water (50 mL x 2), brine (50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with n-hexane/ ethyl acetate (3:1) to give 618 mg (98percent) of the title compound as a white amorphous solid. MS (ESI) m/z: 331 (M+H)+(-BOC). 1H NMR (CDCI3) δ 8.35 (1 H, d, J = 8.3 Hz), 7.74-7.65 (1 H, m), 7.48-7.38 (2 H, m), 7.30-7.25 (1 H, m), 4.95-4.84 (2 H, m), 4.48-4.35 (1 H, m), 3.90-3.55 (5 H, m), 2.70-2.57 (1 H, m), 2.21-2.18 (1 H, m), 1.65-1.60 (6 H, m), 1.48-1.45 (9 H, m). With diethyl cyanophosphonate, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 14h, T= 18 - 25 °C Patent; PFIZER JAPAN INC.; PFIZER INC.; WO2007/10390; (2007); (A1) English View in Reaxys

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HN O

O OH

N O

H 2N

N N

Rx-ID: 30286111 View in Reaxys 3/63 Yield

Conditions & References

43 %

27 :Example 27 To a 50 mL flask containing 20 mL of DMF was added 1 ml_ of oxalyi chloride slowly and stirred for 10 min at RT. 100 mg of i-Methyl-I H-indazole-3-carboxyiic acid was dissolved in 2 mL of the above solution and stirred for 5 min at RT. Then 50 mg of E was dissolved in 1 mL pyridine and added to the above solution. The reaction was completed in 5 min at RT and quenched with 1 mL NH4OH. The solvent was evaporated under vacuum and the residue dissolved in CH3CN and water and purified with prep HPLC (0percent to 95percent water/ Acetonitrile) to afford 27 (32 mg, 43percent).1H-NMR (DMSO, 300 MHz): δ 10.37 (s, 1 H), 8.50 (s, 1 H), 8.10 (d, J = 6.9 Hz, 1 H), 7.72-7.64 (m, 4H), 7.40 (s, 1 H), 7.26-7.23 (m, 2H), 7.04-6.80 (m, 4H), 4.85 (me, 1 H), 4.12 (S, 3H), 3.22-3.10 (m, 3H), 2.78-2.70 (m, 1 H)1 0.66 (m, 2H)1 0.52 (m, 2H). LCMS m/z [M+H]+ C32H27N5O3S requires: 561.65. Found 562.04 HPLC Tr (min), purity percent: 3.46, 98percent Stage 1: With oxalyl dichloride, N,N-dimethyl-formamide, Time= 0.0833333h, T= 20 °C Stage 2: With pyridine in N,N-dimethyl-formamide, Time= 0.0833333h, T= 20 °C Patent; GILEAD SCIENCES, INC.; MACKMAN, Richard, L.; SPERANDIO, David; YANG, Hai; WO2011/5842; (2011); (A1) English View in Reaxys

H 2N

Rx-ID: 38843664 View in Reaxys 4/63 Yield 78 %

Conditions & References Oxalyl dichloride (5.74 g, 45.2 mmol) was slowly added to a stirred solution of 1-pentyl-lH- indazole-3-carboxylic acid (10.0 g, 43.0 mmol) in dichloromethane (100 mL) at 0°C in an ice-bath. The reaction was stirred for 30 minutes. Triethylamine (9.0 mL, 64.58 mmol) was then added, followed by 2-phenylpropan-2-amine (5.82g, 43.0 mmol). The reaction was stirred for 1 hour and monitored by TLC. The reaction was diluted with water and separated into phases. The organic layer was washed with water (2x100 mL), brine (2x100 mL), dried (MgS04), and concentrated. The resulting oil was purified by flash column chromatography using petroleum ethenethyl acetate 60: 1 as eluent. 11.7 g (78percent) of SGT-24 was obtained as a light yellow oil in a 78percent yield. lH NMR (400 MHz, DMSO-d6) δ 8.01 (1H, d, HI), 7.97 (1H, s, H5), 7.74 (1H, d, H4), 7.43 (1H, ddd, H2), 7.38 (1H, dd, H3), 7.19 (2H, m, H7), 4.48 (2H, t, H8), 1.90 (2H, m, Hl l), 1.74 (6H, m, H6), 1.25 (6H, m, H12, H10, H13), and 0.84 (3H, t, H14). MS (ESI+) m/z 350 (MH+). Stage 1: With oxalyl dichloride in dichloromethane, Time= 0.5h, T= 0 °C Stage 2: With triethylamine in dichloromethane, Time= 1h Patent; BOWDEN, Matthew James; WILLIAMSON, James Peter Bernard; WO2014/167530; (2014); (A1) English View in Reaxys

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NH 2

O NH

N N

N N N

N HN

NH O

R(a)-isomer

Rx-ID: 42115355 View in Reaxys 5/63 Yield

Conditions & References

75 %

14 : Example 14: 1 -Methyl-N-[(aR)-6-(4-oxo-3 ,4-dihydrophthalazin- 1 -yl)spiro [3.3 ]heptan-2- yl] - 1H-indazole-3 -carboxamide Intermediate 2 (13 mg, 0.035 mmol) was dissolved in dry DMF (1 mL), then 1-methyl-1H-indazole-3-carboxylic acid (12.4 mg, 0.070 mmol) and DIEA (0.037 mL,0.2 11 mmol) were added. After stirring for 5 mm at rt, HATU (20 mg, 0.053 mmol) was added, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 14 (11.2 mg, 75percent yield). MS(ESI) m/z: 414.2 (M+H) ‘HNMR (500MHz, DMSO-d6) ö ppm 12.49 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.26 (d, J=7.7Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.98 - 7.81 (m, 3H), 7.72 (d, J=8.4 Hz, 1H), 7.46 (t,J7.6 Hz, 1H), 7.30 7.23 (m, 1H), 4.48 - 4.37 (m, 1H), 4.13 (s, 3H), 3.95 - 3.85 (m, 1H),2.65 - 2.55 (m, 2H), 2.46 - 2.29 (m, 4H), 2.24 2.09 (m, 2H). HPLC RT = 1.57 mm(Method E), 1.52 mm (Method F). Stage 1: With N,N- diisopropylethylamine in DMFA, Time= 0.0833333h, T= 20 °C Stage 2: With HATU in DMFA, Time= 2h, T= 20 °C Patent; BRISTOL-MYERS SQUIBB COMPANY; LADZIATA, Vladimir; GLUNZ, Peter W.; HU, Zilun; WANG, Yufeng; (0 pag.); WO2016/10950; (2016); (A1) English View in Reaxys NH 2

-1 F

N N N

N HN

NH O

S(a)-isomer

Rx-ID: 42114984 View in Reaxys 6/63 Yield 67 %

Conditions & References 17 : Example 17: 1 -Methyl-N-[(aS)-6-(4-oxo-3 ,4-dihydrophthalazin- 1- yl)spiro [3.3 ]heptan-2-yl] - 1H-indazole-3 -carboxamide Intermediate 3 (13 mg, 0.035 mmol) was dissolved in dry DMF (1 mL), then 1- methyl-1H-indazole-3-carboxylic acid (12.40 mg, 0.070 mmol) and DIEA (0.037 mL, 0.2 11 mmol) were added. After stirring for 5 mm at rt, HATU (20.1 mg, 0.053 mmol)was added, and the reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with MeOH (0.1 mL), diluted with DMF, filtered and purified by preparative HPLC to afford Example 17 (9.7 mg, 67percent yield). MS(ESI) m/z: 414.2 (M+H) ‘H NMR (500MHz, DMSO-d6) ö ppm 12.50 (s, 1H), 8.53 (d, J=8.1 Hz, 1H), 8.26 (d, J7.7 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 7.95 - 7.81 (m, 3H), 7.71 (d, J=8.4 Hz, 1H), 7.46 (t, J7.6Hz, 1H), 7.30 - 7.23 (m, 1H), 4.48 - 4.37 (m, 1H), 4.12 (s, 3H), 3.95 - 3.85 (m, 1H), 2.65 -2.55 (m, 2H), 2.46 - 2.29 (m, 4H), 2.22 - 2.09 (m, 2H). HPLC RT = 1.57 mm (Method E),1.57 mm (Method F). Stage 1: With N,N- diisopropylethylamine in DMFA, Time= 0.0833333h, T= 20 °C Stage 2: With HATU in DMFA, Time= 2h, T= 20 °C Patent; BRISTOL-MYERS SQUIBB COMPANY; LADZIATA, Vladimir; GLUNZ, Peter W.; HU, Zilun; WANG, Yufeng; (0 pag.); WO2016/10950; (2016); (A1) English View in Reaxys

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OH cis

NH 2 cis

N cis

cis

cis N

cis NH cis

cis HO

N N

Rx-ID: 25678248 View in Reaxys 7/63 Yield

Conditions & References

52 %

1.9 :To a stirred solution of i-isopropyl-IH-indazole-S-carboxylic acid (235 mg, 1.15 mmol),2-[c/s-5-amino-1-benzylpiperidin-2-yl]ethanol (322 mg, 1.37 mmol, step 8 of Example 1), N, Λ/-diisopropylethylamine (177 mg, 1.37 mmol) in Λ/,Λ/-dimethylformamide (3 mL) was added diethyl cyanophosphonate (223 mg, 1.37 mmol) at room temperature. After stirring at room temperature for 20 h, the mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25percent ammonium hydroxide (10:1 :0.2) to give276 mg (52percent) of the title compound as a colorless oil. MS (ESI) m/z: 421 (M+H)+. 1H NMR (CDCI ) δ 8.36 (1 H, d, J = 8.3 Hz), 7.47-7.19 (9 H, m), 4.89 (1 H, septet, J = 6.6 Hz), 4.43-4.32 (1H, m), 3 4.17 (1 H, d, J = 13.2 Hz), 3.91-3.84 (1 H, m), 3.79-3.65 (2 H, m), 2.96 (1 H, dd, J = 13.2, 8.6 Hz),2.86-2.79 (1 H, m), 2.68 (1 H, dd, J = 12.7, 3.5 Hz), 2.23-2.10 (1 H, m), 2.03-1.80 (3 H, m), 1.65-1.62 (9 H, m). Stage 1: With diethyl cyanophosphonate, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 20h, T= 18 - 25 °C Stage 2: With ammonia in methanol, dichloromethane Patent; PFIZER JAPAN INC.; PFIZER INC.; WO2007/10390; (2007); (A1) English View in Reaxys NH 2

O NH

O OH

N N

O R(a)-isomer

R(a)-isomer

Rx-ID: 42114782 View in Reaxys 8/63 Yield 38 %

Conditions & References 266A : Example 266A: N-((aR)-6-(3 -(dicyclopropylmethyl)-4-oxo-3 ,4- dihydrophthalazin- 1 -yl)spiro [3.3 ]heptan-2-yl)- 1-methyl-i H-indazole-3 -carboxamide Toa solution of i-methyl-1H-indazole-3-carboxylic acid (108 mg, 0.611 mmol) was dissolved in anhydrous DMF (2.5 mL), then DIEA (0.291 mL, 1.66 mmol) and HATU (243 mg, 0.638 mmol) were added. After stirring for 30 mm at rt, the obtained solution was added to a solution of Intermediate 76 (194 mg, 0.555 mmol) and DIEA (0.291 mL, 1.66 mmol) in anhydrous DMF (2.5 mL), and the reaction mixture was stirredat rt for 1 h. The reaction mixture was quenched with MeOH (0.5 mL), diluted withEtOAc (100 mL), washed with water (2X) and brine, dried (Na2SO4) and concentrated.The residue was purified by flash chromatography (0-30percent EtOAc/DCM gradient) toafford Example 266a (107 mg, 38percent yield) as a colorless foam. MS(ESI) m/z: 508.4(M+H) ‘H NMR: (500 MHz, CDC13) ö ppm 8.47 (dd, J=7.8, 1.0 Hz, 1H), 8.38 (d, J8.3Hz, 1H), 7.81 - 7.76 (m, 1H), 7.76 - 7.71 (m, 1H), 7.70 - 7.66 (m, 1H), 7.47 - 7.38 (m,2H), 7.29 (ddd, J=8.0, 6.5, 1.1 Hz, 1H), 7.09 (br d, J=8.0 Hz, 1H), 4.61 (sxt, J8.2 Hz,1H), 4.10 (s, 3H), 3.89 (quin, J=8.0 Hz, 1H), 3.82 (br t, J=9.2 Hz, 1H), 2.83 - 2.76 (m,1H), 2.66 (d, J=8.0 Hz, 2H), 2.61 - 2.55 (m, 1H), 2.55 - 2.45 (m, 2H), 2.21 (dd, Ji 1.0, Stage 1: With N,N- diisopropylethylamine, HATU in DMFA, Time= 0.5h, T= 20 °C Stage 2: With N,N- diisopropylethylamine in DMFA, Time= 1h, T= 20 °C Patent; BRISTOL-MYERS SQUIBB COMPANY; LADZIATA, Vladimir; GLUNZ, Peter W.; HU, Zilun; WANG, Yufeng; (0 pag.); WO2016/10950; (2016); (A1) English

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View in Reaxys

O OH N

N N

P O

N N

NH 2

Rx-ID: 24272542 View in Reaxys 9/63 Yield

Conditions & References

90%

24 : N-[2-(4-Benzyl-1-piperazinyl)ethyl]-1-n-propylindazole-3-carboxamide STR121 EXAMPLE 24 N-[2-(4-Benzyl-1-piperazinyl)ethyl]-1-n-propylindazole-3-carboxamide STR121 To a solution of 2-(4-benzyl-1-piperazinyl)-ethylamine (2.19 g) obtained in Preparation Example 48 in DMF (150 ml) were successively added at room temperature 1-n-propylindazole-3-carboxylic acid (2.04 g), triethylamine (1.52 g) and diethyl phosphorocyanidate (1.95 g) with stirring, and the mixture was stirred at room temperature for 12 hours. The reaction solution was distilled off, and the residue obtained was purified by silica gel column chromatography (ethyl acetate-chloroform:methanol aqueous ammonia=10:1:0.05) to give the title compound (3.76 g) as a brown oily substance. Yield 90percent. 1 H NMR(CDCl ) δ 0.96(t, J=7 Hz, 3H), 1.94-2.02(m, 2H), 2.54(bs, 4H), 2.59(bs, 4H), 2.66(t, J=6 Hz, 2H), 3.54(s, 3 2H), 3.59-3.64(m, 2H), 4.36(t, J=7 Hz, 2H), 7.24-7.43(m, 9H), 8.37(d, J=8 Hz, 1H) With triethylamine in N,N-dimethyl-formamide Patent; Nisshin Flour Milling Co., Ltd.; US5945434; (1999); (A1) English View in Reaxys

O O O OH Cl

O N N

Cl O

NH 2

N N

Rx-ID: 25397285 View in Reaxys 10/63 Yield 89%

Conditions & References 89.1 : (Step 1) (Step 1) Synthesis of methyl (3-Chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate To 1-methylindazole-3-carboxylic acid (600 mg, 3.41 mmol) and DMF (27.0 ael, 0.34 mmol) was added methylene chloride (20 ml). Under stirring at room temperature, oxalyl chloride (0.36 ml, 4.09 mmol) was added dropwise to the resulting mixture. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 50 hours and the solvent was distilled off under reduced pressure. The residue was dissolved in methylene chloride (5 ml). The resulting solution was added to a solution of methyl 4-amino-3-chlorophenylacetate (680 mg, 3.41 mmol) and triethylamine (1.42 ml, 10.2 mmol) in methylene chloride (5 ml) under stirring at room temperature. The reaction mixture was heated under reflux at room temperature for 7 hours. After the reaction mixture was cooled to room temperature, water was added thereto, followed by extraction with chloroform.

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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 (2:1, v/v) eluate fractions, methyl (3-chloro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.08 g, 89percent) was obtained as a yellow solid. 1H-NMR (CDCl ) δ: 3.61 (s, 2H), 3.72 (s, 3H), 4.18 (s, 3H), 7.24 (dd, J=8.6,2.0Hz, 1H), 7.34 (m, 1H), 7.38 (d, 3 J=2.0Hz, 1H), 7.45-7.50 (m, 2H), 8.41 (d, J=8.0Hz, 1H), 8.61 (d, J=8.6Hz, 1H), 9.47 (broad s, 1H). MS (LCMS) m/z 358 (M++1). With triethylamine in dichloromethane, water, N,N-dimethyl-formamide Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

NH 2

O OH

N N N

N O

HN O

N N

Rx-ID: 28864367 View in Reaxys 11/63 Yield

Conditions & References D.15.D.1.1 :D.I.I. (R)-l-Methyl-lH-indazole-3-carboxylic acid [l-(2-cyclopropyl-5-m-tolyl- thiazole-4-carbonyl)-piperidin-3-yl]-amide 1 -Methyl- lH-indazole-3-carboxylic acid (21.1 mg, 0.12 mmol) was dissolved in DMF (1 ml) followed by the addition of TBTU (42.4 mg, 0.132 mmol) and DIEA (77.6 mg, 0.60 mmol). Stirring at RT was continued for 15 min. (R)-(3-Amino-piperidin-l-yl)- (2-cyclopropyl-5-m-tolyl-thiazol-4-yl)-methanone (50 mg, 0.12 mmol) was added and stirring at RT was continued for 16h followed by the addition of formic acid (0.25 ml) and direct purification of the reaction mixture via preparative HPLC to give 17.5 mg <n="36"/>of (R)-I -Methyl- lH-indazole-3-carboxylic acid [l-(2cyclopropyl-5-m-tolyl-thiazole- 4-carbonyl)-piperidin-3-yl]-amide. LC-MS: tR = 1.07 min; [M+H]+ = 499.99.(Precursors were prepared according to procedures described above) Stage 1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 0.25h, T= 20 °C Stage 2: in N,N-dimethyl-formamide, Time= 16h, T= 20 °C Patent; ACTELION PHARMACEUTICALS LTD; WO2009/133522; (2009); (A1) English View in Reaxys D.15.D.1.1 :D. Example 15 Synthesis of (R)-1-Methyl-1H-indazole-3-carboxylic acid[1-(2-cyclopropyl-5-m-tolyl-thiazole-4-carbonyl)-piperidin-3-yl]-amideD.1.1. (R)-1-Methyl-1H-indazole-3-carboxylic acid[1-(2-cyclopropyl-5-m-tolylthiazole-4-carbonyl)-piperidin-3-yl]-amide1-Methyl-1H-indazole-3-carboxylic acid (21.1 mg, 0.12 mmol) was dissolved in DMF (1 ml) followed by the addition of TBTU (42.4 mg, 0.132 mmol) and DIEA (77.6 mg, 0.60 mmol). Stirring at RT was continued for 15 min. (R)-(3-Amino-piperidin-1-yl)-(2-cyclopropyl-5-m-tolyl-thiazol-4-yl)-methanone (50 mg, 0.12 mmol) was added and stirring at RT was continued for 16 h followed by the addition of formic acid (0.25 ml) and direct purification of the reaction mixture via preparative HPLC to give 17.5 mg of (R)-1-Methyl-1H-indazole-3-carboxylic acid[1-(2-cyclopropyl-5-m-tolyl-thiazole-4-carbonyl)-piperidin-3-yl]-amide. LC-MS: tR=1.07 min; [M +H]+=499.99. Stage 1: With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, N-ethyl-N,N-diisopropylamine in N,N-dimethyl-formamide, Time= 0.25h, T= 20 °C Stage 2: in N,N-dimethyl-formamide, Time= 16h, T= 20 °C Patent; Aissaoui, Hamed; Boss, Christoph; Koberstein, Ralf; Sifferlen, Thierry; Trachsel, Daniel; US2011/39857; (2011); (A1) English View in Reaxys

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NH 2

Rx-ID: 33304908 View in Reaxys 12/63 Yield

Conditions & References

89 %

7.2. Synthesis of 1-methyl-1H-indazole-3-hydrazide To the suspension of 1-methyl-1H-indazole-3-carboxylate (10 g, 0.52 mol) in ethanol 20 ml were added hydrazine hydrate (5.2 g, 0.10 mol) and 1 ml of glycial acetic acid. The reaction mass was heated at reflux temp for 4-6 h. After completion of reaction, reaction mixture was cooled to room temperature separated solid was filtered and washed with chilled 5 ml ethanol and dried at 50-60 °C. Yield. 89percent With hydrazine hydrate, acetic acid, Reflux Ali, Nasir Ali Shafakat; Zakir, Shaikh; Patel, Muqtadir; Farooqui, Mazahar; European Journal of Medicinal Chemistry; vol. 50; (2012); p. 39 - 43 View in Reaxys

O Cl

N N

O NH

N O NH 2

N N

Rx-ID: 27730185 View in Reaxys 13/63 Yield

Conditions & References 131.B :A mixture of 1 -methyl- 1 H-indazole-3 -carboxylic acid (46.0 mg; 0.26 mmol), HOBt (44.4 mg; 0.33 mmol), EDC (84.0 mg; 0.44 mmol) in DCM (10 mL) was stirred at room temperature for 30 min. 2-(2-chloro-5-nitro-phenyl)-2-methyl-propylamine (50.0 mg; 0.22 mmol), prepared as described in 131(A), was added and the stirring was maintained at the same temperature for additional 16 hours. The reaction was diluted with DCM and washed in sequence with 0.5M IQ2CO3 (twice), IN HCl and brine. The organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure to furnish the title compound as a white solid. This compound was used as such in the next step.LCMS (RT): 4.5 min (Method A); MS (ES+) gave m/z: 387.09 (MH+). Stage 1: With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 0.5h, T= 20 °C Stage 2: in dichloromethane, Time= 16h, T= 20 °C Patent; ADDEX PHARMA SA; WO2008/117175; (2008); (A2) English View in Reaxys

H 2N

N N

Rx-ID: 30564397 View in Reaxys 14/63 Yield

Conditions & References 17 :Preparation Example 17 1-methyl-1H-indazole-3-carboxylic acid (2.64 g) was mixed with methanol (20 ml) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (4.57 g) and methylamine (40percent methanol solution, 2.0 ml) were added thereto at room temperature. After stirring at room temperature for 14 hours, the reaction solution was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the organic layer was washed with water-saturated brine (1:1) and further saturated brine in this order. The organic layer was dried over anhydrous sodium sulfate and was then concentrated under reduced pressure.

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The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain N,1-dimethyl-1H-indazole-3-carboxamide (1.84 g) as a colorless solid. With 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride in methanol, Time= 14h, T= 20 °C Patent; Astellas Pharma Inc.; EP2298747; (2011); (A1) English View in Reaxys OH O OH

NH 2

N N

Rx-ID: 34413714 View in Reaxys 15/63 Yield

Conditions & References 1 : 5.6.1 N-(4-Hydroxy-3,5-dimethylphenyl)-1'-iso-propyl-1H-indazol-3'-carboxyamide 9 General procedure: 5.6. General procedure for the preparation of compounds 9,10 To solutions of carboxylic acid 18a and 18b (5.0 mmol) and 4- dimethylaminopyridine (DMAP) (10 mmol) in CH2Cl2 (30 mL), N,N0-dicyclohexylcarbodiimide (DCC) (10 mmol) was added at rt. After 5 min 4-amino-2,6-dimethylphenol (5.0 mmol) was slowly added. The mixture was stirred overnight at rt. The reaction mixture was filtered and the filtrate washed with a saturated aqueous solution of NH4Cl and brine. After solvent evaporation, the crude residue was purified by flash chromatography (SiO2; hexane/AcOEt¼7/3) followed by crystallization to afford products 9 and 10. Off-white powder. IR (KBrDRIFTS): 3442, 3382, 1654; 1H NMR (DMSO-d6): δ (ppm) 1.58 (d, 6H, J=6.6, CH3CHCH3), 2.19 (s, 6H, 2* CH3), 5.11 (spt, 1H, J=6.6, CH3CHCH3), 7.19-7.33 (m, 1H), 7.42 (s, 2H, H-C(2), H-C(6)), 7.35-7.50 (m, 1H), 7.81 (d, J=8.6 Hz, 1H, H-C(7')), 8.03 (s, 1H, OH), 8.19-8.27 (m, 1H), 9.62 (s, 1H); 13C NMR (DMSO-d6): δ (ppm) 160.1 (C=O), 149.5 (C(4)), 139.8, 136.9, 130.2, 126.4, 124.4, 122.5 (C(5'), C(9')), 121.8, 120.7 (C(2), C(6)), 110.4, 50.4 (CH3CHCH3), 21.9 (CH3CHCH3), 16.8 (2* CH3); mp: 203-205 °C (AcOEt/hexane). Anal. Calcd for C19H21N3O2: C, 70.57; H, 6.55; N, 12.99: found: C, 70.48; H, 6.58; N, 12.94. With 4-(N,N-dimethlyamino)pyridine, dicyclohexyl-carbodiimide in dichloromethane, T= 20 °C Alisi, Maria Alessandra; Brufani, Mario; Cazzolla, Nicola; Ceccacci, Francesca; Dragone, Patrizia; Felici, Marco; Furlotti, Guido; Garofalo, Barbara; La Bella, Angela; Lanzalunga, Osvaldo; Leonelli, Francesca; Marini Bettolo, Rinaldo; Maugeri, Caterina; Migneco, Luisa Maria; Russo, Vincenzo; Tetrahedron; vol. 68; nb. 49; (2012); p. 10180 - 10187 View in Reaxys OH O

H N

N N

N N NH 2

Rx-ID: 41891402 View in Reaxys 16/63 Yield 1.29 g

Conditions & References 5 : Example-5: Preparation of 3-OH- AKB48 [0020] DIPEA (4.2 ml, 0.02445mol) was added to a solution of 1-Pentyl-1H-indazole-3-carboxylic acid (1.013 g, 0.004366mol) in DMF (10 ml) and the solution was stirred at room temperature for 10 minutes. HBTU (2.48 g, 0.00655mol)was added and the solution was stirred again at room temperature for 3 hours. 3-Amino-1-adamantanol hydrate (1.21g, 0.00655mol) was then added and the solution stirred at room temperature for 16 hours. The solvent was removed invacuo and the residue dissolved in EtOAc(100ml) and washed with a saturated aqueous solution of sodium bicarbonate(50ml), water(50ml) and brine, then dried over sodium sulphate, filtered and concentrated in va-

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cuo. The crude residuewas purified by column chromatography (Silica gel 30percent EtOAc in hexane to give (1.29g) of 3-OH-AKB48. Stage 1: With N,N- diisopropylethylamine in DMFA, Time= 0.166667h, T= 20 °C Stage 2: With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate in DMFA, Time= 3h, T= 20 °C Stage 3: in DMFA, Time= 16h, T= 20 °C Patent; Randox Laboratories Ltd.; Fitzgerald, Peter; Benchikh, Elouard; Lowry, Philip; McConnell, Ivan; EP2950103; (2015); (A1) English View in Reaxys NH 2

H 2N

N O

O N N

Rx-ID: 41892519 View in Reaxys 17/63 Yield

Conditions & References Synthesis of 4-(3-amino- 1 -propyl)-7-[(1 -methylindazol-3-yl)carboxamido]-2,3,4,5-tetrahydrobenzo[fj [1,4]oxazepin-5-one (L03) The resin was treated with pyridine (0.5 mE) and anhydrous tin-(II)-chloride (1 mmol) in NMP (1.5 mE) and shaken at room temperature for 5.5 h, whereupon another portion of tin-GO-chloride (0.5 mmol) in NMP (0.5 mE) was added. The mixture was shaken overnight and subsequently washed with methanol. Insoluble reaction by-products were separated from the resin by repeated careful flotation with methanol. Afier washing with dichioromethane, the resin was swollen in NMP. 1 -Methyl-3-indazolecarboxylic acid (0.2 mmol) and HATU (0.2 mmol) in NMP (1.5 mE) were treated with DIPEA (0.4 mmol), and afier 2 mm the mixture was added to the resin and agitated for 5 h. The resin was washed with DMF, methanol and dichloromethane (three times each). The target compound was cleaved from the support by twofold treatment with trifluoroacetic acid (45percent) and triethylsilane (10percent) in dichloromethane, followed by thorough washing of the resin with dichloromethane. Afier evaporation of the solvents, the crude product was purified by preparative reverse-phase HPEC-MS. ESI-MS: 394 (M+1). Stage 1: With pyridine, N-Methyl-2-pyrrolidone, tin(ll) chloride, T= 20 °C Stage 2: With N-Methyl-2-pyrrolidone, N,N- diisopropylethylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate, Time= 5.03h Stage 3: With triethylsilane, trifluoroacetic acid in dichloromethane Patent; GRAFFINITY PHARMACEUTICALS GMBH; BITTERMANN, Holger; ARNOLD, Marc; NEUMANN, Thomas; OTT, Inge; SCHMIDT, Kristina; SEKUL, Renate; (51 pag.); US2016/9760; (2016); (A1) English View in Reaxys O

NH 2

O Cl

O N

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O HO

F NH

N Cl O

O N N

Rx-ID: 25397301 View in Reaxys 18/63 Yield

Conditions & References

63%

87.8 : (Step 8) (Step 8) Synthesis of ethyl (5-chloro-2-fluoro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate In benzene (30 ml), oxalyl chloride (0.54 ml, 6.24 mmol) was added dropwise to 1-methylindazolyl-3-carboxylic acid (1.00 g, 5.68 mmol) and DMF (44.0 ael, 0.57 mmol) under stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hour. A solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (1.31 g, 5.68 mmol) and triethylamine (4.74 ml, 34.0 mmol) in benzene (5.0 ml), which solution had been prepared in advance, was added to the reaction mixture. The resulting mixture was heated under reflux for 4 hours. The reaction mixture was cooled to room temperature, 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 (3:1, v/v) eluate fractions, (5-chloro-2-fluoro-4-((1-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (1.40 g, 63percent) was obtained as a colorless solid. 1H-NMR (CDCl ) δ: 1.28 (t, J=7.1Hz, 3H), 3.62 (s, 2H), 4.17 (s, 3H), 4.18 (q, J=7.1Hz, 2H), 7.33-7.39 (m, 2H), 3 7.44-7.50 (m, 2H), 8.38 (d, J=8.3Hz, 1H), 8.53 (d, J=11.9Hz, 1H), 9.50 (broad s, 1H). MS (ESI) m/z 390 (M++1). With triethylamine in N,N-dimethyl-formamide, benzene Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1346982; (2003); (A1) English View in Reaxys

O OH

N N N

N N

NH 2 N N

Rx-ID: 4420263 View in Reaxys 19/63 Yield 51 %

Conditions & References With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 5h, Ambient temperature Harada; Morie; Hirokawa; Terauchi; Fujiwara; Yoshida; Kato; Chemical and Pharmaceutical Bulletin; vol. 43; nb. 11; (1995); p. 1912 - 1930 View in Reaxys 35 : Preparation of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide: EXAMPLE 35 Preparation of N-(1-benzyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-1-ethyl-1H-indazole-3-carboxamide: A mixture of 1-ethyl-1H-indazole-3-carboxylic acid (8.6 g), thionyl chloride (8 ml) and chloroform (80 ml) is refluxed for 1 hour.

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After removal of solvent, the residue is dissolved in dichloromethane (100 ml), and a solution of 6-amino-1-benzyl-4methylhexahydro-1H-1,4-diazepine (9.9 g) and triethylamine (9.2 g) in dichloromethane (100 ml) is added dropwise to the mixture at 0° C. The reaction mixture is stirred at 25° C. for 2 hours, washed with water, and dried over sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of acetone. Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (13.6 g) as an oil. (a) The free base thus obtained is converted to the fumarate of the title compound in a usual manner, m.p. 135-137° C. (recrystallized from ethanol). 1 H--NMR spectrum (DMSO--D , δppm): 1.48 (3H, t, J=7Hz, --CH CH ), 2.44 (3H, s, --NCH3), 2.6-3.2 (8H, m), 3.66 6 2 3 (2H, s, --NCH2 Ph), 4.0-4.5 (1H, m, --CONHCH--), 4.54 (2H, q, J=7Hz, --CH2 CH3), 7.1-7.6 (7H, m), 7.76 (1H, d, J=8Hz, 7--H), 8.14 (each 1H, each d, each J=9Hz, 4--H, --CONH--). With thionyl chloride, triethylamine in dichloromethane, chloroform Patent; Dainippon Pharmaceutical Co., Ltd.; US5017573; (1991); (A1) English View in Reaxys

O OH

O H

HO O

O NH 2 Cl

N N

Rx-ID: 9139432 View in Reaxys 20/63 Yield

Conditions & References With AtH2 (1+)*HO(1-), N-ethyl-N,N-diisopropylamine, N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate in N,N-dimethyl-formamide, Time= 16h, T= 20 °C Kline, Toni; Andersen, Niels H.; Harwood, Eric A.; Bowman, Jason; Malanda, Andre; Endsley, Stephanie; Erwin, Alice L.; Doyle, Michael; Fong, Susan; Harris, Alex L.; Mendelsohn, Brian; Mdluli, Khisimuzi; Raetz, Christian R. H.; Stover, C. Kendall; Witte, Pamela R.; Yabannavar, Asha; Zhu, Shuguang; Journal of Medicinal Chemistry; vol. 45; nb. 14; (2002); p. 3112 - 3129 View in Reaxys HO

O OH

base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol

O NH

N N

Rx-ID: 24963808 View in Reaxys 21/63 Yield 1.23 g (39%)

Conditions & References 8 : N-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)-1-methyl-1H-indazole-3-carboxamide EXAMPLE 8 N-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-ylmethyl)-1-methyl-1H-indazole-3-carboxamide A suspension of 1-methyl-1H-indazole-3-carboxylic acid (1.76 g, 0.0101 mole) in anhydrous tetrahydrofuran (6 ml) under nitrogen was treated with 1,1'-carbonyldiimidazole (1.87 g, 0.0115 mole). After a few minutes bubbling commenced and the solid dissolved, and, after a few more minutes, a precipitate formed. The suspension was diluted with anhydrous N,N-dimethylformamide (3 ml), stirred for two hours, then degassed over 15 minutes under a stream of nitrogen. A solution of the free base of 3-aminomethyl-1-azabicyclo[2.2.2]octan-3-ol (2.03 g, 0.013 mole) in anhydrous tetrahydrofuran (6 ml) was added, and the mixture was stirred at room temperature for 18 hr and at 50° C. for 4 hr, then concentrated in vacuo. The residue was partitioned between 1.0N sodium carbonate (50 ml) and toluene (75 ml) containing some 2-propanol.

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The organic layer was separated and the aqueous solution was extracted with toluene (2*30 ml) containing some 2propanol). The combined organic solution was concentrated in vacuo, and the residual gum washed with water (50 ml) to remove most of the imidazole and then dried azeotropically with toluene. The gum was taken up in tetrahydrofuran and filtered through alumina (eluted with 20percent methanol/tetrahydrofuran) and the concentrated filtrate was recrystallized from acetonitrile to afford 1.23 g (39percent) of the title compound as a pale yellow solid; mp 147°-149° C. Analysis: Calculated for C17 H22 N4 O2: C, 64.95; H, 7.05; N, 17.82. Found: C, 64.78; H, 7.06; N, 17.82. in tetrahydrofuran Patent; A. H. Robins Company, Incorporated; US5137895; (1992); (A1) English View in Reaxys

O O

O N H

NH 2

N N

Rx-ID: 29255221 View in Reaxys 22/63 Yield

Conditions & References Stage 1: With 1,1'-carbonyldiimidazole in N,N-dimethyl-formamide, T= 20 °C , Inert atmosphere Stage 2: in N,N-dimethyl-formamide, T= 20 °C , Inert atmosphere McKinnell, R. Murray; Armstrong, Scott R.; Beattie, David T.; Choi, Seok-Ki; Fatheree, Paul R.; Gendron, Roland A. L.; Goldblum, Adam; Humphrey, Patrick P.; Long, Daniel D.; Marquess, Daniel G.; Shaw; Smith, Jacqueline A. M.; Turner, S. Derek; Vickery, Ross G.; Journal of Medicinal Chemistry; vol. 52; nb. 17; (2009); p. 5330 - 5343 View in Reaxys

O O

O N

O NH

N N

NH 2

Rx-ID: 29255307 View in Reaxys 23/63 Yield

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N N

H 2N

Rx-ID: 29255311 View in Reaxys 24/63 Yield

Conditions & References

4.52 g

With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, N-ethyl-N,N-diisopropylamine in N,N-dimethylformamide, T= 20 °C , Inert atmosphere, Cooling with ice McKinnell, R. Murray; Armstrong, Scott R.; Beattie, David T.; Choi, Seok-Ki; Fatheree, Paul R.; Gendron, Roland A. L.; Goldblum, Adam; Humphrey, Patrick P.; Long, Daniel D.; Marquess, Daniel G.; Shaw; Smith, Jacqueline A. M.; Turner, S. Derek; Vickery, Ross G.; Journal of Medicinal Chemistry; vol. 52; nb. 17; (2009); p. 5330 - 5343 View in Reaxys

O OH

N N

NH 2

N N

Rx-ID: 4440917 View in Reaxys 25/63 Yield

Conditions & References

61 %

With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride in dichloromethane, Time= 5h, Ambient temperature Harada; Morie; Hirokawa; Terauchi; Fujiwara; Yoshida; Kato; Chemical and Pharmaceutical Bulletin; vol. 43; nb. 11; (1995); p. 1912 - 1930 View in Reaxys

O OH

N N

NH 2 N N

Rx-ID: 4440918 View in Reaxys 26/63 Yield 56 %

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N N

NH 2

N N

Rx-ID: 4440920 View in Reaxys 27/63 Yield

Conditions & References

55 %

O OH

N N N

NH 2

N N

Rx-ID: 4420005 View in Reaxys 28/63 Yield

Conditions & References

46 %

O OH

N N

NH 2 N N

Rx-ID: 4440919 View in Reaxys 29/63 Yield 50 %

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Cl H N N O

N Cl

N H

O NH

NH 2 NH 2

O O

O NH H 2N

N N

Rx-ID: 4610794 View in Reaxys 30/63 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

N O

N N

Rx-ID: 19397725 View in Reaxys 31/63 Yield

Conditions & References Reaction Steps: 2 1: SOCl2 / CHCl3 / Heating 2: Et3N / dioxane With thionyl chloride, triethylamine in 1,4-dioxane, chloroform Fludzinski; Evrard; Bloomquist; Lacefield; Pfeifer; Jones; Deeter; Cohen; Journal of Medicinal Chemistry; vol. 30; nb. 9; (1987); p. 1535 - 1537 View in Reaxys

N O OH

O NH

N N

N N racemate

Rx-ID: 21898946 View in Reaxys 32/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl chloride, DMF / CH2Cl2 / 1 h 2: Et3N / CH2Cl2 / 1 h With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Bermudez, Jose; Fake, Charles S.; Joiner, Graham F.; Joiner, Karen A.; King, Frank D.; et al.; Journal of Medicinal Chemistry; vol. 33; nb. 7; (1990); p. 1924 - 1929 View in Reaxys

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N O OH

O NH

N N

N N racemate

Rx-ID: 21898947 View in Reaxys 33/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl chloride, DMF / CH2Cl2 / 1 h 2: 24 percent / Et3N / CH2Cl2 / 1 h With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Bermudez, Jose; Fake, Charles S.; Joiner, Graham F.; Joiner, Karen A.; King, Frank D.; et al.; Journal of Medicinal Chemistry; vol. 33; nb. 7; (1990); p. 1924 - 1929 View in Reaxys

O OH

O N

Rx-ID: 21898949 View in Reaxys 34/63 Yield

Conditions & References Reaction Steps: 2 1: oxalyl chloride, DMF / CH2Cl2 / 1 h 2: Et3N / CH2Cl2 / 2 h With oxalyl dichloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Bermudez, Jose; Fake, Charles S.; Joiner, Graham F.; Joiner, Karen A.; King, Frank D.; et al.; Journal of Medicinal Chemistry; vol. 33; nb. 7; (1990); p. 1924 - 1929 View in Reaxys

O OH

N N

O N

Rx-ID: 21899114 View in Reaxys 35/63 Yield

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O NH

N N

Rx-ID: 24515555 View in Reaxys 36/63 Yield

Conditions & References 4 : Preparation of 1-methyl-N-(tetrahydro-1H-pyrrolizin7a(5H)-ylmethyl)-1H-indazole-3-carboxamide STR31 EXAMPLE 4 Preparation of 1-methyl-N-(tetrahydro-1H-pyrrolizin7a(5H)-ylmethyl)-1H-indazole-3-carboxamide STR31 Following the procedure of example 1, 7a- Aminomethylhexahydro-1H-pyrrolizine is reacted with N-methylindazole-3-carboxylic acid [J. Medicinal Chemistry (1987) 30: 1535]to afford the title compound. Patent; G. D. Searle and Co.; US5318977; (1994); (A1) English View in Reaxys

N N

O NH

NH 2

N N

Rx-ID: 4420006 View in Reaxys 37/63 Yield

Conditions & References

30 %

O OH

N N N

Rx-ID: 12378356 View in Reaxys 38/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 87 percent / ethanol / 0.03 h / microwave irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

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O OH

N N N N

Rx-ID: 12378358 View in Reaxys 39/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 85 percent / ethanol / 0.33 h / ultrasound irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

O OH

N N N

Rx-ID: 12378359 View in Reaxys 40/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 94 percent / ethanol / 0.33 h / ultrasound irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

O OH

N N N

Rx-ID: 12378360 View in Reaxys 41/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 89 percent / ethanol / 0.33 h / ultrasound irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

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O OH

N N

Rx-ID: 12378361 View in Reaxys 42/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 86 percent / ethanol / 0.33 h / ultrasound irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

O OH

N N N N

Rx-ID: 12378362 View in Reaxys 43/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 86 percent / ethanol / 0.67 h / Heating With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

Cl HN

O OH

N N N

Rx-ID: 12378363 View in Reaxys 44/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 80 percent / ethanol / 0.33 h / ultrasound irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

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O OH

N N N N

Rx-ID: 12378364 View in Reaxys 45/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 82 percent / ethanol / 0.33 h / ultrasound irradiation With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

O O

N N

Rx-ID: 12378365 View in Reaxys 46/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride 1.2: hydrazine hydrate 2.1: 87 percent / ethanol / 0.67 h / Heating With thionyl chloride in ethanol Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

H O

HCl

N N N

Rx-ID: 32896770 View in Reaxys 47/63 Yield

Conditions & References Reaction Steps: 2 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 3 h / Reflux 2.1: triethylamine / dichloromethane / 3 h / 0 - 35 °C 2.2: 0.5 h / 35 °C With thionyl chloride, triethylamine, N,N-dimethyl-formamide in dichloromethane Vishnu, Eda V.R.; Joseph, Suju; Srinivasana, Abayee K.; Gania, Ramesh S.; Reddy, Govindabur R.; Rao, Patakokila V.; Dahanukara, Vilas H.; Ramanatham, Josyula; Devanna, Nayakanti; Letters in Organic Chemistry; vol. 8; nb. 10; (2011); p. 722 - 727 View in Reaxys

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O OH

N N N

Rx-ID: 33304896 View in Reaxys 48/63 Yield

Conditions & References Reaction Steps: 3 1: hydrazine hydrate; acetic acid / Reflux 2: sulfuric acid / ethanol / 6 h / Reflux 3: chloro-trimethyl-silane / acetonitrile / 12 h / Reflux With chloro-trimethyl-silane, sulfuric acid, hydrazine hydrate, acetic acid in ethanol, acetonitrile Ali, Nasir Ali Shafakat; Zakir, Shaikh; Patel, Muqtadir; Farooqui, Mazahar; European Journal of Medicinal Chemistry; vol. 50; (2012); p. 39 - 43 View in Reaxys

O N

O OH

O HN

N N N

Rx-ID: 33304897 View in Reaxys 49/63 Yield

O P

O OH

O O

N N N

Rx-ID: 33304898 View in Reaxys 50/63 Yield

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O OH N

N N N N

Rx-ID: 33304899 View in Reaxys 51/63 Yield

Conditions & References Reaction Steps: 2 1: hydrazine hydrate; acetic acid / Reflux 2: sulfuric acid / ethanol / 6 h / Reflux With sulfuric acid, hydrazine hydrate, acetic acid in ethanol Ali, Nasir Ali Shafakat; Zakir, Shaikh; Patel, Muqtadir; Farooqui, Mazahar; European Journal of Medicinal Chemistry; vol. 50; (2012); p. 39 - 43 View in Reaxys

F F

O OH

N N

Rx-ID: 33304900 View in Reaxys 52/63 Yield

O OH N

N N N N

Rx-ID: 33304901 View in Reaxys 53/63 Yield

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O OH

Br N

N N

Rx-ID: 33304902 View in Reaxys 54/63 Yield

O OH

N N

N N N N

Rx-ID: 33304903 View in Reaxys 55/63 Yield

O OH

Cl N

N N

Rx-ID: 33304904 View in Reaxys 56/63 Yield

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O OH

O NH

N N

Rx-ID: 33304905 View in Reaxys 57/63 Yield

O P

O OH O

O O

HN NH

N N

N F

Rx-ID: 33304906 View in Reaxys 58/63 Yield

O P

O OH

O O F

N N N

Rx-ID: 33304907 View in Reaxys 59/63 Yield

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O O O

O N N

NH N

Rx-ID: 41891400 View in Reaxys 60/63 Yield

Conditions & References Reaction Steps: 2 1.1: N,N- diisopropylethylamine / DMFA / 0.17 h / 20 °C 1.2: 3 h / 20 °C 1.3: 16 h / 20 °C 2.1: triethylamine; dmap / toluene / 15 h / 60 °C With dmap, triethylamine, N,N- diisopropylethylamine in DMFA, toluene Patent; Randox Laboratories Ltd.; Fitzgerald, Peter; Benchikh, Elouard; Lowry, Philip; McConnell, Ivan; EP2950103; (2015); (A1) English View in Reaxys HO

O O

NH O

N N

Rx-ID: 41891401 View in Reaxys 61/63 Yield

Conditions & References Reaction Steps: 3 1.1: N,N- diisopropylethylamine / DMFA / 0.17 h / 20 °C 1.2: 3 h / 20 °C 1.3: 16 h / 20 °C 2.1: triethylamine; dmap / toluene / 15 h / 60 °C 3.1: lithium hydroxide hydrate; water / methanol; tetrahydrofuran / 20 °C With dmap, water, triethylamine, N,N- diisopropylethylamine, lithium hydroxide hydrate in tetrahydrofuran, methanol, DMFA, toluene Patent; Randox Laboratories Ltd.; Fitzgerald, Peter; Benchikh, Elouard; Lowry, Philip; McConnell, Ivan; EP2950103; (2015); (A1) English View in Reaxys

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OH H

NH 2

N N

OH Cl

N N

Rx-ID: 31853418 View in Reaxys 62/63 Yield

Conditions & References With benzotriazol-1-ol, 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride, triethylamine in N,N-dimethyl-formamide An, Hongchan; Kim, Nam-Jung; Jung, Jong-Wha; Jang, Hannah; Park, Jong-Wan; Suh, Young-Ger; Bioorganic and Medicinal Chemistry Letters; vol. 21; nb. 21; (2011); p. 6297 - 6300 View in Reaxys

O OH

N N

NH 2

N N

Rx-ID: 10325989 View in Reaxys 63/63 Yield

Conditions & References Stage 1: With thionyl chloride Stage 2: With hydrazine hydrate Kale; More; Karale; Heterocyclic Communications; vol. 12; nb. 3-4; (2006); p. 265 - 272 View in Reaxys

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