Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]([NH2:12])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[C:13](O)(=[O:22])[C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1>ClCCl.CO.CN(C)C=O>[OH:15][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:22]
Reactant: O=C(O)[C@@H](O)c1ccccc1
Reactant: C[C@H](N)CCCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: CC(CCCc1cccnc1)NC(=O)C(O)c1ccccc1

Procedure:
Under the conditions outlined in Example 14a, 76.2 g of the amine was reacted with 74.2 g of (S)-mandelic acid in the presence of 105.2 g of 1,3-dicyclohexylcarbodiimide and 78.4 g of 1-hydroxybenzotriazole in 1L of dimethylformamide. A similar workup furnished 109 g of [S-(S*,S*)]-alpha-hydroxy-N-[1-methyl-4-(3-pyridinyl)butyl]benzeneacetamide, mp 143°-145° C., [α]D25 +27.8° (c, 1.0, MeOH).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH2:7][N:6](CC2C=CC=CC=2)[CH2:5][CH2:4]1.C(O)=O.C([O-])=O.[NH4+]>[Pd].CO>[CH3:23][N:2]([CH3:1])[C:3]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:4][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: CN(C)C1(Cc2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O=CO
Solvent: CO
Product: CN(C)C1(Cc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.2 %

Procedure:
A suspension of palladium on carbon (10%, 2 g) was added to a solution of 4-(dimethylamino)-1,4-bis(phenylmethyl)piperidine (Description 13, 4.62 g, 15 mmol) and formic acid (90%, 1.4 mL) in methanol (100 mL). Ammonium formate (4.73 g, 75 mmol) was added and the mixture was stirred at room temperature for 20 hours. The mixture was filtered, washing with methanol, and the solvent was evaporated under reduced pressure. Ether (40 mL) was added and the mixture was extracted with hydrochloric acid (1M, 3×40 mL). The combined aqueous layers were washed with ether (40 mL), adjusted to pH 12.0 with aqueous sodium hydroxide (4M) and extracted with dichloromethane (3×40 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane (20 mL) and the solid was collected and dried in vacuo to give the the title compound as a colorless solid (2.20 g, 67%). m/z (ES+) 219 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH2:11][CH2:12][CH2:13][CH3:14].C([Li])(C)(C)C.CCCCC.[B:25](OC)([O:28]C)[O:26]C>C1COCC1>[CH2:11]([O:10][C:3]1[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=1[B:25]([OH:28])[OH:26])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCOc1ccc(OC)cc1Br
Reactant: COB(OC)OC
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCOc1ccc(OC)cc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a −78° C. solution of 2-bromo-1-butoxy-4-methoxybenzene 4.1 (250 mg, 965 μmol) in THF (8.0 mL) was added tert-butyllithium, 1.7 M solution in pentane (1248 μL, 2122 μmol) dropwise under a blanket of nitrogen. The pale yellow solution was stirred for 0.5 h at −78° C. before dropwise addition of neat trimethyl borate (175 μL, 1544 μmol) at the same temperature. The resulting mixture was stirred for 1 hour at −78° C., warmed to 25° C., and stirred for an additional hour. The reaction was quenched with saturated aqueous ammonium chloride and concentrated. The resulting residue was suspended in water/acetic acid (pH=3) and extracted with DCM. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine, dried (MgSO4), and concentrated to afford a light brown solid. The product was purified by trituration with hexane to afford 2-butoxy-5-methoxyphenylboronic acid 4.2 (67.2 mg, 31.1% yield) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C=O.O>[CH3:7][N:6]1[C:2]([NH2:1])=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:4]([O:8][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:5]1
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N)cc1
Reaction time: 2 h
Yield: 25.1 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (50 mg) in dimethylformamide (2 ml) at room temperature was added sodium hydride (60% dispersion in oil, 10 mg) and β-bromophenetole (49.5 mg). The mixture was stirred for 2 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with ether to yield the title compound as a white solid (20 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].[CH3:11][C:12]1[C:17]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[CH:22]=[CH:21][N:20]=2)=[CH:16][C:15]([NH2:31])=[CH:14][N:13]=1>N1C=CC=CC=1>[CH3:11][C:12]1[N:13]=[CH:14][C:15]([NH:31][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)=[CH:16][C:17]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:20]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: Cc1ncc(N)cc1Nc1nccc(-c2cccnc2)n1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ncc(NC(=O)c2ccccn2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.1 %

Procedure:
Picolinoyl chloride hydrochloride salt (96 mg, 0.54 mmol) was added into a solution of 2-methyl-N3-(4-pyridin-3-yl-pyrimidin-2-yl)-pyridine-3,5-diamine (50 mg, 0.18 mmol) in pyridine (1.5 mL). The reaction mixture was stirred at rt under argon atmosphere overnight. After pyridine is removed under reduced pressure, the residue is purified by chromatography to give 10.4 mg of the product as pale yellow solids (Yield: 15%). MS (ESI+) m/z 384.3 [M+H]+
Reaction SMILES: [OH:1][CH:2]([C:7]1[CH:8]=[CH:9][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](=O)[CH:17]([N:25]2[C:29]3=[N:30][CH:31]=[CH:32][C:33]([O:34][CH3:35])=[C:28]3[CH:27]=[N:26]2)[CH2:18][CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:11][CH:12]=1)[C:3]([OH:6])([CH3:5])[CH3:4].C([O-])(=O)C.[NH4+:42].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C>[CH3:35][O:34][C:33]1[CH:32]=[CH:31][N:30]=[C:29]2[N:25]([CH:17]([C:16]3[NH:42][C:13]([C:10]4[N:11]=[CH:12][C:7]([CH:2]([OH:1])[C:3]([CH3:5])([OH:6])[CH3:4])=[CH:8][CH:9]=4)=[CH:14][CH:15]=3)[CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:26]=[CH:27][C:28]=12
Reactant: [NH4+]
Reactant: COc1ccnc2c1cnn2C(CC1CCOCC1)C(=O)CCC(=O)c1ccc(C(O)C(C)(C)O)cn1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccnc2c1cnn2C(CC1CCOCC1)c1ccc(-c2ccc(C(O)C(C)(C)O)cn2)[nH]1
Temperature: 25 °C
Reaction time: 6 h
Yield: 69.8 %

Procedure:
A mixture of 1-[5-(1,2-dihydroxy-2-methylpropyl)pyridin-2-yl]-5-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (265 mg), ammonium acetate (200 mg), acetic acid (0.20 mL) and ethanol (10 mL) was stirred at room temperature for 6 hr. The reaction solution was poured into aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to give the title compound (178 mg, yield 58%) as a colorless amorphous solid from the fraction eluted with ethyl acetate. MS: 492 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:5]=[C:4]2[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:15](=[O:18])[NH:16][CH2:17][C:3]=12.O.C(=O)([O-])[O-].[K+].[K+].CC1(C)C(C)(C)OB([C:42]2[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=2)O1>O1CCOCC1.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:26][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([F:25])[C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])[N:7]=[C:2]([C:42]3[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=3)[C:3]=2[CH2:17][NH:16][C:15]1=[O:18]
Reactant: CN(C)CCNc1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN(C)CCNc1nc(-c2ccc(C(=O)O)cc2)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Yield: 77.7 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)-ethyl]-amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (150 mg, 0.39 mmol) in dioxane (12 mL)/water (4 mL) were added potassium carbonate (325 mg, 2.36 mmol), tetrakis(triphenylphosphine)palladium(0) (23 mg, 0.019 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (146 mg, 0.59 mmol). The reaction mixture was bubbled with N2 for about 5 mins, then microwaved at about 150° C. for about 30 mins. The reaction mixture was concentrated. To the concentrated mixture were added DMSO (2 mL), H2O (0.5 mL) and AcOH (0.05 mL). Separation via a HPLC then provided the title compound as a white solid (142 mg, 77%). LC-MS m/z 469 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH:17]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)[CH3:18])=[CH:15][N:16]=3)[N:13]=2)=[CH:4][C:3]=1[F:29].C(=O)([O-])[O-].[Na+].[Na+].[CH3:36][N:37](C)C(=O)C>CCOC(C)=O.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.O.O.O.[K+].[K+].[K+].[K+].[Fe+2].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:14]([CH:17]([C:19]4[CH:20]=[C:21]5[C:26](=[CH:27][CH:28]=4)[N:25]=[CH:24][CH:23]=[CH:22]5)[CH3:18])=[CH:15][N:16]=3)[N:13]=2)[CH:6]=[CH:7][C:2]=1[C:36]#[N:37]
Reactant: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(Br)c(F)c3)nn12
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(c1ccc2ncccc2c1)c1cnc2ncc(-c3ccc(C#N)c(F)c3)nn12
Temperature: 120 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 6-1-[2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl]ethylquinoline (0.100 g, 0.223 mmol), potassium hexacyanoferrate(II) trihydrate (30 mg, 0.06 mmol), sodium carbonate (0.047 g, 0.45 mmol) and palladium acetate (2 mg, 0.01 mmol) in N,N-dimethylacetamide (1.2 mL) was stirred at 120° C. for 2 h. LCMS showed the reaction was complete. The reaction was diluted with EtOAc, washed with water, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel with MeOH in methylene chloride (0-10%) to afford the desired product (0.10 g, 60%). LCMS: (M+H)=395.0.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[N:4][N:3]=[N:2]1.N1C=CC=CC=1.Cl[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15].O>O1CCCC1>[NH:1]1[C:5]([NH:6][C:14](=[O:15])[O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[N:4][N:3]=[N:2]1
Reactant: Nc1nnn[nH]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1nnn[nH]1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 1H-tetrazole-5-amine (1.00 g, 11.8 mmol) and pyridine (1.15 ml, 14.1 mmol) in tetrahydrofuran (39 ml) was added 2,2,2-trichloroethyl chloroformate (1.95 ml, 14.1 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue was added hexane and a solid was collected by filtration to obtain the desired product (1.29 g, 42.1%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([O:31]CC)=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:7]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([CH3:36])[CH:24]=1)[C:6]1[CH:11]=[N:10][CH:9]=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[N:7]=1
Reactant: CCOC(=O)COc1ccc(CN(CCOC)c2cncc(-c3ccc(C(F)(F)F)cc3)n2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cncc(-c2ccc(C(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of ethyl {4-[((2-methoxyethyl){6-[4-(trifluoromethyl)phenyl]pyrazin-2-yl}amino)methyl]-2-methylphenoxy}acetate (160 mg, 0.32 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 2M sodium hydroxide (2 mL). The resulting mixture was stirred at room temperature for 1 h. The solvents were removed in vacuo and the residue was diluted with water (10 mL) acidified with 2M HCl and extracted with ethyl acetate (2×30 mL). The organic solution was dried (MgSO4) and the solvents removed in vacuo, to afford the title compound as a bright yellow solid (140 mg).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9]Br.[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>O1CCCC1.C(Cl)Cl>[N:16]1([CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]2[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=2[F:1])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Fc1ccc(Br)cc1COCCCCBr
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Fc1ccc(Br)cc1COCCCCN1CCCCC1
Reaction time: 24 h

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butyl bromide (520 mg, 1.53 mmol) in tetrahydrofuran (8 ml) was treated with piperidine (1.5 ml, 15.3 mmol). The resulting reaction mixture was stirred for about 24 hours. The reaction mixture was then diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate and the solvents were removed in vacuo. The desired title intermediate was further purified by radial chromatography.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:31]=[CH:30][C:11]3=[N:12][N:13]([C:15]4[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]=4[OH:29])[N:14]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:37].ClC1C=C(C=CC=1)C(O)=O>C(Cl)Cl>[C:1]1([S:7]([C:8]2[CH:31]=[CH:30][C:11]3=[N:12][N:13]([C:15]4[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[CH:18]=[C:17]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:16]=4[OH:29])[N:14]=[C:10]3[CH:9]=2)=[O:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(-n2nc3ccc(Sc4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Agent: O=C(O)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-n2nc3ccc(S(=O)c4ccccc4)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 87.6 %

Procedure:
A solution of 10.8 g (0.025 mole) of 5-phenylthio-2-(2-hydroxy-3,5-di-tert-butyl-phenyl)-2H-benzotriazole, prepared in Example 2, in 80 mL of methylene chloride is cooled to 3°-5° C. Over a period of 30 min. is added a solution of 5.1 g (0.025 mole) of m-chloroperoxybenzoic acid (MCPBA) 85% in 80 mL of methylene chloride at 3°-5° C. The reaction is stirred for 2 hours at 0°-5° C. with precipitation of m-chlorobenzoic acid. The starting material is shown to be absent. Upon removal of the solvent the residue is dissolved in 200 mL of toluene, m-chlorobenzoic acid is removed by filtration and subsequent washing with 10% aqueous sodium carbonate solution and water. The toluene solution is dried over anhydrous magnesium sulfate, filtered and the solvent removed. The resulting amorphous residue is dissolved in 60 mL of petroleum ether and crystallized. Filtration and washing of the crystals with cold petroleum ether affords 9.8 g (87.6% yield) of the title compound as a solid melting at 152°-154° C.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])=O.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>CCO.O.C(OC)(C)(C)C>[OH:23]/[N:22]=[CH:1]/[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18]
Reactant: C[Si](C)(C)CNC(=O)c1ccc(C=O)c(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CNC(=O)c1ccc(/C=N/O)c(C(F)(F)F)c1

Procedure:
4-Formyl-3-(trifluoromethyl)-N-[(trimethylsilyl)methyl]benzamide (15.0 g, 49.4 mmol), Hydroxylamine hydrochloride (6.9 g, 98.8 mmol) and sodium acetate (6.1 g, 74.1 mmol) in EtOH and H2O were stirred at room temperature over night. The reaction mixture was diluted with t-BuOMe, and washed with brine and dried over MgSO4. After evaporation the product was found to be 15.0 g (95%).
Reaction SMILES: C(OC([N:8]([N:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([C:26]2[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:38])[CH2:9][CH2:10][OH:11])=O)(C)(C)C.Cl>O1CCOCC1>[OH:11][CH2:10][CH2:9][NH:8][N:12]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]([C:26]2[CH:27]=[C:28]([O:36][CH3:37])[C:29]([O:34][CH3:35])=[C:30]([O:32][CH3:33])[CH:31]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:38]
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1N(CCO)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2ccccc2c(=O)n1NCCO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound obtained in Example 73 (170 nig) in dioxane (1 ml) is added a 4M solution of hydrogen chloride in dioxane (10 ml), and the mixture is stirred at room temperature for three hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. The mixture is washed with water, dried, and concentrated under reduced pressure. The residue is purified by Chromatotron (solvent; chloroform:acetone=5:1), and crystallized from diethyl ether to give 2-[-(2-hydroxyethyl)amino]-3-methoxycarbonyl-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone as listed in Table 6.
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C@H:16]3[O:21]C(C)(C)[O:19][C@@H:18]([CH2:24][C:25](N(OC)C)=[O:26])[CH2:17]3)=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.S(=O)(=O)(O)O>C(#N)C>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C@H:16]3[O:21][C:25](=[O:26])[CH2:24][C@H:18]([OH:19])[CH2:17]3)=[C:12]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CON(C)C(=O)C[C@H]1C[C@@H](/C=C/c2c(C3CC3)nc3ccccc3c2-c2ccc(F)cc2)OC(C)(C)O1
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: O=C1C[C@H](O)C[C@@H](/C=C/c2c(C3CC3)nc3ccccc3c2-c2ccc(F)cc2)O1
Reaction time: 5 h
Yield: 50 %

Procedure:
E-(6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}-[(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl])-N-methoxy-N-methyl-acetamide (3.0 g), acetonitrile (50.0 mL), and sulfuric acid (0.3 mL) were added to a reactor. The reaction mixture was stirred at 50˜60° C. for 5 hours and then concentrated under reduced pressure. Ethyl acetate (50.0 mL) and water (50.0 mL) were added to the resulting residue. The separated organic layer was dried under reduced pressure to obtain E-6-{2-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]vinyl}-(4R,6S)-4-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (1.2 g, yield 50%).
Reaction SMILES: [F:1][CH:2](S(C1C=CC=CC=1)(=O)=O)[C:3]1([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH2:6][CH2:5][CH2:4]1.C([O-])(=O)C.[Na+].[Mg].C(=O)([O-])O.[Na+]>CN(C)C=O.C(O)(=O)C.O>[F:1][CH2:2][C:3]1([NH:7][S:8]([C:10]([CH3:13])([CH3:12])[CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)S(=O)NC1(C(F)S(=O)(=O)c2ccccc2)CCC1
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Mg]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NC1(CF)CCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a stirred solution of N-(1-(fluoro(phenylsulfonyl)methyl)cyclobutyl)-2-methylpropane-2-sulfinamide (1.50 g, 4.32 mmol) in N,N-dimethylformamide (270 mL) was added a buffer solution of sodium acetate (22.6 g, 276 mmol) in acetic acid (34.6 mL) and the reaction mixture was stirred for 15 minutes at room temperature. Magnesium turnings (6.92 g, 289 mmol) were added and the mixture stirred at 65° C. for 24 hours. The mixture was treated with water and saturated aqueous sodium hydrogen carbonate and extracted 3 times with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated to give a yellow oil. The residue was purified by flash column chromatography on silica (eluent: heptane:ethyl acetate 1:1 to 0:1) to give N-(1-(fluoromethyl)cyclobutyl)-2-methylpropane-2-sulfinamide (560 mg, 53%) as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:13][CH:12]3[N:14](C(OC(C)(C)C)=O)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:3][CH:2]=1.[ClH:22]>O1CCOCC1>[ClH:22].[ClH:22].[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:13][CH:12]3[NH:14][CH:9]([CH2:10][CH2:11]3)[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1ccncc1)C2
Agent: Cl
Solvent: C1COCCO1
Product: c1cc(C2CC3CCC(C2)N3)ccn1

Procedure:
2.76 g of tert-butyl 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane-8-carboxylate and 4 ml of a 4N solution of hydrochloric acid in dioxane are placed in a 10 ml round-bottomed flask. The reaction mixture is stirred for one and a half hours. The dioxane is evaporated off and 0.341 g of 3-pyridin-4-yl-8-azabicyclo[3.2.1]octane dihydrochloride is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[H-].[Na+].[CH3:12][NH:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:22]=[CH:21][CH:20]=[C:19]2Cl)=[O:15].C(OCC)(=O)C>CS(C)=O.O>[CH3:12][NH:13][C:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[N:22]=[CH:21][CH:20]=[C:19]2[O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([Cl:9])[CH:4]=1)=[O:15]
Reactant: Nc1ccc(O)cc1Cl
Reactant: CNC(=O)c1cc2c(Cl)ccnc2cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc2c(Oc3ccc(N)c(Cl)c3)ccnc2cc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.2 %

Procedure:
After dissolving 4-amino-3-chlorophenol (624 mg, 4.35 mmol) in dimethylsulfoxide (15 ml), sodium hydride (174 mg, 4.35 mmol) was gradually added at room temperature and the mixture was stirred for 30 minutes. N6-Methyl-7-(benzyloxy)-4-chloro-6-quinolinecarboxamide (947 mg, 2.90 mmol) was added, and the mixture was heated at 100° C. while stirring for 2 hours. After cooling to room temperature, the reaction solution was distributed between ethyl acetate and water, and the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, the residue was suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out and blow-dried to obtain the title compound (1.098 g, 2.53 mmol, 87.3%) as light brown crystals.