Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])(=[O:3])[NH2:2].[CH3:18][C:19](=O)[CH2:20][CH2:21][C:22](=O)[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:23][C:22]1[N:2]([S:1]([C:5]2[CH:6]=[C:7]([CH:11]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:13]=2)[C:8]([OH:10])=[O:9])(=[O:3])=[O:4])[C:19]([CH3:18])=[CH:20][CH:21]=1
Reactant: CC(=O)CCC(C)=O
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1S(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1

Procedure:
To a solution of 3-sulfamoyl-5-(trifluoromethyl)benzoic acid (200 mg) and 2,5-hexanedione (0.26 ml) in toluene (1 ml) was added p-toluenesulfonic acid monohydrate (28 mg), and the mixture was stirred under reflux with Dean-Stark Trap for 24 hours. Then 2,5-hexanedione (0.26 ml) and p-toluenesulfonic acid monohydrate (30 mg) was added to the mixture, and the mixture was stirred under the same condition for 24 hours. The mixture was evaporated and purified with column chromatography (silica gel, 50 ml, methanol:dichloromethane (5:95–20:80)) to give 3-[(2,5-dimethylpyrrol-1-yl)-sulfonyl]-5-(trifluoromethyl)benzoic acid (280 mg) as a crude solid. The solid was dissolved in a mixture of 1N sodium hydroxide aqueous solution (10 ml) and water (20 ml), and then adjusted to pH 1–2 with 1N hydrochloric acid (20 ml). The resulting powder was collected by filtration and dried under reduced pressure to give pure product (191.1 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:13])[C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:20][C:21]1[S:22][C:23]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:24][C:25]=1[CH3:26].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl.CN(C)C=O>[CH2:27]([C:23]1[S:22][C:21]([CH3:20])=[C:25]([CH3:26])[C:24]=1[C:5]([C:4]1[CH:8]=[C:9]([CH3:13])[C:10]([O:11][CH3:12])=[C:2]([CH3:1])[CH:3]=1)=[O:7])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1c(C)cc(C(=O)O)cc1C
Reactant: Cc1cc(Cc2ccccc2)sc1C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1c(C)cc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
To a suspension of 3,5-dimethyl-p-anisic acid (15.2 g, 84.4 mmol, RN-21553-46-8) in anhydrous methylene chloride (200 mL) at room temperature under nitrogen was added oxalyl chloride (9.6 mL, 110 mmol) and N,N-dimethylformamide (5 drops). After two hours the solvent was removed. The resulting residue was dissolved in anhydrous methylene chloride (200 mL), and added to 2,3-dimethyl-5-benzylthiophene (17.1 g, 84.4 mmol) under nitrogen. The resulting mixture was, cooled to -78° C., and tin(IV) chloride (10.8 mL, 92.8 mmol) was added quickly. The -78° C. bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was then poured onto ice water (1 L), and the resulting mixture was extracted once with diethyl ether (700 mL), and a second time with diethyl ether (400 mL). The combined diethyl ether extracts were washed with ice water(500 mL), dilute sodium bicarbonate (500 mL), water (500 mL), brine (1L), and then dried (Na2SO4). Concentration under reduced pressure gave the title compound as a yellow oil (25.2 g, 82%): NMR (DMSO-d6) δ 7.40 (s, 2 H), 7.24-7.15 (m, 3 H), 7.06 (d, 2 H), 3.83 (s, 2 H), 3.70 (s, 3 H), 2.28 (s, 3 H), 2.26 (s, 6 H), 1.83 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17]C)=[O:16])[CH2:9]1.[Li+:25].[OH-]>CO>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][CH:7]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][C:15]([O-:17])=[O:16])[CH2:9]1.[Li+:25]
Reactant: COCCCOC(c1ccccc1)C1CCCN(CC(=O)OC)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COCCCOC(c1ccccc1)C1CCCN(CC(=O)[O-])C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(3-((3-methoxypropoxy)(phenyl)methyl)piperidin-1-yl)acetate (19 mg, 0.0567 mmol) was mixed with a 1:1 mixture of 2 N aq LiOH (2 mL) and methanol (2 mL). The mixture was stirred overnight at r.t. LC-MS indicated the reaction was complete. The mixture was concentrated and the crude product was used without purification. LC-MS (3 min) tR=1.05 min, m/z 322 (M+1).
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([N:23]1[C:27]2=[C:28]([N+:35]([O-:37])=[O:36])[C:29](O)=[C:30]([CH3:33])[C:31](=[O:32])[N:26]2[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)(=O)C>C(Cl)Cl>[CH2:16]([N:23]1[C:27]2=[C:28]([N+:35]([O-:37])=[O:36])[C:29]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])=[C:30]([CH3:33])[C:31](=[O:32])[N:26]2[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1c(O)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c2n(c1=O)CCN2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
Triflic anhydride (2.8 g, 0.010 mol) was added to a stirred solution of 1-benzyl-7-hydroxy-6-methyl-8-nitro-2,3-dihydro-1H-imidazo[1,2-a]pyridin-5-one (2 g, 0.007 mol) and TEA (1.34 g, 0.013 mol) in DCM (40 mL) at −78° C. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was monitored by TLC (100% ethyl acetate). The reaction mixture was partitioned between DCM and water. The organic layer was washed with NaHCO3 solution, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 2.5 g of the product (89% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)[CH3:2].S(Cl)([Cl:16])=O>C1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CCOc1ccc(CC(=O)Cl)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a stirred solution of (4-ethoxyphenyl)acetic acid (10.0 g, 55.5 mmol) in benzene (100 mL) was added thionyl chloride (50 mL, 68.5 mmol) and the reaction mixture was stirred at 80° C. for 2 hours. The solvent was evaporated in vacuo and the crude product was purified by distillation (bp 86° C., 0.4 Torr) to provide the title compound (10.39 g, 94%) as a yellow oil. MS of methyl ester: MS (ESI) (M+H)+=194.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32](OC)=[O:33])[N:27]=3)=[C:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:9]2[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:5][CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.O1CCCC1>[OH:33][CH2:32][C:28]1[N:27]=[C:26]([CH2:25][C:7]2[C:6]3[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[C:8]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cccc(Cc2c(-c3ccccc3)n(C(=O)OC(C)(C)C)c3cc(OC)ccc23)n1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2c(Cc3cccc(CO)n3)c(-c3ccccc3)n(C(=O)OC(C)(C)C)c2c1
Yield: 100.4 %

Procedure:
To a solution of tert-butyl 6-methoxy-3-(6-methoxycarbonylpyridin-2-ylmethyl)-2-phenyl-1H-indole-1-carboxylate (628 mg) in methanol/tetrahydrofuran (6 mL/6 mL) was added sodium borohydride (251 mg) under ice-cooling. The mixture was stirred under ice-cooling for 2 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution carefully, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound (593 mg). 1H-NMR (CDCl3) δ ppm: 1.23 (9H, s), 3.89 (3H, s), 3.95-4.01 (1H, m), 4.05 (2H, s), 4.65-4.72 (2H, m), 6.81-6.92 (2H, m), 6.94-7.00 (1H, m), 7.27-7.44 (6H, m), 7.44-7.52 (1H, m), 7.86 (1H, d, J=2.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][C@@H:22]2[CH2:27][OH:28])[NH:12][C:11]([C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[N:10]1.C(OC([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])[C:43]([O:28][CH2:27][C@H:22]1[N:21]([CH2:20][C:13]2[NH:12][C:11]([C:29]3[S:30][CH:31]=[CH:32][N:33]=3)=[N:10][CH:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:26][CH2:25][O:24][CH2:23]1)=[O:44]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)C1=C(CN2CCOC[C@@H]2CO)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC[C@H]2COC(=O)[C@@H](N)C(C)C)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 35.9 %

Procedure:
Ethyl 4-(2,4-dichlorophenyl)-6-(((S)-3-(hydroxymethyl)morpholino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1 g, 1.96 mmol) was reacted with (S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (0.83 g, 3.8 mmol) according to the procedure as described in Example 49 to give the title compound as a yellow solid (0.43 g, 36%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:6]([F:14])=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:8]#[N:9])=[O:4].[BH4-].[Na+].Cl>CO>[Br:1][CH2:2][CH:3]([C:5]1[C:6]([F:14])=[C:7]([CH:10]=[C:11]([F:13])[CH:12]=1)[C:8]#[N:9])[OH:4]
Reactant: N#Cc1cc(F)cc(C(=O)CBr)c1F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1cc(F)cc(C(O)CBr)c1F
Yield: 98.9 %

Procedure:
To a stirred solution of 10.26 g of crude 3-bromoacetyl-2,5-difluorobenzonitrile in 185 mL of MeOH cooled in ice and under N2 is added 1.48 g of NaBH4. 45 Minutes later, 10% HCl is added until pH 4 is reached. The MeOH is evaporated in vacuo and the residue partitioned between 100 mL of saturated NaHCO3 and 3×50 mL of CH2Cl2. The combined CH2Cl2 extracts are washed with 100 mL of H2O, dried with Na2SO4 and stripped to give 10.23 g of 3-(2-bromo-1-hydroxyethyl)-2,5-difluorobenzonitrile as a brown oil with M+1 ions at 262 and 264 in the mass spectrum.
Reaction SMILES: CO.[N+:3]([C:6]1[CH:18]=[C:17](/[CH:19]=[CH:20]/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])([O-])=O>[C].[Pd].C(OCC)(=O)C>[NH2:3][C:6]1[CH:18]=[C:17]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:16]=[CH:15][C:7]=1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccccc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCc2ccccc2)cc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.74 g of 5% palladium-carbon was added to a mixed solution of 56 mL of methanol and 56 mL of ethyl acetate containing 3.7 g of tert-butyl 2-nitro-4-((E)-2-phenylvinyl)benzoate and stirred under hydrogen atmosphere at room temperature for 2 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 3.4 g of tert-butyl 2-amino-4-phenethylbenzoate as white solid.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:17]3[N:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[C:24]([Cl:32])[CH:23]=4)[O:19][N:18]=3)[C:12]=2[CH3:16])[CH2:7]1)C.[OH-].[Na+]>C(O)C.C1COCC1>[Cl:32][C:24]1[CH:23]=[C:22]([C:20]2[O:19][N:18]=[C:17]([C:11]3[C:12]([CH3:16])=[C:13]4[C:8](=[CH:9][CH:10]=3)[CH2:7][N:6]([CH2:5][C:4]([OH:33])=[O:3])[CH2:15][CH2:14]4)[N:21]=2)[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([CH3:30])[CH3:31]
Reactant: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c2C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(CC(=O)O)C2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of ethyl[6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate (Preparation 21; 75 mg; 0.16 mmol) in ethanol (2 ml) and THF (2 ml) at room temperature was added 2N sodium hydroxide, and the resulting mixture was stirred at room temperature for 40 min. The solvents were removed and the residue dissolved in water (ca. 1 ml). Acetic acid (1 ml) was added, all solvents were removed and the residue co-evaporated with toluene to give a pale yellow solid. This solid was triturated with diethyl ether to give the title compound, which was filtered off as a pale yellow solid (50 mg).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][N:11](CC4C=CC=CC=4)[CH2:10]3)=[N:8][C:4]=2[CH:3]=1.Cl.C(Cl)Cl>CO.[Pd]>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[NH:6][C:7]([CH:9]3[O:14][CH2:13][CH2:12][NH:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2[nH]c(C3CN(Cc4ccccc4)CCO3)nc2c1
Agent: [Pd]
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Fc1ccc2[nH]c(C3CNCCO3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
To a solution of 5-fluoro-2-[4-(phenylmethyl)-2-morpholinyl]-1H-benzimidazole (3.0 g, 9.64 mmol), and hydrogen chloride (0.703 g, 19.27 mmol) in CH3OH (50 mL) stirred under nitrogen at room temperature was added palladium on carbon (0.103 g, 0.964 mmol), and the reaction mixture was stirred under hydrogen at 25° C. overnight. CH2Cl2 was added and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was triturated with EtOAc, filtered and dried to afford a hydrochloride salt of the title compound as a off-white solid (2.0 g). LC-MS (ES) m/z=222 [M+H]+.
Reaction SMILES: [CH3:1][NH2:2].CO.[Cl:5][C:6]1[S:7][C:8]([S:12](Cl)(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1.O>ClCCl>[Cl:5][C:6]1[S:7][C:8]([S:12]([NH:2][CH3:1])(=[O:14])=[O:13])=[C:9]([CH3:11])[N:10]=1
Reactant: Cc1nc(Cl)sc1S(=O)(=O)Cl
Reactant: CN
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: CNS(=O)(=O)c1sc(Cl)nc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
177 ml of a solution of methylamine in methanol (2 M, 0.354 mol) are added at 0° C. to a solution of 41 g (0.177 mol) of 2-chloro-4-methyl-1,3-thiazole-5-sulphonyl chloride in 360 ml of dichloromethane. The mixture is stirred at 0° C. for 30 min, 1.8 l of water are added, and the mixture is extracted 5 times with 400 ml of dichloromethane each time. The combined organic phases are dried over sodium sulphate, and the solvent is distilled off. 39.93 g of an oil, which solidifies on standing, are obtained (Rf=0.43 (toluene/ethyl acetate=2/1), yield 99.7%)
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:27]=[CH:26][C:25]([I:28])=[CH:24][C:21]=1[CH:22]=O.N1CCCCC1>CO>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11]([C:12]2[C:13]([CH3:14])=[N:19][C:20]3[C:21]([CH:22]=2)=[CH:24][C:25]([I:28])=[CH:26][N:27]=3)=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Reactant: Nc1ncc(I)cc1C=O
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1nc2ncc(I)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Yield: 63 %

Procedure:
In a screw cap pressure tube were N-(4-tert-butylbenzyl)-3-oxobutanamide (104.2 mg, 0.42 mmol) and 2-amino-5-iodonicotinaldehyde (95.0 mg, 0.38 mmol) suspended in piperidine (151.0 μl, 1.53 mmol). The tube was sealed and the mixture heated to 120° C. for 2 h. The mixture was allowed to cool, diluted with MeOH, adsorbed in silica and purified by flash chromatography (CH2Cl2/MeOH 99:1→97:3) yielding 110 mg of the title compound (63%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]>[Pd].CO>[CH:33]([C@H:30]1[C@@H:21]2[C@@H:22]3[C@@:17]([CH3:46])([CH2:18][CH2:19][C@@:20]2([C:36]([OH:38])=[O:37])[CH2:32][CH2:31]1)[C@@:16]1([CH3:47])[C@@H:25]([C@:26]2([CH3:29])[C@@H:13]([CH2:14][CH2:15]1)[C:12]([CH3:49])([CH3:48])[C@@H:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:10][CH:9]=1)[CH2:28][CH2:27]2)[CH2:24][CH2:23]3)([CH3:35])[CH3:34]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc([C@H]2CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)O)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 82.2 %

Procedure:
A mixture of palladium on carbon (67.4 mg, 0.063 mmol) and (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (140 mg, 0.211 mmol) in methanol (2 mL) was stirred at 20° C. under hydrogen at 1 atmosphere of pressure for 20 hours. The reaction mixture was filtered through a celite pad to remove Pd/C. The filtrates were concentrated under reduced pressure to provide the title compound as a white solid (100 mg, 82%). LCMS: m/e 577.33 (M+H)+, 3.22 min (method 10).
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:4][N:5]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:6]=12.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)(=[O:23])=[O:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=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>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:3]2[C:2]([C:27]3[CH:28]=[CH:29][C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[CH:25][CH:26]=3)=[C:6]3[CH:7]=[CH:8][C:9]([C:11]#[N:12])=[CH:10][N:5]3[N:4]=2)=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: N#Cc1ccc2c(Br)c(-c3ccc(F)cc3)nn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2c(-c3ccc(F)cc3)nn3cc(C#N)ccc23)cc1
Yield: 6.4 %

Procedure:
To a solution of 3-bromo-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-6-carbonitrile (0.24 g 0.76 mmol) in DMF (20 ml) was added 4-methanesulfonylphenylboronic acid (0.202 g 1.1 mmol), ground potassium phosphate (0.45 g 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.03 g) and the mixture heated to 90° for 6 h under nitrogen. The cooled mixture was poured into water (200 ml) and extracted with ethyl acetate (3×40 ml). The combined organic phases were washed with water (50 ml), brine (50 ml) and dried. Removal of solvent gave a solid which was purified by biotage chromatography. Elution with cyclohexane:ethyl acetate (4:1) gave the title compound as a white solid (0.019 g 6%). MH+: 392; NMR: (CDCl3) δ 3.14 (3H, s) 7.09 (2H, t) 7.30 (1H, dd) 7.50-7.56 (4H, m) 7.62 (1H, dd) 8.00 (2H, d) 8.9 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1.[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH:10]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1cccnc1-c1cccc(N)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccnc1-c1cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Reaction time: 18 h
Yield: 68.1 %

Procedure:
To a suspension of 3-(3-methoxypyridin-2-yl)aniline (0.34 g), N,N′-bis(tert-butoxycarbonyl)thiourea (563 mg) and diisopropylethyl-amine (0.681 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (565 mg), and the mixture was stirred for 18 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from methanol. The precipitate was collected by filtration, washed with methanol and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(3-(3-methoxypyridin-2-yl)phenyl)guanidine (512 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:35])([C:29]2[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=2)[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=[C:13]3[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:5][CH:4]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[CH:37]1.C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:28][C:24]1[CH:23]=[C:22]([C:13]2[C:12]3[C:17](=[CH:18][CH:19]=[C:10]([C:9]([OH:35])([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:36]5[CH:40]=[CH:39][N:38]=[CH:37]5)=[CH:4][CH:5]=4)[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=4)[CH:11]=3)[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: c1c[nH]cn1
Reactant: Cn1cncc1C(O)(c1ccc(CCl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1cncc1C(O)(c1ccc(Cn2ccnc2)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Yield: 13.4 %

Procedure:
A mixture of (±)-6-[[4-(chloromethyl)phenyl]hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (described in Example B14) (0.00039 mol), 1-H-imidazole (0.00079 mol) and K2CO3 (0.0016 mol) in CH3CN (2 ml) was stirred and refluxed for 4 hours, poured out into H2O and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. The residue (0.2 g) was purified twice by column chromatography over kromasil (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.5 then CH3OH/H2O 60/40; 10 μm). The pure fractions were collected and the solvent was evaporated, yielding 0.028 g (13%) of (±)-4-(3-chlorophenyl)-6-[hydroxy[4-(1H-imidazol-1-ylmethyl)phenyl](1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone, as a white foam, MS (ESI) m/z:536, 538 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21]([O:23]C)=[O:22])=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:16]=2[Cl:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCCCC>Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[CH:17][C:16]=2[Cl:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(Cl)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(Cl)cc([N+](=O)[O-])cc2C(=O)O)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-chloro-5-methoxycarbonylnitrobenzene (3.4 g) in concentrated hydrochloric acid (30 ml) was stirred at 75° C. for 16 hours. The reaction mixture was concentrated in vacuo. To a solution of the residual colorless solid in a mixture of water (15 ml) and acetone (15 ml) were added sodium hydrogencarbonate (1.6 g) and di-t-butyldicarbonate (2.2 g) in an ice bath. The resulting mixture was stirred at 40° C. for 1 hour. The reaction mixture was extracted with ethyl acetate. The extract was washed with 0.5M hydrochloric acid, water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo to afford a pale yellow solid. To the solid was added hexane and the mixture was filtered to give the desired compound (2.6 g, yield 79%) as a pale yellow solid.