Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[H][H].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Reactant: [H][H]
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2c(c1)CCN2
Reaction time: 3 h

Procedure:
To a solution of 50.0 g (340 mmol) of 5-methoxyindole in 700 ml of glacial acetic acid are added portionwise, at 15-20° C., 53.4 g (850 mmol) of sodium cyanoborohydride. The weakly exothermic addition is carried out over 3 hours and is accompanied by a slight evolution of hydrogen. The mixture is left stirring below 20° C. for 12 hours, 700 ml of water are then added and the pH of the reaction medium is adjusted to between 10 and 12 by addition of 1200 ml of 30% sodium hydroxide solution. The mixture is extracted twice with dichloromethane and the organic phase is then washed with 300 ml of water. The mixture is evaporated and the residue is purified by flash chromatography on a column of silica, the eluent used being a mixture of increasing polarity of methanol in dichloromethane. 41.84 g of colorless oil which becomes pale yellow on storage (to be stored under nitrogen atmosphere and sheltered from the light) are obtained.
Reaction SMILES: [Cl-].[O:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH3+:5].C(Cl)Cl.[C:15](OC(=O)C)(=[O:17])[CH3:16].CCN(C(C)C)C(C)C>CCOC(C)=O>[O:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH:5][C:15](=[O:17])[CH3:16]
Reactant: [NH3+]CC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.4 %

Procedure:
2-oxo-2-phenylethanaminium chloride (5) (1.7 g, 10.0 mmol, 1.0 equiv.) was added to a 100 mL RBF followed by CH2Cl2 (50 mL). The resulting solution was cooled to 0° C. via an ice bath. Next, acetic anhydride (1.4 mL, 15.0 mmol, 15.0 equiv.) and DIEA (5.3 mL, 30.0 mmol, 30.0 equiv.) were added to the reaction flask. The reaction solution stirred for 2 h at 0° C. and was allowed to warm to rt. The solution was stirred at rt for 1 h. The solution was transferred to a separatory funnel with CH2Cl2 (90 mL). The resulting organic layer was washed with 1% HCl (2×50 mL) and sat. NaCl (2×50 mL). The organic layer was dried over Na2SO4, concentrated on a rotary evaporator, and dried under vacuum to give a yellowish solid. The solid was dissolved in EtOAc (15 mL) and precipitated during the slow addition of hexanes (30 mL). The precipitate that formed was dried under vacuum to give 1.3 g (74%) of 10 as a white solid. Rf=0.31 (100% EtOAc); mp=85-87° C.; IR (KBr) 3319, 3059, 2936, 2900, 1683, 1649, 1597, 1556, 1370, 1011 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.98 (d, J=7.5 Hz, 2H, Ph-H), 7.63 (t, J=7.5 Hz, 1H, Ph-H), 7.50 (t, J=7.5 Hz, 2H, Ph-H), 6.69 (br s, 1H, Ac—NH), 4.78 (d, J=4.5 Hz, 2H, Ac—NH—CH2), 2.12 (s, 3H, NH—COCH3); 13C NMR (125 MHz, CDCl3) δ 194.4, 170.5, 134.5, 134.3, 129.1, 128.1, 46.7, 23.2; LRMS (ESI-MS m/z): Mass calcd for C10H11NO2 [M]+, 177.20. Found 178. Anal. calcd for C10H11NO2: C, 67.78; H, 6.26; N, 7.90 Found: C, 67.63; H, 6.29; N, 7.87. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](N(C2C=CC=CC=2)C(=O)OC(C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:29](F)(F)[C:30](O)=O.ClCCl>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:30]2[CH:29]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:8])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)OC(C)(C)C)c2ccccc2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyl (1-t-butoxycarbonylpiperidin-4-yl)phenylcarbamate (290 mg) was dissolved in trifluoroacetic acid-dichloromethane (10%, 20 mL) and stirred at room temperature for 2 h. The solvent was evaporated under reduced pressure and the residue was partitioned between aqueous sodium hydroxide (2M) and ether (30 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled in ice. Di-t-butyldicarbonate (161 mg) was added and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure and the residue was purified by MPLC on silica gel, eluting with EtOAc/Hexane (5:95) to give the title compound as a clear oil (141 mg), δH (CDCl3) 1.55 (9H, s), 1.59 (2H, m), 1.82 (2H, m), 2.58 (1H, m), 2.77 (1H, m), 3.64 (2H, br s), 4.16 (2H, m), 6.68-6.79 (2H, m), 7.01-7.26 (2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:28][CH2:27][C:5]2[N:6]([CH2:14][CH:15](OS(C)(=O)=O)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>O>[CH:29]1([NH:32][CH:15]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:28][CH2:27][C:5]2=3)[CH2:31][CH2:30]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccncc2)CCN(C)C1
Reactant: NC1CC1
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(NC2CC2)c2ccncc2)CCN(C)C1
Temperature: 90 °C

Procedure:
Methanesulfonic acid 2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethylester (1.0 g, 3.5 mmol) was dissolved in 70% cyclopropylamine in water (50 mL) and heated at 90° C. for 18 h. The reaction mixture was concentrated to obtain the crude product that was purified by reverse phase chromatography to obtain 300 mg of cyclopropyl-[2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethyl]-amine. 1H NMR (CDCl3, Free base) δ (ppm): 8.52 (d, 2H), 7.18 (s, 1H), 7.14 (d, 1H), 7.13 (d, 2H), 6.99 (d, 1H), 4.22 (m, 2H), 3.98 (dd, 1H), 3.76 (d, 1H), 3.70 (d, 1H), 2.85 (m, 1H), 2.74 (m, 2H), 2.55 (s, 3H), 2.44 (s, 3H), 2.36 (m, 2H), 0.33 (m, 2H), 0.23 (m, 2H). Separation by chiral HPLC provided enantiomers II-260a-b.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:14])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:7]=1.C([O-])(=O)C.[K+].[B:20]1(B2OC(C)(C)C(C)(C)O2)[O:24]C(C)(C)C(C)(C)[O:21]1>O1CCOCC1.CS(C)=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:14][C:5]1[CH:4]=[CH:3][C:2]([B:20]([OH:24])[OH:21])=[CH:7][C:6]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Fc1ccc(Br)cc1-c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: OB(O)c1ccc(F)c(-c2ccncc2)c1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 46.1 %

Procedure:
A mixture of 4-(5-bromo-2-fluorophenyl)pyridine (3.8 g, 15.1 mmol), potassium acetate (2.96 g, 30.1 mmol) and bis(pinacolato)diboron (4.21 g, 16.6 mmol) in 1,4-dioxane (50 mL) and dimethylsulfoxide (1 mL) was degassed with nitrogen for 1 h. Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (370 mg, 0.5 mmol) was added and the mixture heated at 90° C. for 18 h. The reaction was cooled to ambient temperature, filtered and the filter-cake washed with diethyl ether. The filtrate was evaporated to dryness and the residue stirred with ice-cold 2 N sodium hydroxide (100 mL) for 20 min. The aqueous mixture was filtered and the filtrate washed with diethyl ether (2×75 mL). The organics were discarded and the aqueous phase cooled to 0° C. before lowering the pH to 8 by addition of 36% hydrochloric acid. The resulting solid was collected by filtration and triturated with diethyl ether to afford 4-fluoro-3-(pyridin-4-yl)benzene-boronic acid as a buff-coloured solid (1.51 g, 46%): δH (360 MHz, DMSO) 7.34 (1H, dd, J 11 and 8), 7.61 (2H, d, J 5), 7.88-7.92 (1H, m), 8.05 (1H, dd, J 8 and 1), 8.26 (2H, s), 8.70 (2H, d, J 5); m/z (ES+) 218 (M++H). The aqueous filtrate was extracted with diethyl ether. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate, filtered and evaporated to afford 4-[2-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-pyridine as a dark oil (1.28 g, 29%) that solidified on standing for a few days: δH (360 MHz, CDCl3) 1.36 (12H, s), 7.19 (1H, dd, J 11 and 8), 7.50-7.53 (2H, m), 7.82-7.87 (1H, m), 7.93 (1H, dd, J 8 and 1), 8.67 (2H, dd, J 4 and 1); m/z (ES+) 300 (M++H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([O:26]C)=[O:25])=[C:12]2[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].Cl>CO.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([C:24]([OH:26])=[O:25])=[C:12]2[C:28]1[S:29][CH:30]=[CH:31][CH:32]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c(=O)n1CC(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)Cn1c(C(=O)O)c(-c2cccs2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 87.7 %

Procedure:
To a suspension of methyl 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylate (2.01 g, 4.5 mmol) in methanol (30 ml) was added a solution of lithium hydroxide monohydrate (0.57 g, 13.5 mmol) in water (10 ml). The resulting mixture was refluxed under heating for 48 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crystals were recrystallized from ethyl acetate-n-hexane to give 6-(benzyloxy)-2-isobutyl-1-oxo-4-(2-thienyl)-1,2-dihydro-3-isoquinolinecarboxylic acid (1.71 g, 87.7%) as crystals.
Reaction SMILES: C[O-].[Na+].CCO[CH:7]=[C:8]([C:14]([O:16]CC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:19]([NH:22][NH2:23])([CH3:21])[CH3:20].Cl>C(O)C.[Cl-].[Na+].O>[OH:16][C:14]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:22]([CH:19]([CH3:21])[CH3:20])[N:23]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)NN
Agent: C[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cn(C(C)C)nc1O
Temperature: 80 °C
Reaction time: 4 h
Yield: 35.1 %

Procedure:
To a solution of sodium methoxide (23 g) in ethanol (150 mL) were added diethyl ethoxymethylene malonate (32.7 g) and isopropyl hydrazine (11.2 g) at room temperature. The mixture was stirred at 80° C. for 4 hours and stirred at 100° C. for another 2 hours. The reaction mixture was poured into 2 mol/L hydrochloric acid (300 mL). After the mixture was diluted with brine, the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give 10.5 g of the title compound.
Reaction SMILES: Cl.CO[C:4]1[CH:17]=[CH:16][C:7]([C:8](C2CCNCC2)=[O:9])=[CH:6][CH:5]=1.COC([C:22]1[CH:23]=[CH:24][C:25](C(O)=O)=[N:26][CH:27]=1)=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:8]([N:26]1[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25]1)(=[O:9])[C:7]1[CH:6]=[CH:5][CH:4]=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 161.5 %

Procedure:
To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+(found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[Br:35])[C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)(C)(C)C.[ClH:37].O1CCOCC1>C(#N)C>[ClH:37].[NH2:7][CH:8]([C:9]1[C:14](=[O:15])[CH2:13][CH2:12][CH2:11][C:10]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=1)[C:27]1[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][C:28]=1[Br:35]
Reactant: CC(C)(C)OC(=O)NC(C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O)c1ccc(C#N)cc1Br
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCCC2=O)c(Br)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
{(2-Bromo-4-cyano-phenyl)-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-carbamic acid tert-butyl ester (INTERMEDIATE 20, 20.8 g, 36.9 mmol) is suspended in acetonitrile (150 mL) and a solution of hydrogen chloride in 1,4-dioxane (4 M, 46.1 mL, 184.3 mmol) is added. The mixture is stirred at room temperature for 3 h. The product precipitates from the reaction mixture. The precipitate is filtered off, washed with acetonitrile and dried. Yield: 16.5 g ESI mass spectrum: [M+H]+=464 (bromine isotope pattern), Retention time HPLC: 0.56 min, (X012_S02).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[C:14]2[O:18][CH2:17][O:16][C:15]=12)[C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=O.S(=O)(=O)(O)O.[H][H]>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:13]=[C:14]2[O:18][CH2:17][O:16][C:15]=12
Reactant: [H][H]
Reactant: COC(=O)CC(=O)c1cc(OC)c2c(c1)OCO2
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)CCc1cc(OC)c2c(c1)OCO2
Yield: 99.9 %

Procedure:
550 mg of methyl 3-methoxy-4,5-methylenedioxybenzoylacetate (10) and 55 mg of 5% Pd/C were suspended in 10 ml of methanol containing 2 drops (about 50 mg) of concentrated sulfuric acid. The mixture was subjected to hydrogenation at normal temperature and pressure. It was confirmed by thin layer chromatography that the hydrogenation was completed when twice as much moles of hydrogen as the starting material had been absorbed. After the catalyst was filtered out and washed, the filtrate was concentrated. The resultant residue was dissolved in 15 ml of ethyl ether, then dried over anhydrous magnesium sulfate, again filtered, washed with Et2O and concentrated to obtain 519 mg of pure methyl 3-(3-methoxy-4,5-methylenedioxyphenyl)propionate (12) with a quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][N:25](CC4C=CC=CC=4)[CH:24]([CH3:35])[CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1.[H][H].[OH-].[Na+]>C(O)C.Cl.C(O)C.[C].[Pd]>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:12][C:11]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][CH:24]([CH3:35])[CH2:23]3)=[O:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: COc1ccc(-n2nc(C(=O)N3CCN(Cc4ccccc4)C(C)C3)cc2-c2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-n2nc(C(=O)N3CCNC(C)C3)cc2-c2ccccc2)cn1

Procedure:
To a solution of 1-[1-(6-methoxy-3-pyridyl)-5-phenylpyrazole-3-carbonyl]-4-benzyl-3-methylpiperazine (0.459 g) obtained in Example 14 in ethanol (10 mL), 1M HCl-ethanol (0.980 mL) and 10% palladium-carbon (123 mg) were added at room temperature. The resultant mixture was stirred in a hydrogen atmosphere for 5.5 hours. After the atmosphere was changed to nitrogen, the mixture was neutralized to pH 8 with 1M aqueous sodium hydroxide, followed by removal of insoluble matter through filtration. Solvent of the filtrate was removed under reduced pressure, and then the residue was partitioned between water and chloroform. The aqueous layer was extracted with chloroform. The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate anhydrate. The resultant mixture was subjected to filtration, and the solvent was removed under reduced pressure. The residue was purified through silica gel column chromatography (chloroform-methanol), to thereby give the title compound as an oily product (0.250 g, 67%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2=[N:8][NH:9][C:10]([CH:11]3[CH2:14][CH:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=[O:19])[CH2:12]3)=[C:5]2[CH:4]([C:23]2[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=2[F:31])[CH2:3]1.CO.[BH4-].[Na+]>C1COCC1>[OH:19][CH2:18][C:17]1[CH:16]=[C:15]([CH:13]2[CH2:12][CH:11]([C:10]3[NH:9][N:8]=[C:6]4[C:5]=3[CH:4]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[F:31])[CH2:3][C:2](=[O:1])[NH:7]4)[CH2:14]2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1cccc(C2CC(c3[nH]nc4c3C(c3cc(F)c(F)cc3F)CC(=O)N4)C2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(c2cc(F)c(F)cc2F)c2c(n[nH]c2C2CC(c3cccc(CO)c3)C2)N1
Reaction time: 0.5 h

Procedure:
To 3-{3-[6-oxo-4-(2,4,5-trifluoro-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-yl]-cyclobutyl}-benzaldehyde (15 mg, 0.03 mmol) in THF:MeOH (3 mL 3:1) was added sodium borohydride (10 mg, 0.26 mmol). After 30 min, the reaction was quenched by the addition of 5 drops of aqueous NaOH (1N). The reaction mixture was concentrated under reduced pressure. Purification of this material was accomplished by preparative plated chromatography. The product band was collected, extracted with EtOAc, filtered, and concentrated to give the title compound. LRMS m/z (APCI+) 428 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH2:12][O:13][CH3:14])=[C:4]([OH:10])[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH:21]1([CH2:24]Br)[CH2:23][CH2:22]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:24][CH:21]2[CH2:23][CH2:22]2)[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: BrCC1CC1
Reactant: COCOc1c(Br)ccc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCOc1c(Br)ccc(OC)c1OCC1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.5 %

Procedure:
To a stirring solution of 3-bromo-6-methoxy-2-(methoxymethoxy)phenol (12 g, 0.045 mol) in acetonitrile (100 mL) at 0° C. was added potassium carbonate (18 g, 0.135 mol) and cyclopropylmethyl bromide (9 g, 0.067 mol) and the resultant reaction mixture was stirred for 1 h at RT. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-12% ethyl acetate in pet ether) to afford 1-Bromo-3-(cyclopropylmethoxy)-4-methoxy-2-(methoxymethoxy)benzene as a solid (5.5 g, 38%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[CH3:2].CN(C)C(=N)N(C)C.[N+:24]([CH3:27])([O-:26])=[O:25]>>[CH2:1]([O:3][C:4](=[O:15])[CH2:5][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)[CH2:27][N+:24]([O-:26])=[O:25])[CH3:2]
Reactant: CCOC(=O)C=Cc1ccc(OC)cc1
Reactant: C[N+](=O)[O-]
Agent: CN(C)C(=N)N(C)C
Product: CCOC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1

Procedure:
A solution of 3-(4-methoxy-phenyl)acrylic acid ethyl ester (1.0 g) and tetramethyl-guanidine (125 μL) was stirred for 24 h at 70° C. in 2.5 mL nitromethane. The solvent was evaporated and the resulting residue was partitioned in 50 mL 1 N hydrochloric acid and 50 mL ethyl ether. The ethyl ether phase was collected and washed with 50 mL 1 N hydrochloric acid. The ether phase was dried over sodium sulfate and the solvent was evaporated to furnish 1.15 g of 3-(4-methoxyphenyl)-4-nitrobutyric acid ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8]1[N:14]([CH3:26])[C:15](=[O:25])[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[CH:17][C:7]2=1)(=[O:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][O:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1)C>>[Br:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[C:15](=[O:25])[N:14]([CH3:26])[C:8]3[N:9]([CH3:13])[C:10]4[C:6]([C:7]=3[CH:17]=2)=[CH:5][C:4]([C:1](=[O:3])[CH2:2][C:30](=[O:29])[CH2:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:12][CH:11]=4)=[CH:23][CH:22]=1
Reactant: CCOC(=O)COC1CCCCO1
Reactant: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Br)cc3)c(=O)n(C)c1n2C
Product: Cn1c(=O)c(-c2ccc(Br)cc2)cc2c3cc(C(=O)CC(=O)COC4CCCCO4)ccc3n(C)c21

Procedure:
The process is carried out as in Example 80 above, with the compound from Example 60B above, 6-acetyl-3-(4-bromophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and (tetrahydropyran-2-yloxy)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([P:8](=[O:15])(OCC)OCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+].Br[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br.O>O1CCCC1>[CH2:1]([P:8]1(=[O:15])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: BrCCCCCBr
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=P1(Cc2ccccc2)CCCCC1
Yield: 368.7 %

Procedure:
To a solution of diethyl benzylphosphonate (2.5 g) in tetrahydrofuran (500 ml) was added Red-Al (70% toluene solution) (3.8 g) at room temperature, and the mixture was stirred until gas production stopped. To the reaction mixture was added 1,5-dibromopentane (25.18 g), and the mixture was stirred at 50-60° C. for 16 hours. To the reaction mixture was added water (20 ml), and precipitate was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was separated and purified with column chromatography (ethyl acetate→ethanolethyl acetate=1:2) to give 1-benzylphosphorinane-1-oxide (8.41 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B(O)O)(=[O:3])[CH3:2].Br[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:21][C:22]([CH3:33])=[C:23]([CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][C@H:28]3[CH3:32])[N:24]=2)=[CH:16][CH:15]=1>>[CH3:33][C:22]1[O:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[C:1](=[O:3])[CH3:2])=[CH:15][CH:16]=2)=[N:24][C:23]=1[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH3:32]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: CC(=O)c1ccccc1B(O)O
Product: CC(=O)c1ccccc1-c1ccc(-c2nc(CCN3CCC[C@H]3C)c(C)o2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-acetylphenyl boronic acid (235 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 94 mg (85%). MS (m/e) 389.2 (M+1)