Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P([CH:7]([CH:13]([CH3:15])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(CC)=O)C.[H-].[Na+].C([O:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[CH:30]=C2C=O)C1C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.CN(C)C=O.O>[OH:25][C:26]1[CH:34]=[C:33]2[C:32](=[CH:28][CH:27]=1)[N:31]([CH3:35])[CH:30]=[C:15]2[CH2:13][CH:7]([O:25][CH:26]([CH3:27])[CH3:34])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C(C)C)P(=O)(CC)CC
Reactant: Cn1cc(C=O)c2cc(OCc3ccccc3)ccc21
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Cc1cn(C)c2ccc(O)cc12)OC(C)C
Reaction time: 0.33 h
Yield: 173.8 %

Procedure:
3.2 g of Ethyl 2-(diethylphosphoryl)-2-isopropylacetate was dissolved in 25 ml of tetrahydrofuran, and 0.44 g of 60% sodium hydride was added under ice-cooling, and stirring was continued for 20 minutes under ice-cooling. The reaction solution was treated with a solution of 2 g of 5-benzyloxy-1-methyl-1H-indol-3-aldehyde in 5 ml of tetrahydrofuran and 5 ml of N,N-dimethylformamide, and stirred at 50° C. for one hour and then at room temperature for 16 hours. The reaction solution was cooled with ice, treated with water and ammonium chloride solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to silica gel column chromatography, and the fraction eluting with 20% ethylacetate-hexane was evaporated and the residue was dissolved in 10 ml of ethanol. 0.6 g of 10% Palladium carbon was added to this solution, the atmosphere was replaced with hydrogen, and the mixture was stirred at room temperature for 24 hours. The reaction atmosphere was replaced with nitrogen, the catalyst was filtered off, and the solvent was evaporated. The residue was subjected to silica gel column chromatography (30% ethyl acetate hexane), to give 2 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11](I)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([Si:27]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[SH:28])([CH3:26])[CH3:25].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O-][Si]([O-])=O.[Mg+2]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([C:17]2[N:21]=[C:20]([CH3:22])[O:19][N:18]=2)=[C:11]([S:28][Si:27]([CH:29]([CH3:31])[CH3:30])([CH:32]([CH3:34])[CH3:33])[CH:24]([CH3:25])[CH3:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Reactant: COc1cc(-c2noc(C)n2)c(I)cc1OCc1ccccc1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(-c2noc(C)n2)c(S[Si](C(C)C)(C(C)C)C(C)C)cc1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 3-(4-benzyloxy-2-iodo-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (0.7 g), triisopropylsilanethiol (0.391 mL), tris(dibenzylidene-acetone)dipalladium (0) (152 mg), (oxydi-2,1-phenylene)bis-(diphenylphosphine) (90 mg), sodium bis(trimethylsilyl)amide (1.0 mol/L tetrahydrofuran solution, 0.39 mL) and toluene (20 mL) was stirred at 80° C. under argon atmosphere for 2 hours. After cooling to room temperature, Florisil (registered mark) (1 g) was added to the mixture. After stirring for 10 minutes, the mixture was passed through a layer of Celite (registered mark). The filtrate was concentrated under reduced pressure to give 3-(4-benzyloxy-5-methoxy-2-triisopropylsilanylsulfanyl-phenyl)-5-methyl-[1,2,4]oxadiazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[N:17](COC(=O)C(C)(C)C)[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+]>O1CCCC1.CO.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH:29]=[CH2:30])[C:21]3[C:20](=[O:31])[N:19]([CH2:32][O:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:18](=[O:40])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(COC(=O)C(C)(C)C)c(=O)n2COC(=O)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=Cc1ccccc1-n1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c21
Temperature: 25 °C
Reaction time: 0.28 h
Yield: 87.4 %

Procedure:
4-[1,3-Bis(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-7-(2-vinylphenyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (704 mg) was dissolved in tetrahydrofuran (7 ml) and methanol (14 ml), sodium hydride (51 mg) was added to the solution, and the mixture was stirred at room temperature for 17 minutes. The reaction mixture was diluted with chloroform and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 510 mg of the title compound from the elution fraction of hexane-ethyl acetate (2:3).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:34])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[NH:16][C:15]1=[O:33])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[Br:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH:38]=[CH:39][C:40]([O:48][CH3:49])=[C:41]2[CH2:46]Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:35][C:36]1[CH:45]=[CH:44][CH:43]=[C:42]2[C:37]=1[CH:38]=[CH:39][C:40]([O:48][CH3:49])=[C:41]2[CH2:46][N:16]1[C:15](=[O:33])[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:34])[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:25])=[O:26])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]1=2
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(Br)cccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Br)cccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 49.5 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (46 mg, 92.6 μmol) in DMF (232 μl) was added 5-bromo-1-(chloromethyl)-2-methoxynaphthalene (31.7 mg, 111 μmol), cesium carbonate (39.2 mg, 120 μmol), and sodium iodide (18.1 mg, 120 μmol). The reaction was stirred at rt for 16 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((5-bromo-2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (34.2 mg, 50%) as a white solid. MS m/z 767/769 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([NH:35][CH2:36][C:37]([F:40])([F:39])[F:38])=[O:34])=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:33]([NH:35][CH2:36][C:37]([F:38])([F:39])[F:40])=[O:34])=[CH:41][CH:42]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(C(=O)NCC(F)(F)F)cc1
Product: O=C(NCC(F)(F)F)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.59 mmol) with 4-aminomethyl-N-(2,2,2-trifluoroethyl)-benzamide (273 mg, 1.17 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give 7-chloro-3-(2,2,2-trifluoroacetyl)-6-[4-(2,2,2-trifluoroethyl-aminocarbonyl)-benzylamino]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][CH:12]2[CH2:14][O:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH3:17][NH:18][CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=2)[N:21]=1>C(O)C>[OH:13][CH:12]([CH2:14][N:18]([CH3:17])[CH2:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=2)[N:21]=1)[CH2:11][O:10][C:9]1[CH:15]=[CH:16][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:7][CH:8]=1
Reactant: CNCc1ccc2cc([N+](=O)[O-])ccc2n1
Reactant: CS(=O)(=O)Nc1ccc(OCC2CO2)cc1
Solvent: CCO
Product: CN(Cc1ccc2cc([N+](=O)[O-])ccc2n1)CC(O)COc1ccc(NS(C)(=O)=O)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a stirring solution of 2-[(4-(methanesulfonamido)phenoxy)methyl]oxirane (5.32 g, 21.89 mmol) in ethanol (140 mL) was added the 2-(methylaminomethyl)-6-nitroquinoline (4.75, 21.89 mmol) and the resulting mixture was stirred at 50° C. overnight. The reaction mixture was cooled, concentrated, and subjected to purification by HPLC (10% methanol-ethyl acetate) to afford 1.96 g of product as a yellow amorphous solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[C:4]([C:18]([O:20][CH3:21])=[O:19])[N:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[C:22]1([C:2]2[N:6]3[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]3=[C:4]([C:18]([O:20][CH3:21])=[O:19])[N:3]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CC2
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2
Temperature: 110 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
To a round-bottomed flask charged with Intermediate 1H (2 g, 5.55 mmol), phenyl boronic acid (2.07 g, 16.65 mmol), [Pd-(dppf)Cl2] (0.45 g, 10 mol %), and cesium carbonate (5.45 g, 16.65 mmol) was added toluene (anhydrous and de-gassed; 80 mL). The reaction mixture was heated to 110° C. while stirring under argon for 6 hours. After cooling to room temperature, saturated aqueous NaHCO3 solution was added and the mixture was extracted three times with ethyl acetate. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the crude product. Purification by column chromatography (silica), eluting with ethyl acetate/hexane mixtures, provided Intermediate 3A as a white solid (70% yield). 1H-NMR (400 MHz, CDCl3) δ: 1.52 (s, 9H), 3.79 (m, 2H), 3.93 (s, 3H), 4.12 (m, 2H), 5.00 (s, 2H), 7.43-7.47 (m, 3H), 7.63-7.66 (m, 2H). LCMS (+ESI) m/z 358.28 [M+H]+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[O:13][CH3:14].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[C:24](Cl)=[O:25].Cl>C(Cl)Cl>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][C:10]=1[C:24]([C:16]1[O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=1)=[O:25]
Reactant: COc1cccc(Cl)c1Cl
Reactant: O=C(Cl)c1cc2ccccc2o1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc3ccccc3o2)c(Cl)c1Cl
Temperature: 0 °C
Yield: 76.1 %

Procedure:
14 g (0.1 mole) of aluminium chloride are introduced little by little in a solution of 16 g (0.09 mole) of 2,3-dichloro-anisol and 16 g (0.09 mole) of 2-benzofurancarboxylic acid chloride in 200 ml of methylene chloride the mixture is taken up to reflux for 4 hours, then poured on crushed ice (300 g) and concentrated hydrochloric acid (10 ml); the precipitate is filtered off, washed with an aqueous solution of sodium hydroxide (10 N), then with water and dried. 22 g of 2-benzofuryl (2,3-dichloro-4-methoxy-phenyl) ketone are obtained. Melting point 148° C. after crystallization from ethylacetate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1.[OH:21][CH2:22][C:23]([NH:25][NH2:26])=O>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][OH:21])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[C:6]=2[CH:20]=1
Reactant: NNC(=O)CO
Reactant: Fc1ccc2c(c1)C(c1ccccc1Cl)=NCC(=S)N2
Solvent: CCCCO
Product: OCc1nnc2n1-c1ccc(F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-7-fluoro-5-(o-chlorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol was refluxed to give 8-fluoro-1-(hydroxymethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].Cl.[NH2:22][CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)cc1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and methyl 4-(aminomethyl)benzoate hydrogen chloride (81 mg, 0.39 mmol). The title compound was obtained as a solid (70 mg, 35% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.46 (1H, m), 8.98 (2H, s), 8.48 (1H, s), 7.91 (2H, m), 7.43 (2H, m), 4.49 (2H, m), 3.84 (3H, s). MS m/z: 496.31, 498.15 [M+H]+.
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.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.O>[Br:8][C:7]1[C:2]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1cccnc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Fc1ccc(-c2ncccc2Br)cc1
Temperature: 80 °C

Procedure:
In a 2-5 mL Smith Process Vial, 2,3-dibromopyridine (300.0 mg, 1.266 mmol), 4-fluorophenyl boronic acid (177.2 mg, 1.266 mmol, 1 equiv) and Pd(PPh3)4 (73.2 mg, 0.063 mmol, 0.05 equiv) were placed. The mixture was suspended in 1,4-dioxane (3 mL) and 2M-Na2CO3 (1 mL) under a nitrogen atmosphere. The mixture was heated at 80° C. for 10 min using the microwave reactor. To the mixture were added EtOAc (70 mL) and water (30 mL). The whole was filtered through Celite (3 g) and the filtrate was washed with brine (30 mL), dried over Na2SO4 and concentrated under a reduced pressure. Obtained crude material was purified by Gilson preparative HPLC to give 3-bromo-2-(4-fluorophenyl)pyridine.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:8]([C:9]([O:11]C)=[O:10])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:6]=[N:5]1.Cl>CO>[CH3:3][N:4]1[C:8]([C:9]([OH:11])=[O:10])=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:6]=[N:5]1
Reactant: COC(=O)c1c(-c2ccc(C)cn2)cnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2cnn(C)c2C(=O)O)nc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
An aqueous solution (1.3 ml) of sodium hydroxide (50 mg) was added to a methanol (1.3 ml) solution of the methyl 1-methyl-4-(5-methylpyridin-2-yl)-1H-pyrazole-5-carboxylate (100 mg) obtained in (Example 1.1) <Step 2>. The obtained mixture was stirred at 70° C. for 1 hour. Thereafter, 1 N hydrochloric acid was added to the reaction solution to adjust the pH value to pH 5, and the reaction mixture was then extracted with methylene chloride three times. The organic layer was successively washed with water and a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and a mixed solution of diethyl ether and heptane (1:1) was added to the obtained residue to solidify it, so as to obtain the title compound (74 mg) in the form of a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[Na].[CH3:12][C:13]1[C:14]([CH2:25][S:26]([C:28]2[NH:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[N:29]=2)=[O:27])=[N:15][CH:16]=[CH:17][C:18]=1[O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24]>C(N(CC)CC)C.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:29]2[C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[N:32]=[C:28]2[S:26]([CH2:25][C:14]2[C:13]([CH3:12])=[C:18]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[CH:16][N:15]=2)=[O:27])(=[O:9])=[O:8])[CH:2]=1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cccnc2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
100 mg of pyridine-3-sulfonyl chloride was added to 191 mg of 2-[[[3-methyl-4-(3-methoxypropoxy)-2-pyridyl]methyl]sulfinyl]-1H-benzimidazole sodium salt in a mixture of 0.15 ml of triethylamine and 10 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight. Dichloromethane (20 ml) was added and washed with water, and 0.1M sodium bicarbonate solution. Organic layer was dried over anhydrous magnesium sulfate and evaporated. Residue was dissolved in minimum amounts of acetonitrile and ethyl ether was added for precipitation. Solids was collected and dried to give 127 mg of the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:53]=[CH:52][C:51]([NH:54][C:55]([C:57]2([C:60](O)=[O:61])[CH2:59][CH2:58]2)=[O:56])=[CH:50][CH:49]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[F:37][C:4]1[CH:3]=[C:2]([NH:1][C:60]([C:57]2([C:55](=[O:56])[NH:54][C:51]3[CH:50]=[CH:49][C:48]([F:47])=[CH:53][CH:52]=3)[CH2:58][CH2:59]2)=[O:61])[CH:36]=[CH:35][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=3)[S:15][C:8]=12
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.7 %

Procedure:
To intermediate 13 (0.58 g, 1.1 mmol) and DIPEA (0.58 mL, 0.43 g, 3.3 mmol) in dry DMF (20 mL) was added 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (16) [U.S. 2007/0004675 A1] (0.35 g, 1.5 mmol) and HATU (0.72 g, 1.9 mmol). The mixture was stirred at r.t. for 18 h and partitioned between ethyl acetate and water. The organic phase was collected, washed with water, 1M NaOH, brine, dried (anhydrous MgSO4), filtered, and concentrated. Silica gel chromatography (ethyl acetate) afforded intermediate 17 (0.60 g, 74% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.40 (s, 1H), 10.01 (s, 1H), 8.52-8.49 (m, 2H), 8.33 (s, 1H), 8.27-8.24 (m, 1H), 7.92-7.88 (m, 1H), 7.78 (dd, J=8.2, 2.1 Hz, 1H) 7.65-7.60 (m, 2H), 7.52-7.42 (m, 2H), 7.14 (t, J=8.8 Hz, 2H), 6.65 (d, J=5.1 Hz 1H), 4.47 (s, 2H), 3.42-3.30 (m, 4H), 3.22 (s, 3H), 1.46-1.30 (m, 13H). MS (m/z): 730.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[O:13][C:12]2[CH:14]=[C:15]([F:21])[C:16]([C:18](O)=[O:19])=[CH:17][C:11]=2[O:10]1.[C:29](C1NC=CN=1)([C:31]1[NH:32][CH:33]=CN=1)=O.C(NC)C>CN(C)C=O>[CH2:31]([N:32]([CH3:33])[C:18]([C:16]1[C:15]([F:21])=[CH:14][C:12]2[O:13][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[O:10][C:11]=2[CH:17]=1)=[O:19])[CH3:29]
Reactant: O=C(O)c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: CCNC
Solvent: CN(C)C=O
Product: CCN(C)C(=O)c1cc2c(cc1F)OC(c1ccc(F)cc1)(c1ccc(Cl)cc1Cl)O2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of [2-(2,4-dichloro-phenyl)-6-fluoro-2-(4-fluoro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid (Example 108d, 220 mg; 0.52 mmol; 1 eq.) in N,N-dimethylformamide (5 mL), was added carbonyl diimidazole (110 mg; 0.68 mmol; 1.3 eq.) and the mixture stirred 2 h at 20° C. A solution of ethyl-methylamine in N,N-dimethylformamide (1M, 1 mL; 1.3 mmol; 2.5 eq.) was added and the reaction mixture stirred 4 days at 20° C. Purification by preparative HPLC (YMC pro C18) afforded the title compound as 10 mM DMSO stock solution.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:13])[C:4]2[C:9]([C:10]=1C=O)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:14][N:15]1C2C(=CC=CC=2)C(C=O)=[CH:16]1>>[Cl:1][C:2]1([CH2:14][NH:15][CH3:16])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH3:13]
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: Cn1c(Cl)c(C=O)c2ccccc21
Product: CNCC1(Cl)Cc2ccccc2N1C
Yield: 90 %

Procedure:
According to the procedure of Preparation 12, except substituting 2-chloro-1-methyl-1H-indole-3-carboxaldehyde (3.0 g, 15.5 mmole) for the 1-methylindole-3-carboxaldehyde, the title compound (2.91 g, 90%) was prepared as an oil: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, J=7.9 Hz, 1H), 7.22 (m, 2H), 7.13 (m, 1H), 3.92 (s, 2H), 3.71 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH3:11])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-].C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:11][C:5]1([CH2:3][OH:2])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: COC(=O)C1(C)CCOCC1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A −78° C. solution of 4-methyl-tetrahydro-pyran-4-carboxylic acid methyl ester (Regan, J. et al. J. Med. Chem. 2002, 45, 2994-3008; 9.9 g, 63 mmol) in CH2Cl2 (400 mL) was treated with DIBAL-H (1.0 M in CH2Cl2; 125 mL, 125 mmol). The resulting mixture was stirred for 1 h, and then was diluted with EtOAc (200 mL) and satd. aq. NH4Cl. The mixture was treated with satd. aq. sodium potassium tartrate, allowed to warm to rt, and stirred for 45 min. The mixture was extracted with CH2Cl2 (4×), and the combined extracts were washed with satd. aq. NaCl, dried, and concentrated. Chromatography (EtOAc/hexanes) afforded the title compound as a colorless oil (5.6 g 69%). The spectral data matched that reported in PCT Intl. Pat. Appl. Publ. No. WO 2006/001752.