Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:21][N:22](C)[C:23](=O)OC(C)(C)C)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.C(OCC)(=O)C.[ClH:37]>C(OCC)(=O)C.C(O)C>[ClH:37].[F:1][C:2]1[C:7]([C:8]2[N:12]([S:13]([C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:21][NH:22][CH3:23])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CN(Cc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cc(-c2cccnc2F)n(S(=O)(=O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
tert-Butyl {[5-(2-fluoropyridin-3-yl)-1-(1,3-thiazol-2-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (168 mg) was dissolved in ethyl acetate (2 mL) and ethanol (2 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=1:3 to give the title compound as colorless crystals (yield 101 mg, 70%).
Reaction SMILES: C([O:5][C:6]([CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:6]([CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([OH:7])=[O:5]
Reactant: CC(C)(C)OC(=O)COc1ccc(-c2ccc(C#N)cc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(-c2ccc(OCC(=O)O)cc2)cc1
Reaction time: 3 h

Procedure:
32.9 g of 4-(tert.butyloxycarbonylmethyloxy)-4'-cyano-biphenyl dissolved in 250 ml of methylene chloride is mixed slowly with 137 ml of trifluoroacetic acid. After stirring for 3 hours, the reaction mixture is evaporated to dryness and the solid residue is triturated with water.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([OH:41])=[N:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:24]([N:31]1[CH:35]=[C:34]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:33]([O:41][CH2:2][C:3]2[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)[O:12][C:13]=3[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=2)=[N:32]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
A mixture of 4-(4-chloromethyl-2-methoxyphenoxy)methyl-5-methyl-2-(2-furyl)-1,3-oxazole (1.94 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.31 g), potassium carbonate (0.73 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:1, v/v) to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazole-4-carboxylate (2.48 g, yield 86%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:18][C:19](=[O:25])[O:20]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])O)[C:5]([F:26])=[CH:4][N:3]=1.Cl.C(N(CC)C(C)C)C.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[O:20][C:19](=[O:25])[NH:18]2)[C:5]([F:26])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1ccccc1F
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2ccccc2F)O1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of optically-enriched tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(2-fluorophenyl)-2-hydroxyethylcarbamate (93 mg, 0.108 mmol) in dichloromethane (2 mL) at room temperature was added hydrogen chloride (4M in dioxane, 2 mL, 8 mmol). The reaction was warmed to 45° C. and held at that temperature for 1 h. The reaction was concentrated. The reaction was concentrated twice more from tetrahydrofuran. The resulting residue was suspended in tetrahydrofuran (2 mL), cooled to 0° C., and treated with diethylisopropylamine (0.038 mL, 0.217 mmol) and carbonyldiimidazole (26.3 mg, 0.162 mmol). After 5 min, the ice bath was removed and stirring continued for 3 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was suspended in dichloromethane, diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, and concentrated. Column chromatography (25%→50% EtOAc/Hex) gave 37.8 mg (49%) as a colorless film. HNMR showed that it was a 1:1 mixture of regioisomers. The mixture was used without separation. Mass spec.: 355.0 (MH)+.
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15]3)=[CH:10][CH:9]=2)OC1.Br[C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][C:33]=1[Cl:34])[NH:30][CH:29]=[C:28]2[CH:35]=[O:36].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:34][C:33]1[CH:32]=[C:31]2[C:27]([C:28]([CH:35]=[O:36])=[CH:29][NH:30]2)=[CH:26][C:25]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:20])=[O:21])[CH2:15]2)=[CH:12][CH:13]=1
Reactant: CC1(C)COB(c2ccc(C3CCN(S(C)(=O)=O)C3)cc2)OC1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CS(=O)(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Temperature: 110 °C
Yield: 65.3 %

Procedure:
To a degassed mixture of crude 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]-1-(methylsulfonyl)pyrrolidine (assume 0.38 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (98.4 mg, 0.38 mmol) and 2N aqueous potassium carbonate (0.76 mL, 1.52 mmol) in toluene (2.25 mL) and ethanol (0.75 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.8 mg, 0.038 mmol). The reaction mixture was heated to 110° C. in a microwave for 30 min. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (0:100 to 100:0) to give 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-3-yl]phenyl}-1H-indole-3-carbaldehyde (100 mg) as a yellow solid. MS (ES+) 402.9 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.CC(C)([O-])C.[K+].P1(O)(OC2C=CC3C(C=2C2C4C(C=CC=2O1)=CC=CC=4)=CC=CC=3)=O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].C1(C)C=CC=CC=1>[F:10][C:3]1[C:4]([S:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: CSc1cccc(Br)c1F
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CSc1cccc(N2CCNCC2)c1F

Procedure:
Preparation according to preparation 22: 1-bromo-2-fluoro-3-(methylthio)benzene (2.15 g, 9.7 mmol), toluene (50 ml), piperazine (4.19 g, 48.5 mmol), potassium tert-butoxide (1.31 g, 13.6 mmol), bis(dibenzylideneacetone)palladium(0) (0.27 g, 0.064 mmol) and (+/−)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate (0.18 g, 0.064 mmol). Yield: 1.25 g. MS m/z (rel. intensity, 70 eV) 226 (M+, 20), 191 (12), 185 (10), 184 (bp), 168 (15).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH:28]([CH3:30])[CH3:29])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH2:25][CH2:26][OH:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31]I.[H-].[Na+].[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH:28]([CH3:30])[CH3:29])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@@H:15]([CH2:25][CH2:26][O:27][CH3:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CCO)N(C(=O)OC(C)(C)C)C1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCC[C@H]1CC[C@@H](N(C(=O)OCc2ccccc2)C(C)C)CN1C(=O)OC(C)(C)C
Yield: 99.1 %

Procedure:
To a solution of tert-butyl (2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-2-(hydroxy-ethyl)piperidine-1-carboxylate (2.10 g) in tetrahydrofuran (10 mL) was added methyl iodide (1.42 g), and the mixture was stirred. To the mixture was added 55% sodium hydride (300 mg) under ice-cooling, and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (5 ml), and the mixture was extracted with ethyl acetate (50 ml). The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=4/1) to give the title compound (2.15 g).
Reaction SMILES: [Na].[N:2]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4].[CH3:11][O:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=2)[CH:21]=O)=[CH:15][CH:14]=1.[NH4+].[Cl-]>C(O)C>[N:2]([C:5](=[CH:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:17][C:16]2[CH:26]=[CH:27][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[CH:19]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:3]=[N-:4]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: COc1ccc(Oc2cccc(C=O)c2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc(Oc2ccc(OC)cc2)c1)N=[N+]=[N-]
Temperature: -5 °C
Reaction time: 4.5 h

Procedure:
Sodium metal (2.01 g, 87.43 mmol) cut into small pieces was dissolved in absolute ethanol (67 mL) and the resulting solution cooled to -5° C. A mixture of ethyl azidoacetate (11.32 g, 87.67 mmol) and 3-(4-methoxyphenoxy) benzaldehyde (5.0 g, 21.91 mmol) was added dropwise over 30 min. On completion of addition the mixture was stirred at -5° C. for 4.5 hr, and then kept at room temperature overnight. The red reaction mixture was poured into saturated aqueous NH4Cl solution and extracted (3×) with Et2O. The ethereal extracts were washed (H2O and then saturated aqueous NaCl), dried (MgSO4) and evaporated to give an orange gum which was chromatographed (silica gel; hexane/Et2O; 0-15%). The product: ethyl 2-azido-3-(3-(4-methoxyphenoxy)phenyl)propenoate, was thus obtained as a light yellow gum, 5.5 g (70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:38])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([NH:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([CH3:37])=[C:27]([NH:29]C(=O)OC(C)(C)C)[CH:28]=3)[CH2:17][CH2:16]2)=[CH:5][CH:4]=1.[ClH:39].C(OCC)(=O)C>>[ClH:39].[NH2:29][C:27]1[CH:28]=[C:23]([CH:24]=[CH:25][C:26]=1[CH3:37])[CH2:22][NH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:38])[CH2:16][CH2:17]1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(NC(=O)OC(C)(C)C)c4)CC3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc(C)c(N)c4)CC3)c2c1
Temperature: 25 °C
Reaction time: 41 h

Procedure:
To 0.28 g of tert-butyl (5-(((1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)amino)methyl)-2-methylphenyl)carbamate, 30 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred at room temperature for 41 hours. The solvent was removed under reduced pressure, ethyl acetate was added and the resulting solid was filtered to give 0.26 g of (1-(2-(4-((3-amino-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-7-methoxyquinoxalin-2(1H)-one hydrochloride as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[NH:10][C:9](=[O:12])[C@@H:8]3[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@H:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:26]>CN(C=O)C.C1COCC1.[Cl-].[Na+].O>[CH3:26][N:10]1[C:11]2[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=2[C@H:7]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][C@H:8]2[C:9]1=[O:12]
Reactant: CI
Reactant: Cc1cccc2c1NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc2c1N(C)C(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.5 %

Procedure:
To a solution of (±)-cis tert-butyl 6-methyl-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate (0.5 g, 1.66 mmol) in 10 mL of DMF and 5 mL of THF was added sodium hydride (0.2 g, 60% dispersion in mineral oil, 5.0 mmol). The mixture was allowed to stir at ambient temperature for 1 h and then there was added iodomethane (0.25 mL, 4.0 mmol). The reaction was allowed to stir at ambient temperature for 18 h. The reaction mixture was poured into brine and extracted with ethyl acetate. The organics were washed with water and brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.47 g (90%) of (±)-cis tert-butyl 5,6-dimethyl-4-oxo-3,3a,4,5-tetrahydro-1H-pyrrolo[3,4-c]quinoline-2(9bH)-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]([CH3:10])=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([CH3:10])[C:2]([CH:19]=[O:20])=[CH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(Br)c(C)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(C=O)c(C)n1
Temperature: 25 °C

Procedure:
The 3-bromo-6-methoxy-2-methyl-pyridine (2.0 g, 9.9 mmol) obtained in (18-1) above was dissolved in toluene (dehydrated) (50 mL), and thereafter, n-butyllithium (6.4 mL, 10 mmol, 1.57 mmol/L hexane solution) was added dropwise to the solution at −78° C. in an argon atmosphere. The obtained mixture was stirred at the same temperature as described above for 30 minutes, and DMF (3.0 mL) was then added to the reaction solution. The obtained mixture was further stirred for 30 minutes. Thereafter, a saturated ammonium chloride water (100 mL) was slowly added to the reaction solution, and the temperature of the mixture was then increased to room temperature. The mixture was extracted with diethyl ether (100 mL) three times, and organic layers were gathered. The resultant was washed with water (100 mL) and saturated saline (100 mL), and was dried over anhydrous sodium sulfate and was then filtrated, followed by vacuum concentration. The obtained residue was purified by silica gel column chromatography (SiO2 30 g, hexane:ethyl acetate=98:2 to 90:10), so as to obtain 487 mg of 6-methoxy-2-methyl-3-pyridinecarboxaldehyde.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH2:18])[N:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([NH:18][C:5](=[O:7])[CH3:6])[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc2ccccc2cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc2ccccc2cn1
Reaction time: 3.5 h
Yield: 100 %

Procedure:
Acetic anhydride (5.92 mL, 62.6 mmol) was added to a suspension of isoquinolin-3-amine (3.01 g, 20.9 mmol) and triethylamine (3.18 mL, 23.0 mmol) in CH2Cl2 (80 mL) at ambient temperature. The mixture was stirred 3.5 hours, then the volatiles were evaporated in vacuo. The residue was chased with toluene and concentrated in vacuo (3×25 mL) to provide the title compound (3.89 g) as a yellow solid. This material, which was found to also contain small quantities of acetic acid, was used without further purification. 1H NMR (300 MHz, DMSO-d6) δ 10.58 (s, 1H), 9.13 (s, 1H), 8.45 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.69 (ddd, J=8.2, 6.8, 1.2 Hz, 1H), 7.52 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 2.13 (s, 3H).
Reaction SMILES: [OH:1][C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][O:3]1.[CH3:25]O>>[CH3:25][O:1][C:2]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6](=[O:7])[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[CH:4][O:3]1
Reactant: O=C(O)CCc1ccc(C2=COC(O)(c3ccccc3)C2=O)cc1
Reactant: CO
Product: COC1(c2ccccc2)OC=C(c2ccc(CCC(=O)O)cc2)C1=O
Yield: 83 %

Procedure:
A solution of 3.36 g of 2-hydroxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone in 150 ml of methanol was heated under reflux under a nitrogen atmosphere for 17 hrs. The reaction mixture was evaporated and the residue was recrystallized from methylene chloride-petroleum ether to give 2.28 g (83%) of 2-methoxy-2-phenyl-4-[4-(2-carboxyethyl)phenyl]-3(2H)-furanone as colorless crystals, m.p. 117°-120° C., after drying at 50° C. for 1 hr. under vacuum.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][CH3:15])=[CH:9][C:8]=1[C:16]([F:19])([F:18])[F:17].[C:20](=[O:22])=[O:21].Cl>CCCCCC.CCOCC>[CH2:14]([S:13][C:10]1[CH:11]=[CH:12][C:7]([C:20]([OH:22])=[O:21])=[C:8]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)[CH3:15]
Reactant: CCSc1ccc(Br)c(C(F)(F)F)c1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCSc1ccc(C(=O)O)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of n-butyllithium in hexane (2.5M, 115 ml) was added dropwise with cooling to a stirred solution of 2-bromo-5-(ethylsulphenyl)benzotrifluoride (80.0 g) in anhydrous ether whilst maintaining the temperature below -70° C. The mixture was stirred at -78° C. for 1.5 hours and poured onto solid carbon dioxide pellets. The mixture was stirred for 20 minutes then treated with hydrochloric acid (2M). The layers were separated and the organic layer was washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness. The residue was triturated with cyclohexane and filtered to give 4-(ethylsulphenyl)-2-trifluoromethylbenzoic acid as an off-white solid, m.p. 133.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[O:11][C:7]1([CH2:10][CH2:9][CH2:8]1)[CH2:6][CH:5]2[NH:15][C:16](=[O:27])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-])=O.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][C:16]([NH:15][CH:5]1[C:4]2[C:12](=[CH:13][CH:14]=[C:2]([Cl:1])[CH:3]=2)[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)=[O:27]
Reactant: O=C(Cc1ccccc1[N+](=O)[O-])NC1CC2(CCC2)Oc2ccc(Cl)cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1CC(=O)NC1CC2(CCC2)Oc2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To a well stirred solution of step 1 intermediate (200 mg, 0.512 mmol) in ethanol (5 ml) was added NH4Cl (276 mg, 5.102 mmol) in water (3 ml) at room temperature. The reaction mixture was stirred for 15 min at the same temperature and then heated to 80° C. for 15 min. Iron (86 mg, 1.552 mmol) was added at that same temperature. The reaction mixture was refluxed further for 2 h. The residue obtained after the evaporation of the solvent was extracted with chloroform (2×50 ml). This chloroform layer was passed through celite. The layers were separated. Organic layers were washed with water (2×30 ml), brine (30 ml) and dried over Na2SO4. Solvent was evaporated to give 150 mg of the product.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](=O)[C:35]1[C:36]([O:41][CH3:42])=[CH:37][CH:38]=[CH:39][CH:40]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[O:41][CH3:42])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: COc1ccccc1C=O
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CN1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4)ncnc32)CC1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(2-methoxy-benzyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 25) with o-anisaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.89-1.98 (m, 2H), 2.19-2.26 (m, 4H), 2.95-3.03 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.55 (s, 2H), 3.79 (s, 3H), 4.74-4.80 (m, 1H), 6.93-7.00 (m, 2H), 7.22-7.26 (m, 1H), 7.36-7.38 (m, 2H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=494.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH:7]=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2].[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH2:35][C:36]([F:39])([F:38])[F:37])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:20].[ClH:19].[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7]([CH2:21][C:22]2[C:23]([NH:34][CH2:35][C:36]([F:39])([F:37])[F:38])=[N:24][C:25]3[C:30]([CH:31]=2)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=3)=[C:6]([OH:18])[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2cc(O)nc(C(C)C)c2cc1OC
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2nc(NCC(F)(F)F)c(Cc3c(O)nc(C(C)C)c4cc(OC)c(OC)cc34)cc2c1
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 15 %

Procedure:
To a stirred solution of 1-isopropyl-6,7-dimethoxyisoquinolin-3-ol SIL 32164 (362 mg, 1.46 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. solution of LiOH (1.47 mL, 2.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 95:5) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) provided, after evaporation, 161 mg of 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (1.5 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-isopropyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 51 as a yellow solid (130 mg, 15% yield).