Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]2[N:6]([C:10]([CH:29]3[CH2:32][C:31](=[O:33])[CH2:30]3)=[N:11][C:12]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][N:9]=1>>[Cl:3][C:4]1[C:5]2[N:6]([C:10]([C@@H:29]3[CH2:30][C@H:31]([OH:33])[CH2:32]3)=[N:11][C:12]=2[C:13]2[CH:22]=[C:21]3[C:16]([CH:17]=[CH:18][C:19]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:20]3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][N:9]=1
Reactant: O=C1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Agent: [BH4-]
Agent: [Na+]
Product: O[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
An ethanolic suspension (20 mL) of 3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutanone: (2.5 mmol) was charged with NaBH4 (2.5 mmol) at rt. The reaction mixture was stirred at rt for 30 min until the reaction solution turned clear. The reaction mixture was quenched by an addition of Na2SO4.10 H2O and concentrated under reduced pressure. The crude mixture was dissolved in DCM, washed with water (3×15 mL),dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.19 (d, J=8.0 Hz, 2H), 7.93-7.87 (m, 3H), 7.58-7.52 (m, 3H), 7.47-7.45 (m, 1H), 7.37 (d, J=5.2 Hz, 1H), 4.44 (b, 1H), 3.37 (p, J=8.0 Hz, 1H), 3.03-2.96 (m, 2H), 2.60-2.53 (m, 2H); MS (ES+): m/z 427 (100) [MH+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[F-].[Cs+].[CH2:14](B1OC(C)(C)C(C)(C)O1)[CH:15]=[CH2:16].O>C1COCC1>[CH2:16]([C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[CH:15]=[CH2:14]
Reactant: C=CCB1OC(C)(C)C(C)(C)O1
Reactant: COc1cc(Br)cc(OC)c1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.6 %

Procedure:
5-Bromo-1,3-dimethoxybenzene (2.13 g, 9.8 mmol), CsF (2.88 g, 19.0 mmol), and Pd(Ph3)4 (0.57-1.13 g, 0.5-1.0 mmol) were weighed into a flame-dried Schlenk flask and put under a flow of argon. THF (80 mL) was added to the flask via syringe, and the resulting suspension was stirred for 30 min at room temperature. Allyl boronic acid pinacol ester (2.96 g, 17.6 mmol) in THF (40 ml) was added and the resulting mixture was heated to reflux for 30 h. Another portion of CsF (2.88 g, 19.0 mmol) and Pd(Ph3)4 (0.57-1.13 g, 0.5-1.0 mmol) were added and the reaction was continued to reflux for 24 h. The reaction mixture was diluted with petroleum ether (100 ml) followed by H2O (100 ml). The layers were separated and the aqueous layer was extracted with petroleum ether (2×80 ml). The combined organic layers were washed with H2O (100 ml), and brine (100 ml). The solution was dried over MgSO4 and evaporated to dryness. The crude product was purified by column chromatography (silica, eluent: hexanes/benzene=3:2) to give 1.60 g (92%) of 5-Allyl-1,3-dimethoxybenzene. 1H NMR (CDCl3): δ 3.33 (d, J=6.7 Hz, 2H, CH2CH═CH2), 3.77 (s, 6H, OCH3), 5.02-5.11 (m, 2H, CH2CH═CH2), 5.89-5.99 (m, 1H, CH2CH═CH2), 6.33-6.38 (m, 3H).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.N1C=CC=CC=1>ClCCl>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: NCc1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)NCc3ccc(F)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (5.0 g), 4-fluorobenzylamine (3.0 mL) and pyridine (3.5 mL) in dichloromethane (30 mL) was stirred at room temperature for 4 hours. The precipitate was filtered, washed with dichloromethane and dried to give 5.8 g (84%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid 4-fluoro-benzylamide.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:13](=[O:20])[CH2:12][CH2:11]2.[CH:21]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1>ClC(Cl)C>[N+:17]([C:16]1[CH:15]=[C:14]2[C:10]([CH2:11][CH2:12][C:13]2=[O:20])=[CH:9][C:8]=1[NH:7][C:28](=[O:29])[CH2:27][CH2:26][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)([O-:19])=[O:18]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Reactant: O=C(Cl)CCC1CCCC1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: O=C(CCC1CCCC1)Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.2 %

Procedure:
Pyridine (0.1 g, 1.3 mmol) was added to a suspension of 5-amino-6-nitro-indan-1-one (0.19 g, 1 mmol) in 15 ml of anhydrous dichloroethane followed by the addition of 3-cyclopentylpropionyl chloride (0.193 mg, 1.2 mmol) at room temperature under argon. The mixture was stirred at room temperature for 24 hours. The solvent was removed under reduced pressure and the residue was purified by column (hexane/EtOAc, 5:1) to give a yellow solid (0.26 g, 83%). 1H-NMR (DMSO-d6): δ 10.47 (s, 1H, NH, exchangeable with D2O), 8.06 (s, 1H), 7.87 (s, 1H), 3.15 (m, 2H), 2.69 (m, 2H), 2.38 (t, 2H, J=7.8 Hz), 1.74 (m, 2H), 1.59-1.46 (m, 7H), 1.08 (m, 2H). MS: 317 (M+1).
Reaction SMILES: [Cl-].[NH4+].O.[CH3:4][O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([N+:15]([O-])=O)[CH:12]=[CH:13][CH:14]=1)=[O:7]>[Fe].CC(O)C>[CH3:4][O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[NH2:15])=[O:7]
Reactant: COC(=O)Nc1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)Nc1cccc(N)c1
Yield: 95.3 %

Procedure:
After refluxing a mixture of 37 g of iron powder, 1.9 g of ammonium chloride, 33 g of water, 13 g of 3-(methoxycarbonylamino)nitrobenzene, and 260 g of 2-propanol for 30 minutes, the reaction mixture was filtered under suction using sellaite. After extracting the product formed from the filtrate with ethyl acetate followed by washing with water, the product was dried by Glauber's salt. The solvent was distilled off from the product using an evaporator to provide 10.5 g (yield: 95%) of a black oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][S:16][C:17]1[NH:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=1)=[N:8][CH:7]=[CH:6]2.C1C=C(Cl)C=C(C(OO)=[O:34])C=1.C([O-])(O)=O.[Na+].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][S:16]([C:17]1[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=1)=[O:34])=[N:8][CH:7]=[CH:6]2
Reactant: COc1cc2ccnc(CSc3nc4ccccc4[nH]3)c2cc1OC
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2cc1OC
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To a solution of 246.0 mg of 2-[(6,7-dimethoxyisoquinolin-1-yl)methylthio]benzimidazole (Ia-1) (0.700 mmol) in 10 ml of CHCl3 was added 151.0 mg of 80% 3-CPBA (0.700 mmol) at -10°--15° C., and the mixture was stirred for 30 min. at the same temperature. The reaction mixture was mixed with 3 ml of saturated aqueous solution of NaHCO3 and 0.3 ml of 10% aqueous solution of NaHSO3. The reaction temperature was returned to room temperature, and the reaction mixture was mixed with 2 ml of water and extracted with CHCl3. The CHCl3 layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography, eluting with AcOEt-MeOH. The obtained crystals were washed with CH2Cl2 -benzene to give 216.2 mg of the objective compound 2-[(6,7-dimethoxyisoquinolin-1-yl)methylsulfinyl]benzimidazole (Ic-1) (Yield: 83.7%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:23][CH:22]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12.[CH2:37]([O:41][C:42](Cl)=[O:43])[CH2:38][CH2:39][CH3:40].CO>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH:36][C:42]([O:41][CH2:37][CH2:38][CH2:39][CH3:40])=[O:43])(=[O:35])=[O:34])=[CH:25][CH:26]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12
Reactant: CCCCOC(=O)Cl
Reactant: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CO
Product: CCCCOC(=O)NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(CCC)nc3c(C)c(NC(=O)CCC)cnc32)cc1
Reaction time: 14 h

Procedure:
To a mixture of 7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']biphenyl-4-yl]methyl-6-[(1-oxobutyl)amino]-3H-imidazo[4, 5-b]pyridine (60 mg, 0.112 mmol) and 4-dimethyaminopyridine (41 mg) in pyridine (1.5 mL) was added n-butylchloroformate (0.071 mL, 0.56 mmol). After 14 h at r.t., MeOH (1 mL) was added and the mixture was concentrated, dissolved in CH2Cl2 (40 mL), washed with 5% aqueous citric acid (2×20 mL), concentrated, and purified (SiO2, (89:9:1CH2Cl2 /MeOH/NH4OH) to give the title compound as a solid.
Reaction SMILES: [O:1]1[CH2:23][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>C(O)C>[OH:1][CH:2]([CH2:23][NH:27][CH:24]([CH3:26])[CH3:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC(C)N
Reactant: CC1(C)CC(c2ccccc2)c2ccc(OCC3CO3)cc2O1
Solvent: CCO
Product: CC(C)NCC(O)COc1ccc2c(c1)OC(C)(C)CC2c1ccccc1
Yield: 73 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-2,2-dimethyl-4-phenylchroman (6.35 g.), isopropylamine (16 ml) and ethanol (16 ml) was boiled under reflux for 2 days. Removal of the solvent in vacuo gave 7-(2-hydroxy-3-isopropylaminopropoxy)-2,2-dimethyl-4-phenylchroman (6.7 g., 73%) isolated as the hydrochloride salt, m.p. 171°-174° from ether-ethanol.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:3]1.[ClH:13]>CC(C)=O.CCOCC>[ClH:13].[CH3:1][N:2]1[N:6]=[N:5][C:4]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)=[N:3]1
Reactant: Cn1nnc(-c2cccnc2)n1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Product: Cn1nnc(C2CCCNC2)n1
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of 12 (1.93 g, 0.012 mol) in acetone (50 ml) was added hydrogen chloride in ether until acidic reaction. The precipitate was filtered off, dried, and dissolved in methanol (25 ml). 5% palladium on charcoal (0.6 g) was added, and the mixture was shaked overnight under 3 atm. of hydrogen pressure. The catalyst was filtered off and the filtrate was evaporated to dryness. Crystallization from ethanol yielded 0.63 g (0.0031 mol, 26%) of title product M.P. 168°-172° C. Anal. (C7H14ClN5) C, H, N.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1>C(O)C.N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)[CH3:14]
Reactant: CON
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=C(C)c1cccc(C(F)(F)F)c1
Yield: 93 %

Procedure:
Methoxylamine hydrochloride (2.33 g) is added to a solution of 3′-(trifluoromethy)-acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C:5]2([C:15]([OH:17])=[O:16])[OH:14].CCCCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:12][CH3:13])[CH:11]=1)[S:8][CH2:7][CH2:6][C@@:5]2([C:15]([OH:17])=[O:16])[OH:14]
Reactant: COc1cc(Cl)cc2c1SCCC2(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1cc(Cl)cc2c1SCC[C@]2(O)C(=O)O

Procedure:
The enantiomers of 6-chloro-4-hydroxy-8-methoxythiochromane-4-yl-carboxylic acid (3.00 g, 10.9 mmol; see step (v) above) were separated using chiral chromatography (Kromasil TBB; heptane:ethyl acetate:formnic acid) affording 1.13 g of the faster moving, not wanted S-enantiomer, and 1.19 g (79%) of the slower moving sub-title compound. ee=94.6%
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:1]1([C:7]2[C:8]([C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])=[N:9][NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1n[nH]cc1-c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1n[nH]cc1-c1ccccc1
Yield: 66.8 %

Procedure:
5.0 g (23.12 mmol) of ethyl 4-phenyl-3-pyrazolecarboxylate were heated to 120° under reduced pressure for hours with 7.4 g (46.19 mmol) of t-butyl (2-aminoethyl)carbamate, whereby the ethanol formed was distilled off continuously. The reaction mixture was then taken up in methylene chloride and chromatographed on 150 g of silica gel with a 9:1, 8:2 and 7:3 mixture of methylene chloride and ethyl acetate as the eluting agent. The fractions which were pure according to the thin-layer chromatogram were combined and evaporated, and the residue was crystallized from ethyl acetate/hexane, whereby there were obtained 5.1 g (66.8%) of t-butyl [2-(4-phenylpyrazole-3carboxamido)ethyl]carbamate as white crystals, melting point 71°/162°-163° (still containing 0.05 mol of hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6].[Si]([C:15]#[N:16])(C)(C)C.B.C1COCC1.CO>C1COCC1.[Zn+2].[I-].[I-]>[NH2:16][CH2:15][CH:5]([C:4]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=1)[OH:6]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)C#N
Agent: B
Agent: [I-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CO
Product: NCC(O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 772 %

Procedure:
To a mixture of 3,4-dichlorobenzaldehyde (3.50 g, 20.2 mmol) and ZnI2 (19 mg, 0.06 mmol) at 0° C. was added TMSCN (2.2 g, 2.2 mmol). The reaction mixture was stirred at 0° C. for 10 min and then warmed to rt and stirred for an additional 1 h. The mixture was concentrated to afford an orange-brown colored oil. The oil was dissolved in THF (20 mL) and BH3.THF (1 M in THF; 25 mL, 25 mmol) was added at 0° C. The reaction mixture was warmed to rt and stirred overnight. The mixture was cooled to 0° C. and MeOH (6 mL) was added with continued stirring for 2 h. After being warmed to rt, the mixture was concentrated. The residue was dissolved in MeOH (10 mL) and HCl (2 M in Et2O; 25 mL) was added at 0° C. After 30 min, Et2O (100 mL) was added and the resulting white solid was filtered and washed with Et2O (2×50 mL) to give a white solid (3.5 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]([CH:16]=2)[N:14]=[C:13]([C:17]2[C:18]([C:23]([F:26])([F:25])[F:24])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11]3)=[CH:4][C:3]=1[N+:27]([O-])=O>CCO.CC(O)=O.[Fe]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:15]([CH:16]=2)[N:14]=[C:13]([C:17]2[C:18]([C:23]([F:25])([F:24])[F:26])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=[CH:11]3)=[CH:4][C:3]=1[NH2:27]
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1N
Temperature: 70 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A mixture of 2-(4-methyl-3-nitro-phenyl)-6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazine (7.986 g, 0.02 mol) in EtOH—AcOH (48 mL, 1:1) is added slowly to a solution of iron powder (6.702 g, 0.12 mol) in EtOH—AcOH (60 mL, 2:1) at 60° C. The mixture is stirred at 70° C. for 60 min, cooled to room temperature, filtered through celite, washed with EtOAc and concentrated. The oily residue is dissolved in EtOAc (500 mL) and washed twice with saturated aqueous NaHCO3 (200 mL). Organic layer is dried and concentrated to afford the title compound as a solid (7.3 g). LCMS (m/z)=370.5 [M+H]+, tR=1.85 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10](=[S:13])[NH:11][N:12]=1.[C:15]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:14])[C:10]([S:13][CH3:15])=[N:11][N:12]=1
Reactant: Cn1c(-c2ccccc2F)n[nH]c1=S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CSc1nnc(-c2ccccc2F)n1C
Yield: 72.9 %

Procedure:
A mixture of 5-(2-fluorophenyl)-2 4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione (4.56 g 2.18×10-2 mole), K2CO3 (3.01 g, 2.18×10-2 mole), methyl iodide (1 5 ml 2.4×10-2 mole), and acetone (65 ml) was stirred and warmed to reflux. After refluxing overnight, the solvent was evaporated and the concentrate was treated with water. The aqueous mixture was extracted three times with EtOAc. The EtOAc extracts were combined washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure affording a pale yellow oil which was purified by chromatography and kugel rohr distillation, affording a pale yellow oil 3.55 g (73%), bp=190°-197° C. (0.3 mm).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CC(C)=O>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH2:29][Cl:30])[CH2:12][CH2:13]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
In acetone, 1-(diphenylmethyl)piperazine (18.49 g) was dissolved, and potassium carbonate (1.0 eq.) and 1-bromo-3-chloropropane (2.0 eq.) were added thereto, and the obtained mixture was heated to reflux for 3 hours. The salt produced by the reaction was separated by filtration, and the filtrate was then concentrated in vacuo. The residue was purified by silica gel column chromatography (Wakogel C-200, 200 g) and eluted by a mixed solvent of 99 parts of chloroform and 1 part of methanol to obtain 1-[4-(diphenylmethyl)piperazinyl]-3-chloropropane (13.8 g).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43](O)=[O:44])=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29](OCC)=[O:30])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][N:48]=1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:44])[N:46]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][N:48]=3)[C:29](=[O:30])[N:28]([CH2:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])[C:13]=2[S:14][C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:20][CH:21]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: Nc1ccc(F)cn1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(F)cn2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 31.5 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-(N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (10.0 g, 15.65 mmol) and 2-amino-5-fluoropyridine (3.51 g, 31.30 mmol) gave N-(4-(5-((benzyl(methyl)amino)methyl)-1-(2,6-difluorobenzyl)-3-(5-fluoropyridin-2-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N′-methoxyurea (3.39 g, 32%) as white solids. The similar reaction as described in Reference Example 18 by using the compound (1.0 g, 1.46 mmol) gave the title compound (560 mg, 64%) as white solids.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[NH2:11][C:12]1[CH:13]=[C:14]([C:19]2[S:23][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:21][C:20]=2[CH3:28])[N:15]=[N:16][C:17]=1[Cl:18].[C:29]1([S:35](Cl)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O.C1COCC1>[CH3:28][C:20]1[N:21]=[C:22]([NH:24][C:25](=[O:27])[CH3:26])[S:23][C:19]=1[C:14]1[N:15]=[N:16][C:17]([Cl:18])=[C:12]([NH:11][S:35]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:37])=[O:36])[CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(N)c(Cl)nn2)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2cc(NS(=O)(=O)c3ccccc3)c(Cl)nn2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Lithium hexamethyldisilazane (1M solution in THF; 0.81 mL) was added to a mixture of N-[5-(5-amino-6-chloropyridazin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (77 mg) and THF (1.3 mL) that had been cooled to 0° C. The reaction mixture was allowed to warm and was stirred at room temperature for 30 minutes. Benzenesulfonyl chloride (0.069 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. Water (2 drops) was added to the reaction mixture. The mixture was evaporated and the residual solid was purified by preparative HPLC. The material so obtained was purified further by column chromatography on silica using a solvent gradient of 0% to 20% methanol in dichloromethane as eluent. There was thus obtained the title compound as a solid (2.5 mg); 1H NMR Spectrum: (DMSOd6) 2.15 (s, 3H), 2.40 (s, 3H), 7.05 (s, 1H), 7.45 (m, 3H), 7.80 (m, 2H); Mass Spectrum: M+H+ 424.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3C=N[C:20]4[CH:23]=[CH:24][CH:25]=C[C:19]=4[S:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CI.O.[CH3:32][N:33]([CH3:36])[CH:34]=[O:35]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH:17]3[C:34](=[O:35])[N:33]([CH3:36])[C:32]4[CH:25]=[CH:24][CH:23]=[CH:20][C:19]=4[S:18]3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCN(CCCC3C=Nc4ccccc4S3)CC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN1C(=O)C(CCCN2CCN(c3ccc(F)cc3)CC2)Sc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 193 mg of 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-2H-1,4-benzothiazine in 2 ml of dimethylformamide was added 20 mg of 60% sodium hydride in oil. The mixture was stirred at room temperature for 30 minutes and cooled with ice. To the resultant was added 0.07 ml of methyl iodide, and the mixture was stirred for further one hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and concentrated to give 2-[3-[4-(4-fluorophenyl)-1-piperazinyl]propyl]-4-methyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate and hexane gave prisms, m.p. 103°-104° C. The yield was 84 mg (42%). IR and NMR spectra of this product was in agreement with those of the compound obtained in Example 34.