Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:49])[CH2:9][N:10]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH:34][S:35]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:37])=[O:36])=[O:33])=[C:28]([O:42][CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)[CH:27]=3)=[CH:22][CH:21]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO.O>[CH:43]1([O:42][C:28]2[CH:27]=[C:26]([C:23]3[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][N:10]([CH2:9][C@H:8]([OH:49])[C:5]4[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=4)[C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[CH:21][CH:22]=3)[CH:31]=[CH:30][C:29]=2[C:32]([NH:34][S:35]([CH2:38][CH2:39][CH2:40][OH:41])(=[O:36])=[O:37])=[O:33])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc(Cl)nc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N(CCc1ccc(-c2ccc(C(=O)NS(=O)(=O)CCCO)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1cccnc1
Yield: 84.8 %

Procedure:
The mixture of tert-butyl [(2R)-2-(6-chloro-3-pyridyl)-2-hydroxyethyl][2-[3′-(cyclohexyloxy)-4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl]-ethyl]carbamate (145 mg), ammonium formate (128 mg) and palladium on carbon powder (50 mg) in methanol (2 ml) and water (0.2 ml) was refluxed for 50 minutes. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform/methanol=94/6) to give tert-butyl [2-[3′-(cyclohexyloxy)-4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (117 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>C(O)C>[ClH:1].[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([NH2:15])=[O:14])=[C:2]2[NH:21][C:20]1[CH:22]=[CH:23][CH:24]=[C:18]([O:17][CH3:16])[CH:19]=1
Reactant: NC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: COc1cccc(N)c1
Solvent: CCO
Product: COc1cccc(Nc2c(C(N)=O)cnc3ccc(I)cc23)c1
Product: Cl

Procedure:
Intermediate 13 (5.0 g) was dissolved in ethanol (60 ml), 3-methoxyaniline (3.37 ml) (available from Aldrich) was added, and the mixture was heated under reflux for 2.5 h. The resulting precipitate was filtered off and washed with ether to give the title compound.
Reaction SMILES: N[C@H](CC1C=CC(Cl)=CC=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([Br:17])=[CH:15][N:14]=[C:13]3[NH:18][CH:19]=[CH:20][C:12]=23)[CH2:7][CH2:6]1)=[O:4].[C:29]([O:33][C:34]([N:36]([CH:49]([CH3:51])[CH3:50])[CH2:37][C@H:38]([C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1)C(O)=O)=[O:35])([CH3:32])([CH3:31])[CH3:30].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.C(N(CC)CC)C>C(Cl)Cl>[Br:17][C:16]1[C:11]([N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:38]([C:42]3[CH:43]=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=3)[CH2:37][N:36]([CH:49]([CH3:51])[CH3:50])[C:34](=[O:35])[O:33][C:29]([CH3:31])([CH3:32])[CH3:30])[CH2:10][CH2:9]2)=[C:12]2[CH:20]=[CH:19][NH:18][C:13]2=[N:14][CH:15]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Yield: 60.4 %

Procedure:
5-Bromo-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.100 g, 0.282 mmol, see Example 1), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.145 g, 0.424 mmol, see Example H), HOBT-H2O (0.0606 g, 0.395 mmol), EDCI (0.0704 g, 0.367 mmol), and triethylamine (0.0394 mL, 0.282 mmol) were stirred in DCM (5 mL) at room temperature for 5 hours. The reaction was then quenched with saturated Na2CO3 and extracted into DCM. The organics were dried, filtered, and concentrated to give the crude product. Purification (500:6 DCM:MeOH) gave (S)-tert-butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.103 g, 60.2% yield).
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33]2([CH:39]([C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=3)[OH:40])SCCCS2)[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].BrN1C(=[O:54])CCC1=O.ClCCl>CC(C)=O.O.CC(C)=O>[CH2:1]([O:13][C:14]1[CH:15]=[C:16]([C:33](=[O:54])[C:39]([C:41]2[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=2)=[O:40])[CH:17]=[CH:18][C:19]=1[O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCOc1ccc(C2(C(O)c3ccc(Br)cc3)SCCCS2)cc1OCCCCCCCCCCCC
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CCCCCCCCCCCCOc1ccc(C(=O)C(=O)c2ccc(Br)cc2)cc1OCCCCCCCCCCCC
Temperature: 0 °C

Procedure:
A solution of [2-(3,4-bis-dodecyloxy-phenyl)-[1,3]dithian-2-yl]-(4-bromo-phenyl)-methanol (JYC-I-049-A). (10.99 g, 0.015 mol) in 400 mL of acetone was added dropwise to a solution of N-bromosuccinimide (NBS) (45.4 g, 0.255 mol) in 300 mL of 3% water/acetone (v/v) at 0° C. in an ice bath. The reaction mixture was stirred at 0° C. and gradually warmed up to room temperature over 30 min. The mixture was then poured into a saturated aqueous NaSO3 solution (400 mL) and dichloromethane (400 mL). The mixture was stirred for an additional 10 min. The organic layer was washed with water several times and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give a pale yellow solid. Purification was carried out by first recrystallization from hexanes, followed by column chromatography (silica gel, hexanes:dichloromethane=1:1 (v/v)) to afford two products. The major product, 1-(3,4-bis-dodecyloxy-phenyl)-2-(4-bromo-phenyl)-ethane-1,2-dione (JYC-I-053-B), was isolated as a yellow solid. (3.21 g, 33%). 1H NMR (200 MHz, CDCl3, δ): 7.81 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.7 Hz, 2H), 7.54 (d, J=2.0 Hz, 1H), 7.39 (dd, J=2.0 Hz, 8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 1.82 (m, 4H), 1.20-1.52 (m, 40H), 0.85 (t, J=6.2 Hz, 6H). 13C{(H} NMR (50 MHz, CDCl3, δ): 193.60, 192.64, 155.37, 149.46, 132.30, 132.08, 131.24, 130.17, 126.22, 125.60, 112.13, 111.58, 69.23, 69.15, 31.91, 29.61, 29.36, 29.03, 28.88, 25.97, 25.90, 22.68, 14.10. HRMS-FAB (m/z): [M+H]+ calcd for C38H58BrO4, 657.3518; found, 657.3515. Anal. Calcd for C39H57BrO4: C, 69.39; H, 8.73. Found: C, 69.27; H, 8.71. The minor product, 1-(2-bromo-4,5-bis-dodecyloxy-phenyl)-2-(4-bromo-phenyl)-ethane-1,2-dione (JYC-I-053-A), was isolated as a white solid (0.31 g). 1H NMR (200 MHz, CDCl3, δ): 7.85 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.39 (s, 1H), 6.98 (s, 1H), 4.02 (t, J=6.6 Hz, 2H), 4.01 (t, J=6.6 Hz, 2H), 1.82 (m, 4H), 1.20-1.52 (m, 36H), 0.86 (t, J=6.4 Hz, 6H). HRMS-FAB (m/z): [M+H]+ calcd for C38H57Br2O4, 735.2624; found, 735.2638.
Reaction SMILES: [CH2:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[C:5]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:2]=C.ClCCl.[BH4-].[Na+].C[OH:29]>>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:6]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH2:1][CH2:2][OH:29])[NH:8][N:7]=1
Reactant: C=CCc1[nH]nc(-c2ccc(C)cc2F)c1-c1ccccc1
Reactant: CO
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(-c2n[nH]c(CCO)c2-c2ccccc2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Allyl-3-(2-fluoro-4-methylphenyl)-4-phenyl-1H-pyrazole (1.0 g, 3.42 mmol) was dissolved in methanol (40 mL) and dichloromethane (10 mL) and cooled to −78° C. on a dry-ice/acetone bath. Ozone was bubbled through the solution for 2 h, until the solution appeared light blue. To the reaction added sodium borohydride (0.129 g, 3.42 mmol) slowly. Upon complete addition, the reaction was removed from the dry-ice bath and stirred at room temperature for 1 h. Excess solvent was removed under reduced pressure and the reaction was extracted with EtOAc/H2O, dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (0.70 g). LCMS m/z=297.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.30 (s, 3H), 2.79 (t, J=7.20 Hz, 2H), 3.62 (t, J=7.33 Hz, 2H), 6.93-7.00 (m, 1H), 7.09-7.14 (m, 2H), 7.15-7.23 (m, 3H), 7.25-7.31 (m, 2H), 12.86 (bs, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.CO.O.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>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[C:15]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1cnc(Br)cn1
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: O
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
Into a 500-mL sealed tube purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 5-bromopyrazin-2-amine (4 g, 22.99 mmol, 1.00 equiv) in 1,4-dioxane (68 mL) and methanol (23 mL), 3-(trifluoromethyl)phenylboronic acid (4.46 g, 23.48 mmol, 1.02 equiv), a solution of sodium carbonate (4.88 g, 46.04 mmol, 2.00 equiv) in water (23 mL), and Pd(PPh3)4 (532 mg, 0.46 mmol, 0.02 equiv). The resulting solution was stirred overnight at 135° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 4.4 g (80%) of 5-(3-(trifluoromethyl)phenyl)pyrazin-2-amine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[CH:21]=1.[O:30]1[CH2:34]CCC1.[CH3:35][NH:36][CH3:37]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][N:36]([CH3:37])[C:34]([C:2]1[CH:3]=[C:4]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([S:11]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)(=[O:13])=[O:12])[C:6]=2[CH:21]=1)=[O:30]
Reactant: CNC
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(Br)cc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(C)nc3c(OCc4ccccc4)cc(C(=O)N(C)C)cc32)cc1
Temperature: 65 °C
Reaction time: 32 h
Yield: 42 %

Procedure:
A mixture of 6-bromo-2-methyl-1-[(4-methylphenyl)sulfonyl]-4-[(phenylmethyl)oxy]-1H-benzimidazole (53.0 g, 112 mmol, STEP 2) and tetrakis(triphenylphosphine)palladium(0) (25.9 g, 22.4 mmol) in 2M dimethylamine tetrahydrofuran solution (580 mL) was stirred at 65° C. under carbon mono-oxide gas (1 atmosphere) for 32 hours. The mixture was cooled to room temperature, and diluted with ethyl acetate (600 mL). The organic mixture was washed with saturated ammonium chloride aqueous solution (800 mL) and brine (500 mL), dried over magnesium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate gradient elution from 1:2 to 1:3) to afford the title compound as a white solid (21.8 g, 42%).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH2:7][S:8][CH3:9])=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:9][S:8][CH2:7][C:5]1[O:6][C:2]([C:19]2[CH:20]=[CH:21][C:16]([C:15]([F:26])([F:25])[F:14])=[CH:17][CH:18]=2)=[CH:3][C:4]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cc(Br)oc1CSC
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: COCCOC
Solvent: O
Product: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CSC
Reaction time: 8 h
Yield: 75.7 %

Procedure:
A mixture of methyl 5-bromo-2-[(methylsulfanyl)methyl]furan-3-carboxylate (5.3 g), 4-(trifluoromethyl)phenylboronic acid (4.6 g), tetrakis(triphenylphosphine)palladium(0) (1.2 g), 2N aqueous sodium carbonate solution (24 mL) and 1,2-dimethoxyethane (50 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (5.0 g, 75%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]([O:17][CH3:18])[O:15][CH3:16])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].OOS([O-])=O.[K+].[CH:25](=O)[CH:26]([CH3:28])[CH3:27]>CN(C=O)C.O>[CH3:16][O:15][CH:14]([O:17][CH3:18])[CH2:13][N:12]1[C:3]2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=2[N:1]=[C:25]1[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C=O
Reactant: COC(=O)c1cccc(N)c1NCC(OC)OC
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2nc(C(C)C)n(CC(OC)OC)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a stirred solution of methyl 3-amino-2-(2,2-dimethoxyethylamino)benzoate (0.5 g, 2.0 mmol) from Step C of Example 13 in DMF (15 mL) and H2O (0.5 mL) were added oxone (0.8 g, 1.3 mmol) and iso-butyraldehyde (0.2 mL, 2.2 mmol) and the reaction was stirred overnight at room temperature. The reaction mixture was washed with saturated aqueous sodium bicarbonate, re-extracted with methylene chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 0% to 30% ethyl acetate in hexanes) to afford methyl 1-(2,2-dimethoxyethyl)-2-isopropyl-1H-benzo[d]imidazole-7-carboxylate (0.5 g, 85%): 1H NMR (500 MHz, DMSO-d6) δ 7.79 (dd, J=8.0, 1.0 Hz, 1H), 7.56 (dd, J=7.5, 1.0 Hz, 1H), 7.22 (t, J=8.0 Hz, 1H), 4.61 (d, J=5.0 Hz, 2H), 4.38 (t, J=5.0 Hz, 1H), 3.90 (s, 3H), 3.38-3.33 (m, 1H), 3.19 (s, 6H), 1.32 (d, J=7.0 Hz, 6H); MS (ESI+) m/z 306 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([S:20][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Sc1ccccc1
Reactant: COc1ccc2c(Cl)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1ccc2c(Sc3ccccc3)ccnc2c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
In a 25 mL sealed tube under N2, were dissolved 4-chloro-7-methoxyquinoline (1.00 g, 5.16 mmol), thiophenol (0.528 ml, 5.16 mmol) and cesium carbonate (2.52 g, 7.75 mmol) in 5 mL of DMSO then heated at 100° C. After 2 h, the crude reaction mixture was directly purified by MPLC (ISCO, dichloromethane:MeOH 100:0 to 90:10) to afford 7-methoxy-4-(phenylthio)quinoline (1.32 g, 95.6% yield) as an off-white solid. MS (ESI pos. ion) m/z: 268 (MH+). Calc'd exact mass for C16H13NOS: 267. 1H NMR (400 MHz, CDCl3): 8.49 (d, J=4.93 Hz, 1H), 8.13 (d, J=9.22 Hz, 1H), 7.56-7.62 (m, 2H), 7.45-7.53 (m, 4H), 7.23-7.29 (m, 1H), 6.68 (d, J=4.93 Hz, 1H), 3.98 (s, 3H).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O.N1C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:10]1[C:11]2[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=2[N:8]=[CH:9]1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: OB(O)c1ccccc1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ncn2-c2ccccc2Cl)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.9 %

Procedure:
Theophylline (510 mg), 2-chlorophenyl boronic acid (1 g), and copper (II) acetate (220 mg) were suspended in N,N-dimethylformamide (10 ml), and pyridine (1 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 30% aqueous ammonia. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with ether to give 147 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC(C)C.[CH2:29]([O:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[C:39]([N+:44]([O-:46])=[O:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1.C(OCC)(=O)C>[CH2:29]([O:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:11](=[O:13])[CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:10])=[C:39]([N+:44]([O-:46])=[O:45])[CH:38]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(NC(=O)OC(C)(C)C)C(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-D,L-alanine (3.49 g, 18.4 mmol) and triethylamine (2.56 mL, 18.4 mmol) in THF (100 mL) was added 2-methylpropyl chlorocarbonate (2.39 mL, 18.4 mmol) under ice-cooling, and the mixture was stirred for 30 min. To this solution was added 4-(benzyloxy)-2-nitroaniline (3.00 g, 12.3 mmol), and the mixture was heated under reflux at 90° C. for 16 hr under a nitrogen atmosphere. After being allowed to cool to room temperature, the reaction mixture was diluted with ethyl acetate, and the mixture was washed with 0.5N hydrochloric acid, 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. This solution was applied to basic silica gel column chromatography (ethyl acetate). The solvent was evaporated under reduced pressure to give tert-butyl (2-{[4-(benzyloxy)-2-nitrophenyl]amino}-1-methyl-2-oxoethyl)carbamate (5.10 g) as a crude product. To a solution (66 mL) of the obtained oil (5.10 g, 12.3 mmol) in 90% aqueous acetic acid was slowly added zinc powder (8.03 g, 123 mmol) under ice-cooling, and the mixture was stirred for 30 min. The reaction mixture was filtered through celite, and the filtrate was stirred under heating at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The obtained residue was diluted with ethyl acetate, and the mixture was washed with 10% aqueous potassium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solution was applied to basic silica gel column chromatography (ethyl acetate), and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1 to ethyl acetate), and triturated with diisopropyl ether to give the title compound (663 mg, yield in 3 steps 15%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:29]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][C:37]1=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>ClC(Cl)C>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([N:2]2[CH2:3][CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:1]2)[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CCC(N3CCc4ccccc4C3)CC2)cc1

Procedure:
1,2,3,4-Tetrahydroisoquinoline (700 mg, 5.3 mmol), acetic acid (3.2 g, 5.3 mmol), sodium triacetoxyborohydride (2.2 g, 11 mmol) and benzylpiperidone (1.0 g, 5.3 mmol) were stirred at room temperature for 3.5 hours in dichloroethane (7 ml). The reaction solution was alkalified by adding sodium hydroxide aqueous solution, the reaction product was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine and then dried with anhydrous sodium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 900 mg (3.0 mmol, 56% in yield) of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.[CH3:13][Si](C=[N+]=[N-])(C)C.CCCCCC>C1COCC1.CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:2]1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)c1n[nH]c2ccccc12
Temperature: 0 °C
Yield: 68 %

Procedure:
Indazole-3-carboxylic acid (5.00 g, 30.8 mmol) was dissolved in THF (200 ml) and methanol (15 ml). To the resulting solution was added (trimethylsilyl)diazomethane (a 2.0M n-hexane solution, 20 ml, 40.1 mmol) under stirring at 0° C. After stirring at room temperature for 3 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was crystallized by the addition of n-hexane, and the crystals thus obtained were collected by filtration and dried under reduced pressure to give methyl indazole-3-carboxylate (3.71 g, 68%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][S:7][CH:6]=1)=[O:4].[Br:22]N1C(=O)CCC1=O>C(O)(=O)C.C(Cl)(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:8]([Br:22])[S:7][CH:6]=1)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cscc1NS(=O)(=O)c1ccc(OC)cc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1csc(Br)c1NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 18 h
Yield: 81 %

Procedure:
To a solution of the product of Example 2 in 5.0 mL of acetic acid-chloroform (1:1) at room temperature was added 0.299 g (1.682 mmol) of N-bromosuccinimide. The reaction was stirred for 18 h and then diluted with ether, washed with water and saturated sodium bicarbonate solution, dried over MgSO4, filtered and concentrated in vacuo. The tan solid residue was washed with ether-hexanes (1:1) to provide 0.504 g (81%) of the desired product as a tan solid. Electrospray Mass Spec: 406.1 (M+H)+