Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ICC[C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1.[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[C:20]([F:27])[C:19]=1[F:28])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>[Pd].C1(C)C=CC=CC=1.O.C(O)C>[CH2:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:4]2[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=2)=[C:20]([F:27])[C:19]=1[F:28])[CH3:16]
Reactant: CCOc1ccc(B(O)O)c(F)c1F
Reactant: CCOC(=O)c1ccc(CCI)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(-c2ccc(OCC)c(F)c2F)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
Ethyl 4-iodoethylbenzoate (1) (25.0 g), 4-ethoxy-2,3-difluorophenylboronic acid (2) (20.1 g), potassium carbonate (25.0 g), Pd/C (0.25 g), toluene (100 ml), ethanol (100 ml) and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 2 hours. The reaction mixture was cooled to 25° C., and then poured into water (500 ml) and toluene (500 ml), and mixed. The mixture was then allowed to stand until it had separated into two phases of organic and aqueous phases. The extraction to an organic phase was carried out. The organic phase obtained was washed with water, and then dried over anhydrous magnesium sulfate. The solution obtained was concentrated under reduced pressure, and the residue obtained was purified by means of column chromatography (silica gel; toluene). The product was further purified by means of recrystallization from ethanol and dried, giving 18.8 g of ethyl 4-ethoxy-2,3-difluoro-4′-biphenylcarboxylate (3). The yield based on the compound (1) was 67.9%.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:12])[O:7][CH:8]([CH3:11])[C:9]=1O)([CH3:4])([CH3:3])[CH3:2].O.[NH2:14][NH2:15]>C(O)C>[C:1]([C:5]1[C:6](=[O:12])[N:14]=[N:15][C:9]=1[CH:8]([OH:7])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC1OC(=O)C(C(C)(C)C)=C1O
Solvent: O
Solvent: CCO
Product: CC(O)C1=C(C(C)(C)C)C(=O)N=N1
Reaction time: 48 h

Procedure:
3-tert-Butyl-4-hydroxy-5-methyl-5H-furan-2-one (3 g, 17.7 mmol) was dissolved in ethanol (40 ml) with hydrazine hydrate (2.73 ml, 88.5 mmol) and heated under reflux for 14 h. The volume was reduced by evaporation to ˜15 ml and heating continued for a further 48 h. The solvents were removed under high vacuum and the residue was triturated with diethyl ether to leave a white solid (crude 4-tert-butyl-5-(1-hydroxyethyl)pyrazol-3-one, 2.6 g). This white solid (2.6 g, 14 mmol) was dissolved in dichloromethane (70 ml) with tosyl chloride (3.24 g, 16.8 mmol) then cooled to 0° C. and triethylamine (2.56 ml, 18.2 mmol) was added dropwise. The reaction mixture was allowed to warm to ambient temperature then diluted with more dichloromethane (50 ml) and washed with saturated brine (1×100 ml). The organic layer was dried (Na2SO4), filtered and concentrated under vacuum to leave a residue which was purified on silica gel using 20-50% ethyl acetate in isohexane as eluent to give 4-tert-butyl-5-(1-hydroxyethyl)-3-(4-methylphenyl)sulfonyloxypyrazole (3.8 g) as a white solid. 1H NMR (360 MHz, CDCl3) δ 1.34 (9H, s), 1.50 (3H, d, J=6.7 Hz), 2.45 (3H, s), 5.26 (1H, q, J=6.7 Hz), 7.35 (2H, d, J=8.2 Hz), 7.95 (2H, d, J=8.2 Hz), 10.72 (1H, br s); MS (ES+) m/e 339 [MH]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([N+:25]([O-])=O)=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe]>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH2:25])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1N
Reaction time: 1 h

Procedure:
A mixture of 2-(2-(2-acetoxyethyl)-5-nitro-1-oxo-1,2-dihydroisoquinolin-6-ylamino)ethyl acetate (350 mg, 0.00093 mol), ethanol (20 mL, 0.3 mol), ammonium chloride (496.1 mg, 0.009275 mol) and water (10 mL, 0.6 mol) was added at 85° C. Iron (207 mg, 0.00371 mol) was added in two portions, five minutes apart, and was stirred at that temperature for 1 hour. The reaction mixture was then poured onto methylene chloride (100 mL) and the layers were separated. The organic layer was washed with brine and dried. the solvent was removed under reduced pressureunder reduced pressure and the product was used in the next step without purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.[CH3:21][O:22][C:23]1[CH:37]=[CH:36][C:26]([CH2:27][N:28]2[C:32]([CH2:33][NH:34][CH3:35])=[N:31][CH:30]=[N:29]2)=[CH:25][CH:24]=1.C(N(C(C)C)CC)(C)C>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:34]([CH3:35])[CH2:33][C:32]1[N:28]([CH2:27][C:26]3[CH:36]=[CH:37][C:23]([O:22][CH3:21])=[CH:24][CH:25]=3)[N:29]=[CH:30][N:31]=1)=[N:6]2
Reactant: CNCc1ncnn1Cc1ccc(OC)cc1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncnc2CN(C)c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)cc1

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol), N-[[2-(4-methoxybenzyl)-2H-[1,2,4]triazol-3-yl]methyl]methylamine (I-163) (0.18 g, 0.77 mmol) and diisopropylethylamine (0.13 ml, 0.76 mmol) were dissolved in dichloromethane (10 ml), followed by heating under reflux for 3 hours. This was diluted with dichloromethane, washed with water, and dried over anhydrous sodium sulfate.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH2:5][CH:6]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+]>C(O)C>[CH:6]1([CH2:5][CH:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:3]([OH:23])=[O:2])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCCCC1)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCCCC2)C(=O)O)cc1
Temperature: 47.5 °C
Yield: 85.9 %

Procedure:
A solution of 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid methyl ester (95 mg, 0.28 mmol) in ethanol (2 mL) was treated with a 1N aqueous sodium hydroxide solution (1.5 mL). The solution was heated at 45-50° C. for 15 h, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was concentrated in vacuo to remove ethanol. The residue was diluted with water (10 mL) and extracted with diethyl ether (1×20 mL) to remove any neutral impurities. The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution, and the resulting acid was extracted into ethyl acetate (2×15 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cycloheptyl-2-(4-methanesulfonyl-phenyl)-propionic acid (78 mg, 86%) as a white solid: EI-HRMS m/e calcd for C17H24O4S (M+H)+ 325.1474, found 325.1478.
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>ClCCl>[Br:35][CH2:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])[CH:6]=[CH:5][CH:4]=1
Reactant: O=C1CCCN1c1cccc(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1CCCN1c1cccc(CBr)n1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
A stirred solution of 1-(6-hydroxymethylpyridin-2-yl)pyrrolidin-2-one (10.19 g, 53.01 mmol), in dichloromethane (600 mL), was treated with triphenylphosphine (15.29 g, 58.31 mmol) followed by carbon tetrabromide (15.66 g, 58.31 mmol), stirred for 1 h, concentrated in vacuo and purified by column chromatography (SiO2; EtOAc:hexane (1:1)) to give the title compound (10.19 g) as a white solid also containing triphenylphosphine oxide as an impurity; NMR δH (400 MHz, d6-DMSO) inter alia 8.22 (1H, d, J 8.5 Hz), 7.81 (1H, t, J 7.5 Hz), 7.28 (1H, d, J 7.5 Hz), 4.63 (2H, s), 3.98 (2H, t, J 7.0 Hz), 2.58 (2H, t, J 8.0 Hz) and 2.08-2.00 (2H, m); (M+H)+ 255, 257.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][OH:42])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][CH2:41][OH:42])[CH2:38][CH2:39]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(CCO)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(CCO)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 2-(1-((2-bromophenyl)sulfonyl)piperidin-4-yl)ethanol. MS (ESI): mass calcd. for C23H25FN4O3S, 456.16; m/z found, 457.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.31 (d, J=1.2, 1H), 8.10-8.07 (m, 1H), 7.98 (m, 1H), 7.73-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.44-7.41 (m, 1H), 7.34 (s, 1H), 7.32-7.30 (m, 1H), 3.56-3.48 (m, 2H), 3.32 (d, J=4.5, 2H), 2.45-2.36 (m, 2H), 1.61-1.54 (m, 2H), 1.46-1.34 (m, 3H), 1.01-0.87 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:15]=3[N:16]=2)[C:5]([NH:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[CH:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]2[C:31]([O:33][C:34](=O)[C:24]=2[CH:23]=1)=[O:32]>>[CH3:21][C:18]1[CH:19]=[CH:20][C:14]2[O:13][C:12]([C:4]3[CH:3]=[C:2]([N:1]4[C:31](=[O:32])[C:25]5[C:24](=[CH:23][CH:22]=[C:27]([C:28]([OH:30])=[O:29])[CH:26]=5)[C:34]4=[O:33])[CH:7]=[CH:6][C:5]=3[NH:8][CH2:9][CH2:10][CH3:11])=[N:16][C:15]=2[CH:17]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CCCNc1ccc(N)cc1-c1nc2cc(C)ccc2o1
Product: CCCNc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(C)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-propylaminophenyl)-5-methylbenzoxazole (112 mg, 0.4 mmol) and 1,2,4-benzenetricarboxylic anhydride (96 mg, 0.5 mmol) the title compound was obtained (92 mg, 50%). 1H NMR (DMSO) δ 8.60(t, 1H), 8.41(d, 1H), 8.29(s, 1H), 8.08(m, 2H), 7.54(d, 1H), 7.45(d, 1H), 7.30(t, 1H), 7.22(d, 1H), 6.99(d, 1H), 3.34(m, 2H), 2.59(s, 3H), 1.79(m, 2H), 1.12(t, 3H). MS 454.1 m/z (M−H)−.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[C:23]([Cl:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:9]=1[C:10]([N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])=[O:11].[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:43])[F:42])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1.O>C1(C)C=CC=CC=1>[Cl:26][C:27]1[C:28]([N:33]2[C:37]([C:38]([NH:7][C:8]3[C:9]([C:10](=[O:11])[N:12]=[S:13]([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:15])[CH3:16])=[CH:20][C:21]([Cl:25])=[CH:22][C:23]=3[Cl:24])=[O:39])=[CH:36][C:35]([C:41]([F:44])([F:42])[F:43])=[N:34]2)=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(Cl)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1N)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)S(=NC(=O)c1cc(Cl)cc(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl)C(C)C
Reaction time: 0.75 h
Yield: 87.9 %

Procedure:
To a suspension of potassium carbonate (0.892 g, 6.46 mmol, 1.10 equiv) and 2-amino-3,5-dichloro-N-(bis-2-propyl-λ4-sulfanylidene)benzamide (2.05 g, 5.87 mmol) in toluene (30 mL) was added a solution of 2-(3-chloro-2-pyridyl)-5-(trifluoromethyl)pyrazole-3-carbonyl chloride (2.02 g, 5.87 mmol, 1.00 equiv.) in toluene (20 mL) at 60° C. After 45 min at this temperature, the mixture was cooled and water was added. The resulting precipitate was collected by filtration, washed with water and toluene and dried to obtain the title compound (3.07 g, 84%).
Reaction SMILES: Br[C:2]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24][CH3:25])=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([CH3:14])[C:6]1=[O:15].[CH2:26]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:26]([O:33][C:34]1[C:39]([C:2]2[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:17]([O:24][CH3:25])=[CH:16][C:3]=2[CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[N:7]([CH3:14])[C:6]2=[O:15])=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(Br)cc1C(C)(C)C
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: CO
Solvent: ClCCl
Product: COc1cc(Cn2c(=O)n(C)c3ccccc32)c(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Yield: 78 %

Procedure:
step 2—A sealed tube containing 96 (100 mg, 0.25 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (85 mg, 0.37 mmol), Na2CO3 (80 mg, 0.74 mmol) and Pd(PPh3)4 (29 mg, 0.025 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated on a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 30% EtOAc/hexanes to afford 99 mg of 1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-3-methyl-1,3-dihydro-benzoimidazol-2-one (98).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[NH2:32]>>[N:36]1[CH:37]=[CH:38][C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:19][CH:20]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1ccncc1
Product: O=C(N1CCOCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccncc3)no2)C1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 30 mg (0.22 mmol, 1.1 eq.) of N′-hydroxypyridine-4-carboximidamide were reacted according to the General Method 1. Yield: 52 mg (52% of theory)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>C1COCC1.O.CCOC(C)=O>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH3:34])[N:18]=[C:17]3[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(c1ccccc1)c1n[nH]c2ccc(N3CCN(Cc4ccccc4)CC3)cc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1nc(S(=O)(=O)c2ccccc2)c2cc(N3CCN(Cc4ccccc4)CC3)ccc21
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A solution of 5-(4-benzylpiperazin-1-yl)-3-(phenylsulfonyl)-1H-indazole (433 mg, 1.00 mmol) in THF at room temperature is treated with NaH (80 mg, 60% in mineral oil, 2.00 mmol), stirred for 0.5 h, treated with methyl iodide (142 mg, 1.00 mmol), stirred for 16 h, and diluted with water and EtOAc. The organic phase is separated, dried over MgSO4, and concentrated in vacuo. The resultant residue is chromatographed (SiO2, 90:10 EtOAc:hexanes as eluent) to afford the title compound as a white solid, 190 mg (43% yield), mp 195-197° C., identified by mass spectral and NMR analyses.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]([NH:12][C:13](=[O:16])[CH2:14]Cl)([CH3:11])[CH2:9][OH:10])[CH:7]=1.CC([O-])(C)C.[K+]>ClCCl.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C:8]2([CH3:11])[NH:12][C:13](=[O:16])[CH2:14][O:10][CH2:9]2)[CH:7]=1
Reactant: CC(CO)(NC(=O)CCl)c1cc(Br)ccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CC1(c2cc(Br)ccc2F)COCC(=O)N1

Procedure:
The cyclization of the (RS)-N-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide [preparation of building block B e)] with potassium tert-butylate yielded, after chromatography on silica gel using a gradient of dichloromethane/methanol=100/0 to 75/25 as the eluent, the title compound as a white solid. Mass (calculated) C1H11BrFNO2 [288.118]; (found) [M+H]+=288 and [M+2+H]+=290.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]2[C:14]3[CH:13]=[CH:12][C:11]([OH:15])=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:16]=1)[CH3:2].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)(Cl)Cl>[CH3:33][S:34]([O:15][C:11]1[CH:12]=[CH:13][C:14]2[C:5]3[N:4]([CH2:17][CH2:18][O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:3]([CH2:1][CH3:2])=[N:16][C:6]=3[CH:7]=[N:8][C:9]=2[CH:10]=1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1nc2cnc3cc(O)ccc3c2n1CCOc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3cc(OS(C)(=O)=O)ccc3c2n1CCOc1ccccc1
Reaction time: 72 h
Yield: 33.9 %

Procedure:
2-Ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-ol (1.5 g, 4.5 mmol), chloroform (45 mL), and triethylamine (0.697 mL, 5.00 mmol) were combined. Methanesulfonyl chloride (0.348 mL, 4.50 mmol) was added dropwise to the mixture; a flocculent precipitate formed. The reaction was stirred for 72 hours and then quenched with methanol. The volatiles were removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluting with a dichloromethane:methanol gradient) to provide 0.628 g of 2-ethyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c]quinolin-7-yl methanesulfonate as a white solid.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].[C:17]1([C:23]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([CH2:25][C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([OH:24])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(C)=O
Reactant: COc1cccc(CC(=O)c2ccccc2)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(Cc1cccc(OC)c1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 86 %

Procedure:
Lithium hexamethyidisilazane (88.5 mL, 88.5 mmol) was added to THF (150 mL) at −78° C. After 15 minutes, ethyl acetate (7.79 g, 88.5 mmol) was added over 10 minutes and stirred at −78° C. for 30 minutes. The m-methoxybenzyl phenyl ketone in (10.0 g, 44.25 mmol) THF (100 mL) was added over 15 minutes and kept at that temperature for 3 hours. The reaction mixture was quenched at that temperature with saturated ammonium chloride (15 mL). The reaction mixture was diluted with ether (200 mL) and the organic layer was washed with brine, (100 mL), dried and concentrated to afford the desired product (12 g, 86% yield). NMR was consistent with the desired structure.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([O:15]CC)=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[K+].Cl.[Cl-].[Na+]>CO.O>[CH2:1]([C:5]1[S:9][C:8]([CH:10]2[CH2:12][CH:11]2[C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C2CC2C(=O)OCC)s1
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCc1ccc(C2CC2C(=O)O)s1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
Ethyl 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylate (12.6 g, 0.05 mol) was dissolved in methanol (70 ml) and a solution of potassium hydroxide (6.5 g, 0.12 mol) in water (70 ml) added dropwise at room temperature. The solution was refluxed for 3 hours, cooled to room temperature and carefully neutralised with 2M HCl. Saturated sodium chloride was added, the aqueous solution extracted with ethyl acetate (4×75 ml) and dried over anhydrous sodium sulphate. Removal of the solvent gave 2-(5-n-butylthiophen-2-yl)-cyclopropanecarboxylic acid (10.0 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3cccnc3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 3-chloromethyl-pyridine gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[C:16]([CH3:17])=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=[C:13]([CH3:21])[C:8]=3[S:9](=[O:12])(=[O:11])[CH2:10][C:5]=2[CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH2:29]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][N:2]1[C:6]2[C:7]3[C:16]([CH3:17])=[C:15]([C:18]([O:20][C:28]4[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH:29]=4)=[O:19])[CH:14]=[C:13]([CH3:21])[C:8]=3[S:9](=[O:11])(=[O:12])[CH2:10][C:5]=2[CH:4]=[N:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)Cc1cnn(C)c1-2
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1S(=O)(=O)Cc1cnn(C)c1-2
Temperature: 0 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
2.0 g (0.0065 mol) of the title compound of Step B, 1.71 mL (0.0196 mol) of oxalyl chloride (purchase from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and it was then evaporated to dryness. Another 50 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. 0.80 g (0.0071 mol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.8 mL (0.020 mol) of triethylamine, and the mixture was stirred for 3 days while warming to room temperature. The mixture was evaporated to dryness and the crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (6:4) to yield 0.86 g of the title compound of Step C as a solid melting at 196° C. (decomposed). 1H NMR (CDCl3): δ2.2(m,2H), 2.5 (m,2H), 2.64 (s,3H), 2.7 (m,2H), 2.8 (s,3H), 3.8 (s,3H), 4.3 and 4.4 (2d, 2H), 6.06 (s,1H), 7.65 (s,1H), 7.94 (s,1H).