Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:26]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:24]([OH:31])=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:22]=2)([CH3:19])[CH3:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[CH2:67]([O:69][CH:70]1[O:74][C@@H:73]([CH2:75]O)[C@H:72]([CH2:77][OH:78])[O:71]1)[CH3:68]>C1COCC1>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]([S:20][C:21]2[CH:22]=[C:23]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:24]([O:31][CH2:75][C@H:73]3[C@H:72]([CH2:77][OH:78])[O:71][CH:70]([O:69][CH2:67][CH3:68])[O:74]3)=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=2)([CH3:18])[CH3:19])[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: CCOC1O[C@@H](CO)[C@H](CO)O1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC1O[C@@H](CO)[C@H](COc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Yield: 39 %

Procedure:
To a solution of probucol (5.16 g, 10 mmol) in THF (20 mL) cooled to 0° C. were added triphenylphosphine (1.3 g, 5 mmol), diethyl azodicarboxylate (0.8 mL g, 5 mmol) and 2-ethoxy-1,3-dioxolane-4(S),5(S)-dimethanol (0.89 g, 5 mmol; Nicolaou, K. C. et al.: J. Org. Chem. 1985, 50, 1440–1456). The resultant mixture was stirred at reflux for 3 hours and then evaporated. Silica gel chromatography (hexanes/ethyl acetate 4:1) gave 2,6-di-tert-butyl-4-{1-[3,5-di-tert-butyl-4-(2-ethoxy-5(S)-hydroxymethyl[1,3]dioxolan-4(S)-yl-methoxy)-phenylsulfanyl]-1-methyl-ethylsulfanyl}-phenol in three parts: diasteroisomer A (0.36 g), diastereoisomer B (0.22 g) and a mixture of the two (0.72 g) all as viscous residues (total yield: 39%). Diastereoisomer A: 1H-NMR (CDCl3) δ 7.56 (s, 2H, Ph-H), 7.44 (s, 2H, Ph-H), 5.89 [s, 1H, CH(O) 3], 5.37 (s, 1H, PhOH), 4.7{tilde over (3)}4.81 (m, 1H, PhOCH2CH), 4.1{tilde over (9)}4.25 (m, 1H, CHCH2OH), 3.8{tilde over (0)}4.01 (m, 3H, CH2O), 3.6{tilde over (2)}3.96 (m, 3H, CH2O), 2.80 (dd, J=9, 3, 1H, OH), 1.45 (s, 6H, S,S′-isopropylidene), 1.44 (s, 18H, tert-butyls), 1.43 (s, 18H, tert-butyls), 1.25 (t, 3H, OCH2CH3). Diasteroisomer B: 1H-NMR (CDCl3) δ 7.56 (s, 2H, Ph-H), 7.44 (s, 2H, Ph-H), 5.92 [s, 1H, CH(O) 3], 5.36 (s, 1H, PhOH), 4.5{tilde over (0)}4.59 (m, 1H, PhOCH2CH), 4.1{tilde over (3)}4.30 (m, 3H, CHCH2OH, CH2O), 3.8{tilde over (9)}4.00 (m, 3H, CH2O), 3.61 (quad, J=7, 2H, OCH2CH3), 1.86 (dd, J=6, 8, 1H, OH), 1.4{tilde over (1)}1.46 (m, 42H, S,S′-isopropylidene, tert-butyls), 1.21 (t, 3H, OCH2CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([C:13]([OH:37])([S:25]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-])=O)=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([C:13]([OH:37])([S:25]([C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)(=[O:27])=[O:26])[CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)C(O)(COCCOCCOCCO)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)C(O)(COCCOCCOCCO)S(=O)(=O)c2ccc(N)cc2)cc1

Procedure:
Bis-(4-nitrobenzenesulfonyl)-tetraethylene glycol (10 g, from Part A) was dissolved in distilled ethyl acetate (200 ml) and hydrogenated over palladium on carbon (10%, 0.5 g) at 40 p.s.i. in a Parr hydrogenation apparatus. The solution was filtered and evaporated under reduced pressure to give bis-(4-aminobenzenesulfonyl)-tetraethylene glycol in quantitative yield as a thick, yellow oil which was homogeneous by TLC.
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=1.[OH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[O:25][C:26]([CH3:33])([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH3:33][C:26]([O:25][C:24]1[CH:34]=[CH:35][CH:36]=[C:22]([CH2:21][CH2:20][CH2:19][O:18][C:2]2[C:3](=[O:17])[N:4]([CH3:16])[C:5](=[O:15])[N:6]([CH2:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])[N:7]=2)[CH:23]=1)([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)(C)Oc1cccc(CCCO)c1
Reactant: Cn1c(=O)c(Br)nn(CCCC(F)(F)F)c1=O
Product: CCOC(=O)C(C)(C)Oc1cccc(CCCOc2nn(CCCC(F)(F)F)c(=O)n(C)c2=O)c1

Procedure:
Compound 4 (oil) is prepared from triazine 4a and from intermediate 12a according to synthesis method 1.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1.N1C=CC=CC=1.[F:30][C:31]1[CH:32]=[C:33]([S:37](Cl)(=[O:39])=[O:38])[CH:34]=[CH:35][CH:36]=1>ClCCl>[CH3:1][C:2]1([CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][CH:4]([C:16]2[CH:17]=[C:18]([NH:22][S:37]([C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([F:30])[CH:32]=3)(=[O:39])=[O:38])[CH:19]=[CH:20][CH:21]=2)[CH2:3]1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C(F)(F)F)cc21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(=O)(=O)c3cccc(F)c3)c2)Nc2ccc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a stirred solution of 3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (100 mg, 0.31 mmol) in pyridine (49 mg, 0.62 mmol) and dichloromethane (1.5 mL) at 0° C. was added dropwise a solution of 3-fluoro-benzenesulfonyl chloride (73 mg, 0.37 mmol) in dichloromethane (0.5 mL). The mixture was stirred at room temperature overnight. The mixture was quenched with water (5 mL) and extracted with dichloromethane (5 mL×2). The combined organic layers were dried over anhydrous sodium sulfate and evaporated. The residue was purified by column chromatography on silica gel to afford N-[3-(4,4-dimethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-3-fluoro-benzenesulfonamide (141 mg, 94.6%) as a white solid. MS (ESI+APCI) M+1=479.1.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][NH2:7])[CH3:2].Cl[CH2:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].[H-].[Na+]>C(OCC)C>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][N:7]1[CH2:12][CH2:13][CH2:14][NH:15][C:16]1=[O:17])[CH3:2]
Reactant: O=C=NCCCCl
Reactant: CCOC(CCN)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(CCN1CCCNC1=O)OCC
Yield: 98.2 %

Procedure:
To a stirred and ice-cooled solution of 3-aminopropionaldehyde diethylacetal (5.88 g, 40 mmole) in diethyl ether (35 mL) was added dropwise 3-chloropropyl isocyanate (4.78 g, 40 mmole). The reaction mixture was stirred at room temperature for 4 hours. The mixture was concentrated and dissolved in N,N-dimethylformamide (40 mL). To this solution was added de-oiled sodium hydride (0.96 g, 40 mmole). The reaction mixture was stirred at 70° C. for 18 hours, concentrated, taken up in diethyl ether (40 mL), and filtered. The filtrate was concentrated and purified by silica gel chromatography, eluting with hexane-ethyl acetate-methanol (10:9.7:0.3), gave 1-(3,3-diethoxypropyl)-tetrahydropyrimidin-2-one (9.05 g) as an oil.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH2:14]>C1COCC1>[CH3:9][O:10][C:11]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:12]=1[CH2:13][NH:14][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[N:7]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Fc1ccnc(F)n1
Solvent: C1CCOC1
Product: COc1ccc(CNc2ccnc(F)n2)c(OC)c1
Yield: 43.6 %

Procedure:
A solution of 2,4-difluoropyrimidine (600 mg, 5.17 mmol) and 2,4-dimethoxybenzylamine (860 mg, 5.17 mmol) in THF (17 mL) was stirred at room temperature for 1 hour. The reaction solution was vacuum concentrated, and the residue was then purified with silica gel chromatography (hexane/ethyl acetate=1:2) to yield the title compound (594 mg, 43%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:24]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C1CCCNCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCCCCC3)c2n1

Procedure:
Prepared similarly to Intermediate 27 from 2-(butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine and hexahydro-1H-azepine but with sequential purifications by MDAPs using Method A followed by Method E.
Reaction SMILES: [C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:24])=[CH:19][CH:18]=1)([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:6][O:7][C:8](=[O:10])[CH3:9])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:41])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:41])=[O:24])=[CH:19][CH:18]=1)([CH2:6][O:7][C:8](=[O:10])[CH3:9])[CH2:11][O:12][C:13](=[O:15])[CH3:14])(=[O:3])[CH3:2]
Reactant: CCCCCCCCS(=O)c1ccc(CC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCS(=O)(=O)c1ccc(CC(COC(C)=O)(COC(C)=O)NC(C)=O)cc1
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
To a solution (10 ml) of 2-acetamido-1,3-diacetoxy-2-(4octylsulfinylbenzyl)propane (330 mg) in chloroform was added m-chloroperbenzoic acid (244 mg) under ice-cooling. The mixture was stirred for 2.5 hours and then at room temperature for 1.5 hours. Calcium hydroxide (0.1 g) was added to the reaction mixture and the mixture was stirred at room temperature for 45 minutes. The insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized from hexane-ethyl acetate to give 162 mg of the subject compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[NH2:17][CH2:18][C:19]1[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=1[CH2:25][CH2:26][CH3:27]>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][CH2:18][C:19]2[C:20](=[O:29])[NH:21][C:22]([CH3:28])=[CH:23][C:24]=2[CH2:25][CH2:26][CH3:27])=[O:16])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:12][CH2:13]3)[C:9]=2[CH:10]=1
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Reactant: O=C(O)c1cc(Br)cc2c1cnn2C1CC1
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C1CC1
Reaction time: 12 h

Procedure:
The title compound was prepared in the same manner as described for example 3 (step c) from 6-bromo-1-cyclopropyl-1H-indazole-4-carboxylic acid (0.22 g, 0.783 mmol) and 3-(aminomethyl)-6-methyl-4-propyl-2(1H)-pyridinone (0.236 g, 1.089 mmol), wherein the reaction stir time was 12 h. The title compound was collected as a white solid (0.36 g, 91%); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (t, J=7.33 Hz, 3H), 1.06-1.16 (m, 4H), 1.50 (sxt, J=7.53 Hz, 2H), 2.13 (s, 3H), 3.76-3.86 (m, 1H), 4.36 (d, J=5.05 Hz, 2H), 5.90 (s, 1H), 7.74 (d, J=1.52 Hz, 1H), 8.09 (s, 1H), 8.31 (s, 1H), 8.64 (t, J=4.80 Hz, 1H), 11.54 (br. s., 1H); LC-MS (ES) m/z=443.0 [M+H].
Reaction SMILES: [CH3:1][P:2]([O:6]CC)[O:3][CH2:4][CH3:5].Br[C:10]1[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:4]([O:3][P:2]([C:10]1[CH:11]=[C:12](/[CH:16]=[CH:17]/[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:14][CH:15]=1)([CH3:1])=[O:6])[CH3:5]
Reactant: CCOP(C)OCC
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCOP(C)(=O)c1cccc(/C=C/C(=O)OC(C)(C)C)c1
Temperature: 100 °C

Procedure:
Diethyl methylphosphonite (0.15 ml, 0.992 mmol), tert-butyl (2E)-3-(3-bromophenyl)acrylate (0.25 g, 0.883 mmol), triethylamine (0.37 ml, 2.65 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.1559 g, 0.135 mmol) were combined and allowed to heat at 100° C. for approximately eight hours. The reaction was cooled and filtered over celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane. MS: calc'd 311 (MH+), exp 311 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13](F)=[N:14][CH:15]=1.CCOC(C)=O>CN(C=O)C>[Br:9][C:10]1[CH:11]=[C:12]([F:17])[C:13]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:1])[CH:7]=2)=[N:14][CH:15]=1
Reactant: Fc1cc(Br)cnc1F
Reactant: Nc1cc(O)ccn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Nc1cc(Oc2ncc(Br)cc2F)ccn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 46.1 %

Procedure:
Mix 2-aminopyridin-4-ol (1.13 g, 10.3 mmol), 5-bromo-2,3-difluoro-pyridine (2 g, 10.3 mmol) in DMF (10 mL). Stir the mixture at 120° C. for 3 hrs. TLC (EtOAc:PE=1:1) shows the reaction is complete. Filter, add water (50 mL) to the filtrate, extract with EtOAc (50 mL×3). Combine the organic layers, dry over anhydrous Na2SO4. Concentrate to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=1:4) affords the title compound (1.35 g, 46.3%). MS: (M+1): 284.
Reaction SMILES: [F:1][CH:2]([CH2:6][F:7])[C:3](Cl)=[O:4].[F:8][C:9]([F:18])([CH:12]([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:10][OH:11].N1C=CC=CC=1.O>ClC(Cl)(Cl)Cl>[F:1][CH:2]([CH2:6][F:7])[C:3]([O:11][CH2:10][C:9]([F:8])([F:18])[CH:12]([F:17])[C:13]([F:15])([F:16])[F:14])=[O:4]
Reactant: OCC(F)(F)C(F)C(F)(F)F
Reactant: O=C(Cl)C(F)CF
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=C(OCC(F)(F)C(F)C(F)(F)F)C(F)CF
Reaction time: 1 h
Yield: 75.7 %

Procedure:
34.6 g (0.27 mole) of 2,3-difluoropropanoyl chloride were added dropwise to a solution of 50 g (0.27 mole) of 2,2,3,4,4,4-hexafluoro-1-butanol and 21.6 g (0.27 mole) of pyridine in 200 ml of dry tetrachloromethane. Stirring was continued for a further 1 hour and then the mixture was poured into water, extracted, dried and distilled. In this manner, 56 g of 2,2,3,4,4,4-hexafluorobutyl 2,3-difluoropropionate were obtained having a melting point of 84° to 86° C. at 20 mbar. The purity of the product prepared was 95% (determined by gas chromatography).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.3 %

Procedure:
To a mixture of methyl 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzoate (510 mg) in methanol (5 ml) and tetrahydrofuran (5 ml) was added 1N aqueous sodium hydroxide solution (4 ml) and the mixture was stirred at room temperature for 12 hrs. The solvent was evaporated under reduced pressure and water was added. The mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from methanol to give the title compound (467 mg, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH2:14]([S:16][C:17]1[C:22]([C:23]([NH:1][C:2]2[C:3]([SH:12])=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=2)=[O:24])=[CH:21][N:20]=[CH:19][CH:18]=1)[CH3:15]
Reactant: CCSc1ccncc1C(=O)O
Reactant: Nc1cc(C(F)(F)F)cnc1S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1ccncc1C(=O)Nc1cc(C(F)(F)F)cnc1S
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A mixture of 450 mg of 3-amino-5-trifluoromethylpyridine-2-thiol, 637 mg of 4-ethylsulfanylnicotinic acid hydrochloride, 532 mg of EDCI hydrochloride, 31 mg of HOBt and 5 ml of pyridine was stirred at room temperature for 2 hours and then stirred at 60° C. for 30 minutes. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 494 mg of 4-ethylsulfanyl-N-[2-mercapto-5-(trifluoromethyl)pyridin-3-yl]nicotinamide. 4-ethylsulfanyl-N-[2-mercapto-5-(trifluoromethyl)pyridin-3-yl]nicotinamide
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].[N+:7]([C:10]1[CH:20]=[CH:19][C:13]2[N:14]([CH3:18])[C:15](=O)[NH:16][C:12]=2[CH:11]=1)([O-:9])=[O:8]>P(Cl)(Cl)(Cl)=O>[N+:7]([C:10]1[CH:20]=[CH:19][C:13]2[N:14]([CH3:18])[C:15]([Cl:2])=[N:16][C:12]=2[CH:11]=1)([O-:9])=[O:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cn1c(=O)[nH]c2cc([N+](=O)[O-])ccc21
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(Cl)nc2cc([N+](=O)[O-])ccc21
Temperature: 125 °C
Reaction time: 2 h

Procedure:
2.1 g (0.01 mol) of phosphorus pentachloride are dissolved in 2.5 ml phosphorus oxychloride and after the addition of 1.9 g (0.01 mol) of 5-nitro-1-methyl-benzimidazol-2-one the mixture is stirred for two hours at 125° C. The solvent is evaporated off, the residue is poured onto ice water and neutralised with ammonia. The precipitate formed is suction filtered and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([OH:17])=[O:16])=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1.S(=O)(=O)(O)O.[CH3:30]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:30])=[O:16])=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1
Reactant: CO
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Temperature: 25 °C

Procedure:
A 250 mL rb flask equipped with a magnetic stir bar was charged with 6.68 g (19.0 mmol) of the product of Step A, 100 mL methanol, 3 mL of concentrated sulfuric acid and the suspension was refluxed overnight. The resulting clear solution was then cooled to room temperature and evaporated. The residue was partitioned between EtOAc and 5% aqueous Na2CO3 and separated. The organic layer was washed with water, brine, dried (MgSO4), filtered and evaporated to afford the title compound.
Reaction SMILES: [H-].[Na+].O1CCCC1.[CH3:8][O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([NH:17][CH:18]=[C:19]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[N:28][C:27]=2Cl)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13]1)=[O:11]>O>[CH3:8][O:9][C:10]([N:12]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:26](=[CH:31][CH:30]=[CH:29][N:28]=3)[C:25](=[O:33])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18]2)[CH2:13]1)=[O:11]
Reactant: CCOC(=O)C(=CNC1CCN(C(=O)OC)C1)C(=O)c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CCN(C(=O)OC)C2)c2ncccc2c1=O
Reaction time: 0.08 h
Yield: 84.2 %

Procedure:
45 mg of sodium hydride (abt. 60% oil suspension 1.13 mmol) was added to 5 ml of a tetrahydrofuran solution of 411 mg of the compound obtained in Example 1 (1.08 mmol) under an argon atmosphere at 0° C. and the solution was stirred at the same temperature for 5 minutes. It was further stirred at room temperature for 30 minutes, then water (15 ml) was added and extraction was performed with ethyl acetate (30 ml). Next, the organic layer was washed with saturated saline (10 ml), then dried over anhydrous sodium sulfate, then the solvent was distilled off under vacuum. The precipitated crystal was washed with diethyl ether and the crystal was obtained by filtration to obtain 314 mg (84%) of the above-identified compound as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH3:10])[C:7]([OH:9])=O.S(Cl)(Cl)=O>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:18](=[CH:19][CH:20]=1)[C:7](=[O:9])[C:6]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)([CH3:10])[CH2:5]2
Reactant: CC(Cc1cccc(Cl)c1)(C(=O)O)c1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CC1(c2ccc(Cl)cc2)Cc2cc(Cl)ccc2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.5 %

Procedure:
A solution of 2-(3-chlorobenzyl)-2-(4-chlorophenyl)propionic acid (10 g) which had been prepared in paragraph 2), and thionyl chloride (14 g) in hexane (100 ml) was heated under reflux for 5 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in carbon disulfide (100 ml), and the solution was cooled with ice, to which anhydrous aluminum chloride (4.2 g) was added in three portions at intervals of 15 minutes. After allowing the temperature to gradual increase to room temperature, the reaction mixture was diluted with dichloromethane (100 ml), poured into 20% hydrochloric acid and ice-water, followed by stirring for 2 hours. The organic layer was dried over anhydrous magnesium sulfate, and reduced under reduced pressure. The resulting residue was subjected to chromatography on silica gel to give 5-chloro-2-(4-chlorophenyl)-2-methyl-2,3-dihydro-1H-inden-1-one (yield, 7.2 g) as white crystals, m.p., 92.2° C,.
Reaction SMILES: O[C:2]1([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]3)[C:9]2[N:5]([CH:6]=[N:7][CH:8]=2)[CH2:4][CH2:3]1.Cl.[H][H]>CO.[C].[Pd]>[CH:8]1[N:7]=[CH:6][N:5]2[CH2:4][CH2:3][CH:2]([C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[CH:16]=[C:15]([C:20]([NH:22][CH3:23])=[O:21])[CH:14]=[CH:13]4)[C:9]=12
Reactant: CNC(=O)c1ccc2cc(C3(O)CCn4cncc43)ccc2c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNC(=O)c1ccc2cc(C3CCn4cncc43)ccc2c1
Yield: 72.6 %

Procedure:
6-(7-Hydroxy-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-7-yl)-N-methyl-2-naphthamide (77 mg) was dissolved in methanol (5 ml). 1 N Hydrochloric acid (0.5 ml) and 10% palladium carbon (50% wet, 39 mg) were added, and the mixture was vigorously stirred for 12 h under 4 kg/cm2 hydrogen atmosphere. The catalyst was filtered off and the residue was washed with methanol. The filtrate and the washing were combined and aqueous potassium carbonate solution (0.25 M; 1 ml) was added. After neutralization, the solvent was evaporated under reduced pressure, and the residue was purified by flash silica gel column chromatography (eluent, chloroform/methanol containing ammonia (7%); 19/1). The eluate was recrystallized from chloroform-ether to give the title compound (53 mg) as colorless crystals.