Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][CH2:24][C:25]2[NH:26][CH:27]=[CH:28][N:29]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])[CH3:2].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:38][N:39]1[CH:43]=[CH:42][N:41]=[C:40]1[CH:44]=O>CO>[CH2:1]([N:3]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:24][C:25]2[NH:29][CH:28]=[CH:27][N:26]=2)[CH2:44][C:40]2[N:39]([CH3:38])[CH:43]=[CH:42][N:41]=2)=[CH:18][CH:17]=1)[CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:9][CH2:10][CH3:11])[CH2:12][CH2:13][CH3:14])[CH3:2]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN(CC)Cc1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(CC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
The compound (317 mg) obtained in Example 23-7 was dissolved in anhydrous methanol (6.0 ml) and added with sodium cyanoborohydride (74.8 mg), acetic acid (1.00 ml), and 1-methyl-2-imidazole carboxaldehyde (105 mg) and the whole was stirred overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution. The whole was stirred for a while and subjected to extraction with chloroform, followed by washing with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer obtained was dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (318 mg) of the subject compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:5])[CH3:4].[CH3:6][C:7]1[C:8](N2C=NC=N2)=[N:9][C:10](=[O:13])[NH:11][CH:12]=1.C(O)(=O)C>CN(C)C=O>[CH2:3]([S:5][C:8]1[C:7]([CH3:6])=[CH:12][NH:11][C:10](=[O:13])[N:9]=1)[CH3:4]
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCSc1nc(=O)[nH]cc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.7 %

Procedure:
786 mg (18 mmol) of a 55% strength sodium hydride emulsion are added to 0.7 ml (9 mmol) of ethylmercaptan in 25 ml of dry dimethylformamide at 0° C. and the mixture is stirred for 30 minutes at 0° C. 1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are then added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is neutralized by addition of acetic acid, concentrated and chromatographed on silica gel using dichloromethane/methanol 20/1. 0.64 g (62.7% of theory) of 4-ethylthio-5-methylpyrimidin-2(1H)-one is obtained with melting point 181°-184° C. 1H NMR (60 MHz, d6 -DMSO), δ[ppm]: 11.45 (s, 1H), 7.55 (s, 1H), 3.10 (q, 2H), 1.90 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:7])[CH:4]=[CH:5][CH:6]=1.[N+:8]1([O-])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[Pd]>[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:6]1[CH:5]=[CH:4][C:3](=[O:7])[NH:2][N:1]=1
Reactant: [O-][n+]1ccccc1
Reactant: O=c1cccn[nH]1
Agent: [Pd]
Product: O=c1ccc(-c2ccccn2)n[nH]1

Procedure:
Haginiwa et al., [Yakugaku Zasshi 98 (1), 67-71 (1978); Chem. Abstrs. 88, 170,096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone.
Reaction SMILES: Br[CH:2](C)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([C:17]3[C:18]([NH2:33])=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[N:25][N:26]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:27]=4)[CH:22]=3)=[N:15][N:14]=[N:13]2)=[C:8]([F:34])[C:7]=1[F:35].[NH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.O.O1CCN(CCCCOC2C=CC(N3C(C4C(N)=NC=C(C5C=NN(CCC(C)C)C=5)C=4)=NN=N3)=C(F)C=2F)CC1>C1COCC1>[N:37]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[C:16]([C:17]4[C:18]([NH2:33])=[N:19][CH:20]=[C:21]([C:23]5[CH:24]=[N:25][N:26]([CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:27]=5)[CH:22]=4)=[N:15][N:14]=[N:13]3)=[C:8]([F:34])[C:7]=2[F:35])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCC(C)Br)c(F)c3F)c2)cn1
Reactant: C1CCNCC1
Agent: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCCCN4CCOCC4)c(F)c3F)c2)cn1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCn1cc(-c2cnc(N)c(-c3nnnn3-c3ccc(OCCCN4CCCCC4)c(F)c3F)c2)cn1
Temperature: 0 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
As shown in step 5-iii of Scheme 5,3-(1-(4-(3-bromobutoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)pyridin-2-amine (Compound 1021, 111 mg, 0.203 mmol) was dissolved in 5 mL of THF and cooled to 0° C. The mixture was treated with piperidine (0.06 mL, 0.61 mmol), warmed to 70° C., and stirred for 16 hours. The reaction was cooled to room temperature, treated with cold water, and extracted with CHCl3 (50 mL). The organics were washed with water, washed with brine, dried over sodium sulfate, filtered, and the volatiles removed under reduced pressure. The residue was purified by silica gel chromatography (5% MeOH/CHCl3) to provide 3-(1-(4-(3-(piperidin-1-yl)propoxy)-2,3-difluorophenyl)-1H-tetrazol-5-yl)-5-(1-isopentyl-1H-pyrazol-4-yl)pyridin-2-amine (Compound 150, 70 mg, 78% yield).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][S:4](Cl)(=[O:6])=[O:5].CS([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)(=O)=O>>[F:1][C:2]([F:9])([F:8])[CH2:3][S:4]([N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=2)=[O:22])[CH2:16][CH2:15]1)(=[O:6])=[O:5]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)CC(F)(F)F)CC1
Yield: 46 %

Procedure:
2,2,2-trifluoroethylsulfonyl chloride (89 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (48 mg, 0.111 mmol, 46% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.81 (s, 1H), 7.56 (s, 4H), 6.41 (d, J=6.9 Hz, 1H), 4.51 (q, J=9.9 Hz, 2H), 3.58 (d, J=12 Hz, 1H), 3.58 (m, 1H), 3.02 (t, J=11.4 Hz, 2H), 1.92 (d, J=12.4 Hz, 2H), 1.45 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-])=O)[CH2:7][CH2:6]1)=[O:4].CC(O)=O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:6][CH2:7][C@H:8]([CH2:11][NH:12][C:13](=[O:23])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:9][CH2:10]1)=[O:4]
Reactant: [H][H]
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1

Procedure:
A solution 0.01 M of trans-4-[(2-Nitro-benzoylamino)-methyl]-cyclohexanecarboxylic acid methyl ester (1.8 g) in MeOH (550 mL) with ˜1% of glacial AcOH (5.5 mL) was submitted to continuous flow rate hydrogenation by H-Cube (ThalesNano®) using a 10% Pd/C cartridge (small cartridge, full hydrogen mode, flowrate of 1 mL/min). Finally, the solvent was removed under reduced pressure to obtain the titled compound as acetate salt (1.9 g, quantitative yield).
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:12]([F:13])[C:6]=2[CH2:5][O:4]1.[CH3:18][CH:19]([CH3:22])[CH2:20][NH2:21]>CCO>[F:13][C:12]1[C:6]2[CH2:5][O:4][CH:3]([CH2:2][NH:21][CH2:20][CH:19]([CH3:22])[CH3:18])[O:8][C:7]=2[CH:9]=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=1
Reactant: CS(=O)(=O)c1cc(F)c2c(c1)OC(CBr)OC2
Reactant: CC(C)CN
Solvent: CCO
Product: CC(C)CNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 34 using 2-(bromomethyl)-5-fluoro-7-(methylsulfonyl)-4H-1,3-benzodioxine (7 mg, 0.021 mmol), 2-methylpropan-1-amine (0.5 ml) and EtOH (3 ml). MS m/z (rel. intensity, 70 eV) 317 (M+, 0.4), 274 (11), 141 (15), 86 (bp), 72 (29), 57 (14).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]2=1)([O-])=O.C(O)C>[C].[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[C:13](=[O:17])[CH2:12][CH2:11][CH2:10][C:9]2=1
Reactant: O=C1CCCc2c1[nH]c1c([N+](=O)[O-])cccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A mixture of 8-nitro-2,3,4,9-tetrahydro-1H-carbazol-1-one (1.50 g), 10% palladium-carbon (0.20 g), ethanol (5 mL) and tetrahydrofuran (10 mL) was stirred at room temperature overnight under a hydrogen atmosphere. Palladium-carbon was filtered off, and the filtrate was concentrated to give the title compound (1.20 g, yield 92%) as yellow crystals. melting point 233-234° C.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.I[C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: Ic1cccnc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccnc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 34, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-iodopyridine. The title compound was obtained in 82% yield as light brown foam. MS (m/e): 483.3 (MH+, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:9]1[NH:13][C:12]2[CH:14]=[C:15]([N:19]3[CH2:24][CH2:23][CH2:22][C:21]4([CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[CH2:20]3)[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=1.[NH2:30][CH2:31][C@H:32]([C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=1)[OH:33].CCN(CC)CC>CCO>[Cl:40][C:36]1[CH:35]=[C:34]([C@H:32]([OH:33])[CH2:31][NH:30][C:2]2[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=2[C:9]2[NH:13][C:12]3[CH:14]=[C:15]([N:19]4[CH2:24][CH2:23][CH2:22][C:21]5([CH2:29][CH2:28][CH2:27][NH:26][CH2:25]5)[CH2:20]4)[CH:16]=[C:17]([CH3:18])[C:11]=3[N:10]=2)[CH:39]=[CH:38][CH:37]=1
Reactant: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCCC3(CCCNC3)C2)cc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 25 °C
Yield: 46.9 %

Procedure:
A solution of 4-Chloro-3-[6-(2,8-diaza-spiro[5.5]undec-2-yl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyridin-2-one (16 mg, 0.039 mmol), (S)-2-amino-1-(3-chlorophenyl)-ethanol (20 mg, 0.117 mmol) and Et3N (16 mg, 0.156 mmol) in EtOH (0.5 mL) was heated at 80° C. for 16 h. After it was cooled to room temperature, the reaction mixture was filtered to furnish yellow solid that was washed with MeOH (3×3 mL). The yellow solid then was mixed with 3 mL MeOH and the mixture was heated at 100° C. for 1 h. After it was cooled to room temperature, the mixture was filtered to furnish yellow solid that was washed with MeOH (3×2 mL) to afford the title compound (10 mg, 47%). ESI-MS m/z 547 (MH+).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH3:25])=[CH:23][N:22]([CH3:26])[C:21]=1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:19])[CH3:16]>ClCCCl>[CH3:26][N:22]1[C:23]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:10])=[CH:2][CH:3]=2)=[O:8])=[C:24]([CH3:25])[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])=[C:21]1[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(C)cn1C
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(C)c(C(=O)c2ccc(C)cc2)n1C

Procedure:
A solution of 30.8 g. p-toluoyl chloride and 26.6 g. (0.2 mole) of aluminum chloride in 250 ml. of 1,2-dichloroethane is added to a refluxing solution of 50.6 g. (0.2 mole) of ethyl 3-ethoxycarbonyl-1,4-dimethylpyrrole-2-acetate in 250 ml. of 1,2-dichloroethane over 30 min. The mixture is heated under reflux for 90 min. and poured into ice-diluted hydrochloric acid. The organic solution is separated, washed with brine, and dried over magnesium sulfate. The solvent is evaporated in vacuo and the residue is recrystallized from methanol to give ethyl 1,4-dimethyl-3-ethoxycarbonyl-5-(p-toluoyl)-pyrrole-2-acetate as a white solid, m.p. 108°-111° C.
Reaction SMILES: [S:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.FC(F)(F)S(O[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])(=O)=O>C(Cl)Cl>[O:7]([C:4]1[CH:3]=[CH:2][S:1][CH2:6][CH:5]=1)[Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C1C=CSCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1=CCSC=C1
Reaction time: 0.17 h
Yield: 60.8 %

Procedure:
2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.1 mmol, synthesized as described in Richards et al. J. Org. Chem. 46,4836–4842 (1981)) was dissolved in CH2Cl2 (130 mL) and triethylamine (5.47 mL, 39.4 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.8 mmol) was then added. After 10 minutes, the volatiles were removed in vacuo at 25° C. The resulting yellow oil was passed through a short column of SiO2 eluting with 3% TEA in hexanes to yield 1.82 g (7.97 mmol, 61%) of compound 1A as an orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][CH:14]=[N:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][CH:14]=[N:13]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), pyrazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (30 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole as a solid (1.80 g). MS 208.3 (M+H)
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#[N:2].Br[CH2:11][C:12]([O:14][CH3:15])=[O:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][CH2:11][C:12]([O:14][CH3:15])=[O:13])#[N:2]
Reactant: N#Cc1ccccc1N
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CNc1ccccc1C#N
Temperature: 0 °C
Yield: 80.4 %

Procedure:
A mixture of 2.2 g of 2-cyanoaniline, 2.0 g of methyl bromoacetate and 1.3 g of potassium carbonate in 12 ml of dry N,N-dimethylformamide is heated at 150°-155° C. for 40 minutes. The cooled mixture is poured into ice-water and the mixture filtered to give 2 g of methyl [N-(2-cyanophenyl)amino]acetate as a yellow solid, m.p. 70°-78° C. The preceding compound (2.0 g) is added to a solution of 0.5 g of sodium methoxide in 50 ml of methanol. The mixture is shaken under an atmosphere of hydrogen with the catalyst Raney-Ni for 19 hours. The mixture is filtered through diatomaceous earth and the filtrate evaporated. Water is added to the residue and the mixture filtered to give 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-3-one as a yellow solid, m.p. 167°-170° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21]Cl)=[CH:20][C:14]=2[C:13]=1[CH3:23])=[O:11]>CN(C)C=O>[CH3:8][O:9][C:10]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([CH2:21][C:2]3[NH:1][CH:5]=[CH:4][N:3]=3)=[CH:20][C:14]=2[C:13]=1[CH3:23])=[O:11]
Reactant: COC(=O)c1sc2ccc(CCl)cc2c1C
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc2ccc(Cc3ncc[nH]3)cc2c1C
Reaction time: 0.5 h
Yield: 32.5 %

Procedure:
To a solution of imidazole (0.23 g.) in dry N,N-dimethylformamide (10 ml.) was added sodium hydride (0.17 g. of 50% dispersion in mineral oil) and the mixture was stirred for 30 minutes. A solution of 5-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.82 g.) in dry N,N-dimethylformamide (10 ml.) was then added dropwise with stirring and the resulting mixture was stirred at room temperature for 2.5 hours and then evaporated. The residue was poured into water and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated to give a solid which was chromatographed on silica gel. Elution with chloroform gave first some impurity followed by pure product. The product containing fractions were combined to give a solid which was crystallized from ethyl acetate/petrol (b.p. 60°-80°) to give 5-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.30 g.), m.p. 136°-138°.
Reaction SMILES: C(NC1C=C([C:11]2[C:16]([C:17]([C:19]3[C:20]([C:25]4C=CC=[C:27]([NH:31][C:32](=[O:34])[CH3:33])[CH:26]=4)=NC=C[CH:24]=3)=O)=[CH:15][CH:14]=[CH:13][N:12]=2)C=CC=1)(=O)C.[Br-].[C:36]([CH2:39][CH2:40][CH2:41][CH2:42][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:38])=[O:37].CC(C)([O-])C.[K+].O>O1CCCC1>[C:32]([NH:31][C:27]1[CH:24]=[C:19]([C:17]([C:16]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:42][CH2:41][CH2:40][CH2:39][C:36]([OH:38])=[O:37])[CH:20]=[CH:25][CH:26]=1)(=[O:34])[CH3:33]
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)Nc1cccc(-c2ncccc2C(=O)c2cccnc2-c2cccc(NC(C)=O)c2)c1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1cccc(C(=CCCCC(=O)O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At -25° C., 94 g of 3-acetylaminophenyl-3-pyridylketone are added to a mixture of 217 g of 4-carboxybutyl-triphenylphosphonium bromide and 154 g of potassium tert.butoxide in 1.8 litres of tetrahydrofuran. After 2 hours stirring at ambient temperature, 200 ml of water are added to the reaction mixture and then it is evaporated down. The residue is taken up in 500 ml of water and washed with ethyl acetate. The agueous phase is then neutralised by the addition of citric acid and extracted with ethyl acetate. The organic phase is evaporated down and the residue is recrystallised from ethyl acetate/acetone.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[S:8][C:7]([CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][C:5]=1[C:16]([OH:18])=O)[CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:53]=[C:54]([NH2:61])[C:55]4[CH:56]=[N:57][NH:58][C:59]=4[CH:60]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:43]1[C:51]2[C:46](=[C:47]([C:52]3[CH:60]=[C:59]4[C:55]([CH:56]=[N:57][NH:58]4)=[C:54]([NH:61][C:16]([C:5]4[N:6]=[C:7]([CH2:9][N:10]5[CH2:11][CH2:12][O:13][CH2:14][CH2:15]5)[S:8][C:4]=4[CH:2]([CH3:1])[CH3:3])=[O:18])[CH:53]=3)[CH:48]=[CH:49][CH:50]=2)[CH:45]=[CH:44]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CC(C)c1sc(CN2CCOCC2)nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1sc(CN2CCOCC2)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 30.5 %

Procedure:
To a solution of 5-(1-methylethyl)-2-(4-morpholinylmethyl)-1,3-thiazole-4-carboxylic acid (31 mg) in DMF (3 ml) was added HATU (44 mg) and the mixture stirred at 20° C. for 10 min, then 6-(1H-indol-4-yl)-1H-indazol-4-amine (13 mg) and DIPEA (0.037 ml) were added and the mixture allowed to stand for 18 h. The mixture was blown to dryness under a stream of nitrogen and the residue purified by mass directed preparative HPLC (Method A) to give the title compound (8 mg) as a pale brown solid.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[CH3:13][O:14][CH2:15][C:16]1([N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>CN(C)C(=O)C>[CH3:13][O:14][CH2:15][C:16]1([N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:21][CH2:20][N:19]([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)[CH2:18][CH2:17]1
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C

Procedure:
A mixture of 20 parts of 1-(2-bromoethyl)-4-nitrobenzene, 21.8 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide, 14.4 parts of N,N-diethylethanamine and 270 parts of N,N-dimethylacetamide is stirred and heated for 4.50 hours at 70° C. The reaction mixture is cooled to room temperature and poured onto water. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 4% of methanol as eluent. The first fraction is collected and the eluent is evaporated, yielding a first fraction of 14 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 98.7° C. The second fraction is collected and the eluent is evaporated. The residue is purified once more by column-chromatography over silica gel using a mixture of trichloromethane and 4% of methanol as eluent. The pure fraction is collected and the eluent is evaporated, yielding a second fraction of 2.8 parts of N-{4-(methoxymethyl)-1-[2-(4-nitrophenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 98.7° C.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[C@H:4]([OH:7])[CH2:5][OH:6].[Si:16](OS(C(F)(F)F)(=O)=O)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Si:16]([O:7][C@H:4]([CH2:5][O:6][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:3]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)[NH2:2])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: N[C@@H](c1ccc(Cl)c(Cl)c1)[C@H](O)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](N)c1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h
Yield: 32.9 %

Procedure:
To a solution of 252 (0.50 g, 1.83 mmol) and DCM (5 mL) at RT was added TEA (1.28 mL, 9.17 mmol) followed by TBDMSOTf (1.05 mL, 4.59 mmol) and the reaction was stirred for 30 min. The reaction poured into aq. NaHCO3 and extracted with DCM. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with hexane/EtOAc/DCM (8:1:1) to afford 0.280 g (32.9%) of (1S,2S)-2,3-bis-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)propan-1-amine (254).