Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N-]C.[C:5]1([Mg]Br)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.CCO[CH2:17][CH3:18]>C1COCC1>[CH:18]1([C:1]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:2])[CH2:17][CH2:7][CH:6]=[CH:5][CH2:10][CH2:9]1
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Reactant: C[N-]OC
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C1CCC=CCC1
Temperature: 0 °C

Procedure:
The N-methoxy-N-methyl amide was dissolved in dry THF (10 ml) and cooled down to 0° C. A 3M etheral phenyl magnesium bromide solution (17.5 ml, 52.5 mmol) was added dropwise and then the mixture was heated at 65° C. for 1 hour. The mixture was cooled at room temperature and carefully treated with a 1 N HCl solution for 30 minutes at 40° C. The solution was diluted with ether and the organic phase separated, dried over MgSO4 and concentrated. The residual oil was chromatographied on silica gel (CH2Cl2/hexane 10/90) and the 4-cyclohepten-1-yl(phenyl)methanone 21 was isolated as a colorless oil (1.35 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[CH:5]2.Cl[C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[C:13]1[C:22]2[C:17](=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][CH:14]=1
Reactant: FC(F)(F)c1cccc2c(Cl)ccnc12
Reactant: Cc1cc2cc(F)ccc2[nH]1
Product: Cc1[nH]c2ccc(F)cc2c1-c1ccnc2c(C(F)(F)F)cccc12

Procedure:
The sub-title compound was prepared from 5-fluoro-2-methylindole and 4-chloro-8-trifluoromethylquinoline by the method of Example 31, step a).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[Na].O>C(O)CC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([C:11]([CH3:21])([CH3:20])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:10][N:22]2[CH:26]=[CH:25][N:24]=[CH:23]2)=[CH:4][CH:3]=1
Reactant: [Na]c1ncc[nH]1
Reactant: CC(C)(Cc1ccc(Cl)cc1)C1(c2ccc(Cl)cc2)CO1
Solvent: CCCO
Solvent: O
Product: CC(C)(Cc1ccc(Cl)cc1)C(O)(Cn1ccnc1)c1ccc(Cl)cc1
Yield: 34.9 %

Procedure:
30 g (0.0935 mol) of 2-(4-chlorophenyl)-2-(4-chlorophenyl-tert.-butyl)-oxirane in 40 ml of n-propanol are added dropwise to a solution of 7.7 g (0.108 mol) of imidazolyl-sodium in 60 ml of n-propanol at the reflux temperature. The reaction mixture is stirred under reflux for a further 48 hours and cooled, water is added, and the mixture is extracted with methylene chloride. The organic phase is dried over sodium sulphate and concentrated in vacuo. The oily residue is stirred in diisopropyl ether. The crystalline precipitate formed is filtered off under suction and dried. 12.7 g (35% of theory) of 2,4-bis(4-chlorophenyl)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol of melting point 174° C. are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[CH:17])[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C#CCCCCCC.I[C:28]1[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][C:35]2[CH:36]3[CH2:41][CH:38]([CH2:39][CH:40]=2)[C:37]3([CH3:43])[CH3:42])=[CH:30][CH:29]=1.IC1C=C2C(=CC=1)CN(C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C2>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1([C:16]#[C:17][C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][CH2:34][C:35]3[CH:36]4[CH2:41][CH:38]([CH2:39][CH:40]=3)[C:37]4([CH3:43])[CH3:42])=[CH:44][CH:45]=2)[CH2:13][O:12][C:11]([CH3:15])([CH3:14])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1
Reactant: CC1(C)C2CC=C(CCOc3ccc(I)cc3)C1C2
Agent: C#CCCCCCC
Agent: Ic1ccc2c(c1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Product: CC(C)(C)OC(=O)NC1(C#Cc2ccc(OCCC3=CCC4CC3C4(C)C)cc2)COC(C)(C)OC1
Yield: 66 %

Procedure:
When tert-butyl-5-ethynyl-2,2-dimethyl-1,3-dioxan-5-ylcarbamate was substituted for 1-octyne and the product of Step B was substituted for 5-iodo-2-tritylisoindoline in Example 2, Step D, the similar process afforded the title compound in 66% yield, as pale paste. 1H-NMR (CDCl3) 0.80 (s, 3H); 1.25 (s, 3H); 1.41 (s, 3H); 1.46 (s, 9H); 2.06 (d, 2H, J=5.47 Hz); 2.21 (d, 2H, J=8.44 Hz); 2.33-2.44 (m, 4H); 3.93 (tr, 2H, J=7.0 Hz); 3.98 (d, 2H, J=11.4 Hz); 4.08 (d, 2H, J=11.5 Hz); 5.18 (s, 1H); 5.32 (s, 1H); 6.76 (d, 2H, J=8.8 Hz); 7.29 (d, 2H, J=8.7 Hz).
Reaction SMILES: [C:1]([C:3]1[C:29]([F:30])=[CH:28][C:6]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:12][C:11]=2[CH3:27])=[O:8])=[C:5]([F:31])[C:4]=1[N+:32]([O-])=O)#[N:2].[H][H]>CO.[Pd]>[NH2:32][C:4]1[C:5]([F:31])=[C:6]([CH:28]=[C:29]([F:30])[C:3]=1[C:1]#[N:2])[C:7]([NH:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]([F:26])([C:18]([F:19])([F:20])[F:21])[C:22]([F:24])([F:25])[F:23])=[CH:12][C:11]=1[CH3:27])=[O:8]
Reactant: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c([N+](=O)[O-])c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C(F)(C(F)(F)F)C(F)(F)F)cc(C)c1NC(=O)c1cc(F)c(C#N)c(N)c1F
Yield: 16.9 %

Procedure:
A solution of 4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-3-nitro-benzamide (5.99 g, 12 mmol) (Example I16) in methanol was reacted with hydrogen for 16 hours in the presence of 10% palladium on carbon (40 bar, 40° C.). The reaction mixture was filtered to remove the catalyst and the filtrate concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 7:3) to give 3-amino-4-cyano-2,5-difluoro-N-[2,6-dimethyl-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenyl]-benzamide (0.953 g, 17% yield). 1H-NMR (400 MHz, CDCl3): 2.36 (6H, s), 4.82 (2H, bs), 7.12 (1H, m), 7.38 (2H, s), 7.78 (1H, d) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)([CH2:11][OH:12])[CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22].CCN(CC)CC>ClCCl>[CH3:20][S:21]([O:12][CH2:11][C:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[CH2:9][O:10][S:21]([CH3:20])(=[O:23])=[O:22])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CO)(c1cccc(Br)c1)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC(COS(C)(=O)=O)(c1cccc(Br)c1)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
To a stirred solution of 2,2-bis(3-bromophenyl)propane-1,3-diol (6.0 g, 15.54 mmol) in dichloromethane (50 mL) at 0° C. was added methanesulfonic chloride (27.1 g, 155 mmol) and Et3N (17.3 mL, 124 mmol) to give an orange solution. The reaction mixture was stirred at 0° C. for 1 h, then at 40° C. for 8 h. The reaction was washed with aq. NH4Cl (80 mL). The aqueous layer was extracted with dichloromethane (50 mL×3). The combined organic layers were dried and concentrated. The residue was purified by chromatography (on silica gel column, Petroleum ether: EtOAc=2:1) to afford 3.2 g of the title compound (5.9 mmol, 38%). LC/MS: [M+18]=560. 1HNMR (CDCl3), 400 MHz: δ 2.93 (s, 6H), 4.49 (s, 4H), 7.15-7.48 (m, 8H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1)=[O:3].C(Cl)Cl.CCN(CC)CC.[BH3:21].[OH:22][C:23]([C:26]([OH:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)C>[CH3:24][C:23]1([CH3:25])[C:26]([CH3:28])([CH3:27])[O:29][B:21]([C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[O:22]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: B
Reactant: CC(=O)c1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Yield: 64 %

Procedure:
4-Iodo acetophenone (10.00 g, 40.64 mmol), PdCl2(dppf).CH2Cl2 (1.00 g, 1.22 mmol) dry dioxane (160 mL) and Et3N (17.0 mL, 121.96 mmol) were combined in a dry flask which had been purged with N2 several times. Pinacol borane (8.80 mL, 60.96 mmol) was added and the reaction mixture was heated at reflux for 4 h then cooled to ambient temperature, poured into Diethyl ether (250 mL) and extracted with H2O and washed with brine. The Diethyl ether was dried (MgSO4), filtered and the filtrate concentrated in vacuo. Purification by gradient chromatography on silica (hexane, 5% EtOAc/hexane) followed by recrystallization (hexane) gave 6.4 g (64%) of the intermediate title compound as a white powder.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:14][CH2:13][CH2:12][NH2:15])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2sccc2n1
Reactant: CCCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: NCCCc1nc(Cl)nc2ccsc12
Yield: 91.9 %

Procedure:
3.95 g (19.26 mmol) of 2,4-dichlorothieno[3,2-d]pyrimidine (III), 1.90 mL (23.11 mmol) of propylamine, and 6.71 mL (38.52 mmol) of diisopropylethylamine are stirred for 16 hours in 40 mL of tetrahydrofuran at ambient temperature. Then the reaction mixture is concentrated by evaporation, the residue is combined with water. The precipitate formed is suction filtered and dried. 4.03 g of product IV (92%) is obtained as a powder.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=[O:28])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)[N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[S:31]1[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH2:29]([N:3]([CH2:1][CH3:2])[C:4](=[O:28])[C:5]1[CH:6]=[CH:7][C:8]([CH:11]([N:12]2[CH2:13][CH2:14][N:15]([CH2:36][C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)[CH2:16][CH2:17]2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:27]=2[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:9][CH:10]=1)[CH3:30]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCNCC2)cc1
Reactant: O=Cc1ccsc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C(c2cccc3cccnc23)N2CCN(Cc3ccsc3)CC2)cc1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
To a solution of compound 1 (500 mg; 0.99 mmol) in methanol (10 ml) was added thiophene 3-carboxaldehyde (104 ul; 1.19 mmol) followed by acetic acid (0.1 ml; 1%) and sodium cyano borohydride (186.6 mg; 2.97 mmol). The reaction mixture was stirred overnight, then sodium hydroxide 2N was added and the mixture extracted with methylene chloride (3×). The combined methylene chloride extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by reverse phase using 10%-30% CH3CN/H2O (TFA as the buffer) gave 258 mg of desired product (TFA salt).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12]Cl.[Cl:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:17][C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.O>C(Cl)Cl>[Cl:14][C:15]1[CH:20]=[C:19]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:17][C:16]=1[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:12][O:11][CH3:10])=[CH:28][CH:27]=1
Reactant: COCCl
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(Cl)c1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc(-c2ccc(CC(=O)OC)cc2Cl)cc1
Reaction time: 3 h

Procedure:
Diisopropylethylamine (936 μl, 5.37 mmol) and chloromethyl methyl ether (303 μl, 4.02 mmol) were successively added to a solution of methyl (2-chloro-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (650 mg, 2.68 mmol) obtained in Example (23-3) in methylene chloride (10 ml) under ice-cooling, and the mixture was stirred for 3 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give crude methyl [2-chloro-4′-(methoxymethoxy)-1,1′-biphenyl-4-yl]acetate. According to a method similar to Example (104-1), Example (12-4), Example (40-2), Example (33-5) and Example (17-4), from the compound obtained in the above, the title compound was obtained as a colorless powder (260 mg, six-step total yield: 18%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C(O)C.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>O>[OH:23][NH:22][C:14](=[NH:15])[C:13]1[CH:16]=[CH:17][C:10]([N:7]2[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]2)=[N:11][CH:12]=1
Reactant: NO
Reactant: CC(C)N1CCN(c2ccc(C#N)cn2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2ccc(C(=N)NO)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
A mixture of 6-(4-isopropylpiperazin-1-yl)nicotinonitrile (2.3 g, 10 mmol), ethanol (25 mL), hydroxylamine hydrochloride (2.1 g, 30 mmol), potassium carbonate (2.2 g, 16 mmol) and water (5 mL) was stirred for 30 min at rt and then at reflux temperature for 3 h. The reaction mixture was left at rt for 2 days and then the solid formed was isolated by filtration. The solid was dried, boiled with ethanol (200 mL) and filtered hot to remove inorganic impurities. The filtrate was evaporated to give 2.0 g (76%) of N-hydroxy-6-(4-isopropylpiperazin-1-yl)nicotinamidine.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(=O)([S:9][CH2:10][CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C.O>CO>[CH2:13]([O:12][CH2:11][CH2:10][SH:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)SCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: SCCOCc1ccccc1
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
Potassium carbonate (11.20 g) was added to S-2-(benzyloxy)ethyl ethanethioate (8.52 g) in methanol (170 mL)/water (85 mL) and the reaction was stirred for 20 min. Water was added and the mixture extracted with ethyl acetate. The organic layers were combined, washed with aqueous ammonium chloride and dried (MgSO4) and concentrated in vacuo to give the subtitle compound (6.64 g).
Reaction SMILES: C([C:3](CC)(CC)[CH:4](P(O)(O)=O)[C:5]([O-:7])=[O:6])C.[H-].[Na+].[CH2:18]([O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:34](OCC)[CH3:35]>>[CH2:34]([O:7][C:5](=[O:6])[C:4]([CH3:3])=[CH:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:27][CH:28]=1)[CH3:35]
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOCC
Reactant: CCC(CC)(CC)C(C(=O)[O-])P(=O)(O)O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)=Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
Triethyl-2-phosphonopropionate (22.2 mL, 103.65 mmol, d=1.111) is added to a 0° C. slurry of sodium hydride (4.15 g, 103.65 μmmol, 60% dispersion on mineral oil) in anhydrousTHF (150 mL), then allowed to warm to ambient temperature over thirty minutes. The slurry is re-cooled to 0° C. and 4-benzyloxybenzaldehyde (20 g, 94.23 mmol) is added in one portion as a solid. The reaction mixture is stirred 18 h at ambient temperature, then diluted with diethyl ether. The organic layer is washed with a saturated solution of aqueous ammonium chloride, water, and brine, then dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography to provide the title compound (24.3 g, 87%). 1H NMR (400 MHz, CDCl3): δ 7.67 (s, 1H), 7.46-7.35 (m, 6H), 7.01 (d, 2H, J=8.1 Hz), 5.10 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 2.15 (s, 3H), 1.36 (t, 3H, J=7.2 Hz). Rf=0.31 in 20% acetone in hexanes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=4)[CH:21]=3)[NH:16][N:15]=2)[CH2:10][CH2:9]1)(=[O:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[OH:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>CN(C=O)C>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[C:18]([C:30]([NH2:32])=[O:31])[CH:19]=2)[NH:16][N:15]=[C:14]3[CH:11]2[CH2:12][CH2:13][N:8]([S:5]([CH2:4][CH2:3][CH2:2][N:43]3[CH2:44][CH2:45][CH:40]([OH:39])[CH2:41][CH2:42]3)(=[O:7])=[O:6])[CH2:9][CH2:10]2)[CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCCl)CC3)n[nH]c12
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1cc(-c2cccc(F)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCC(O)CC4)CC3)n[nH]c12
Yield: 26.6 %

Procedure:
The title compound was prepared according to the general procedure of Example 38b. Thus, 3-{1-[(3-Chloropropyl)sulfonyl]-4-piperidinyl}-5-(3-fluorophenyl)-1H-indazole-7-carboxamide (Example 38a) (0.222 mmol) in DMF (4 mL) was reacted with K2CO3 (61 mg, 0.444 mmol) and 4-hydroxy piperidine (112 mg, 1.11 mmol) to afford the title compound (32.07 mg, 27% for 2 steps).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.[S:21]1[CH2:27][C:25](=[O:26])[NH:24][C:22]1=S.C([O-])(=[O:30])C.[Na+]>C(O)(=O)C>[O:30]=[C:22]1[NH:24][C:25](=[O:26])[C:27](=[CH:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:21]1
Reactant: O=C1CSC(=S)N1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1-c1ccccc1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnc2ccc(C=C3SC(=O)NC3=O)cc2c1-c1ccccc1

Procedure:
Similar procedure as described in example 61j was used, starting from 6-formyl-4-phenyl-quinoline-3-carbonitrile (example 62c), rhodanine, sodium acetate, and acetic acid to give 6-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-4-phenyl-quinoline-3-carbonitrile. LC-MS m/e 374 (MH+).
Reaction SMILES: CS(Cl)(=O)=O.C(N(CC)CC)C.O[C@H:14]1[CH2:23][C@@H:22]2[N:17]([C:18](=[O:24])[CH2:19][CH2:20][CH2:21]2)[C@H:16]([C:25]2[CH:30]=[C:29]([F:31])[C:28]([F:32])=[C:27]([F:33])[CH:26]=2)[CH2:15]1>C(Cl)Cl>[F:31][C:29]1[CH:30]=[C:25]([C@@H:16]2[CH:15]=[CH:14][CH2:23][C@@H:22]3[N:17]2[C:18](=[O:24])[CH2:19][CH2:20][CH2:21]3)[CH:26]=[C:27]([F:33])[C:28]=1[F:32]
Reactant: O=C1CCC[C@@H]2C[C@H](O)C[C@@H](c3cc(F)c(F)c(F)c3)N12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC[C@@H]2CC=C[C@@H](c3cc(F)c(F)c(F)c3)N12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
Methanesulfonyl chloride (776 μL) and triethylamine (2.79 mL) were added to a solution of (6S*,8S*,9aR*)-8-hydroxy-6-(3,4,5-trifluorophenyl)octahydroquinolizin-4-one (1.0 g) in methylene chloride (20 mL) under ice-cooling, and the reaction solution was stirred at room temperature for two hours. The solvent was removed by an evaporator. Then, sodium methoxide (28% solution in methanol, 3.22 g) was added to a mixed solution of the resulting residue in THF-ethanol (17 mL), and the reaction solution was stirred at room temperature for four hours. To make the starting material disappear, sodium methoxide (28% solution in methanol, 5.0 mL) was added to the reaction solution, which was then stirred at room temperature overnight. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 681 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[F:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[N:13]([CH3:25])[C:12]2[CH:26]=[CH:27][C:9]([N:8]([CH3:28])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:29][C:30]4[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:37])=[O:38])[CH:35]=4)[N:7]=3)=[CH:10][C:11]=2[N:15]=1
Reactant: CN(c1ccc2c(c1)nc(NCc1cccc(F)c1)n2C)c1ccnc(Cl)n1
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCc3cccc(F)c3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example one with N5-(2-chloro-pyrimidin-4-yl)-N2-(3-fluoro-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (99 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (47 mg, 0.25 mmol) as a white solid (96 mg, 66%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ10.06 (br s, 1H), 9.34 (br s, 1H), 8.49 (s, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.65 (d, J=6.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.08-7.44 (m, 9H), 5.72 (d, J=6.6 Hz, 1H), 4.75 (d, J=6.6 Hz, 2H), 3.71 (s, 3H), 3.48 (s, 3H), 2.51 (s, 3H). MS (ESI) m/z=547 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][C:7]2[CH:30]=[CH:29][C:10]([CH2:11][S:12][C:13]3[NH:14][CH:15]=[C:16]([CH2:20][C:21]4[CH:22]=[N:23][C:24]([O:27][CH3:28])=[N:25][CH:26]=4)[C:17](=[O:19])[N:18]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:33][CH2:34]N(C(C)C)C(C)C.C(I)C>ClCCCl>[CH2:33]([N:14]1[CH:15]=[C:16]([CH2:20][C:21]2[CH:26]=[N:25][C:24]([O:27][CH3:28])=[N:23][CH:22]=2)[C:17](=[O:19])[N:18]=[C:13]1[S:12][CH2:11][C:10]1[CH:29]=[CH:30][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:32][CH:31]=2)=[CH:8][CH:9]=1)[CH3:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ncc(Cc2c[nH]c(SCc3ccc(Oc4ccc(F)cc4)cc3)nc2=O)cn1
Solvent: ClCCCl
Solvent: CCI
Product: CCn1cc(Cc2cnc(OC)nc2)c(=O)nc1SCc1ccc(Oc2ccc(F)cc2)cc1
Temperature: 55 °C
Yield: 5.6 %

Procedure:
To a solution of 2-((4-(4-fluorophenoxy)benzyl)thio)-5-((2-methoxypyrimidin-5-yl)methyl)pyrimidin-4(1H)-one (167 mg, 0.371 mmol) in DCE (5 mL) was added Hunig's base (0.194 mL, 1.112 mmol) and EtI (0.045 mL, 0.556 mmol). The mixture was heated at 55° C. for 2 days. Purification via reverse phase flash chromatography then afforded the title compound (10 mg, 5.64% yield). LCMS: rt=3.24 min, [M+H+]=479
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].Cl.[NH2:13][OH:14]>C(O)C.O>[CH2:2]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[NH:1][C:2](=[O:3])[C:4]2=[N:13][OH:14])[CH2:4][CH2:6][CH2:7][CH3:8]
Reactant: NO
Reactant: O=C1Nc2ccccc2C1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCCc1cccc2c1NC(=O)C2=NO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A suspension of the isatin described in Example 10c (5.51 g) in ethanol (20 ml) was warmed slightly followed by addition of hydroxylamine hydrochloride (2.47 g) dissolved in water (10 ml). The mixture was warmed to about 80° with stirring for 10 minutes, followed by cooling to ambient temperature and stirring for 30 minutes. The precipitated yellow solid was filtered off, washed with water and dried to afford the title product (4.50 g, 76%) as a fluffy yellow powder; tlc, Rf =0.16, silica gel, ethyl acetate:hexane (2:3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])([O-])=O.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Pd].CCCCCC.C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[CH:6][C:5]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1N
Yield: 97.6 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[2-nitro-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (5.32 g), palladium on carbon (10%, 0.68 g) and toluene/ethyl acetate=1/1 (140 ml) and the reaction mixture was purified to give the title compound (4.82 g).