Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.Cl.[F:21][C:22]1[CH:23]=[N:24][C:25]([C@@H:28]([NH2:30])[CH3:29])=[N:26][CH:27]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[C:5]([N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=[C:2]([NH:30][C@H:28]([C:25]4[N:26]=[CH:27][C:22]([F:21])=[CH:23][N:24]=4)[CH3:29])[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)n1)c1ncc(F)cn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A mixture of 6-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 9, 0.5 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.35 g) in n-BuOH (10 mL) with diisopropylethylamine (1 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.5 g of desired product. MS (electrospray): 385 (M+1) for C17H18FN8O2. 1H NMR (300 MHz, CD3OD) δ ppm 8.70 (s, 2H) 8.20 (d, 1H) 6.40 (m, 1H) 6.20 (d, 1H) 5.45 (m, 1H), 1.90 (m, 1H) 1.70 (d, 3H) 1.05 (m, 2H) 0.90 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:9])=[O:8])[S:5][CH:6]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>>[CH3:12][N:13]([CH:15]=[N:9][C:7]([C:4]1[S:5][CH:6]=[C:2]([Br:1])[CH:3]=1)=[O:8])[CH3:14]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1cc(Br)cs1
Product: CN(C)C=NC(=O)c1cc(Br)cs1
Temperature: 85 °C

Procedure:
A mixture of 4-bromo-thiophene-2-carboxylic acid amide (206 mg, 1.0 mmol) and N,N-dimethylformamide dimethyl acetal (0.5 mL, 3.8 mmol) was heated at 85° C. for 1.5 h. The resulting mixture was cooled, and then concentrated under high vacuum to yield 4-bromo-thiophene-2-carboxylic acid dimethylaminomethyleneamide as a light tan solid, which was directly used in the next step without purification.
Reaction SMILES: [Na+].[Br-:2].CS(O[CH2:8][C@@H:9]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][N:10]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1)(=O)=O>C(#N)C.C(OCC)(=O)C.O>[Br:2][CH2:8][C@@H:9]1[CH2:13][C:12]([F:15])([F:14])[CH2:11][N:10]1[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)OC[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CBr)cc1C(F)(F)F
Temperature: 80 °C
Yield: 72.1 %

Procedure:
NaBr (420 mg, 131 μL, 4.08 mmol) was added to a solution of (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methyl methanesulfonate (330 mg, 0.82 mmol) in acetonitrile (2.0 mL) and heated at 80° C. for 16 h. The reaction mixture was diluted with ethyl acetate (10 mL) and water (5 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (15-50% ethyl acetate/hexane) to obtain (S)-2-(bromomethyl)-4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (230 mg, 72%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 8.14 (d, J=8.7 Hz, 1H), 7.09-7.07 (m, 2H), 4.76-4.71 (m, 1H), 4.16-3.99 (m, 2H), 3.74 (dd, J=10.6, 3.0 Hz, 1H), 3.60 (t, J=9.7 Hz, 1H), 2.94-2.80 (m, 1H), 2.66-2.55 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:20])[C@@H:9]([C:17](O)=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O[N:23]1[C:27]2C=CC=CC=2N=N1.CN.C(Cl)Cl>CN(C)C=O.CO.O>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:20])[C@@H:9]([C:17](=[O:18])[NH:23][CH3:27])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: On1nnc2ccccc21
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccccc1)C(=O)O
Agent: CN
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
N-Tert-butoxycarbonyl-N-methyl-D-phenylalanine (1.22 g, 4.4 mmol), 1-hydroxybenzotriazole hydrate (0.59 g, 4.4 mmol) and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimid hydrochloride (0.88 g, 4.6 mmol) were dissolved in N,N-dimethylformamide (25 mL) and stirred for 30 min. Methylamine (0.51 g of a 40% solution in methanol, 6.6 mmol) was added and the mixture was stirred overnight. Methylene chloride (80 mL) and water (100 mL) were added and the phases were separated. The organic phase was washed with sodium hydroxide (20 mL, 1 N), sodium hydrogensulfate (50 mL, 10%) and water (50 mL). The organic phase was dried (magnesium sulfate) and the solvent removed in vacuo to afford 1.39 g of N-methyl-N-((R)1-(methylcarbamoyl)-2-phenylethyl)carbamic acid tert-butyl ester.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([CH:15]=O)[CH2:10]1)=[O:8].Cl.[NH2:18]O.C1(P(Cl)(Cl)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCl.N1C=CC=CC=1.CO>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]#[N:18])[CH2:10]1)=[O:8]
Reactant: O=C[C@H]1CCCN(C(=O)Cc2cccs2)C1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: O=P(Cl)(Cl)c1ccccc1
Solvent: CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#C[C@H]1CCCN(C(=O)Cc2cccs2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
(S)-1-(2-thiopheneacetyl)-3-piperidinecarboxaldehyde (117.4 mg. 0.50 mmol) was dissolved in dichloromethane (2.5 ml). Anhydrous methanol (80 l), dry pyridine (100 g), and hydroxylamine hydrochloride (38.2 mg; 0.55 mmol) were added and the mixture was allowed to stir at ambient temperature for 1 hour. The mixture was then evaporated under reduced pressure at ambient temperature. The residue was suspended in fresh dichloromethane (3 ml). Dry pyridine (80 μl) was added to this mixture, followed by dropwise addition of commercially available phenylphosphonic dichloride (140 μl; 1.0 mmol). After addition was complete, the mixture was allowed to stir at ambient temperature for 22 hours. Saturated sodium bicarbonate solution was then added. The mixture was diluted with dichloromethane and washed with fresh saturated sodium bicarbonate solution. The dichloromethane was then washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving (S)-1-(2-thiopheneacetyl)-3-piperidinonitrile (71.4 mg) as a pale yellow oil. MS m/z (positive ion) 235 (MH+; 100).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]3[CH:18]([CH2:19][CH2:20][C:21]=2[CH:22]=1)[CH:17]1[CH2:23][C:24]2[C:28]([C:16]1([CH3:31])[CH2:15][CH2:14]3)=[N:27][NH:26][C:25]=2[CH2:29][OH:30])C1C=CC=CC=1>[Pd].C1COCC1.C(O)C>[OH:30][CH2:29][C:25]1[NH:26][N:27]=[C:28]2[C:24]=1[CH2:23][CH:17]1[CH:18]3[CH:13]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:22][C:21]=4[CH2:20][CH2:19]3)[CH2:14][CH2:15][C:16]12[CH3:31]
Reactant: CC12CCC3c4ccc(OCc5ccccc5)cc4CCC3C1Cc1c2n[nH]c1CO
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC12CCC3c4ccc(O)cc4CCC3C1Cc1c2n[nH]c1CO
Reaction time: 24 h

Procedure:
Palladium on charcoal (50 mg, 5% Pd) was added to a solution (2-Benzyloxy-6a-methyl-4b,5,6,6a,8,10,10a,10b,11,12-decahydro-7,8-diaza-pentaleno[2,1-a]phenanthren-9-yl)-methanol (120 mg, 0.289 mmol, CAB03058) in THF (20 mL) and ethanol (20 mL). The resulting mixture was stirred under a hydrogen-atmosphere (balloon) for 24 hours, filtered through a 3 cm layer of celite and concentrated under reduced pressure. The residue was dried under high vacuum. Yield: 93 mg (99%) white solid. 1H-NMR (DMSO-d6, 270 MHz), δ: 0.82 (s, 3H, —CH3), 1.20-2.80 (m, 13H), 4.31 (s, 2H, —CH2OH), 4.95 (bs, 1H, —OH), 6.37 (s, 1H), 6.44 (d, J=8.5 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 8.92 (s, 1H, —OH), 11.78 (bs, 1H, NH). LRMS (FAB+): 3.25.2 (100, [M]+). HRMS (FAB+): 325.192528 C20H25N2O2 requires 325.191603.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([C:19]3[CH:20]=[C:21]([CH2:24][NH:25][C:26]([C:28]4[C:29](=[O:43])[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[CH:31]=[CH:32][CH:33]=4)=[O:27])[S:22][CH:23]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.C(Cl)Cl.C[O-].[Na+]>CO>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([C:19]2[CH:20]=[C:21]([CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])[S:22][CH:23]=2)=[CH:11]1
Reactant: O=C(NCc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1cc(-c2c[nH]c3ncccc23)cs1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [4-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide (0.050 g, 0.000081 mol;) was dissolved in Methylene chloride (3 mL, 0.05 mol;) then 0.5 M of Sodium methoxide in methanol (3 mL) was added and the reaction was heated at 75 C for 1 hour. LC-MS showed the disappearance of starting material and the appearance of product at 1.34 477.10. The reaction was concentrated and dissolved in DMSO and methanol 1:1 for purification by Gilson Preparative HPLC. Pure fractions were combined and concentrated. ES (+) MS m/e=477.10; NMR (400 MHz, DMSO-d6) δ ppm 4.72 (m, 2H), 5.21 (s, 2H), 6.60 (t, 1H, J=8 Hz), 7.19 (m, 2H), 7.37-7.50 (m, 3H), 7.62 (s, 1H), 7.86 (m, 1H), 7.64 (s, 1H), 8.24 (m, 1H), 8.41 (m, 1H), 10.04 (t, 1H, J=6 Hz).
Reaction SMILES: Cl.O1CCOCC1.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH:25]=[C:24]([Br:26])[CH:23]=[N:22]2)[CH2:17][CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[Br:26][C:24]1[CH:23]=[N:22][N:21]([CH:18]2[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]2)[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Br)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cnn(C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 4 M solution of HCl in 1,4-dioxane (13.5 ml, 54 mmol) is added to a solution of 4-(4-Bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (as obtained in preparation 62, 5.92 g, 17.94 mmol) in CH2Cl2 (50 ml) and the reaction mixture is stirred at RT for 6 h. The suspension is filtered on a Por. 4 Fritte and the cake dissolved in EtOAc. A saturated solution of NaHCO3 is added and the phases are separated. The aqueous phase is extracted 3× with EtOAc. The combined organic layers are washed with NaHCO3, brine, dried over Na2SO4, filtered and the filtrate is concentrated in vacuo. The residue is used without further purification in the next step, and afford the title compound as pale orange solid, Rt=0.582 min (Acquity HPLC BEH C18, 2.1×50 mm, 1.7 micron, detection 215 nM, 0.1 min 2% CH3CN in H2O, 2% to 100% CH3CN in H2O in 1.5 min, 0.4 min 100% CH3CN+0.1% TFA, flow rate 1.0 ml/min); MS: 330 (M+1, 79Br)+
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[C:13]([CH3:14])=[C:12]([OH:15])[C:11](=[O:16])[N:10]1[C:17]1[CH:32]=[CH:31][C:20]2[N:21](C(OC(C)(C)C)=O)[CH:22]=[N:23][C:19]=2[CH:18]=1.[F:33][C:34]([F:38])([F:37])[CH2:35]I>>[F:33][C:34]([F:38])([F:37])[CH2:35][O:15][C:12]1[C:11](=[O:16])[N:10]([C:17]2[CH:32]=[CH:31][C:20]3[NH:21][CH:22]=[N:23][C:19]=3[CH:18]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[C:13]=1[CH3:14]
Reactant: CC1=C(O)C(=O)N(c2ccc3c(c2)ncn3C(=O)OC(C)(C)C)C1c1cccc(F)c1F
Reactant: FC(F)(F)CI
Product: CC1=C(OCC(F)(F)F)C(=O)N(c2ccc3[nH]cnc3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from tert-butyl 5-(2-(2,3-difluorophenyl)-4-hydroxy-3-methyl-5-oxo-2H-pyrrol-1(5H)-yl)-1H-benzo[d]imidazole-1-carboxylate (0.441 g, 1 mmol), trifluoroiodoethane (0.15 ml, 1.5 mmol) and P1-tBu (1.38 ml, 1.5 mmol) according to the method described above and was further purified by semi-preparative HPLC.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Br)[C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][C:18]1=[O:23]>>[CH2:1]([S:8][C:9]1[C:10]([Cl:16])=[C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C:18]2=[O:23])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1COCCN1
Reactant: Clc1c(Br)cccc1SCc1ccccc1
Product: O=C1COCCN1c1cccc(SCc2ccccc2)c1Cl

Procedure:
Intermediate 9 (10 g, 31.38 mmol) was treated with morpholin-3-one (389 mg, 3.85 mmol) according to the procedure described in example 1; 1.5).
Reaction SMILES: Br.[F:2][C:3]1[C:8]([O:9]C)=[C:7]([CH:11]=[O:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1>C(O)(=O)C>[F:2][C:3]1[C:8]([OH:9])=[C:7]([CH:11]=[O:12])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: COc1c(C=O)ccc(-c2ccc(F)cc2)c1F
Agent: Br
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2ccc(F)cc2)c(F)c1O
Temperature: 120 °C
Reaction time: 18 h
Yield: 94.5 %

Procedure:
48% hydrobromic acid (28.4 mL) was added at room temperature to an acetic acid (150 mL) solution of 2,4′-difluoro-3-methoxybiphenyl-4-carbaldehyde (6.18 g), and the mixture was stirred at 120° C. for 18 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then, the solvent was distilled off under reduced pressure. The obtained residue was diluted with ethyl acetate and water. The organic layer was separated, and then, the obtained aqueous layer was neutralized with a 1 M aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. Combined organic layers were washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was passed through a short silica gel column (hexane/ethyl acetate) to obtain the title compound (5.51 g).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][OH:8])[N:6]=1.[CH3:9][CH2:10][O:11][C:12]([C:14]1[N:15]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16]2[C:21]([CH:22]=1)=[C:20](OCC1C=CC=CC=1)[CH:19]=[CH:18][CH:17]=2)=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1>[CH3:9][CH2:10][O:11][C:12]([C:14]1[N:15]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:16]2[C:21]([CH:22]=1)=[C:20]([O:8][CH2:7][C:5]1[N:6]=[C:2]([CH3:1])[S:3][CH:4]=1)[CH:19]=[CH:18][CH:17]=2)=[O:13]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Reactant: Cc1nc(CO)cs1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3csc(C)n3)cccc2n1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
(2-Methyl-thiazol-4-yl)-methanol (168, 670 mg, 5.2 mmol) is dissolved in 12 ml of dry THF under argon, followed by addition of 4-Hydroxy-indole-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (102, see example 42, 1.58 g, 5.2 mmol), triphenylphosphine (1.63 g, 6.2 mmol).) and the solution is cooled to 0° C. A 40% solution of ethyl azadicarboxylate in toluene (2.7 ml, 6.2 mmol) is added dropwise and the mixture is stirred for 2.5 h at 0° C. The solvents are removed under reduced pressure and the residue is dissolved in ethyl acetate and washed with sodium hydrogencarbonate solution and brine. The organic layers are dried over sodium sulphate, filtrated and evaporated. The crude product is purified by flash chromatography (silica gel, ethyl acetate/hexanes 3:7)
Reaction SMILES: [NH2:1][C:2]1[CH:47]=[C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)[CH:45]=[CH:44][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH:14]=2)[N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:8]=1)=[O:5].[CH3:55][S:56]([Cl:59])(=[O:58])=[O:57].Cl>ClCCl.N1C=CC=CC=1.O1CCOCC1>[ClH:59].[F:23][C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([F:24])[CH:20]=1)[CH2:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4](=[O:5])[C:3]1[CH:44]=[CH:45][C:46]([N:48]2[CH2:53][CH2:52][N:51]([CH3:54])[CH2:50][CH2:49]2)=[CH:47][C:2]=1[NH:1][S:56]([CH3:55])(=[O:58])=[O:57]
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(c2ccc(C(=O)Nc3nn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(NS(C)(=O)=O)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.5 %

Procedure:
To a solution of 2-amino-N-[5-(3,5-difluoro-benzyl)-1-trityl-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-benzamide (29 mg, 0.04 mmol) in anhydrous dichloromethane (2 mL) and dry pyridine (0.05 mL), methanesulfonyl chloride (14.7 mg, 0.01 mL, 0.13 mmol) was added and the reaction mixture was stirred at room temperature for 8 hours. The mixture was poured into ice and was extracted with dichloromethane. The organic layer was washed with 0.1N HCl, then with water, dried over anhydrous Na2SO4 and concentrated to yield a crude whitish solid that was suspended in dioxane (1 mL). After adding 4M HCl in dioxane (0.1 mL) the suspension was stirred overnight. After concentration the residue was suspended in diethyl ether/MeOH 1:1, stirred for 20 min., filtered, washed with the same solvent mixture and dried. The desired product was obtained as the hydrochloride (15 mg, 0.025 mmol, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[K+].O1CCCC1.Cl.[CH3:29][N:30]([CH2:32][CH2:33][CH2:34]Cl)[CH3:31]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.O>[CH3:29][N:30]([CH3:31])[CH2:32][CH2:33][CH2:34][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CN(C)CCCCl
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 40 °C
Reaction time: 4 h

Procedure:
To a solution of 3.2 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 17 ml of a 10% aqueous potassium hydroxide solution and 1.2 ml of tetrahydrofuran are added at room temperature with stirring 1.75 g of N,N-dimethyl-3-chloropropylamine hydrochloride and 100 mg of benzyltriethylammonium chloride, and the resulting mixture is stirred on a water bath at 40° C. for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 4.40 g of 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 154°-156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:25]([O:29][C:30](=[O:33])[NH:31][NH2:32])([CH3:28])([CH3:27])[CH3:26]>O1CCCC1>[CH3:26][C:25]([CH3:28])([O:29][C:30]([NH:31][NH:32][C:4](=[O:5])[C:3]1[CH:7]=[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])[C:9]([F:11])=[CH:10][C:2]=1[Cl:1])=[O:33])[CH3:27]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)Cl)c(Cl)cc2F)c1=O
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)NNC(=O)OC(C)(C)C)c(Cl)cc2F)c1=O
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-5-(3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl)-4-fluoro-benzoyl chloride (0.5 g) in tetrahydrofuran (20 ml) was added t-butylcarbazate (0.18 g) at ambient temperature. After 1 hour, the resulting mixture was concentrated under reduced pressure and the residue was subjected to column chromatography on silica gel eluted with a mixed solvent of ethyl acetate and hexane (2:3) to give the titled compound (0.48 g).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:7][CH2:6]1.[ClH:20]>>[ClH:20].[ClH:20].[CH3:19][N:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([NH2:11])[CH2:9][CH2:10]1
Reactant: CN(C)CC[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CN(C)CC[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure IV-1, tert-butyl {trans-4-[2-(dimethylamino)ethyl]-cyclohexyl}carbamate (330 mg, 1.2 mmol) was reacted with 6 N HCl (2 mL) to afford the desired product as a viscous colorless oil that was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH:22]=O)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[N:24]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:29][CH2:28][CH2:27][CH2:26][C:25]1=[O:30].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:21][CH2:22][N:34]2[CH2:33][CH2:32][CH:31]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][C:25]3=[O:30])[CH2:36][CH2:35]2)[CH2:10][N:11]([CH3:20])[C:12](=[O:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reactant: O=C1CCCCN1C1CCNCC1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN(C[C@@H](CCN1CCC(N2CCCCC2=O)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 98.6 %

Procedure:
(S)—N-[2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methylbenzamide (0.78 g) in methanol (3 mL) was added to a solution of [1,4′]bipiperidinyl-2-one (0.34 g) and acetic acid (0.15 mL) in methanol (8 mL). After 10 minutes, sodium cyanoborohydride (0.17 g) in methanol (4 mL) was added in a single portion. After being stirred overnight, the reaction mixture was diluted with saturated aqueous sodium bicarbonate, stirred for 30 minutes, and extracted with dichloromethane (4×50 mL). The organic extracts were dried, evaporated, and purified by chromatography, with dichloromethane:methanol (gradient 95:5, 90:10) as eluent to give the title compound (0.95 g). MS: m/z=516(M+). The product was dissolved in methanol (2 mL) and citric acid was added. The solution was concentrated and the residue was triturated with ether. The product was obtained as a white foam (1.2 g).