Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6](OC(C)C)=[O:7].[NH3:33]>O1CCOCC1>[F:1][C:2]1[C:15]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=3)[CH:21]=[CH:20][C:19]=2[F:31])=[C:14]([F:32])[CH:13]=[CH:12][C:3]=1[O:4][CH2:5][C:6]([NH2:33])=[O:7]
Reactant: CC(C)OC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Reactant: N
Solvent: C1COCCO1
Product: NC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a mixture of isopropyl 2-[2,4-difluoro-3-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]phenoxy]acetate (II(d)) (1.0 g, 2.24 mmol, 1.0 eq) in dioxane (10 mL) was added NH3 (35% aqueous solution, 30 mL). The reaction was then heated to 100° C. and stirred overnight. The resulting mixture was concentrated in vacuo. Water was added and the aqueous layer was extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as a white solid (320 mg, 36%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH:24]=O)[CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:27]1([C:33]2([OH:39])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[BH3-]C#N.[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:36]2[CH2:37][CH2:38][C:33]([OH:39])([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:34][CH2:35]2)[CH2:10][C:11]([N:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CCC(CC(=O)N1CCc2ccccc2C1)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(CCN1CCC(O)(c2ccccc2)CC1)c1ccc(Cl)c(Cl)c1)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.9 %

Procedure:
2-[3-(3,4-dichlorophenyl)-1,5-dioxopentyl]-1,2,3,4-tetrahydroisoquinoline (800 mg), in MeOH/THF (1:1, 20 mL) was treated sequentially with molecular sieves 3A (900 mg), 4-phenyl-4-hydroxypiperidine HCl (900 mg) and NaBH3CN (130 mg). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was with quenched with water (20 mL) and diluted with CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer extracted with CH2Cl2 (3×50 mL) The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the crude oil. Silica gel chromatography eluting with 1-2% MeOH/CH2Cl2 gave the title compound (810 mg). Mass spectrum (FAB): 537.2075.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.[NH2:10][C:11]1[C:12](=[O:26])[N:13]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1.[CH2:27]([S:34](Cl)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[CH2:27]([S:34]([NH:10][C:11]1[C:12](=[O:26])[N:13]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])=[CH:15][CH:16]=1)(=[O:36])=[O:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1ccc(N)c(=O)n1CC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: Cc1cc(C)nc(C)c1
Solvent: CC#N
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 46.1 %

Procedure:
Collidine (0.59 mL, 4.5 mmole) was added in one portion to a stirred solution of the compound of Example 94 (0.89 g, 3.7 mmole) and benzylsulfonyl chloride (0.86 g, 4.5 mmole) in acetonitrile (20 ml) cooled in an ice bath. The solution was stirred for 5 minutes at 0° C., followed by 45 min at room temperature. The reaction mixture was quenched with water, then diluted with ethyl acetate (100 mL), washed with 3% HCl (until aqueous layer is pH 1), and brine, dried over magnesium sulfate, and the solvent was removed. The residue was dissolved in methanol, concentrated to a volume of approximately 3 mL, and the product was precipitated with the addition of diethyl ether. The precipitate was filtered to give 0.67 g of the title compound. The filtrate was concentrated and chromatographed on flash silica gel using 20-67% ethyl acetate hexanes as eluent. An additional 0.20 g of the title compound was recovered. A total of 0.87 g of the title compound (59% yield) was recovered. Rf=0.29 (silica gel, 33% ethyl acetate/hexanes).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.CCN(CC)CC>COCCOC>[C:1]([NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: NC1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCCC(=O)NC1CCc2ccccc21
Yield: 58 %

Procedure:
A solution of butyryl chloride (5.33 g, 50 mmole) in anh. DME (60 ml) was added slowly to a stirred and ice-cooled solution of 1-aminoindan (6.66 g, 50 mmole) and Et3N (10.0 g, 100 mmole) in anh. DME (75 ml), and the mixture stirred at ambient temperature for 24 hr. After removal of volatiles under reduced pressure, the residue was taken up in 1:1 water/EtOAc mixture (300 ml). The organic layer was separated, dried on Na2SO4 and evaporated to dryness. The crude product was crystallized from EtOAc, to give 5.9 g (58%) of the title compound as a white solid, m.p.: 84°-5° C.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[O:15][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.[OH-].[Na+]>C1COCC1>[CH:16]1([O:15][C:5]2[CH:6]=[CH:7][C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]=2[C:3]([OH:21])=[O:2])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC2CCCC2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2.68 mmol 2-cyclopentyloxy-5-methylsulfamoyl-benzoic acid methyl ester in 10 ml THF was added 20 mmol 2 M aq NaOH and the mixture was stirred at RT for 2 h. The mixture was then extracted twice with ether. The aqueous phase was acidified with 10% aq citric acid and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo followed by trituration in ether afforded the title compound as a white solid. MS (m/e): 298.3 ([M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH2:14].[O:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[S:28][C:27](Cl)=[N:26][CH:25]=2)=[O:23])[CH2:17][CH2:16]1>CN(C=O)C>[O:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[S:28][C:27]([NH:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:26][CH:25]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(NC1CCOCC1)c1cnc(Cl)s1
Reactant: Cc1onc(-c2ccccc2)c1CN
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1CNc1ncc(C(=O)NC2CCOCC2)s1
Yield: 5.7 %

Procedure:
A stirred solution of (5-methyl-3-phenyl-4-isoxazolyl)methylamine (100 mg, 0.53 mmol) and 2-chloro-thiazole-5-carboxylic acid (tetrahydro-pyran-4-yl)-amide (131 mg, 0.53 mmol) in DMF (3 mL) was heated at 150° C. under microwave irradiation for 1 h. The reaction mixture was cooled and concentrated in vacuo, then purified by chromatography (silica, 0 to 3% methanol in dichloromethane) to give the title compound (12 mg, 6%) as a white solid. MS: m/e=399.1 [M+H]+.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][C@@H:41]([OH:44])[CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl:45][C:46]1[C:51]([Br:52])=[CH:50][C:49](O)=[CH:48][N:47]=1>C1COCC1>[Cl:45][C:46]1[C:51]([Br:52])=[CH:50][C:49]([O:44][C@@H:41]2[CH2:42][CH2:43][N:39]([C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:38])[CH2:40]2)=[CH:48][N:47]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1cnc(Cl)c(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cnc(Cl)c(Br)c2)C1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 96.6 %

Procedure:
To 3.15 gm (12 mmol) of PPh3 in 100 mL of dry THF at −20° C. was added 1.89 mL (12 mmol) of DEAD dropwise. The solution was allowed to stir 10 min. at −20° C. After 10 min, a solution containing 1.87 gm (10 mmol) of 1-t-butoxycarbonyl-3-(R)-hydroxypyrrolidine in 20 mL of dry THF was added dropwise. The solution was again allowed to stir 10 min at −20° C. After 10 min, to the solution was added 2.08 gm (10 mmol) of 2-chloro-3-bromo-5-hydroxypyridine at once. The solution was allowed to stir at room temperature overnight. Next day, solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:1, hexane:ethyl acetate) to obtain 3.65 gm (65%) of a foamy residue: 1H NMR (300 MHz, CD3OD) δ 8.05 (1H, d, J=2.5 Hz), 7.78 (1H, d, J=2.5 Hz), 5.09 (1H, s), 3.66-3.32 (4H, m), 2.18 (2H, m), 1.46 (9H, s).
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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-])=O)[CH:17]=1.O>Cl.[Fe].CCO>[NH2:23][C:18]1[CH:17]=[C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: COc1cc2ncnc(Oc3ccc(O)c([N+](=O)[O-])c3)c2cc1OC
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc2ncnc(Oc3ccc(O)c(N)c3)c2cc1OC

Procedure:
4-(6,7-Dimethoxyquinazolin-4-yloxy)-2-nitrophenol (Step c, 350 mg, 1.02 mmol) was combined with Fe (1.17 g), 6N HCl (2 drops), water (2.1 mL) and EtOH (9 mL) and heated at reflux for 2.5 h. The hot mixture was filtered through Celite and evaporated. The residue was purified by column chromatography using 0-30% of a 90:10:1 (CH2Cl2:MeOH:NH4OH) solution in CH2Cl2 as the eluent. MS(MH+)=NA; Calc'd 313.31 for C16H15N3O4.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Br:14][C:15]1[C:16]([O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][C:18]([CH3:22])=[N+:19]([O-])[CH:20]=1>ClCCl>[Br:14][C:15]1[C:16]([O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][C:18]([CH2:22][OH:4])=[N:19][CH:20]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: Cc1cc(OCC2CC2)c(Br)c[n+]1[O-]
Solvent: ClCCl
Product: OCc1cc(OCC2CC2)c(Br)cn1
Temperature: 25 °C
Reaction time: 65 h
Yield: 90.1 %

Procedure:
Trifluoroacetic anhydride (24.4 g, 16.2 mL, 116 mmol) was added dropwise over a period of 10 min. to an ice cold solution of 5-bromo-4-(cyclopropylmethoxy)-2-methylpyridine 1-oxide (10.0 g, 38.7 mmol) in dichloromethane (100 mL). The ice bath was removed and the mixture was stirred at ambient temperature for 65 h. Under cooling 5.4N aqueous NaOH solution (50 mL) was added and the mixture was extracted with dichloromethane/methanol 9/1 (3×200 mL). The combined extracts were dried over Na2SO4, filtered and the filtrated was brought to dryness under reduced pressure. The residue was crystallized from ethyl acetate/heptane to yield the title compound (9 g, 90%) as brown solid; LC-MS (UV peak area, m/z) 99.5%, 258.0130 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC(CC)=O.[CH2:14]([CH:32]1[CH2:37][C:36](=[O:38])[O:35][C:33]1=[O:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].N#N>COCCOCCOC>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([N:1]=[C:33]([OH:34])[CH:32]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:37][C:36]([OH:38])=[O:35])=[CH:3][CH:4]=1
Reactant: Nc1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCCCC1CC(=O)OC1=O
Agent: N#N
Solvent: CCC(C)=O
Solvent: COCCOCCOC
Product: CCCCCCCCCCCCCCCCCCC(CC(=O)O)C(O)=Nc1ccc(O)cc1
Temperature: 25 °C

Procedure:
3.7 Grams of 4-aminophenol and 80 ml of ethyl methyl ketone were charged in a 300 ml flask equipped with a stirrer and a condenser and stirred in an atmosphere of room temperature. Thereto was added 12.0 g of powdery n-octadecylsuccinic anhydride little by little in several parts, followed by stirring at 70°-75° C. for 1 hour. Then, 120 ml of diglyme was added thereto, followed by heating with gently passing N2 gas to first distill off ethyl methyl ketone and then slowly distill off diglyme. After distilling off most of diglyme (the time required: about 3 hours), 120 ml of toluene was added to the residue, followed by leaving to cool. The precipitated crystal was filtered off and washed. The crystal was recrystallized from n-propanol to obtain 10.6 g of the desired product. m.p. 133°-134° C.
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[N:22]=[C:21](O)[CH:20]=[CH:19][CH:18]=4)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Br)(Br)[Br:25].C(=O)([O-])[O-].[K+].[K+]>>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([Br:25])[N:22]=4)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrP(Br)Br
Reactant: Oc1cccc(-c2nnc3ccc(N4CCCCCC4)nn23)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cccc(-c2nnc3ccc(N4CCCCCC4)nn23)n1
Temperature: 130 °C
Reaction time: 6 h

Procedure:
A mixture of 6-(6-azepan-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl)pyridine-2-ol (700 mg) and phosphorus tribromide (7 ml) was stirred at 130° C. for 6 hours. After allowing to cool to room temperature, an ice-water was added, and the mixture was neutralized with saturated aqueous solution of potassium carbonate, and extracted with chloroform. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (eluent: chloroform:methanol=98:2) and recrystallized from ethanol to obtain 6-azepan-1-yl-3-(6-bromopyridin-2-yl)-1,2,4-triazolo[4,3-b]pyridazine (240 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][N:15]1C(=O)C2=CC=CC=C2C1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.CN>C(O)C>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][NH2:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCON1C(=O)c2ccccc2C1=O)OCc1ccccc1
Agent: CN
Solvent: CCO
Solvent: C1CCOC1
Product: NOCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of N-[2-(benzyloxycarbonylamino)ethoxy]phthalimide (1.36 g, 4.0 mmol), as prepared in the preceding step, in ethanol (20 mL) and tetrahydrofuran (20 mL) was added 40% methylamine (2 mL, 25 mmol). The reaction mixture was stirred at room temperature for 1 h. After evaporating the solvent, the residue was passed through silica gel (3:1 ethyl acetate:hexane to ethyl acetate) to give the title compound as a white solid (800 mg, 95%). 1H-NMR (300 MHz, CDCl3) δ7.36 (m, 5H), 5.47 (br s, 2H), 5.21 (br s, 1H), 5.10 (s, 2H), 3.72 (t, J=5.0 Hz, 2H), 3.44 (q, J=5.0 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH2:15][CH2:16][N:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:22][CH:21]=4)[CH2:18][CH:19]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34])([O-])=O.C(O)C.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:31]([CH3:32])[CH:8]2[CH2:9][C:10]([CH2:13][C:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[CH:30]=[CH:29][N:28]=[CH:27]5)=[CH:24][CH:25]=4)[CH2:16][CH:15]=3)([CH3:12])[O:11][C:7]2=[C:6]([CH3:33])[C:5]=1[CH3:34]
Reactant: CC1=C2OC(C)(CC3=CCN(c4ccc(-n5ccnc5)cc4)CC3)CC2C(C)C([N+](=O)[O-])=C1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1=C(N)C(C)C2CC(C)(CC3=CCN(c4ccc(-n5ccnc5)cc4)CC3)OC2=C1C
Yield: 82.9 %

Procedure:
To 1.2 g of 4-(±)-(5-nitro-2,4,6,7-tetramethyldihydrobenzofuran-2-ylmethyl)-1-(4-imidazol-1-ylphenyl)-1,2,3,6-tetrahydropyridine, 30 ml of ethanol was added and 3.6 g of stannous chloride-dihydrate and 15 ml of concentrated hydrochloric acid were added, followed by heating at reflux for 8 hours. The reaction solution was poured into water, neutralized with a 1N sodium hydroxide solution and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform:methanol=20:1) to obtain 0.93 g of the objective product (mp: 161-163° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[S:17][C:10]=12.[C:29]1([CH2:35][C:36]([N:38]=[C:39]=[S:40])=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:39]([NH:38][C:36](=[O:37])[CH2:35][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[S:40])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:22][CH:23]=3)[S:17][C:10]=12
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)cc1
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
To a solution of 49 (46.7 mg, 0.1 mmol) in dry THF (5 mL), 2-phenylacetyl isothiocyanate (40 mg, 0.2 mmol) was added and the reaction was allowed to stir for 30 minutes. The THF was removed under reduced pressure and the resultant product was purified by column chromatography on silica gel, eluent hexane/EtOAc (1:1), to afford the title compound 50 (35.4 mg, 53% yield). 1HNMR (DMSO) δ (ppm): 12.49 (s, 1H),1 1.85 (s, 1H), 8.57 (d, J=5.5 Hz, 1H), 8.30 (s, 1H), 8.17 (d, J=8.4Hz, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.52 (m, 5H), 7.34 (d, J=4.1 Hz, 2H), 6.71 (d, J=5.3 Hz, 1H), 3.82 (brs, 2H), 3.27 9s, 3H) MS (m/z) 592.0 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[S:10])[NH:8][NH2:9].[CH2:11]([N:13]1[C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]([CH3:21])=[N:14]1)[CH3:12].C(Cl)(=O)C(Cl)=O>>[CH2:11]([N:13]1[C:17]([C:18]([NH:9][NH:8][C:7]([NH:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[S:10])=[O:19])=[CH:16][C:15]([CH3:21])=[N:14]1)[CH3:12]
Reactant: CCn1nc(C)cc1C(=O)Cl
Reactant: COCCCNC(=S)NN
Agent: O=C(Cl)C(=O)Cl
Product: CCn1nc(C)cc1C(=O)NNC(=S)NCCCOC

Procedure:
The title compound was synthesized in a manner similar to that described in Example 1. 3-Methoxy-n-propyl isothiocyanate was prepared from 3-methoxy-n-propylamine and thiophosgene at high temperature and then reacted with hydrazine in pyridine to give the intermediate 4-(3-methoxy-n-propyl)-3-thiosemicarbazide. 4-(3-Methoxy-n-propyl)-3-thiosemicarbazide (1.64 g) was reacted with 1-ethyl-3-methylpyrazole-5-carboxylic acid chloride (1.73 g, prepared from the acid and oxalyl chloride) to give 2 g of 1-(1-ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide. Treatment of 1-(1-ethyl-3-methylpyrazole-5-carbonyl)-4-(3-methoxy-n-propyl)-3-thiosemicarbazide with potassium hydroxide in ethanol gave 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole. Reaction of the sodium salt of 3-(1-ethyl-3-methylpyrazol-5-yl)-5-mercapto-4-(3-methoxy-n-propyl)-1,2,4-triazole(0.73 g) with 2-bromo-5-nitrothiazole (0.52 g) yielded crude 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole as in Example 1. Crystallization from ethanol and water gave 0.3 g of 3-(1-ethyl-3-methylpyrazol-5-yl)-4-(3-methoxy-n-propyl)-5-[5-(nitrothiazol-2-yl)mercapto]-1,2,4-triazole, a light brown solid, MP 117-118° C.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(N(CC)CC)C.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>O1CCCC1>[CH:14]([NH:17][C:18]([N:4]([CH3:3])[NH:5][CH3:6])=[O:19])([CH3:16])[CH3:15]
Reactant: CC(C)N=C=O
Reactant: CNNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNN(C)C(=O)NC(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
To a solution of N,N'-dimethylhydrazine dihydrochloride (1.33 g) and triethylamine (2.02 g) in dry tetrahydrofuran (20 ml) which was cooled to 0° C., was added isopropyl isocyanate (851 mg). The mixture was stirred at 0° C. for 2 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml). The solution was washed with 1 M sodium bicarbonate solution and water successively, and dried over magnesium sulfate. The solvent was evaporated to give N-(isopropylcarbamoyl)-N,N'-dimethylhydrazine (771 mg) as an oil.
Reaction SMILES: COC[N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])(=[O:17])=[O:16])[CH3:14])[CH:6]=[C:5]1[C:26]([O:28]CC)=[O:27].Cl.O1CCCC1>CO>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[S:15]([N:13]([CH3:14])[C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[NH:4][C:5]([C:26]([OH:28])=[O:27])=[CH:6]2)(=[O:17])=[O:16]
Reactant: CCOC(=O)c1cc2cccc(N(C)S(=O)(=O)c3ccccc3OC)c2n1COC
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1S(=O)(=O)N(C)c1cccc2cc(C(=O)O)[nH]c12
Temperature: 90 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
A mixture of ethyl 1-(methoxymethyl)-7-[[(2-methoxyphenyl)sulfonyl](methyl)amino]-1H-indole-2-carboxylate (10.9 g), 6N-hydrochloric acid (50 mL), tetrahydrofuran (50 mL) and methanol (50 mL) was stirred at 90° C. for 24 hr. The organic solvent of the reaction solution was evaporated under reduced pressure, and the residue was diluted with ethyl acetate. The solution was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in a mixed solvent of tetrahydrofuran (50 mL)-methanol (50 mL), aqueous potassium hydroxide solution (prepared by dissolving potassium hydroxide (4.2 g) in water (30 mL)) was added to this solution, and the mixture was stirred at room temperature for 15 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-brown crystals were filtered off, and washed with ethyl acetate-hexane. The filtrate was concentrated under reduced pressure; and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (6.47 g, crude yield: 71%) as pale-yellow crystals. MS: 361(MH+).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=O)[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[S:1]1[CH:5]=[C:4]([CH2:6][NH:20][CH2:19][CH2:18][CH:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH3:12])[C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1csc2ccccc12
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1csc2ccccc12
Yield: 51 %

Procedure:
Experimental condition analogous to Example 5, from benzo[b]thiophen-3-carbaldehyde 0.16 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL Dichloromethane. Purification using silica chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 140 mg of compound.