Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([CH2:20][CH2:21][Cl:22])[C:5]1[C:6]([N+:17]([O-:19])=[O:18])=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].CCOC(C)=O.O(C(C)C)C(C)C>O=S(Cl)Cl.CN(C=O)C.O>[OH:27][CH2:26][CH2:25][CH2:24][NH:23][C:10](=[O:12])[C:9]1[CH:13]=[C:5]([N:4]([CH2:3][CH2:2][Cl:1])[CH2:20][CH2:21][Cl:22])[C:6]([N+:17]([O-:19])=[O:18])=[CH:7][C:8]=1[N+:14]([O-:16])=[O:15]
Reactant: NCCCO
Reactant: O=C(O)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Product: O=C(NCCCO)c1cc(N(CCCl)CCCl)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
A suspension of 5-[bis(2-chloroethyl)amino]-2,4-dinitrobenzoic acid [Palmer et al., J. Med. Chem., 1994, 37, 2175] (1) (2.50 g, 7.1 mmol) in SOCl2 (20 mL) containing DMF (2 drops) was heated under reflux for1 h, then concentrated to dryness under reduced pressure and re-evaporated with benzene. The resulting crude benzoyl chloride was dissolved in Me2CO (50 mL) and the cooled (−5° C.) solution was treated with a cold solution of 3-amino-1-propanol (1.09 g, 14.5 mmol) in water (25 mL). The reaction mixture was shaken at room temperature for 5 min, then diluted with water (25 mL), concentrated to half volume, and extracted with CH2Cl2 (2×). The organic extract was washed with 0.1 N HCl and water then worked up to give a solid which was chromatographed on silica gel, eluting with EtOAc to give IIa-3 (2.37 g, 82%): mp (EtOAc/i-Pr2O) 90-91° C.; 1H [(CD3)2SO] δ8.63 (t, J=5.6 Hz, 1 H, CONH), 8.53 (s, 1 H, H-3), 7.42 (s, 1 H, H-6), 4.46 (t, J=5.1 Hz, 1 H, OH), 3.82 (t, J=5.9 Hz, 4 H, N(CH2CH2Cl)2), 3.68 (t, J=5.9 Hz, 4 H, N(CH2CH2Cl)2), 3.49 (q, J=6.0 Hz, 2 H, CH2OH), 3.29 (q, partially obscured, J=5.9 Hz, 2 H, CONHCH2), 1.68 (pent, J=6.7 Hz, 2 H, CH2CH2CH2). Anal. (C14H18Cl2N4O6) C, H, N, Cl.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:21]=1>C(Cl)Cl>[C:1]([NH:11][C@H:12]([C:17]([N:26]([C:22]1[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=1)[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:19])[C@H:13]([CH2:15][CH3:16])[CH3:14])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCOC(=O)CNc1cccnc1
Solvent: ClCCl
Product: CCOC(=O)CN(C(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)CC)c1cccnc1

Procedure:
A methylene chloride solution of N-carbobenzyloxy-L-isoleucine and ethyl N-(3-pyridyl)-glycinate was treated with N,N-dicyclohexylcarbodiimide as in example 5A. Purification of the product was accomplished by chromatography on silica-gel.
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[CH3:19]O>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:19])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 100 °C
Yield: 95 %

Procedure:
2-amino-3-nitrobenzoic acid 1 (5 g, 27.4 mmol) was dissolved in methanol (100 mL) and con H2SO4 was added. The mixture was heated at 100° C. for 12 h, concentrated to dryness and suspended in H2O (50 mL). The mixture was extracted with CH2Cl2 (50 mL), dried (MgSO4) and concentrated. The crude residue was purified by flash chromatography to give 11 (5.1 g, 95% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[NH:23])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[N:23][C:26](=[O:28])[CH3:27])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=N)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Product: CCn1c(=NC(C)=O)c(-c2cc(OC)cc(OC)c2)cc2nnc(SC)nc21
Temperature: 90 °C

Procedure:
To 4.7 g (13.2 mmol) of 7-(3,5-dimethoxy-phenyl)-5-ethyl-3-methylsulfanyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-ylideneamine was added 55 mL of acetic anhydride. The reaction mixture was warmed at 90° C. overnight, and the very dark red solution was concentrated under house vacuum at 40° C. to give a dark brown residue, N-[7-(3,5-dimethoxy-phenyl)-5-ethyl-3-methylsulfanyl-5H-pyrido[2,3-e]-1,2,4-triazin-6-ylidene]-acetamide. MS (APCI) (m+1)/z 400.1.
Reaction SMILES: [C:1](=O)([O-])[O-].[Cs+].[Cs+].IC.[N:9]1[CH:10]=[CH:11][N:12]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[CH:14][C:13]=12>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:19][C:18]([C:16]1[CH:15]=[CH:14][C:13]2[N:12]([CH:11]=[CH:10][N:9]=2)[CH:17]=1)=[O:20]
Reactant: O=C(O)c1ccc2nccn2c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COC(=O)c1ccc2nccn2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.8 %

Procedure:
Cesium carbonate (15.7 g, 48.2 mmol) and iodomethane (1.50 ml, 24.2 mmol) were added to a solution of imidazo[1,2-a]pyridine-6-carboxylic acid (2.61 g, 16.1 mmol) in DMF (100 ml). The reaction was stirred at ambient temperature overnight, then poured into brine (100 ml) and extracted with ethyl acetate (3×100 mL). The combined organics were washed with saturated sodium bicarbonate solution (25 mL), and a 1N HCl solution (25 mL) then dried over MgSO4 and evaporated to give imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester as a yellow solid (1.1 g, 39%). 1H NMR (250 MHz, CDCl3): δ 8.96 (s, 1H), 7.8-7.6 (m, 4H), 3.98 (s, 3H). MS [EI+] 177 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[CH3:8][C:9]1([CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19](O)=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[CH3:34])[CH2:10]1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O.O>[CH3:8][C:9]1([CH3:35])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:17]=2)[NH:12][CH:11]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:25]=[CH:24][C:23]=2[CH3:34])[CH2:10]1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)O)ccc2N1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N2CCOCC2)cc1C1CC(C)(C)c2cc(C(=O)NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.1 %

Procedure:
To a suspension of 60% sodium hydride (560 mg, 14 mmol) in N,N-dimethylformamide (5 mL) was added methanesulfonamide (1.33 g, 14 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h to afford Solution A22. A solution of 4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (800 mg, 2 mmol) and 1,1′-carbonyldiimidazole (690 mg, 4 mmol) in N,N-dimethylformamide (3 mL) was stirred at 70° C. for 1 h and cooled to room temperature to afford Solution B22. Solution B22 was added to Solution A22 and the resulting mixture was stirred at 25° C. for 1 h. To the reaction mixture was added water (0.5 mL). The mixture was filtered to remove the insoluble solid, and the filtrate was purified by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[4,4-dimethyl-2-(2-methyl-5-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-methanesulfonamide (239 mg, 26%) as a white solid: MS (ESI) M+1=458.1.
Reaction SMILES: [C:1]([N:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[NH:10][C:11]([NH2:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(=O)C>[C:2]1([C:1]2[N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:10]=[C:11]([OH:12])[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)NN(C(=O)c1ccccc1)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1nc(-c2ccccc2)n(-c2ccccn2)n1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
A mixture was prepared by admixing 1.84 g (0.00718 m) of 2-benzoyl-2-(2-pyridinyl)hydrazinecarboxamide with 30 ml of 10 percent sodium hydroxide. The mixture was warmed to 50° C. to dissolve the carboxamide. The solution was held at 50° C. for 10 minutes and the reaction mixture was cooled to room temperature. The reaction product was acidified with 30 ml or 50 percent acetic acid and the white solid which precipitated was recovered by filtration, washed with water and air dried. The 5-phenyl-1-(2-pyridinyl)-1H-1,2,4-triazol-3-ol product was recovered in a yield of 1.12 g (66 percent of theoretical). The product melted at 240°-241° C. and upon analysis was found to have carbon, hydrogen and nitrogen contents of 64.83, 4.35 and 22.46 percent, respectively, as compared with the theoretical contents of 65.53, 4.23 and 23.52.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([NH:20][CH3:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>>[Cl:1][C:2]1[N:11]=[C:10]([N:20]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=2)[CH3:21])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: CN(c1ccc([N+](=O)[O-])cc1)c1nc(Cl)nc2ccccc12

Procedure:
The title compound was prepared from 2,4-dichloroquinazoline (50 mg, 0.251 mmol) and 4-nitro-N-methylaniline (46 mg, 0.302 mmol) by a procedure similar to example 1b and was isolated as yellow powder (6 mg, 12%). 1H NMR (CDCl3): 8.24 (d, J=8.7 Hz, 2H), 7.81 (dd, J=8.1, and 2.4 Hz, 1H), 7.68 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.28 (d, J=8.7 Hz, 2H), 7.18 (ddd, J=8.1, 7.5 and 2.4 Hz, 1H), 7.07 (d, J=7.8 Hz, 1H), 3.75 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][S:21](Cl)(=[O:23])=[O:22])=[C:15]([O:25][CH3:26])[CH:14]=1>N1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][S:21]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:22])=[O:23])=[C:15]([O:25][CH3:26])[CH:14]=1
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: COc1cc(Cl)ccc1C=CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Cl)ccc1C=CS(=O)(=O)Nc1ccccc1S(N)(=O)=O
Reaction time: 1 h
Yield: 40.4 %

Procedure:
2-Aminobenzene sulfonamide (194 mg, 1.13 mmol) was added in one portion to a solution of 2-(4-chloro-2-methoxyphenyl)-ethenesulfonyl chloride (300 mg, 1.13 mmol) in pyridine (3 mL) at RT. After 1 h stirring, no more starting material was detected by tlc. The reaction mixture was concentrated and the residue was taken up in ethyl acetate with a small amount of methanol. The organic phase was washed with 1N HCl, saturated sodium bicarbonate, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified on silica gel using DCM/methanol, 99:1 to afford material which was further purified by recrystallization from methanol to give the title compound (184 mg, 41%) as a white solid.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:5]1
Reactant: COc1ccc(CCCN2CCCC[C@@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 18 h

Procedure:
(R)-2-Hydroxymethyl-1-[3-(4-methoxyphenyl)propyl]piperidine (422 mg) was dissolved in 10 ml of dichloromethane. Triethylamine (210 mg, 2.08 mmol) and methanesulfonyl chloride (238 mg, 2.08 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 18 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-[3-(4-methoxyphenyl) propyl]homopiperidine in the form of a light yellow oil (278 mg, 62%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH2:36][CH:37]=[O:38])[CH:31]([NH:39][C:40](=[O:79])[C:41](=[N:67][O:68][C:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])([CH3:71])[CH3:70])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[S:45][CH:46]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[CH:36]=[CH:37][O:38][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:31]([NH:39][C:40](=[O:79])[C:41](=[N:67][O:68][C:69]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])([CH3:70])[CH3:71])[C:42]1[N:43]=[C:44]([NH:47][C:48]([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)[S:45][CH:46]=1)[C:30]2=[O:80])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CC=O)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC(C)(C)C(=O)OC(C)(C)C)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3SC2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 8.3 %

Procedure:
p-Toluenesulphonyl chloride (1.31 g) is added to a solution, cooled to 5° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-3-formylmethyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (product 5e) (4.45 g) in pyridine (50 cc). The temperature is left to rise to 20° C. in the course of 30 minutes, the mixture is stirred for 1 hour at 20° C. and poured into iced water (300 cc), the water is decanted and the insoluble pasty product is taken up in ethyl acetate (300 cc). The solution is washed with 1 N hydrochloric acid (100 cc), a saturated solution of sodium bicarbonate (100 cc) and a saturated solution of sodium chloride (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa). The product thus obtained is used as such for the remainder of the synthesis. This product (1 g) is purified by chromatography on a column of silica gel (0.05-0.2) (20 g) (diameter of the column: 1.7 cm), elution being carried out with an 80/20 (by volume) mixture of cyclohexane and ethyl acetate, and 50 cc fractions being collected. Fractions 4 to 12, containing the pure product, are evaporated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give a product (5d) (0.43 g), which is a mixture of the E and Z forms (in proportions--determined by NMR--of 75% of the E form and 25% of the Z form), in the form of a pale yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.Cl.[C:20]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[C:20]1([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][N:27]2[CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=3)=[CH:5][CH:4]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C2CCCCN2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCCC3c3ccccc3)cc2)nc1
Reaction time: 21 h
Yield: 2 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.152 g, 0.628 mmol), 2-phenyl-piperidine hydrochloride salt (0.122 g, 0.620 mmol), triethylamine (0.178 mL, 1.28 mmol) in methanol (6.0 mL) and stir. After 21 hours, add sodium borohydride (0.108 g, 2.85 mmol). After about 24 hours, concentrate and purify the residue by silica gel chromatography (25:1→4:1 methylene chloride:methanol) then reverse-phase HPLC to provide 0.0047 g (2%) of the title compound as a white solid: mass spectrum (electrospray): m/z=388.2 (M+1); 1H NMR (methanol-d4): 8.66 (d, 1H, J=2.4 Hz), 8.29 (dd, 1H, J=2.4, 8.3 Hz), 7.52 (d, 2H, J=7.3 Hz), 7.41 (t, 2H, J=7.3 Hz), 7.37-7.28 (m, 3H), 7.11 (d, 2H, J=8.3 Hz), 7.02 (d, 1H, J=8.8 Hz), 3.81 (d, 1H, J=10.7 Hz), 3.39 (s, 2H), 3.20-2.94 (m, 2H), 2.17 (s br, 1H), 1.93-1.61 (m, 4H), 1.59-1.44 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1.O.NN>CCO.[Pd]>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1
Reactant: COCOc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: COCOc1ccc(N2CCN(c3ccc(N)cc3)CC2)cc1
Yield: 99 %

Procedure:
The nitro group in 11 (250.8 mg, 0.73 mmol) was reduced in the presence of 10% Pd/C (46.8 mg, 5% mole ratio) and hydrazine monohydrate (365.4 mg, 7.3 mmol) in EtOH (10 mL) at reflux. Once the starting material was fully consumed (about 3.5 h), the reaction mixture was filtered through a Celite pad and concentrated to afford 12 as white amorphous solid (226.5 mg, 99%), which was used directly for the next step without any purification: 1H NMR (400 MHz, CDCl3, δH) 7.07-6.81 (m, 6H), 6.72-6.63 (m, 2H), 5.13 (s, 2H), 3.49 (d, J=1.3 Hz, 3H), 3.46-3.34 (m, 2H), 3.22 (qd, J=7.1, 3.1 Hz, 8H); 13C NMR (100 MHz, CDCl3, δC) 151.53, 146.97, 144.63, 140.64, 119.05, 118.30, 117.51, 116.43, 95.36, 56.10, 51.45, 50.93. MALDI-MS: 314.2 (M+H+), 336.2 (M+Na+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24]Cl)=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:26])[CH:12]=3)=[CH:10][C:3]=12.[I-:37].[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:27]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:9]([C:11]3[C:19]4[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][I:37])=[C:17]([O:20][CH3:21])[CH:18]=4)[N:13]([CH3:26])[CH:12]=3)=[CH:10][C:3]=12
Reactant: [I-]
Reactant: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCCl
Agent: [Na+]
Product: COc1cc2c(-c3cc4c(Cl)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OCCI

Procedure:
4-Chloro-2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine is prepared by following the procedure described in example 147c, but using 1.15 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-chloroethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.950 g of sodium iodide. After purification by flash chromatography (silica, 40/60 by volume ethyl acetate/cyclohexane as eluents, argon), 1.21 g of 4-chloro-2-[1-methyl-5-methoxy-6-(2-iodoethoxy)-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[N:7][NH:8]2)=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=1>C(O)(=O)C.[Zn]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[Cl:1])[NH:8][N:7]=[C:6]3[NH:11][C:12](=[O:16])[CH2:13][CH2:14][CH3:15])=[CH:18][CH:19]=1
Reactant: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc([N+](=O)[O-])cc3)cc12
Agent: [Zn]
Solvent: CC(=O)O
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccc(N)cc3)cc12
Reaction time: 1 h
Yield: 12.9 %

Procedure:
845 mg of zinc powder are added to 0.93 g of N-[6-chloro-5-(4-nitrophenyl)-1H-indazol-3-yl]butanamide, described previously, in 50 cm3 of acetic acid, followed, 1 hour later, by addition of a further 845 mg of zinc; the reaction medium is filtered through a sinter funnel packed with Celite and the filtrate is concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is taken up in 100 cm3 of ethyl acetate and 75 cm3 of water and the organic phase is separated out after settling of the phases has taken place, washed successively with 75 cm3 of water and with 50 cm3 of saturated sodium hydrogen carbonate solution, dried over magnesium sulphate, filtered and concentrated to dryness to give 480 mg of crude product, which is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (60/40 by volume). The fractions containing the expected product are combined and the solid is triturated in 10 cm3 of diethyl ether, filtered off, washed with 2×5 cm3 of diethyl ether and then dried (90 Pa; 45° C.) to give 110 mg of N-[5-(4-aminophenyl)-6-chloro-1H-indazol-3-yl]butanamide in the form of an ochre-coloured solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:18])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:18]
Reactant: Cc1ccnc(C)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc[n+]([O-])c(C)c1C

Procedure:
A solution of 14 g of 2,3,4-trimethylpyridine in 140 ml of methylene chloride is treated cautiously while cooling with ice with 21 g of m-chloroperbenzoic acid. The reaction mixture is boiled at reflux for 1 hour, then made basic with a saturated soda solution and subsequently extracted. The organic phase is dried and concentrated. The residue is purified on a silica gel column, the medium pressure flash chromatography method (solvent: methylene chloride/methanol [5:1 ) being used and the pressure being produced with nitrogen gas. The 2,3,4-trimethylpyridine N-oxide obtained is processed directly.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]2[O:43][CH2:44][O:45][C:39]=2[CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]4[O:43][CH2:44][O:45][C:39]=4[CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1ccc2c(c1)OCO2
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2ccc3c(c2)OCO3)CC1
Yield: 50.6 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (0.88 g) as starting compound, potassium carbonate (2.0 g) and 6-bromo-1-(3,4-methylenedioxyphenyl)-1-hexanone (0.80 g) were reacted and treated in the same manner as in Example 172 to give 0.62 g of 4-amino-5-chloro-2-methoxy-N-((1-(6-(3,4-methylenedioxyphenyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.