Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: COc1ccc(C(C)=O)c(F)c1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)O)c(F)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a solution of 2′-fluoro-4′-methoxyacetophenone (4.45 g, 26.5 mmol) in dry THF (50 mL) at 0° C., a solution of 2.4 M methyl magnesium bromide (11.6 mL, 27.8 mmol) was added. The mixture was stirred at 0° C. and then room temperature for 4 h. The reaction was quenched with saturated NH4Cl solution. The organic was extracted with EtOAc (3×50 mL). The combined EtOAc layers were washed with brine and dried over Na2SO4. The resulting alcohol was obtained as an oil after flash chromatography using EtOAc:hexane=2:8 as the eluant.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]([OH:13])(O)[C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[OH:22]>C(O)(=O)C>[OH:13][C:9]1([C:19]2[CH:18]=[C:17]([CH3:21])[C:16]([OH:22])=[C:15]([CH3:14])[CH:20]=2)[C:10](=[O:11])[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:7]1=[O:8]
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Reactant: Cc1cccc(C)c1O
Solvent: CC(=O)O
Product: Cc1cc(C2(O)C(=O)c3ccccc3C2=O)cc(C)c1O
Yield: 19.6 %

Procedure:
Ninhydrin (1.00 g, 5.61 mmol) and 2,6-dimethylphenol (686 mg, 5.61 mmol) was dissolved in acetic acid (15 ml), and this solution was heated for 13 hrs. The reaction mixture was concentrated, and extracted with dichloromethane, and then concentrated organic layer was purified using column chromatography (ethylacetate:hexane=1:2) to afford the title compound (0.31 g, 20%).
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[SH:5][C:6]1[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1>C[O-].[Na+]>[CH:11]([C:8]1[N:7]=[C:6]([S:5][CH2:3][C:2]#[CH:1])[NH:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1n[nH]c(S)n1
Reactant: C#CCBr
Agent: C[O-]
Agent: [Na+]
Product: C#CCSc1nc(C(C)C)n[nH]1

Procedure:
11.9 g. Prop-2-ynyl bromide was added to a solution of 14.3 g. 5-mercapto-3-isopropyl-1,2,4-triazole in sodium methoxide solution (2.3 g. sodium dissolved in 200 ml. methanol). Then the solution was boiled under reflux for 2 1/2 hours. The solvent was evaporated under reduced pressure from the steam bath and the residual solid triturated with 500 ml. cold water, filtered off and dried under vacuum to give 3-isopropyl-5-prop-2-ynylthio-1,2,4-triazole which was purified by recrystallisation in the presence of charcoal, from petroleum ether (boiling point 80°-100° C.). The melting point of the product was 91°-92° C.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:13]=[N:12][C:5]=3[CH:6]=[N:7][C:8]=2[CH:9]=[CH:10][CH:11]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][CH:16]([CH3:18])[CH2:15][N:14]1[C:4]2[C:3]3[C:2]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]=[CH:6][C:5]=2[N:12]=[CH:13]1
Reactant: CC(C)Cn1cnc2cnc3cccc(Br)c3c21
Reactant: OB(O)c1ccccc1
Product: CC(C)Cn1cnc2cnc3cccc(-c4ccccc4)c3c21

Procedure:
9-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (0.34 mmol) and benzene boronic acid (62 mg, 0.51 mmol) were coupled according to Part J of Example 1. The work-up procedure described in Parts 125–135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 85:15) to provide 1-(2-methylpropyl)-9-phenyl-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].CC([O-])=O.[Na+].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[CH:34]=O.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH2:9][O:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([NH:21][CH2:34][C:30]3[O:29][CH:33]=[CH:32][CH:31]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(N)ccc2F)COC1
Reactant: O=Cc1ccco1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=NC(C)(c2cc(NCc3ccco3)ccc2F)COC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of [5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (77.5 mg, 0.240 mmol) and NaOAc (59.0 mg, 0.719 mmol) in MeOH (1 ml) was added 2-furaldehyde (0.020 ml, 23.0 mg, 0.240 mmol). The reaction mixture was degassed with Ar and stirred for 15 min at 100° C. in a microwave. After cooling to 0° C., NaBH4 (10.02 mg, 0.252 mmol) was added portionwise and stirring was continued at rt for 1 h. The reaction mixture was quenched with water and diluted with EtOAc. The phases were separated and the aq. layer was twice reextracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting title compound was purified by FC (cyclohexane:EtOAc 100:0 to 80:20).
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH2:22][CH2:23][N:24]([CH3:34])[C:25](=[O:33])[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:17](=[O:35])[CH2:16][CH2:15]2>C(O)C>[CH3:34][N:24]([CH2:23][CH2:22][N:18]1[C:19]2[C:14](=[CH:13][C:12]([NH:11][C:7]([C:3]3[S:2][CH:6]=[CH:5][CH:4]=3)=[NH:8])=[CH:21][CH:20]=2)[CH2:15][CH2:16][C:17]1=[O:35])[C:25](=[O:33])[O:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(CCN1C(=O)CCc2cc(N)ccc21)C(=O)Oc1ccccc1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CN(CCN1C(=O)CCc2cc(NC(=N)c3cccs3)ccc21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (1.62 g, 5.71 mmol) was weighed into a round bottom flask with a stirbar. Phenyl 2-(6-amino-2-oxo-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (0.969 g, 2.85 mmol) was dissolved in ethanol (50 mL) and added to the flask. The resulting suspension was stirred overnight at room temperature. When the reaction was finished, argon was bubbled through the reaction mixture for 1 h, then the mixture was neutralized with sodium carbonate (sat. aq. solution). The product was extracted with dichloromethane (3×). The combined organics were dried over sodium sulfate, filtered and concentrated. The residue was chromatographed in (1:1) ethyl acetate:CH2Cl2 then 10% (2M NH3 in methanol) in dichloromethane. Yield: 700 mg, 55%. 1H NMR (DMSO-d6) δ 7.91 (m, 2H), 7.38 (m, 2H), 7.26 (m, 3H), 7.04 (m, 4H), 4.23 and 4.14 (2m, 2H), 3.63 and 3.51 (2m, 2H), 3.06 and 2.92 (2s, 3H), 2.84 (t, 2H, J=6.9 Hz), 2.56 (t, 2H, J=6.9 Hz); ESI-MS (m/z, %): 449 (MH+, 100).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)#[N:2].[Cl:12]N1C(=O)CCC1=O>CN(C=O)C>[Cl:12][C:6]1[C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:1]#[N:2])[CH:4]=2)[NH:8][CH:7]=1
Reactant: N#Cc1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To a solution of 5-cyanoindole (3.0 g, 21 mmol) in dry DMF (50 ml) was added N-chlorosuccinimide (2.94 g, 22 mmol) and the solution stirred at room temperature for 1 hour. The solution was left standing over the weekend. LC/MS showed a single product. Added ethyl acetate (150 ml) and diethyl ether (50 ml) and washed with water (3×300 ml). Dried over MgSO4 and evaporated off the solvent to yield 3.9 g of the title compound as a pale yellow solid. δH (400 MHz, d6-DMSO) 7.54 (1H, dd), 7.61 (1H, dd), 7.78 (1H, d), 8.01-8.02 (1H, m), 12.2 (1H, broad s). MS (from LCMS of reaction mixture) (ES):C9H5ClN2 requires 176; found 177 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([O:23][CH3:24])[CH:5]=1.[CH3:26][C:27]1[N:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:1][O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:33][C:30]2[CH:29]=[N:28][C:27]([CH3:26])=[CH:32][N:31]=2)=[O:13])=[C:6]([O:23][CH3:24])[CH:5]=1
Reactant: Cc1cnc(N)cn1
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(OC)c1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)Nc2cnc(C)cn2)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 3-methoxy-4-(4-nitro-phenoxycarbonylamino)-benzoic acid methyl ester (11.7 g, 33.8 mmol) in 34 mL NMP at room temperature under nitrogen was added 5-methyl-2-aminopyrazine (3.69 g, 33.8 mmol) and the reaction was immersed in an 85° C. oil bath. After 6 hours the reaction was allowed to cool to room temperature and a precipitate formed. EtOAc (200 mL) was added and the precipitate was isolated by filtration (4.7 g, 44%). 1H-NMR (400 MHz, d6-DMSO) 6 8.79 (br s, 1H), 8.36 (d, 1H), 8.23 (s, 1H), 7.60 (d, 1H), 7.52 (s, 1H), 3.98 (s, 3H), 3.81 (s, 3H), 2.42 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:27]O)[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[C:24]2[C:20]([C:21](=[CH:27][NH:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:14][CH:13]=3)[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Product: O=C1Nc2cc(F)ccc2C1=CNc1ccc(OCCN2CCCC2)cc1
Yield: 48.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (690 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (500 mg, 2.79 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (500 mg, 48%).
Reaction SMILES: C(ON=O)(C)(C)C.[C:8]([C:10]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][C:15](N)=[CH:16][CH:17]=2)[O:12][C:11]=1N)#[N:9]>CN(C=O)C>[C:8]([C:10]1[CH:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12][CH:11]=1)#[N:9]
Reactant: N#CC1=C(N)Oc2cc(N)ccc2C1c1ccccc1
Agent: CC(C)(C)ON=O
Solvent: CN(C)C=O
Product: N#CC1=COc2ccccc2C1c1ccccc1
Reaction time: 0.08 h
Yield: 27.4 %

Procedure:
To a three-neck RB flask equipped with a thermometer and a condenser containing anhydrous DMF (1 mL) at 65° C. was added tert-butylnitrite (0.4 mL, 3.02 mmol), followed by slow addition of 3-cyano-2,7-diamino-4-phenyl-4H-chromene (263 mg, 1.0 mmol) in anhydrous DMF (1 mL) in 10 min. The reaction was stirred further for 5 min, then quenched with addition of water (10 mL). The mixture was extracted with EtOAc (3×10 mL). The EtOAc was washed with water (5 mL), brine (5 mL), dried over MgSO4, and evaporated. The red residue was purified by chromatography on silica gel with EtOAc and hexane (1:4) as eluant to yield 64 mg (26%) of the product as an off-white solid. 1H NMR (CDCl3): 7.4-7.18 (m, 7H), 7.07-7.01 (m, 2H), 6.96-6.62 (m, 1H), 4.77 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:6]([CH3:14])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2.O.O.[Sn](Cl)Cl.[OH-].[Na+].Cl.O1CCOCC1>C(O)C.O1CCOCC1.C(OCC)C.O>[ClH:1].[Cl:1][C:2]1[CH:18]=[C:17]([CH:16]=[CH:15][C:3]=1[O:4][C:5]1[C:6]([CH3:14])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)[NH2:19]
Reactant: Cc1c(Oc2ccc([N+](=O)[O-])cc2Cl)ccc2[nH]ncc12
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1c(Oc2ccc(N)cc2Cl)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 73.5 %

Procedure:
Under nitrogen, the 5-(2-chloro-4-nitrophenoxy)-4-methyl-1H-indazole (120 mg, 0.395 mmol) obtained in Example 738 was dissolved in ethanol (6 ml), followed by adding thereto tin(II) chloride dihydrate (446 mg, 1.98 mmol), and the resulting mixture was stirred at 80° C. for 1 hour. The reaction solution was cooled to room temperature and then poured into water, and the resulting mixture was adjusted to pH>8 with a 1N aqueous sodium hydroxide solution and extracted twice with ethyl acetate/tetrahydrofuran=5/1. The combined extract layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, 1/1, 1/2) to obtain a yellow solid. The solid obtained was dissolved in 1,4-dioxane (2 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (2 ml), and the resulting mixture was stirred at room temperature. Thereafter, diethyl ether (about 15 ml) was added thereto and stirred, and the yellow solid precipitated was collected by filtration, washed with diethyl ether and then dried under reduced pressure to obtain 3-chloro-4-[(4-methyl-1H-indazol-5-yl)oxy]aniline monohydrochloride (45 mg, yield 42%).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22]Br)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]>CN(C)C=O.O>[C:10]([O:13][C:14]1[C:15]([CH3:27])=[C:16]([CH3:26])[C:17]2[O:21][CH:20]([CH2:22][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][C:18]=2[C:24]=1[CH3:25])(=[O:12])[CH3:11]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CBr)O2
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC(CSc1ccccc1)O2
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
To a solution of thiophenol [425 mg (3.8 mmol)] in dimethylformamide (10 ml) was added, under ice-cooling, sodium hydride [167 mg (4.2 mmol, content:60%)]. To the reaction mixture was added, after stirring for 20 minutes, a solution of 5-acetoxy-2-bromomethyl-4,6,7-trimethyl-2,3-dihydrobenzofuran [1.2 g (3.8 mmol)] dimethylformamide (5 ml). The mixture was stirred for further 30 minutes. The reaction mixture was diluted with water, which was subjected to extraction with ethyl acetate. The extract solution was washed with water, dried and concentrated. The concentrate was crystallized from isopropylether-hexane to afford 5-acetoxy-4,6,7-trimethyl-2-phenylthiomethyl-2,3-dihydrobenzofuran (Compound 4) [1.2 g (yield : 91.3%)]. In a manner as above, compounds 2, 6, 8, 10, 12 and 18 were synthesized by employing the corresponding thio compounds (3-mercaptopropionic acid, 1-octanethiol, 2-mercaptopyridine, 4-fluorothiophenol, 2-naphthalene thiol and benzyl mercaptan). Incidentally, when 3-mercaptopropionic acid was employed as the starting compound, 2.2 equivalents of sodium hydride was used.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl[C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[O:26])[CH2:20]2)[CH:16]=[CH:15][N:14]=1>CS(C)=O>[O:1]1[CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([NH:11][C:13]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([NH:27][CH2:28][C:29]5[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[O:26])[CH2:20]4)[CH:16]=[CH:15][N:14]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Cc1ccc(CNC(=O)[C@H]2CCCN(c3ccnc(Cl)n3)C2)cc1
Solvent: CS(C)=O
Product: Cc1ccc(CNC(=O)[C@H]2CCCN(c3ccnc(Nc4ccc5c(c4)OCCO5)n3)C2)cc1
Temperature: 90 °C
Yield: 18 %

Procedure:
A mixture of 1,4-benzodioxan-6-amine (Sigma-Aldrich, 65.8 mg, 0.435 mmol) and (S)-1-(2-chloropyrimidin-4-yl)-N-(4-methylbenzylipiperidine-3-carboxamide (M5, 100 mg, 0.290 mmol) in DMSO (0.6 mL) was heated at 90° C. for 16 hours. The mixture was then cooled to room temperature, filtered and was purified with reversed-phase HPLC (Phenomenex Gemini-NX 10 μL 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% ACN/H2O, 0.1% TFA, 10 min gradient). After concentration of the fractions by vacuum distillation, the product was diluted with saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide the desired product in 18% yield. 1H NMR (300 MHz, CDCl3) δ ppm 1.66-1.79 (m, 2H), 1.85-2.00 (m, 1H), 2.04-2.19 (m, 1H), 2.30 (s, 3H), 2.45 (br. s., 1H), 3.24 (t, J=9.9 Hz, 1H), 3.69 (dd, J=13.7, 8.0 Hz, 1H), 3.83 (d, J=12.6 Hz, 1H), 4.12 (d, J=12.1 Hz, 1H), 4.19 (s, 4H), 4.34 (d, J=5.4 Hz, 2H), 6.00 (d, J=6.1 Hz, 1H), 6.39 (br. s., 1H), 6.76 (d, J=8.6 Hz, 1H), 6.85 (dd, J=10.7, 9.1 Hz, 1H), 6.79-6.92 (m, 1H), 7.07 (s, 4H), 7.17-7.22 (m, 1H), 7.89 (d, J=6.3 Hz, 1H); M+H 460.23367.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:26]=[CH:27][C:28]=2[CH3:29])[CH2:11][N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@@H:13]2[CH3:25])[CH:5]=[CH:4][N:3]=1.[F:30][C:31]1[CH:32]=[C:33]([CH2:38][CH2:39][NH2:40])[CH:34]=[C:35]([F:37])[CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:38][CH2:39][NH:40][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]3[CH3:25])[CH:26]=[CH:27][C:28]=2[CH3:29])[CH:5]=[CH:4][N:3]=1
Reactant: NCCc1cc(F)cc(F)c1
Reactant: Cc1ccc(CN2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1-c1ccnc(Cl)n1
Product: Cc1ccc(CN2CCNC[C@@H]2C)cc1-c1ccnc(NCCc2cc(F)cc(F)c2)n1

Procedure:
Intermediate 158 from above was coupled with 2-(3,5-difluorophenyl)ethanamine following procedure F. The product was deprotected by procedure G2. LC-MS showed the product had the expected M+H+ of 438. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.31 ppm) δ 8.4 (d, 1H) 8.0 (d, 1H) 7.7 (d, 1H) 7.5 (d, 1H), 7.4 (d, 1H), 6.9 (d, 2H) 6.7 (t, 1H), 3.9-3.8 (m, 3H) 3.7-3.6 (m, 6H) 3.5-3.4 (m, 2H) 3.0 (t, 2H), 2.5 (s, 3H), 1.7 (d, 3H).
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C@@H:10]1[C@@H:17]2[C@@H:13]([O:14][C:15]([CH3:19])([CH3:18])[O:16]2)[CH:12]=[CH:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>ClCCl>[C:1]([Si:5]([O:8][CH2:9][C@@H:10]1[C@H:17]2[O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]2[C@@H:12]2[O:28][C@H:11]12)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C=C[C@@H]2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)O[C@H]2[C@@H]3O[C@@H]3[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
To a stirred solution of compound 9 (5.0 g, 17.5 mmol) in dichloromethane (40 mL) at room temperature was added portion wise m-CPBA (13.6 g, 78.9 mmol). Mixture was stirred at room temperature for 6 h, quenched with saturated NaHCO3 solution and the mixture was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (40 mL×2) dried over Na2SO4. The solvent was removed under reduced pressure and residue was purified by silica gel column chromatography (3% EtOAc/Hexane) to give epoxide 10 (3.5 g, 66%) as an oil. [α]24D+58.19° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.54-4.52 (m, 1H), 3.91-3.90 (m, 1H), 3.73-3.69 (m, 1H), 3.59-3.55 (m, 3H), 2.316-2.311 (m, 1H), 1.38 (s, 3H), 1.22 (s, 3H), 0.83-0.82 (m, 9H), 0.006-0.000 (m, 6H); HR-MS Calcd. For (C15H28O4Si+H)+ 301.1757. found 301.1895.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[OH:12])=[CH:4][CH:3]=1.O[CH2:21][C:22]([O:24][CH3:25])=[O:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[O:12][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][CH:3]=1
Reactant: COC(=O)CO
Reactant: Oc1ccc(C(O)CCCc2ccc(Cl)cc2)cc1
Product: COC(=O)COC(CCCc1ccc(Cl)cc1)c1ccc(O)cc1
Temperature: 80 °C

Procedure:
A mixture of the alcohol of Step 3 (138 mg), methyl hydroxyacetate (80 μL), dry fused ZnCl2 (82 mg) in 1,2-dichloroethane (5 mL) was heated to 80° C. for an hour. The title compound was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using EtOAc:toluene 5:95 and 7.5:92.5. (For reference, see J. Org. Chem., 52 3917 (1987)).
Reaction SMILES: C(S(N1CCC(C2C3C(=C(C(N)=O)C=C([C:21]4[S:22][C:23]([CH2:26][NH:27][CH2:28][CH:29](C)[CH2:30][CH3:31])=[CH:24][CH:25]=4)C=3)NC=2)CC1)(=O)=O)C.C(C1SC([B:43]([OH:45])[OH:44])=CC=1)=O.C(N)CCC.[BH3-]C#N.[Na+]>>[CH2:28]([NH:27][CH2:26][C:23]1[S:22][C:21]([B:43]([OH:45])[OH:44])=[CH:25][CH:24]=1)[CH2:29][CH2:30][CH3:31]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCN
Product: CCCCNCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 49 mg of crude {5-[(butylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(butylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 27.2 mg of the title compound (24%).
Reaction SMILES: [OH:1][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]=2[CH:23]=O)[CH2:7][CH2:6]1)=[O:4].[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])[CH2:33]2)(=[O:29])=[O:28]>>[CH3:25][NH:26][S:27]([C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34](=[O:39])/[C:33]/2=[CH:23]\[C:15]1[NH:16][C:17]2[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=2[C:14]=1[CH2:13][CH2:12][CH2:11][N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[CH2:2][OH:1])[CH2:10][CH2:9]1)(=[O:29])=[O:28]
Reactant: O=Cc1[nH]c2c(c1CCCN1CCN(C(=O)CO)CC1)CCCC2
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c3c(c1CCCN1CCN(C(=O)CO)CC1)CCCC3)C(=O)N2
Yield: 35.7 %

Procedure:
3-{3-[4-(2-Hydroxy-acetyl)-piperazin-1-yl]-propyl}-4,5,6,7-tetrahydro-1H-indole-2-carbaldehyde (134 mg, 0.3 mmol) was condensed with 5-methylaminosulfonyloxindole (76 Mg, 0.33 mmol) following the procedure used in Example 1 to give 58 mg of the desired product.
Reaction SMILES: [CH:1]12[CH2:18][CH:4]([CH:5]([NH:7]C(=O)OCC3C=CC=CC=3)[CH2:6]1)[CH2:3][O:2]2.C[OH:20]>[Pd]>[NH2:7][CH:5]1[CH2:6][CH:1]2[CH2:18][CH:4]1[C:3](=[O:20])[O:2]2
Reactant: O=C(NC1CC2CC1CO2)OCc1ccccc1
Reactant: CO
Agent: [Pd]
Product: NC1CC2CC1C(=O)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of benzyl 2-oxa-bicyclo[2.2.1]heptan-5-ylcarbamate (0.05 g, 2.0 mmol) and Pd/C (10%, 50 mg) in methanol (20 mL) was stirred under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through Celite®. The filtrate was concentrated under reduced pressure to afford 5-amino-2-oxa-bicyclo[2.2.1]heptan-3-one (360 mg, over 100%), which was used in the next step without further purification. LCMS (ESI) m/z: 128.1 [M+H]+.