Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:37])[C:13]([C:21]2[N:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:23]=[C:24]3[C:29]=2[CH2:28][CH2:27][CH2:26][CH2:25]3)([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[OH:14])=[C:7]([F:38])[CH:6]=1)C.[OH-].[Li+]>C1COCC1.CO>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([N:22]2[C:21]([C:13]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)([OH:14])[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:39])=[O:3])=[CH:6][C:7]=3[F:38])=[O:37])=[C:29]3[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)=[N:23]2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)c1ccc(NC(=O)C(O)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(NC(=O)C(O)(c2c3c(nn2-c2ccc(Cl)cc2)CCCC3)C2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 121 %

Procedure:
To a solution of 4-{2-[2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-2-cyclohexyl-2-hydroxy-acetylamino}-3-fluoro-benzoic acid ethyl ester (6 mg, 11 μmol) in THF/MeOH 1/1 (0.2 ml) was a added a 1 N aqueous lithium hydroxide solution (60 μl, 60 μmol) at ambient temperature under an argon atmosphere. The reaction mixture was stirred for 12 h at ambient temperature and poured onto ice water/1 N aqueous NaOH solution 1/1. The layers were separated, the aqueous layer was acidified with ice cold 1 N aqueous HCl solution and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give the title compound (7 mg; quant.) as yellow solid. MS: m/e=526.4 [M+H+].
Reaction SMILES: [C:1]([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)([CH3:3])=[CH2:2].C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:4]1[C:5]([CH3:13])=[N:6][N:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)([CH3:3])[CH3:2]
Reactant: C=C(C)c1c(C)nn2ccccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nn2ccccc2c1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 43.6 %

Procedure:
A solution of 3-isopropenyl-2-methylpyrazolo[1,5-a]pyridine (0.43 g, 2.5 mmol) in CH2Cl2 (30 mL) was treated with triethylsilane (3 mL, 18.8 mmol) and TFA (6 mL). The reaction was stirred at room temperature for 15 hours then quenched with saturated NaHCO3.The layers were separated and the aqueous layer was extracted with CH2Cl2 and the combined organic layers was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (20% ethyl acetate/heptane) to give 0.19 g (44%) of a yellow oil as the title compound: 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.0 Hz, 1H), 7.59 (d, J=8.9 Hz, 1H), 7.07–7.03 (m, 1H), 6.71–6.68 (m, 1H), 3.20–3.09 (m, 1H), 2.35 (s, 3H), 1.31 (d, J=7.1 Hz, 6H); 13CNMR (100 MHz, DMSO-d6)δ 147.5, 137.1, 128.1, 121.9, 116.6, 113.5, 110.2, 23.8, 22.7, 12.4; HRMS (FAB) calcd for C11H14N2+H 175.1235. found 175.1236.
Reaction SMILES: C([O:8][C:9]([C:11]1[O:36][C:14]2=[CH:15][CH:16]=[C:17]3[C:21]([N:20]([CH2:22][C@@H:23]([NH:25][C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH3:24])[N:19]=[CH:18]3)=[C:13]2[CH:12]=1)=O)C1C=CC=CC=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C.C1COCC1>[CH2:29]([O:28][C:26](=[O:27])[NH:25][C@@H:23]([CH3:24])[CH2:22][N:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]3[O:36][C:11]([CH2:9][OH:8])=[CH:12][C:13]3=2)[CH:18]=[N:19]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(C(=O)OCc4ccccc4)cc3c21)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](Cn1ncc2ccc3oc(CO)cc3c21)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 48.8 %

Procedure:
To a stirred solution of the product from Step A (0.13 g, 0.27 mmol) in ethanol (10 mL) was added calcium chloride (0.06 g, 0.54 mmol) in THF (2 mL) followed by sodium borohydride (0.04 g, 1.07 mmol) at 0° C. and the mixture was stirred at room temperature for 20 h. The reaction mixture was evaporated to a residue and a saturated aqueous solution of ammonium chloride (20 mL was added followed by ethyl acetate (50 mL). The organic layer was separated and the aqueous was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (30 mL), dried and evaporated to a residue, which was purified by chromatography (silica, 50% ethyl acetate in hexane) to give an oil (0.05 g, 49%); MS (ES) m/z 380 (M+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.Br[C:17]1[CH:22]=[CH:21][N:20]2[C:23]([C:26]([NH:28][C:29]3[CH:37]=[CH:36][CH:35]=[C:34]4[C:30]=3[C:31]([CH2:46][CH3:47])=[N:32][N:33]4[CH2:38][C:39]3[CH:43]=[CH:42][N:41]([CH2:44][CH3:45])[N:40]=3)=[O:27])=[CH:24][N:25]=[C:19]2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O.CN(C=O)C.CC#N>O.CO.C(Cl)Cl.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>[CH2:46]([C:31]1[C:30]2[C:34](=[CH:35][CH:36]=[CH:37][C:29]=2[NH:28][C:26]([C:23]2[N:20]3[CH:21]=[CH:22][C:17]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)=[CH:18][C:19]3=[N:25][CH:24]=2)=[O:27])[N:33]([CH2:38][C:39]2[CH:43]=[CH:42][N:41]([CH2:44][CH3:45])[N:40]=2)[N:32]=1)[CH3:47]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(Br)ccn34)c12
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: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: CCc1nn(Cc2ccn(CC)n2)c2cccc(NC(=O)c3cnc4cc(-c5cnn(C)c5)ccn34)c12
Temperature: 80 °C
Yield: 61.2 %

Procedure:
A dry, 10 mL round bottom flask equipped with a reflux condenser and a nitrogen line was charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.4 mg, 0.122 mmol), 7-bromo-N-(3-ethyl-1-((1-ethyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (50 mg, 0.102 mmol), Pd(PPh3)4 (5.9 mg, 0.005 mmol), and potassium carbonate (70 mg, 0.51 mmol). To the flask was added a water:DMF:CH3CN (1:1:4.5; 0.3:0.3:1.4 mL) mixture, and the reaction mixture was degassed under nitrogen, and heated at 80° C. for 5 hours. The cooled reaction mixture was diluted with water, the resulting suspension was extracted thoroughly with EtOAc and DCM, the combined organic extracts were dried over anhydrous sodium sulfate, and concentrated to afford the crude product. The crude product was subjected to preparative thin-layer chromatography on silica with 5% MeOH-DCM as eluent to afford 30.8 mg of product as a yellow solid. MS (ES+APCI) m/z=494 (M+H) detected
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][NH:28][CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[F:38])[CH:30]2[CH:26]([CH2:27][N:28]([C:10](=[O:12])[CH2:9][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[CH3:13])[CH2:29]2)[C:25](=[O:31])[CH2:24][CH2:23]1
Reactant: CN(C)c1ccccc1CC(=O)O
Reactant: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3F)(c3ccccc3F)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
N,N'-Carbonyldiimidazole (0.44 g) is added to a solution, cooled to +4° C., of (2-dimethylaminophenyl)acetic acid (0.49 g) in dry dichloromethane (20 cc). The mixture is stirred for 1 hour at 25° C. and a solution of 7,7-bis(2-fluorophenyl)perhydro-4-isoindolone hydrochloride (1 g) and triethylamine (0.76 cc) in dry dichloromethane (25 cc) is then added dropwise. The reaction mixture is stirred for 20 hours at 25° C. and washed with water (2×100 cc) and with saturated sodium chloride solution (100 cc). The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 2 cm, height 23 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50:50) and collecting 10-cc fractions. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-7,7-bis(2 -fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone (1 g), the hydrochloride of which is prepared by dissolution in ethyl acetate (2 cc) and the addition of a 3N solution of hydrochloric acid in isopropyl ether. The precipitate is drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-Bis(2-fluorophenyl)-2-[(2-dimethylaminophenyl)acetyl]perhydro-4-isoindolone hydrochloride (0.87 g) is obtained in the form of a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH:6]([OH:26])[CH2:7][N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]([CH3:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[C:38]([NH:41][CH2:42][CH2:43][C:44](O)=[O:45])(=[O:40])[CH3:39].C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[C:38]([NH:41][CH2:42][CH2:43][C:44]([NH:2][C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][C:29]=1[O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH:6]([OH:26])[CH2:7][N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:9]([CH3:18])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:45])(=[O:40])[CH3:39]
Reactant: CC(=O)NCCC(=O)O
Reactant: CC(Cc1ccc(O)cc1)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c(N)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NCCC(=O)Nc1cc(C(O)CN(Cc2ccccc2)C(C)Cc2ccc(O)cc2)ccc1OCc1ccccc1
Reaction time: 8 h

Procedure:
In 30 ml. of anhydrous pyridine there were dissolved 4g. of 3-amino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)-aminomethyl]benzyl alcohol hydrochloride and 3.5 g of N-acetyl-β-alanine and after adding to the solution 5.5 g. of dicyclohexylcarbodiimide under ice-cooling, the mixture was stirred overnight. After filtering off the precipitates thus formed, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in 30 ml. of methanol. Then, after adding to the solution 10 ml. of 4N sodium hydroxide solution, the mixture was stirred for 3 hours and further after adding thereto 1N hydrochloric acid solution to adjust the pH to 3 and adding excessive sodium carbonate, the resultant mixture was stirred for 30 minutes. The reaction product was concentrated under a reduced pressure and then extracted with 50 ml. of chloroform. The extract was washed three times with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to five 4 g. of a yellow oily material. By subjecting the product to a silica gel column chromatography (75 ml.) and further to a silica gel column chromatography (35 ml.), 800 mg. of a pure caramel-like 3-(N-acetyl-β-alanyl)amino-4-benzyloxy-α-[N-benzyl-N-(1-methyl-2-p-hydroxyphenylethyl)aminomethyl]benzyl alcohol was obtained. In the above chromatographic purification treatments, 4 : 2 : 1 ethyl acetate-benzene-methanol was used as the developing solvent.
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH:4]=[CH:3][CH2:2]1.[H-].[Na+].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[CH:1]1([O:6][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: OC1CC=CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C1=CCC(OCc2ccccc2)C1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a cooled solution of cyclopent-3-enol (30.40 g, 0.36 mol) in THF (300 mL) at 0° C. was added NaH (18.82 g, 0.47 mol, 60% in mineral oil). After effervescence had ceased, benzyl bromide (80.45 g, 0.47 mol) was added dropwise at 0° C. over a 45 min period. The reaction mixture was allowed to warm to RT over a 6 h period. Excess NaH was quenched with MeOH (120 mL) at a temperature below 5° C. The mixture was warmed to RT, diluted with H2O, and the two layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were combined, concentrated, and purified by column chromatography eluting with petroleum ether and EtOAc (PE/EA=40/1 to 30/1) to give the title compound as an oil (45.28 g, 72%). 1H NMR (400 MHz, CDCl3) δ ppm 2.38-2.41 (m, 2H), 2.49-2.54 (m, 2H), 4.20-4.24 (m, 1H), 4.42 (s, 2H), 5.62 (s, 2H), 7.17-7.28 (m, 5H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:20])([F:19])[CH:9]([C:15]([F:18])([F:17])[F:16])[C:10](OCCl)=O>>[F:7][C:8]([F:20])([F:19])[C:9]([C:15]([F:18])([F:17])[F:16])=[CH2:10]
Reactant: O=C(OCCl)C(C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: C=C(C(F)(F)F)C(F)(F)F
Temperature: 70 °C
Yield: 70.1 %

Procedure:
In a four necked 100 ml flask equipped with a condenser, a dropping funnel and a thermometer, pyridine (19.3 g, 244 mmol) was charged and warmed to 70° C. Monochloromethyl 2-trifluoromethyl-3,3,3-trifluoropropanoate (4.88 g, 20 mmol) was dropwise added thereto while stirring. The reaction was continued at the same temperature as above for 2 hours while stirring. The gas evolved from a top of the condenser was washed with an alkaline solution, dried with alumina and cooled. The resultant liquid was distillated to give 2-trifluoromethyl-3,3,3-trifluoropropene (b.p., 14° C.) (2.30 g). Yield, 70 %.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[S:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH2:28][NH2:29].Cl>>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:29]([CH2:28][C:24]4[S:23][CH:27]=[CH:26][CH:25]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:21][CH3:22]
Reactant: NCc1cccs1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(Cc1cccs1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 2-thiophene-methylamine (0.13 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 CH2Cl2/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 119 as a white solid (m.p. 220-225° C.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[C:31]([O:38][CH3:39])[CH:30]=1)#[N:28].C(=O)([O-])[O-].[K+].[K+]>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>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]4[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=4[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[C:31]([O:38][CH3:39])[CH:30]=1)#[N:28]
Reactant: COc1cc(C#N)ccc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
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+]
Product: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Yield: 66.5 %

Procedure:
A vial was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see Example 73, Step 1) (210 mg, 0.513 mmol), (4-cyano-2-methoxyphenyl)boronic acid (181 mg, 1.025 mmol), potassium carbonate (213 mg, 1.538 mmol), and Pd(Ph3P)4 (59.2 mg, 0.051 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (1922 μl) and water (641 μl) were added. The vial was sealed and placed in a 50° C. heating bath for 1.5 h. The mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (40-g column with 0 to 40% EtOAc/Heptane) to give perfluorophenyl 1-(4-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (172.6 mg, 0.341 mmol, 66.5% yield) as a white foam: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=8.86 (d, J=5.7 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 7.99 (dd, J=2.0, 8.9 Hz, 1H), 7.91-7.82 (m, 2H), 7.61-7.57 (m, 1H), 7.54-7.47 (m, 1H), 7.34 (d, J=1.4 Hz, 1H), 3.77 (s, 3H); m/z (ESI) 507.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+].[CH:37]1([O:43][C:44](Cl)=[O:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:44](=[O:45])[O:43][CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: O=C(Cl)OC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.87 g, 0.002 mol) and sodium bicarbonate (5%, 1 mL) in toluene (10 mL) at 0° was added, dropwise, a solution of cyclohexylchloroformate (0.32 g, 0.002 mol) in toluene (5 mL). The reaction mixture was allowed to warm to ambient temperature and stirred overnight. The solvent was removed under vacuum. The residue (1.0 g) was chromatographed with 7:3 hexane-ethyl acetate to give the title compound (0.61 g, 0.0011 mol) as a yellow oil. 1H NMR (CDCl3) δ11.1(bs,1H), 7.7-7.2(m,10H), 4.6(bs,1H), 3.3(t,2H,J=5.1Hz), 3.2(t,2H,J=7.5Hz), 3.0(t,2H,J=5.2Hz), 1.9-1.2(m,26H), 0.9-0.8(m,3H).
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[N:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH2:3]1>[Ni]>[CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[C:10]([CH2:11][NH2:12])=[CH:13][CH:14]=[CH:15][N:16]=2)[CH2:3]1
Reactant: CC1CN(c2ncccc2C#N)CC(C)O1
Agent: [Ni]
Product: CC1CN(c2ncccc2CN)CC(C)O1

Procedure:
The product of Example 134A and Raney/nickel were processed according to the method of Example 131C to provide the product. MS (ESI+) m/z 222 (M+H)+;
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])(OCC)=O)C.[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([O:36]COC)=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2[CH:32]=O)[CH3:21].O>CN(C)C=O>[CH2:20]([C:22]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:23]=1[C:24]([OH:36])=[C:25]([O:34][CH3:35])[CH:26]=[C:27]2/[CH:32]=[CH:11]/[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13])[CH3:21]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOP(=O)(CC(=O)N1CCCCC1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c(/C=C/C(=O)N3CCCCC3)cc(OC)c(O)c12
Reaction time: 0.17 h
Yield: 111.1 %

Procedure:
0.15 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide, to which 1.15 g of N-(diethoxyphosphoryl)acetylpiperidine was gradually added at room temperature. After stirring for 10 minutes, a solution of 800 mg of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde in N,N-dimethylformamide (10 ml) was gradually added. After stirring for 20 minutes, water was added, followed by extraction with ethyl acetate. The combined extracts were washed with water and dried over anhydrous magnesium sulfate. After removal of the solvent, the resultant residue was purified by silica gel column chromatography (30% ethyl acetate/hexane) to obtain 1.1 g of the titled compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:19]2[CH2:23][CH2:22][C@H:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[O:20]2)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH2:15]Br)(=[O:6])=[O:5])[CH2:2][CH3:3].[CH3:36][N:37]([CH3:45])[C:38]1[CH:43]=[CH:42][C:41]([SH:44])=[CH:40][CH:39]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([S:4]([C:7]1[CH:8]=[C:9]([C@H:19]2[CH2:23][CH2:22][C@H:21]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=3)[O:20]2)[CH:10]=[C:11]([O:17][CH3:18])[C:12]=1[O:13][CH2:14][CH2:15][S:44][C:41]1[CH:42]=[CH:43][C:38]([N:37]([CH3:45])[CH3:36])=[CH:39][CH:40]=1)(=[O:6])=[O:5])[CH2:2][CH3:3]
Reactant: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCBr
Reactant: CN(C)c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)c1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(OC)c1OCCSc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trans-2-[3-n-propylsulfonyl-4-(2-bromoethoxy)-5-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (100 mg) (Step 30G) was added to a stirred solution of 4-dimethylaminothiophenol (76 mg, 0.5 mmol) and sodium hydride (56%; 20 mg, 0.5 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 20 min and partitioned between ethyl ether and water. The organic layer was separated, dried, and evaporated to a crystalline mass. Recrystallized from ethyl ether-hexane gave pure product: mp 113°-115° C.; NMR (CDCl3) δ 1.0 (t, CH2CH2CH3), 1.70 (m, CH2CH2CH3), 2.0 & 2.49 (2 m, H-3 & H-4), 3.0 [m, (CH3)2N], 3.4 (m, CH2CH2CH3), 3.84 3.88 & 3.9 (3 s, 3 OCH3), 4.30 (t, SCH2CH2O), 5.22 (m, H-2 & H-5), 6.62 (s, C5ArH), 7.23 & 7.47 (2 d, J=1.5 Hz, C2ArH), 7.42 (m, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([C@@H:19]([NH:21][C:22]1[N:30]=[CH:29][N:28]=[C:27]3[C:23]=1[N:24]=[CH:25][N:26]3C1CCCCO1)[CH3:20])=[CH:7]2>Cl.CCO>[N:30]1[C:22]([NH:21][C@H:19]([C:8]2[N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:12])[C:11]3[C:6]([CH:7]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[Cl:1])[CH3:20])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: CCO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
8-Chloro-2-phenyl-3-((1S)-1-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-ylamino)ethyl)-isoquinolin-1(2H)-one (Compound 10) (0.42 mmol) was dissolved in HCl/EtOH (3 M, 5 mL), and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and the pH was adjusted to about 7-8. The mixture was extracted with CH2Cl2 (50 mL×3), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated in vacuo, and the residue was recrystallized from ethyl acetate and hexanes (1:1). The solid was collected by filtration and dried in vacuo to afford the product (S)-3-(1-(9H-purin-6-ylamino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (Formula (I)) (90% yield) as a white solid as polymorph Form A.