Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl([O-])=O.[Na+].[OH2:5].OP([O-])(O)=O.[Na+].[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([C@@H:26]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH:41]=[O:42])=[CH:36][CH:35]=3)[CH2:27][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:16][CH2:15][CH2:14][CH2:13]1.CC(=CC)C>O.CC(O)(C)C.C(O)(=O)C>[CH:12]1([O:17][C:18]2[CH:19]=[C:20]([C@@H:26]([C:34]3[CH:35]=[CH:36][C:37]([CH2:40][C:41]([OH:5])=[O:42])=[CH:38][CH:39]=3)[CH2:27][C:28]3[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=3)[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1ccc([C@H](Cc2ccncc2)c2ccc(CC=O)cc2)cc1OC1CCCC1
Reactant: O
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: COc1ccc([C@H](Cc2ccncc2)c2ccc(CC(=O)O)cc2)cc1OC1CCCC1
Yield: 82.8 %

Procedure:
A solution of sodium chlorite (80%; 131 mg, 1.16 mmol) and sodium phosphate monobasic monohydrate (160 mg, 1.16 mmol) in water (1.1 mL) was added to a solution of (R)-4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenylacetaldehyde from Step 5 (371 mg, 0.893 mmol) and 2-methyl-2-butene (665 μL, 6.25 mmol) in t-BuOH (8 mL). The reaction mixture was stirred at room temperature for 1.5 h before 25% aqueous NH4OAc buffer was added (a few drops of acetic acid were necessary to bring the pH at 7). The mixture was then extracted with EtOAc (2×), and the combined organics were washed successively with 25% aqueous NH4OAc buffer, water and brine, dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica (EtOAc containing 0.5% AcOH). Residual AcOH was co-evaporated with toluene (2×) to afford the title compound as a white foam (319 mg, 83%). 1H NMR (400 MHz, acetone-d6): δ 1.50-1.61 (m, 2H), 1.63-1.88 (m., 6H), 3.40 (d; 2H), 3.54 (s, 2H), 3.70 (s, 3H), 4.34 (t, J=8 Hz, 1H), 4.75 (m, 1H), 6.78 (m, 2H), 6.90 (s, 1H), 7.15 (d, J=6 Hz, 2H), 7.20 (d, J=8 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 8.33 (d, J=5 Hz, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.C(O)C>[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(CCCOc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(CCCOc2ccc(N)cc2)CC1
Temperature: 25 °C

Procedure:
Into a Round bottom flask, 1-Methyl-4-[3-(4-nitro-phenoxy)-propyl]-piperazine (4.10 g, 0.0147 mol), 10% Pd/C (10:90, Palladium:carbon black, 1.6 g, 0.0015 mol), and Ethanol (100 mL, 2 mol) were added. The mixture was evacuated under house vacuum and charged with a hydrogen balloon (3×). The reaction was stirred at room temperature under an atmosphere of Hydrogen via a balloon. The solid was filtered. The solvent was removed under vacuum to give 4-[3-(4-Methyl-piperazin-1-yl)-propoxy]-phenylamine a white solid (2.86, 78%). 1H (DSMO-d6)-6.62 (dd, 1H, J=2.08, 4.57 Hz), 6.49 (dd, 2H, J=2.16, 5.64 Hz), 4.56 (bs, 2H), 3.82 (t, 2H, J=6.40 Hz), 2.20-2.45 (m, 10H), 2.13 (s, 3H), 1.70-1.83 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][CH2:22][OH:23])[CH:18]=3)[N:13]=[C:12]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39].O>C(Cl)Cl>[CH3:37][S:38]([O:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[N:11]=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)(=[O:40])=[O:39]
Reactant: OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc2nc(-c3cccnc3)nc(Nc3ccc(F)c(Cl)c3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a suspension of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propan-1-ol (0.25 g, 0.61 mmol) and triethylamine (0.17 ml, 1.22 mmol) in CH2Cl2 (10 mL) was added methanesulfonyl chloride (0.057 ml, 0.73 mmol). The mixture was stirred at room temperature for 1 h. Water (10 mL.) was added to the mixture and stirred for a while. The resultant precipitate was collected by filtration and washed with CH2Cl2 and dried to give 0.27 g of 3-(4-(3-chloro-4-fluorophenylamino)-2-(pyridin-3-yl)quinazolin-6-yl)propyl methanesulfonate as pale yellow solid (91%), which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH:19]C(=O)C)=[CH:7]2.Cl>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH2:18][NH2:19])=[CH:7]2
Reactant: CC(=O)NCc1cc2cccc(F)c2nc1-c1ccccc1
Agent: Cl
Product: NCc1cc2cccc(F)c2nc1-c1ccccc1

Procedure:
To N-((8-fluoro-2-phenylquinolin-3-yl)methyl)acetamide (28 mg, 95 μmol) was added added hydrochloric acid (2M solution in water, 2 mL, 4000 μmol). The reaction was heated to 80 C for 24 h. The reaction was cooled to it and quenched with 15% NaOH. The product was extracted into ether (2×10 mL) and the combined organics were washed with brine, dried over MgSO4, filtered, and concentrated to afford (8-fluoro-2-phenylquinolin-3-yl)methanamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.34 (s, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.61 (m, 2H), 7.48 (m, 4H), 7.39 (ddd, J=10.6, 7.8, 1.6 Hz, 1H), 4.05 (s, 2H), 2.03 (br s, 2H). Mass Spectrum (ESI) m/e=253.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.41 g, 2.2 mmol). The product was isolated as a white foam. Yield 370 mg (41%). mp 85°-90° C. FDMS m/e=421 (M+of free base). α[D]589 =+3.62 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]=[O:26])[CH:5]=[CH:6][CH:7]=1.[CH3:27][Mg+].[Br-].O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:11](=[O:24])[CH:10]=[C:9]2[CH:25]([OH:26])[CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg+]
Reactant: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C=O)cc2=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(COc2cn(-c3cccc(Br)c3)c(C(C)O)cc2=O)cc1
Temperature: -30 °C
Yield: 58 %

Procedure:
To a solution of 1-(3-bromophenyl)-5-[(4-methoxybenzyl)oxy]-4-oxo-1,4-dihydropyridine-2-carbaldehyde (3.0 g, 7.25 mmol), in dry THF (50 mL) was added MeMgBr (7.25 mL of a 3 M solution in THF, 21.8 mmol) dropwise at −30° C., and the reaction mixture was stirred at −30° C. then warmed to room temperature and stirred for another 2 h. The reaction mixture was cooled to 0° C., 2 mL water was added, and the mixture was diluted with ethyl acetate. The layers were separated, and the organic fraction was dried (MgSO4), concentrated under reduced pressure, and purified by Prep-HPLC to give 1.8 g (58%) of 1-(3-bromophenyl)-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one. Chiral resolution of 12.0 g 1-(3-bromophenyl)-2-(1-hydroxyethyl)-5-[(4-methoxybenzyl)oxy]pyridin-4(1H)-one was accomplished by SFC of racemic material using a Chiral Technologies ChiralPak AD-H column (25% MeOH in CO2, 3 cm diameter×25 cm length, 70 mL/min flow, 200 mg per injection), and afforded (80%) of the first eluting enantiomer and (79%) of the second eluting enantiomer. 1H-NMR (CD3OD, 400 MHz) δ 7.76 (d, J=8.0 Hz, 1H), 7.64 (s, 1H), 7.51-7.41(m, 2H), 7.38-7.35 (m, 2H), 7.33-7.31 (m, 2H), 6.88-6.86 (m, 2H), 6.76 (s, 1H), 4.95 (s, 2H), 4.39-4.34 (m, 1H), 3.76 (s, 3H), 1.26 (d, J=6.0 Hz, 2H). MS (ESI) m/z (M+H)+ 430.1/432.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=[CH:11][C:10]=1[CH:42]=[CH:43][C:44]1[S:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([N:15]([CH2:38][CH2:39][CH2:40][CH3:41])[CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:12]=[CH:11][C:10]=1[CH:42]=[CH:43][C:44]1[S:48][C:47]([CH:49]=[O:50])=[CH:46][CH:45]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCN(CCCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCN(CCCCO)c1ccc(C=Cc2ccc(C=O)s2)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
In 10 ml of tetrahydrofuran was dissolved 1.2 g (1.71 mmol) of 5-[2-[2-benzyloxy-4-[butyl[4-(tert-butyldiphenylsiloxy) butyl]amino]phenyl]vinyl]thiophene-2-carboaldehyde. To this mixture, 7.6 ml of tetrabutylammonium fluoride (1 mol/L solution in tetrahydrofuran) (7.6 mmol) was added dropwise with stirring at room temperature. The mixture was stirred for 1.5 hours. After the reaction mixture was poured into water, extraction with ethyl acetate, washing with a saturated saline solution, drying over anhydrous sodium sulfate, and concentration were performed. The residual liquid was purified by silica gel column chromatography to give 554 mg of a red crystal (yield: 70.1%).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:14]([O:16][C:17](=[O:27])[C:18]([CH:25]=O)([CH3:24])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[C:18]([CH2:24][NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)([CH3:25])[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH3:15]
Reactant: NC1CCC1
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
Cyclobutylamine (1.23 mL, 14.4 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.81 g, 28.8 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (prepared as described in Example 19c; 2.88 g, 14.4 mmol) in ethanol (40 mL) at 25° C. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclobutylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.76 g, 6.89 mmol, 48%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (3H, d, J=3.0 Hz), 0.88 (3H, d, J=4.0 Hz), 0.99-1.07 (1H, m), 1.17 (3H, s), 1.26 (3H, t, J=7.5 Hz), 1.42-1.68 (4H, m), 2.43 (1H, d, J=11.7 Hz), 2.73 (1H, d, J=11.7 Hz), 3.15-3.23 (1H, m), 4.13 (2H, q, J=7.0 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C1OCCOCCOCCOCCOCCOC1.[CH:37]1(Br)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>CS(C)=O.O>[CH:37]1([O:7][N:8]2[C:9](=[O:18])[C:10]3[C:11](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:13])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: BrC1CCCCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
Solid potassium carbonate (6.91 g, 50.0 mmol) was added to a solution of N-hydroxyphthalimide (4.08 g, 25.0 mmol) and 18-crown-6 (661 mg, 2.5 mmol) in dimethyl sulfoxide (62 mL), and the mixture was stirred at 25° C. for 5 min. To the mixture cyclohexyl bromide (12.3 mL, 100.0 mmol) was added, and the mixture stirred at 80° C. for 3 h. After ice-cooling, the mixture was poured into cold water and the resulting precipitate was collected by filtration in vacuo, washed with water (25 mL) and hexanes (15 mL) and dried in vacuo to afford 2-cyclohexyloxy-isoindole-1,3-dione (5.67 g, 93%) as a white solid which was used in the next step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([NH2:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[N:24][C:22]([C:16]1([C:13]2[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:12]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:23])[CH3:29]
Reactant: NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 100 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid amide (0.561 g, 1.69 mmol) and N,N-dimethylformamide dimethyl acetal (5 mL) were combined and heated at reflux for 4 hours. The reaction mixture was concentrated in vacuo and azeotroped with toluene (2×10 mL) to provide the title compound (0.655 g, 100%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ 1.80-1.85 (m, 4H), 1.85-1.95 (m, 2H), 2.0-2.10 (m, 2H), 2.6-2.78 (m, 8H), 3.0 (s, 3H), 3.05 (s, 3H), 3.60 (m, 2H), 3.90 (m, 2H), 4.0 (t, 2H), 6.80 (d, 2H), 7.35 (d, 2H), 8.30 (s, 1H). LRMS APCI+ m/z 388 [MH]+.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH2:35][CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][C:23]=2[CH3:37])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[Li+].[OH-]>C1COCC1.CO>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH2:34][CH2:35][CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:24][C:23]=2[CH3:37])=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: CCC[C@H](CC(=O)OC)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC[C@H](CC(=O)O)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)c(C)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a solution of 27.5 (0.039 g, 0.076 mmol) in THF/MeOH (2/1) (1.5 mL) was added LiOH (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1 N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford a 27 (0.024 g, 64% yield). MS ESI (neg.) m/e: 491.2 (M−H)+.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[CH2:13][Mg]Br>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][CH:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[OH:8])[CH:16]=[CH:17][CH:18]=1
Reactant: Br[Mg]Cc1cccc(Br)c1
Reactant: O=CC1CCCCC1
Product: OC(Cc1cccc(Br)c1)C1CCCCC1

Procedure:
Grignard reaction between cyclohexanecarbaldehyde and 3-bromobenzyl magnesium bromide (0.25M in ether) gave 2-(3-bromophenyl)-1-cyclohexylethanol as a white solid. Yield (1.62 g, 23%): 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J=0.8 Hz, 1H), 7.34-7.31 (m, 1H), 7.20-7.17 (m, 2H), 4.37 (d, J=6.0 Hz, 1H), 3.38-3.32 (m, 1H), 2.69 (dd, J=13.6, 3.6 Hz, 1H), 2.51-2.45 (dd, obs., 1H), 1.78-1.60 (m, 5H), 1.24-0.94 (m, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1C=CC=CC=1>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)c2ccc(S(C)(=O)=O)cc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)c2ccc(O)cc2)cc1
Temperature: 0 °C

Procedure:
A mixture of [4-(Methyloxy)phenyl][4-(methylsulfonyl)phenyl]methanone (92) (0.20 g, 0.69 mmol) and aluminum chloride (0.38 g, 2.76 mmol) were refluxed in benzene (10 mL) for 2 h and then cooled to 0° C. in an ice bath. Water (10 mL) was added slowly, and the mixture was extracted with EtOAc (2×75 mL). The combined organic extract was washed with water, brine, and dried over Na2SO4. Concentration of the extract gave the title compound (93) as light brown solid (0.19 g, 100%), which was used without further purification. 1H NMR (400 MHz, DMSO-d6): δ 3.28 (s, 3H), 6.89 (d, J=8.6 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H), 8.05 (d, J=8.2 Hz, 2H), 10.56 (s, 1H). LCMS (ES): m/z 277 (M+H)+, m/z 275 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[C:7]2=[O:13].CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[F:57][C:58]([F:70])([F:69])[C:59]1[CH:64]=[CH:63][C:62]([CH2:65][C:66](O)=[O:67])=[CH:61][CH:60]=1>>[Cl:12][C:11]1[C:2]([NH:1][C:66](=[O:67])[CH2:65][C:62]2[CH:61]=[CH:60][C:59]([C:58]([F:69])([F:57])[F:70])=[CH:64][CH:63]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:13])[N:6]([C@H:14]([CH3:18])[C:15]([NH2:17])=[O:16])[CH:5]=[CH:4]2
Reactant: C[C@H](C(N)=O)n1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](C(N)=O)n1ccc2c(NC(=O)Cc3ccc(C(F)(F)F)cc3)c(Cl)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)propanamide (50 mg, 0.0002 mol), N,N-dimethylformamide (1 mL, 0.01 mol), N,N-diisopropylethylamine (60 μL, 0.0004 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.0004 mol) and 2-(4-(trifluoromethyl)phenyl)acetic acid (46 mg, 0.00022 mol) and the reaction stirred at room temperature overnight. The reaction was only 60% complete. Stirring for an additional 6 hours did not improve the reaction. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the product as an off white solid. MS m/z=452.2 (M+H). 1H NMR (400 MHz; DMF) δ 10.41 (s, 1H), 8.34 (d, J=8.71 Hz, 1H), 7.93 (d, J=8.22 Hz, 1H), 7.84 (d, J=10.96 Hz, 1H), 7.80 (t, J=9.13 Hz, 1H), 7.68 (d, J=8.53 Hz, 1H), 7.44 (bs, 1H), 6.62 (d, J=7.89 Hz, 1H), 5.67-5.61 (q, J=7.24 Hz, 1H), 4.09 (s, 2H), 1.72 (d, J=7.50 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48]([NH:1][C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])=[CH:4][CH:3]=2)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.3 %

Procedure:
tert-Butyl 4-aminobenzoate (0.620 g, 6.209 mmol), triethylamine (0.325 g, 3.209 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.542 g, 3.209 mmol) were added to a methylene chloride solution (150 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.400 g, 1.070 mmol) and the resulting solution was stirred at room temperature for 6 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate:hexane=1:2→1:0) to obtain the titled compound (0.302 g, 0.549 mmol, 57%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:10]([C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[O:12])=[CH:9][CH:8]=[CH:7][N:6]=1.C(O)C>O>[CH3:3][O:4][C:5]1[C:10]([CH:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[OH:12])=[CH:9][CH:8]=[CH:7][N:6]=1
Reactant: COc1ncccc1C(=O)c1cccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ncccc1C(O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
303 mg of sodium borohydride was added little by little to a solution containing 1.46 g of 2-methoxy-3-(2-thienylcarbonyl)pyridine and 10 ml of ethanol under ice-cooling. After stirring at room temperature for 2 hours, water was slowly added thereto and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and the solvent was removed, to give 1.47 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[C:5]([NH:7][C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])=[O:6].CN(CCN(C)C)C.CN([CH:32]=[O:33])C>C1COCC1>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:4]2[C:3]=1[CH:32]([OH:33])[N:7]([C:8]([CH3:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:9])[C:5]2=[O:6]
Reactant: CN(C)C=O
Reactant: CC(C)(NC(=O)c1ccc(F)c(Cl)c1)c1ccccc1
Agent: CN(C)CCN(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccc1)N1C(=O)c2ccc(F)c(Cl)c2C1O
Yield: 45.5 %

Procedure:
In a similar manner to Step 2 of Example 16, 3-chloro-4-fluoro-N-(1-methyl-1-phenylethyl)benzamide (3.00 g, 10.3 mmol) was dissolved in THF (120 mL), and the solution was treated with TMEDA (5.00 mL, 32.9 mmol), sec-butyl lithium-hexane solution (1.01 mol/L, 32.6 mL, 32.9 mmol) and DMF (1.80 mL, 22.6 mmol), followed by purification by flash column chromatography (chloroform) and by slurry (chloroform) to obtain 4-chloro-3-hydroxy-5-fluoro-2-(1-methyl-1-phenylethyl)isoindolinone (1.50 g, yield 46%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:15](=[S:16])[C:14]2[CH:17]=[CH:18][CH:19]=[C:12]3[C:13]=2[C:8](=[CH:9][CH:10]=[CH:11]3)[C:7]1=[O:20])C.[OH-].[Na+]>CO>[O:20]=[C:7]1[C:8]2[C:13]3[C:12](=[CH:19][CH:18]=[CH:17][C:14]=3[C:15](=[S:16])[N:6]1[CH2:5][C:4]([OH:21])=[O:3])[CH:11]=[CH:10][CH:9]=2
Reactant: CCOC(=O)CN1C(=O)c2cccc3cccc(c23)C1=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1C(=O)c2cccc3cccc(c23)C1=S
Temperature: 20 °C
Reaction time: 18 h
Yield: 72.1 %

Procedure:
A suspension of 1-oxo-3-thioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid ethyl ester (34.35 g, 0.115 mole, described in Example 6) in methanol (200 ml) and aqueous 4 N sodium hydroxide (43 ml, 0.1721 mole) was stirred at 20° C. for 18 hr. The solvent was removed and the residue suspended in water (1 liter). The aqueous suspension was extracted with ethyl acetate (2×1 liter) to remove unreacted ethyl ester. The aqueous phase was rendered acidic with 2 N hydrochloric acid. The resulting precipitate was collected. Recrystallization of the precipitate from methanol gave 22.5 g of the title compound, mp 265° C. (dec.); UV (MeOH) 244, 251, 333, 344, 390 nm, ε=20,210, 19,150, 8,640, 8,225, 13,995, respectively; IR (nujol) 2900, 1720 and 1683 cm-1 ; NMR (DMSO-d6) δ5.33 (s, 2H), 7.3-8.93 (m, 6H); Anal. Calc'd.: C, 61.98%; H, 3.34%; N, 5.16%; Found: C, 62.07%; H, 3.42%, N, 5.00%.