Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7]([CH:9]=[CH:10][CH:11]3[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]3)=[N:8][C:4]=2[CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[C:23]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.[Pd](Cl)Cl.C(C1C=C[C-](P)C=1C(C)(C)C)(C)(C)C.[CH-]1C=CC=C1.[Fe+2].O>[F:17][C:14]1([F:18])[CH2:15][CH2:16][CH:11]([CH:10]=[CH:9][C:7]2[NH:6][C:5]3[CH:19]=[CH:20][C:2]([C:23]4[C:24]([C:28]([F:30])([F:31])[F:29])=[CH:25][CH:26]=[CH:27][C:22]=4[F:21])=[CH:3][C:4]=3[N:8]=2)[CH2:12][CH2:13]1
Reactant: FC1(F)CCC(C=Cc2nc3cc(Br)ccc3[nH]2)CC1
Reactant: OB(O)c1c(F)cccc1C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)c1cc[c-](P)c1C(C)(C)C
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Fc1cccc(C(F)(F)F)c1-c1ccc2[nH]c(C=CC3CCC(F)(F)CC3)nc2c1
Temperature: 25 °C

Procedure:
A solution of 5-bromo-2-[2-(4,4-difluoro-cyclohexyl)-vinyl]-1H-benzimidazole (0.030 g, 0.088 mmol, prepared as in STEP F above), 2-fluoro-6-trifluoromethylphenyl boronic acid (0.040 g, 0.19 mmol), 1,1-bis(di-t-butyl-phosphinoferrocene palladium chloride (0.012 g, 0.018 mmol) in dimethoxyethane (2 mL) and 2M sodium carbonate (1.0 mL, 2 mmol) was stirred at 95° C. for 18 h. The resulting solution was cooled to room temperature and poured into a solution of ethyl acetate and water (1:1, 50 mL). The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica using ethyl acetate/hexanes 3:7 as eluent to yield 2-[2-(4,4-difluoro-cyclohexyl)-vinyl]-5-(2-fluoro-6-trifluoromethyl-phenyl)-1H-benzimidazole.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:3]([CH3:29])=[C:2]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 57.1 %

Procedure:
A mixture of N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.654 mmol) obtained in Example 35, phenylboronic acid (88 mg, 0.720 mmol), and palladium (0) tetrakis(triphenylphosphine) (27 mg, 0.023 mmol) in an aqueous 2 M sodium carbonate solution (10 mL)-1,2-dimethoxyethane (5 mL) was refluxed with heating for 16 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate. Insoluble materials were filtered off, and the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 170 mg (yield: 57%) of the title compound. Melting point: 178-182° C. (hexane-ethyl acetate).
Reaction SMILES: [CH2:1]1COCC1.[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCN(CC)CC>C1(C)C=CC=CC=1>[C:6]1([CH:12]2[CH2:17][CH2:16][C:15](=[CH2:1])[CH2:14][CH2:13]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CCC(c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C1CCC(c2ccccc2)CC1
Reaction time: 0.17 h
Yield: 10 %

Procedure:
BDAM (2.83 grams) was suspended in 40 milliliters of toluene and 2.2 milliliters of THF were added dropwise. After 10 minutes of stirring, 2.10 grams of 4-phenylcyclohexanone were added. The reaction mixture was refluxed for 1 hour and hydrolyzed with hydrated Ca(OH)2 in the presence of Et3N. After the usual work up, 0.21 grams of 4-phenyl-1-methylenecyclohexane was isolated (10% yield).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]4)[C:12]=3[C:11]1=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[OH:8][CH2:9][C@H:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[N:16]=[CH:15][N:14]=[C:13]([O:22][CH:23]4[CH2:24][CH2:25][CH:26]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH2:27][CH2:28]4)[C:12]=3[C:11]1=2
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
A solution of tert-butyl N-(4-[[(3S)-3-[[(tert-butyldimethylsilyl)oxy]methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (963 mg, 1.76 mmol, 1.00 equiv) in 5 mL of THF was added TBAF (919 mg, 3.51 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at 25° C. and diluted with water, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to afford the tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]cyclohexyl)-N-methylcarbamate (691 mg, 91%) as a white solid. MS: m/z 434 (M+H)+.
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:29])[NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][C:17]([N:26]([CH3:28])[CH3:27])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=CC=1)([O-])=O.[F:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[NH:36][CH:35]=[C:34]2[CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>O1CCOCC1>[CH3:28][N:26]([CH3:27])[C:17]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:11]([N:42]2[CH2:43][CH2:44][CH2:45][CH:40]([C:34]3[C:33]4[C:37](=[CH:38][CH:39]=[C:31]([F:30])[CH:32]=4)[NH:36][CH:35]=3)[CH2:41]2)=[O:29])[CH2:15][CH2:16]1
Reactant: Fc1ccc2[nH]cc(C3CCCNC3)c2c1
Reactant: CN(C)C1(c2ccccc2)CCC(CNC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Solvent: C1COCCO1
Product: CN(C)C1(c2ccccc2)CCC(CNC(=O)N2CCCC(c3c[nH]c4ccc(F)cc34)C2)CC1
Yield: 24.8 %

Procedure:
The diastereoisomer mixture of (4-dimethylamino-4-phenylcyclohexylmethyl)-carbamic acid 4-nitrophenyl ester (400 mg, 1 mmole) was added to a solution of 5-fluoro-3-piperidine-3-yl-1H-indole (220 mg, 1 mmole) in dioxane (8 ml). The reaction mixture was then boiled under reflux for 8 hours. The reaction mixture was worked up by distilling off the solvent. The residue contained, apart from nitrophenol, also the two diastereoisomers of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide. The diastereoisomers were separated and purified by flash chromatography on silica gel (30 g). Methanol/EE (1:1; 850 ml) was used as eluent. The non-polar diastereoisomer of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (143 mg, m.p. 110°-115° C., 30%) and the polar diastereoisomer of 3-(5-fluoro-1H-indol-3-yl)piperidine-1-carboxylic acid-(4-dimethylamino-4-phenylcyclohexylmethyl)-amide (118 mg, m.p. 98°-101° C., 25%) were thereby obtained in pure form.
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[NH2:17][C:18]([CH3:34])([CH2:21][N:22]1[N:26]=[C:25]2[C:27]([Cl:33])=[CH:28][C:29]([Cl:32])=[C:30]([Cl:31])[C:24]2=[N:23]1)[C:19]#[N:20]>C1COCC1>[C:19]([C:18]([NH:17][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([O:6][C:2]([F:16])([F:1])[CH:3]([F:5])[F:4])=[CH:8][CH:9]=1)([CH3:34])[CH2:21][N:22]1[N:26]=[C:25]2[C:27]([Cl:33])=[CH:28][C:29]([Cl:32])=[C:30]([Cl:31])[C:24]2=[N:23]1)#[N:20]
Reactant: O=C(Cl)c1ccc(OC(F)(F)C(F)F)cc1
Reactant: CC(N)(C#N)Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1nc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(OC(F)(F)C(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 169, except using a solution of 4-(1,1,2,2-tetrafluoroethoxy)benzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,5,7-trichloro-2H-benzotriazol-2-yl)-propionitrile (0.075 mmole, described in Example 39) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (4.2 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=524, RT=0.72 min.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=O.C[O:13][C:14](=[O:42])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)=[CH:17][CH:16]=1>>[C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:21]([CH:31]1[CH2:32][CH2:33][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:4](=[O:6])[C:3]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=2[CH3:1])[CH2:35][CH2:36]1)[C:18]1[CH:17]=[CH:16][C:15]([C:14]([OH:42])=[O:13])=[CH:20][CH:19]=1)#[N:30]
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Reactant: Cc1cccc(C)c1C(=O)O
Product: Cc1cccc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure F with 2,6-dimethylbenzoic acid (93 mg, 0.62 mmol) and 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(3-cyano-benzyl)-amino]-benzoic acid methyl ester (see EXAMPLE 107) (130 mg, 0.31 mmol) followed by general procedure K with the resulting ester afforded 4-((3-cyano-benzyl)-{1-[3-(2,6-dimethyl-benzoylamino)-1-methyl-propyl]-piperidin-4-yl}-amino)-benzoic acid as a white solid (107 mg, 64% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]([CH2:9][C:10]12[CH2:17][CH2:16][C:13]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)([CH2:14][CH2:15]1)[CH2:12][CH2:11]2)C(OC)=O.[OH-]>>[CH3:1][O:2][C:3](=[O:35])[CH2:4][CH2:9][C:10]12[CH2:15][CH2:14][C:13]([C:18]3[NH:26][C:25]4[C:24](=[O:27])[N:23]([CH2:28][CH2:29][CH3:30])[C:22](=[O:31])[N:21]([CH2:32][CH2:33][CH3:34])[C:20]=4[N:19]=3)([CH2:12][CH2:11]1)[CH2:16][CH2:17]2
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(CC(C(=O)OC)C(=O)OC)(CC3)CC4)nc2n(CCC)c1=O
Agent: [OH-]
Product: CCCn1c(=O)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc2n(CCC)c1=O

Procedure:
Hydrolysis of 2-[4-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-ylmethyl]malonic acid dimethyl ester (XLI, Example 107) with hydroxide at elevated temperature gives the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:20]1[CH2:22][CH2:21]1)=[N:5][N:6]2[CH2:11][C:12]1[N:17]=[C:16]([CH3:18])[C:15]([OH:19])=[CH:14][CH:13]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C>[Si:27]([O:19][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[C:3]=3[C:4]([CH:20]3[CH2:22][CH2:21]3)=[N:5]2)=[N:17][C:16]=1[CH3:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: Cc1nc(Cn2nc(C3CC3)c3c(N)cccc32)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1nc(Cn2nc(C3CC3)c3c(N)cccc32)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To 6-((4-amino-3-cyclopropyl-1H-indazol-1-yl)methyl)-2-methylpyridin-3-ol (100 mg, 0.340 mmol) in DMF (5 mL) was added tert-butylchlorodimethylsilane (66.6 mg, 0.442 mmol) and 1H-imidazole (116 mg, 1.70 mmol). The reaction mixture was stirred for 18 hours at ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography (1:4 EtOAc/hexanes) to give final product (97%).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][CH:12]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]([N:15]2[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]2)=[O:14])[CH:5]=1.[OH-].[Na+]>CO.O1CCOCC1>[C:26]([O:25][C:23]([NH:22][CH:12]([C:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH2:20]1)=[O:14])[CH2:11][CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cccc(CCC(NC(=O)OC(C)(C)C)C(=O)N2CCC(C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Yield: 95.5 %

Procedure:
A solution of 90 mg (0.22 mmol) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid methyl ester (prepared in the synthesis of Example 77) in 1 mL of 1:1 MeOH/1,4-dioxane and 0.5 mL of 1 N NaOH is stirred for 3 h. The organic phase is separated and suspended in 2 mL of water. The pH is adjusted to 2 with HCl, and the resulting precipitate is filtered to provide 85 mg (98%) of 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[ClH:37].[CH2:38]([C@H:40]1[CH2:45][O:44][CH2:43][CH2:42][NH:41]1)[CH3:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:18].[ClH:37].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:41]2[CH2:42][CH2:43][O:44][CH2:45][C@@H:40]2[CH2:38][CH3:39])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CC[C@H]1COCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H]1COCCN1CC#CCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc(C)c(C)c2)C1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 91.8 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(4-chloro-2-butynyl)-2-(3,4-dimethylbenzyl)piperazine (150 mg), (3S)-3-ethylmorpholine hydrochloride (47 mg) and powdered potassium carbonate (117 mg) in dry N,N-dimethylformamide (1 ml) was stirred at 50° C. for 1.5 hours. The reaction mixture was poured into water (10 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue was purified by column chromatography on silica gel using ethyl acetate as eluent. The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[4-((3S)-3-ethylmorpholino)-2-butynyl]-2-(3,4-dimethylbenzyl)piperazine dihydrochloride (177 mg).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)#[CH:22].CC(C)([O-])C.[K+]>O1CCCC1>[C:7]([S:8]/[CH:22]=[CH:21]\[C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C#Cc1cccnc1
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C(=C\c1cccnc1)\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
To a solution of triphenylmethanethiol (1.41 g) and 3-ethynylpyridine (0.5 g) in anhydrous tetrahydrofuran (10 ml) was added potassium t-butoxide (571 mg) at ambient temperature. The mixture was refluxed for 2 hours. After the reaction mixture was cooled to ambient temperature, the reaction mixture was poured into ice-water. The mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo to give a crystal. The crystal was washed with ethanol and dried to give 3-[(Z)-2-(tritylthio)vinyl]pyridine (1.11 g).
Reaction SMILES: [NH3:1].[CH3:2][C:3](=[CH2:5])[CH3:4].[C:6]1(=[O:12])[O:11][C:9](=[O:10])[CH:8]=[CH:7]1.C=CC(=C)C>>[CH3:4][C:3](=[CH2:2])[CH3:5].[C:6]1(=[O:12])[NH:1][C:9](=[O:10])[CH:8]=[CH:7]1.[C:9]1(=[O:10])[O:11][C:6](=[O:12])[CH:7]=[CH:8]1
Reactant: N
Agent: C=C(C)C
Agent: O=C1C=CC(=O)O1
Solvent: C=CC(=C)C
Product: O=C1C=CC(=O)N1
Temperature: 180 °C

Procedure:
In an ammonia gas atmosphere, 100 parts of an isobutylene-maleic anhydride copolymer (sold under the trade name "ISOBAN 04" by KURARAY ISOPRENE K.K. of Kita-ku, Osaka, Japan) was heated to 180° C. to obtain an isobutylene-maleic imide-maleic anhydride copolymer. Then placed in a reactor were 40 parts of the isobutylene-maleic imide-maleic anhydride copolymer, 7 parts of 25% ammonia water and 160 parts of water. The mixture in the reactor was heated at 85° C. for 2 hours, thereby obtaining an aqueous solution of isobutylene-maleic imide-maleic anhydride copolymer. The aqueous solution contained 20% nonvolatile matter, and the viscosity of the aqueous solution was measured at 6,000 mPa.s.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][NH:6][C@H:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([O:14]C)=O.[CH3:19][S:20]([NH:23][C:24]1[CH:39]=[CH:38][C:27]2[NH:28][C:29]([CH2:34][C:35](O)=[O:36])=[N:30][S:31](=[O:33])(=[O:32])[C:26]=2[CH:25]=1)(=[O:22])=[O:21].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[OH:14][C:12]1[C@H:8]2[C@H:7]([CH2:11][CH2:10][CH2:9]2)[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[C:2]([CH3:1])[CH:3]=2)[C:35](=[O:36])[C:34]=1[C:29]1[NH:28][C:27]2[CH:38]=[CH:39][C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[CH:25][C:26]=2[S:31](=[O:33])(=[O:32])[N:30]=1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NCc1cccc(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1cccc(CN2C(=O)C(C3=NS(=O)(=O)c4cc(NS(C)(=O)=O)ccc4N3)=C(O)[C@@H]3CCC[C@@H]32)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of methyl (1R,2S)-2-[(3-methylbenzyl)amino]cyclopentane-carboxylate (74 mg, 0.30 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 100 mg, 0.30 mmol) in anhydrous N,N-dimethylformamide (3 mL) under a nitrogen atmosphere, N-methylmorpholine (0.10 mL, 0.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63 mg, 0.33 mmol) were added sequentially. The mixture was stirred at 25° C. for 16 h, diluted with ethyl acetate, washed with 1.0 M aqueous hydrochloric acid and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to afford the amide intermediate, which was used directly in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:18]=[CH:17]2.C(OCC)(=O)C>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([CH:24]([CH3:28])[CH2:25][OH:26])[CH:18]=[CH:17]2
Reactant: COc1ccc2cc(C(C)C(=O)O)ccc2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc2cc(C(C)CO)ccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 0.4 g. of lithium aluminum hydride and 100 ml. of ethyl ether, there is added a mixture of 2.3 g. of d 2-(6-methoxy-2-naphthyl)propionic acid and 100 ml. of ethyl ether. The mixture is stirred at 0°C for 30 minutes, and 10 ml. of ethyl acetate is added. After 1 hour, 4 ml. of water is added to the mixture. The resulting mixture is filtered and evaporated under reduced pressure to yield l 2-(6-methoxy-2-naphthyl)-l-propanol.
Reaction SMILES: BrC1C=C2C(C(Cl)=CN=C2[Cl:12])=CC=1.[Br:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21](O)=[O:22])=[CH:17][CH:16]=1>O=S(Cl)Cl>[Br:14][C:15]1[CH:25]=[CH:24][C:18]([CH:19]=[CH:20][C:21]([Cl:12])=[O:22])=[CH:17][CH:16]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Reactant: Clc1cnc(Cl)c2cc(Br)ccc12
Solvent: O=S(Cl)Cl
Product: O=C(Cl)C=Cc1ccc(Br)cc1

Procedure:
7-Bromo-1,4-dichloroisoquinoline ##STR100## A solution of 4-bromocinnamic acid (5.03 g, 22.2 mmol) in SOCl2 (15 mL) was stirred at 23° C. for 16 h, and then heated at reflux for a further 2 h. The solvents were evaporated in vacuo and the residue azeotroped with PhMe (×3) to yield 4-bromocinnamoyl chloride (22 mmol) as an orange-brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][O:7][C:8]2[C:33]([F:34])=[CH:32][C:11]([CH2:12][C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[N:15]([Si](C(C)C)(C(C)C)C(C)C)[CH:14]=3)=[C:10]([F:35])[CH:9]=2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[C:33]([F:34])=[CH:32][C:11]([CH2:12][C:13]3[C:21]4[C:16](=[N:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)=[C:10]([F:35])[CH:9]=2)=[CH:36][CH:37]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Cc2cc(F)c(OCc3ccc(Cl)cc3)cc2F)c2cccnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Fc1cc(OCc2ccc(Cl)cc2)c(F)cc1Cc1c[nH]c2ncccc12
Reaction time: 0.17 h
Yield: 28.6 %

Procedure:
To 3-[4-(4-chloro-benzyloxy)-2,5-difluoro-benzyl]-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (604, 0.150 g, 0.28 mmol) in tetrahydrofuran (10.0 mL) was added tetra-n-butylammonium fluoride (80.0 mg, 0.31 mmol). After 10 minutes, the reaction was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give the compound as a white solid (P-1974, 30.8 mg, 28.9%). MS (ESI) [M+H+]+=385.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1CC1C=CC=CC=1S(C1C=CC=CC=1)(=O)=O.[N:39]1([S:44]([C:47]2[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=2[CH:49]=O)(=[O:46])=[O:45])[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:1][C:2]1[N:3]([CH2:35][C:36]([OH:38])=[O:37])[C:4]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:6]=1[CH2:49][C:48]1[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=1[S:44]([N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)(=[O:46])=[O:45]
Reactant: Cc1c(Cc2ccccc2S(=O)(=O)c2ccccc2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O
Reactant: O=Cc1ccccc1S(=O)(=O)N1CCCC1
Product: Cc1c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c(-c2ccccc2)n1CC(=O)O

Procedure:
2-(2-methyl-4,5-diphenyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid was synthesized according to 2-(2-methyl-4,5-diphenyl-3-(2-(phenylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetic acid using 2-(pyrrolidin-1-ylsulfonyl)benzaldehyde in the general procedure I (step 1). 1H NMR (CDCl3/400 MHz) δ (ppm) 8.00 (d, 1H), 7.50-7.45 (m, 1H), 7.34-7.24 (m, 5H), 7.19-7.16 (m, 2H), 7.05-7.00 (m, 3H), 6.92-6.88 (m, 2H), 4.65 (s, 2H), 4.21 (s, 2H), 3.15 (t, 4H), 2.10 (s, 3H), 1.69-1.65 (m, 4H). MS m/z: 515.34 (M+1).