Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[CH:8][N:7]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1cccc2[nH]cnc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-n2cnc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 15.6 %

Procedure:
A round bottom flask charged with molecular sieves, 4A (189 mg, 1.918 mmol) was flame-dried, then allowed to cool to room temperature. To this vial were added 4-bromo-1H-benzo[d]imidazole (0.378 g, 1.918 mmol), copper (II) acetate (0.523 g, 2.88 mmol), and 4-fluorophenylboronic acid (0.805 g, 5.76 mmol) followed by CH2Cl2 (Volume: 9.59 ml) and triethylamine (0.695 ml, 4.99 mmol). The heterogeneous green reaction was stirred at room temperature. After 19 h, the reaction mixture was filtered through a disposable filter funnel and the filter cake rinsed with CH2Cl2. The filtrate was concentrated to afford a green residue. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-100% EtOAc in hexanes over 25 min, tr=13 min) gave 4-bromo-1-(4-fluorophenyl)-1H-benzo[d]imidazole (158 mg, 0.299 mmol, 15.56% yield) as a white solid. LC-MS showed by-product was present. The material was re-dissolved in a minimal amount of CH2Cl2 (required a few drops of MeOH). Purification of the crude material by silica gel chromatography using an ISCO machine (12 g column, 30 mL/min, 0-25% EtOAc in hexanes over 13 min, tr=10 min) gave Preparation 47A (158 mg, 0.299 mmol, 15.56% yield) as a white solid. LC-MS showed the product was 55% pure. The mixture was further purified by MPLC (40 g column, 36 mL/min, 30-60% EtOAc in hexanes) to afford Preparation 47A as a white solid (51 mg, 9.1%). MS (ESI): m/z=291.0 [M+H]+. HPLC Peak tr=1.70 minutes was product. HPLC conditions: Column:Luna C18 4.6×30 mm 3u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17]C(OCC2C=CC=CC=2)=O)=[CH:9][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:36])[CH:4]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])=[CH:11][CH:12]=1
Reactant: COC(=O)C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(COc1ccc(CCCCN)cc1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Compound 15 (505 mg, 1.00 mmol) was dissolved in methanol (20 mL) and 10% palladium on carbon (100 mg) was added. The flask was evacuated, filled with hydrogen gas under balloon pressure and stirred overnight. Filtration through celite to remove the catalyst followed by removal of the solvent under reduced pressure provided compound 16 (366 mg, 98%). 1H NMR (300 MHz, CDCl3) δ 7.08 (d, 2H), 6.80 (d, 2H), 5.51 (d, 1H), 4.66 (m, 1H), 4.38 (m, 1H), 4.17 (m, 1H), 3.78 (s, 3H), 2.73 (m, 2H), 2.58 (m, 2H), 1.90 (br s, 2H), 1.62 (m, 2H), 1.50 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[C:14]([CH3:21])[N:13]=2)[CH2:8]1>CO.[Pd]>[CH3:21][C:14]1[C:15]([NH2:18])=[CH:16][CH:17]=[C:12]([N:9]2[CH2:10][CH2:11][C@H:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])[CH2:8]2)[N:13]=1
Reactant: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N2CC[C@H](N3CCC[C@@H]3C)C2)ccc1N
Yield: 95.8 %

Procedure:
To a solution of (2S,3′S)-2-methyl-1′-(6-methyl-5-nitro-pyridin-2-yl)-[1,3′]bipyrrolidinyl (0.633 g, 2.18 mmol) in methanol (60 mL) in a 250 mL parr shaker bottle was added 5% Pd/C (0.200 g). The reaction mixture was allowed to shake under a hydrogen atmosphere (55 psi) at room temperature for 4 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated under vacuum to afford 0.544 g (96%) of title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([CH3:17])[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[C:9]1[C:25]([N:27]1[CH2:32][CH2:31]S[CH2:29][CH2:28]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[O:34][S:35]([O-:37])=O.[K+]>CO.O>[CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:11]([CH3:17])[C:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[C:9]1[C:25]([N:27]1[CH2:28][CH2:29][S:35](=[O:37])(=[O:34])[CH2:31][CH2:32]1)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCSCC2)n(Cc2ccccc2)c1C(F)(F)F
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCS(=O)(=O)CC2)n(Cc2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (1-benzyl-3-(4-chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(thiomorpholino)methanone (162 mg, 0.34 mmol) in MeOH (4 mL) and H2O (1 mL) was added oxone (624 mg, 1.015 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O and extracted with DCM (60 mL). The organic layer was washed with brine, dried (Na2SO4) and purified by flash column chromategraphy (silica, heptane/EtOAc, 4:1→3:2) to give SC-26 (66 mg, 38%) as a white solid.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[N+:6]1([O-])[CH:11]=[CH:10][CH:9]=[C:8]2[CH2:12][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:7]=12>>[Cl:3][C:9]1[CH:10]=[CH:11][N:6]=[C:7]2[CH2:14][N:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12][C:8]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)N1Cc2ccc[n+]([O-])c2C1
Product: CCOC(=O)N1Cc2nccc(Cl)c2C1
Temperature: 50 °C
Yield: 46 %

Procedure:
POCl3 (20 mL, 218 mmol) was added into ethyl 5H-pyrrolo[3,4-b]pyridine-6(7H)-carboxylate N-oxide (1 g, 4.80 mmol) and heated to 35° C. for 12 hours and 50° C. for another 5 hours. The solvent was evaporated and poured into water. The material was extracted with CH2Cl2, washed with NaHCO3 and brine, dried with Na2SO4, filtered and concentrated. The residue was purified on silica gel to afford the title compound (0.5 g, 45.9% yield).
Reaction SMILES: O.NN.[CH2:4]([O:11][C:12]1[C:26]([O:27][CH3:28])=[CH:25][C:15]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH:19]2[CH2:23][OH:24])=[O:17])=[C:14]([N+:29]([O-])=O)[C:13]=1[O:32][CH3:33])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO.[Ni]>[NH2:29][C:14]1[C:13]([O:32][CH3:33])=[C:12]([O:11][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:26]([O:27][CH3:28])=[CH:25][C:15]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[CH2:23][OH:24])=[O:17]
Reactant: COc1cc(C(=O)N2CCCC2CO)c([N+](=O)[O-])c(OC)c1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCCC2CO)c(N)c(OC)c1OCc1ccccc1
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Hydrazine hydrate (2.31 g, 72.2 mmol) was added dropwise to a solution of 125 (6.01 g, 14.4 mmol) in methanol (60 mL) gently refluxing over Raney nickel (1.1 g, slurry). The resulting vigorous evolution of hydrogen gas subsided after approximately 10 minutes and the reaction was deemed to be complete by TLC after 2 h. The reaction mixture was filtered through celite and the solvent evaporated. Distilled water (100 mL) was added to the residue, and the aqueous mixture was extracted with EtOAc (3×100 mL) and the combined organic phase washed with H2O (3×100 mL) and brine (3×100 mL) and dried over anhydrous MgSO4. Evaporation of the solvent afforded the produce as a brown oil (3.97 g, 10.3 mmol, 73%): 1H NMR (270 MHz, CDCl3) δ1.6-2.2 (m, 4H), 3.5-3.8 (m, 4H), 3.8 (s, 3H), 3.9 (s, 3H), 4.4 (br s, 1H), 5.1 (s, 2H), 6.6 (s, 1H), 7.3-7.6 (m, 5H); 13C NMR (67.8 MHz, CDCl3) δ171.5, 144.9, 143.5, 141.9, 137.5, 134.6, 128.6, 128.5, 128.3, 128.2, 128.0, 115.1, 107.3, 75.1, 66.9, 61.0, 60.6, 60.4, 56.9, 50.9, 28.5, 24.9, 21.1, 14.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][C:7]=2[CH:14]=1)#[N:2].[NH2:15][CH:16]1[CH2:21][CH2:20][CH:19]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([C:11]([NH:15][CH:16]3[CH2:17][CH2:18][CH:19]([CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21]3)=[O:13])=[CH:8][C:7]=2[CH:14]=1)#[N:2]
Reactant: N#Cc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)(C)OC(=O)CCC1CCC(N)CC1
Product: CC(C)(C)OC(=O)CCC1CCC(NC(=O)c2cc3cc(C#N)ccc3o2)CC1
Yield: 38.5 %

Procedure:
In the same manner as in Example 1 (2), 5-cyano-2-benzofurancarboxylic acid (203 mg, 1.08 mmol) and t-butyl 3-(4-aminocyclohexyl)propionate (295 mg, 1.30 mmol) were condensed and purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1) to give 165 mg of t-butyl 3-[4-[(5-cyano-2-benzofuranyl)carbonylamino]cyclohexyl]propionate as a colorless solid (38%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[C:4]1[C:5]([F:19])=[C:6]([F:18])[C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[C:8]=2[CH:17]=1.Cl.[F:23][C:24]1([F:28])[CH2:27][NH:26][CH2:25]1>>[F:23][C:24]1([F:28])[CH2:27][N:26]([C:12]([C:9]2[C:8]3[CH:17]=[C:4]([CH:3]([O:2][CH3:1])[O:20][CH3:21])[C:5]([F:19])=[C:6]([F:18])[C:7]=3[O:11][N:10]=2)=[O:14])[CH2:25]1
Reactant: FC1(F)CNC1
Reactant: CCOC(=O)c1noc2c(F)c(F)c(C(OC)OC)cc12
Agent: Cl
Product: COC(OC)c1cc2c(C(=O)N3CC(F)(F)C3)noc2c(F)c1F

Procedure:
Starting materials: ethyl 5-(dimethoxymethyl)-6,7-difluorobenzo[d]isoxazole-3-carboxylate (Intermediate 206) and 3,3-difluoroazetidine hydrochloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:28][C:29](=O)[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)[C:11]([C:20]#[N:21])=[CH:10][C:9]=1[NH:22][C:29](=[O:28])[CH2:30][C:31](=[O:51])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([N:38]2[C:42]([CH2:43][O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)=[CH:41][N:40]=[N:39]2)[CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C#N)cc1NC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1

Procedure:
The title compound was prepared from (2-amino-4-cyano-5-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (Example J12) (318 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown foam (370 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11]>>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:17]([C:16]3[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Nc1cc(Br)cnc1N
Product: O=[N+]([O-])c1ccc(-c2nc3cc(Br)cnc3[nH]2)cc1

Procedure:
The title compound was prepared from 5-bromo-2,3-diaminopyridine (0.94 g, 5 mmol) and 4-nitrobenzaldehyde (0.76 g, 5 mmol).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH:11]=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]([Si](C)(C)C)([F:22])[F:21]>CN(C)C=O>[F:19][C:20]([F:22])([F:21])[CH:11]([C:3]1[N:2]([CH3:1])[C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)[OH:12]
Reactant: Cn1c(C=O)cc2ccccc21
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(O)C(F)(F)F)cc2ccccc21
Yield: 78.7 %

Procedure:
According to Reference Example 8-2, by use of 1-methyl-1H-indole-2-carbaldehyde (300 mg, 1.88 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (52 mg, 0.38 mmol) and (trifluoromethyl)trimethylsilane (0.416 mL, 2.82 mmol), the mixture was stirred and reacted at room temperature for 4 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=100/1) was performed to give 2,2,2-trifluoro-1-(1-methyl-1H-indol-2-yl)ethanol (Compound DQ) (339 mg, yield: 79%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH:26]1[CH2:31][CH2:30][CH:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1)(=O)=O.CN(C=O)C>C(OCC)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)C1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 90 °C
Reaction time: 22 h

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (325 mg, 1.67 mmol), cesium carbonate (600 mg, 1.84 mmol), and tert-butyl 4-[(methylsulfonyl)oxy]cyclohexanecarboxylate (513 mg, 1.84 mmol) followed by DMF (5.6 mL) were added to an oven-dried flask. The reaction mixture was stirred at 90° C. for 22 hours then cooled to room temperature, diluted with diethyl ether, washed with water (3×50 mL), and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (mixture of cis and trans). 1H NMR (500 MHz, CDCl3) δ 7.99 (s, 1H), 7.86 (s, 1H), 2.98 (s, 1H), 2.24-1.85 (m, 5H), 1.75-1.43 (m, 4H), 1.41 (s, 9H), 1.29 (s, 12H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].Cl.[O:10]1CCC[CH2:11]1>[Cl-].[Na+].O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[CH2:11][OH:10]
Reactant: C1CCOC1
Reactant: O=C(Cl)CCCCBr
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)CCCCBr
Temperature: 10 °C

Procedure:
To 191.4 g of tris-trimethylsilyloxyethylene (Example 267) containing 15 drops of stannic tetrachloride under argon with stirring at 10° C. is added 87 g of 5-bromopentanoyl chloride (Example 274) dropwise. After one-half of the acid chloride is added, the mixture is stirred until an exotherm ensues. The remaining acid chloride is added dropwise maintaining the reaction exotherm at 65° C. The mixture is then stirred for 2.5 hours. The mixture is slowly poured into a stirred mixture of 100 ml of 0.6N hydrochloric acid and 200 ml of tetrahydrofuran. The mixture is stirred for 30 minutes and poured into brine. The mixture is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. The residue is mixed with petrolium ether and cooled in dry-ice-acetone to induce crystallization. The petrolium ether is decanted and the solid is dried at reduced pressure to give 64.72 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[C:12](\[C:17]#[N:18])/[C:13]([O:15][CH3:16])=[O:14])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[C-:19]#[N:20].[K+]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:17]#[N:18])[C:13]([O:15][CH3:16])=[O:14])([C:19]#[N:20])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: COC(=O)/C(C#N)=C1\C(=O)Nc2cc(Cl)ccc21
Reactant: [C-]#N
Agent: [K+]
Product: COC(=O)C(C#N)C1(C#N)C(=O)Nc2cc(Cl)ccc21
Yield: 61 %

Procedure:
Following the general method as outlined for Intermediate 5, starting from methyl (2Z)-(6-chloro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)(cyano)acetate (intermediate 4) and potassium cyanide, the title compound was isolated, after evaporation, as a light brown solid in 61% yield. This was a mixture of diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9](Cl)(=[O:11])=[O:10])[CH:8]=1)#[N:2].[NH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(CC)CC)C>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C@@H:13]2[C:18]([C:19]#[N:20])=[C:17]([CH3:21])[N:16]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15](=[O:32])[N:14]2[CH3:33])=[C:7]([S:9]([NH:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)(=[O:11])=[O:10])[CH:8]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cl)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reactant: NN1CCOCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)NN2CCOCC2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfonyl chloride (50 mg, 101 μmol) was dissolved in absolute THF (2.5 ml), N-aminomorpholine (29 μl, 303 μmol; 3 eq.) and triethylamine (10.2 mg, 101 μmol; 1 eq.) were added at room temperature and the mixture was stirred overnight. The reaction mixture was then concentrated under reduced pressure and the residue was purified by preparative HPLC (column: Kromasil C-18, 5 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). This gave a colorless amorphous solid (38 mg, 67% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7]([CH3:12])=[C:6]2[CH2:13][C:14]([OH:16])=[O:15].[OH-].[K+].[NH2:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(O)(=O)C>CO>[NH2:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[C:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:13][C:14]([OH:16])=[O:15])=[C:7]2[CH3:12])=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)C(CC(=O)O)=C(C)C2=Cc1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of 5-methoxy-2-methyl-3-indenylacetic acid (1a) (3.95 g) in 90% methanol (24 ml) containing 85% potassium hydroxide (2.7 g) was added a solution of p-aminosulfonylbenzaldehyde (3.70 g) in 90% methanol (24 ml). The resulting mixture was refluxed under nitrogen for 4-6 hours. A solution of 50% aqueous acetic acid (50 ml) was then added to the reaction mixture during 40 minutes at 50°-60° C. The crystals were collected after aging at 15° C. for 1 hour. The crude product was recrystallized five times from acetone-hexane to give pure Z form of 1-(4-aminosulfonylphenyl) methylene-5-methoxy-2-methyl-1H-3-indenylacetic acid (2a) (4.0 g, 57%): m.p. 224°-225° C.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].I[CH2:13][CH2:14][CH3:15].O>CN(C=O)C>[CH2:13]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:14][CH3:15]
Reactant: CCCI
Reactant: O=Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1C=O
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of salicylaldehyde (12.21 g, 0.1 mol) in DMF (65 ml) was cooled in an ice/water bath under argon and 60% sodium hydride in mineral oil (4.0 g, 0.1 mol) was added in several portions. The mixture was stirred for one hour and then iodopropane (16.99 g, 0.1 mol) was added at room temperature. The reaction mixture was stirred at room temperature overnight, poured into water (800 ml) and stirred. The mixture was extracted with chloroform (3×), the chloroform layer was concentrated in vacuo and the dark oil thus obtained was distilled under vacuum (92-94° C. at 1.15 mm Hg) to afford 12.68 g (77%) of 2-propoxybenzaldehyde.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:16])([CH3:15])[CH2:9][C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[CH3:17].[CH3:18]I.O>CS(C)=O>[Br:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:15])([CH3:16])[CH2:9][C:10](=[O:14])[N:11]2[CH3:18])=[CH:6][C:5]=1[CH3:17]
Reactant: Cc1cc2c(cc1Br)NC(=O)CC2(C)C
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc2c(cc1Br)N(C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101.3 %

Procedure:
A mixture of powdered KOH (14.06 g, 0.250 mol) in DMSO (150 mL) was stirred at 0° C. for 10 min. 7-Bromo-4,4,6-trimethyl-3,4-dihydro-1H-quinoline-2-one (33.59 g, 0.125 mol) was added cautiously, followed immediately by the addition of methyl iodide (39 mL, 0.625 mol). The reaction mixture was kept at 0° C. for 30 min then slowly warmed up to room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and extracted with dichloromethane washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 35.74 g of 7-bromo-1,4,4,6-tetramethyl-3,4-dihydro-1H-quinoline-2-one (99%) and used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 1.27 (s, 6 H), 2.37 (s, 3 H), 2.48 (s, 2 H), 3.35 (s, 3 H), 7.12 (s, 1 H), 7.16 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19].[I-].[CH3:22][N:23]1[C:31]2[C:26](=[C:27]([CH3:32])[CH:28]=[CH:29][CH:30]=2)[C:25]([CH2:33][N+](C)(C)C)=[CH:24]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:33][C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])[N:23]([CH3:22])[CH:24]=2)[C:11]1=[O:19]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: COC(=O)c1ccccc1-n1c(=O)[nH]c2ccccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1-n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccccc21
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a solution of 2-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-benzoic acid methyl ester (30 mg, 0.11 mmol) in DMF (1.0 mL) are added (1,4-Dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (46 mg, 0.13 mmol) and K2CO3 (31 mg, 0.22 mmol) at room temperature. The solution is heated to 60° C. for 16 hr and it is cooled down to room temperature for another 48 hr. Then 30 mL of water is added. The mixture is extracted with EtOAc (3×30 mL) and the combined organic layers are washed with water (3×100 mL), dried with Na2SO4 and concentrated to give crude product. Purification by preparative TLC affords 40 mg (86%) of 2-[3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([O:17]C)=[O:16])[N:13]=2)=[CH:5][CH:4]=1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=[O:16])[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1csc(-c2ccc(OC)nc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2nc(CC(=O)O)cs2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
This material was prepared according to the procedure described for Example 24(b) using methyl 2-[2-(6-methoxy-3-pyridyl)-1,3-thiazol-4-yl]acetate (Step a, 1.1 g, 4.2 mmol) and LiOH (2 N, 7.0 mL) in THF (10 mL) and MeOH (3 mL). The solution was stirred at RT for 18 h, and HCl (aq. 1 N) was added to adjust the reaction mixture to pH ˜2. The solvents were evaporated and the resulting residue was partitioned between EtOAc (75 mL) and H2O (75 mL). The layers were separated and the aqueous layer was extracted again with EtOAc (75 mL). The organic layers were combined, dried (Na2SO4) and concentrated to afford the title compound as a light yellow solid. MS m/z: 251 (M+1). Calc'd for C11H10N2O3S: 250.04.