Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][CH2:9]2)=[CH:4][CH:3]=1.C[O:14][CH:15](OC)[CH:16](N(CC1C=CC=C(Cl)C=1)C(=O)C)Cl>>[C:15]([N:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([Cl:12])[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:9]1)(=[O:14])[CH3:16]
Reactant: Clc1ccc2c(c1Cl)CNCC2
Reactant: COC(OC)C(Cl)N(Cc1cccc(Cl)c1)C(C)=O
Product: CC(=O)N1C=Cc2ccc(Cl)c(Cl)c2C1

Procedure:
The method of preparing 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, which comprises the steps of reacting N-acetyl-2,3-dichlorobenzylaminoacetaldehyde dimethyl acetal with a Lewis acid to form N-acetyl 7,8-dichloro-1,2-dihydroisoquinoline, catalytically hydrogenating said dihydroisoquinoline to N-acetyl-7,8-dichloro-1,2,3,4-tetrahydroisoquinoline, and hydrolyzing said tetrahydroisoquinoline to 7,8-dichloro-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: C([O:5][C:6](=[O:39])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:19][S:20]([C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=3)(=[O:22])=[O:21])[C:13]=2[CH:12]=[C:11]([Cl:37])[C:10]=1[F:38])(C)(C)C.[OH-].[Li+].CO>O1CCCC1>[F:36][C:33]([F:34])([F:35])[C:25]1[CH:24]=[C:23]([S:20]([NH:19][CH:14]2[CH2:15][CH2:16][CH2:17][C:18]3[C:9]([O:8][CH2:7][C:6]([OH:39])=[O:5])=[C:10]([F:38])[C:11]([Cl:37])=[CH:12][C:13]2=3)(=[O:21])=[O:22])[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=1
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1c(F)c(Cl)cc2c1CCCC2NS(=O)(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirred solution of [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (163.4 mg, 0.27 mmol) in tetrahydrofuran (4 mL) were added an aqueous (2 mL) solution of lithium hydroxide (0.036 g, 0.87 mmol) and methanol (1 mL) at room temperature and the resulting reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with water (15 mL) and acidified with dilute hydrochloric acid, which resulted in the formation of a precipitate. The resulting mixture was extracted with ethyl acetate (15 mL×3). The combined organic layers was washed with water (15 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography (silica gel, 100-200 mesh, 50% ethyl acetate in hexane) gave [5-(3,5-bis-trifluoromethyl-benzenesulfonylamino)-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid (130.4 mg, 88%). MS cald. for C20H15ClF7NO5S 549, obsd. 548 (ESI+) [(M−H)+].
Reaction SMILES: [CH:1]([CH:9]1[CH2:14][C:13](=[O:15])[O:12][C:10]1=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:16].[K+]>>[CH:1]([CH:9]([CH2:14][C:13]([OH:12])=[O:15])[C:10]([OH:16])=[O:11])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: [OH-]
Reactant: CCCCCCC=CC1CC(=O)OC1=O
Agent: [K+]
Product: CCCCCCC=CC(CC(=O)O)C(=O)O

Procedure:
Octenyl succinic anhydride was added to an aqueous, 45% potassium hydroxide solution, and heated to form the di-potassium salt of 2-octenyl-1,4-butanedioic acid (the friction modifier). A lubricant, methyl 9EO tallowate, and the friction modifier were mixed together to form a composition having a ratio of 9:1 by weight, respectively.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16](OC(=O)C)(=[O:18])[CH3:17]>N1C=CC=CC=1>[C:16]([O:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(NC(C)=O)ccc1O
Solvent: c1ccncc1
Product: COC(=O)c1cc(NC(C)=O)ccc1OC(C)=O
Reaction time: 48 h
Yield: 84 %

Procedure:
Methyl 2-hydroxy-5-acetamidobenzoate (13.6 g, 68 mmole) was dissolved in pyridine (20 ml), acetic anhydride (7.4 ml) was added, and the reaction mixture was left at room temperature for 48 hours after which time it was evaporated to dryness, in vacuo. The remaining product was recrystallized from ethanol-water (1:3) to give the title compound (14.4 g, 84%), m.p. 133°-135° C. Found (Calc. for C12H13NO5) C 57.11 (57.37), H 5.28 (5.18), N 5.47 (5.58).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:26][NH:27][O:28][CH3:29].CCOC(C)=O>C(Cl)Cl>[CH3:29][O:28][N:27]([CH3:26])[C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CON(C)C(=O)CNC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 82.5 %

Procedure:
2-{[(tert-Butoxy)carbonyl]amino}acetic acid (5.00 g, 28.5 mmol) was dissolved in DCM (50 mL), CDI (5.09 g, 31.4 mmol) was added and the reaction mixture was stirred for 1 h. N,O-dimethylhydroxylamine hydrochloride (3.06 g, 31.4 mmol) was added and the reaction mixture was stirred for 16 h. EtOAc (150 mL) was added and the reaction mixture was washed with 1 M aq HCl (50 mL), sat aq NaHCO3 (2×50 mL), dried (Na2SO4) and concentrated in vacuo to give the crude title compound (5.13 g, 82%) as a white solid.
Reaction SMILES: [CH2:1]([N:10]1C(=O)C2=CC=CC=C2C1=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.NN>CO>[CH2:1]([NH2:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CC=Cc1ccccc1
Agent: NN
Solvent: CO
Solvent: O
Product: NCC=Cc1ccccc1
Temperature: 70 °C
Yield: 30 %

Procedure:
N-cinnamyl phthalimide (3 mmol) was mixed with 65% hydrazine hydrate (6 mmol, 2 equiv) and MeOH (10 mL), and the mixture was heated at 70° C. for 2 h. After the solvent was removed by a rotary evaporator, the solid residue was treated with 1 N NaOH (30 mL), and the resulting mixture was extracted with EtOAc (4×50 mL) and dried. Evaporation of the solvent under reduced pressure afforded the crude product, which was purified by flash silica gel column chromatography (eluting with 5-20% MeOH in DCM) to give cinnamyl amine. Compound 117 (white solid) was obtained at 30% yield, and compound 119 (off-white solid) was obtained at 80% yield. Identity was confirmed by 1H NMR (400 MHz, CD3OD).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:17]=3)[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]O)[N:6]2[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1>ClCCl>[CH2:23]([O:22][C:18]1[CH:17]=[C:16]([C:8]2[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][CH2:14][N:48]3[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]3)[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)[CH:21]=[CH:20][CH:19]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ncnn2c(CCCCO)cc(-c3cccc(OCc4ccccc4)c3)c12
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ncnn2c(CCCCN3CCCCC3)cc(-c3cccc(OCc4ccccc4)c3)c12
Temperature: 0 °C
Reaction time: 4 h
Yield: 4.2 %

Procedure:
To a cooled (0° C.) solution of 4-{4-amino-5-[3-(benzyloxy)phenyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}butan-1-ol (80 mg, 0.21 mmol) in dichloromethane (1 mL) was added triethylamine (32 μL, 0.23 mmol) and methanesulfonyl chloride (17 μL, 0.22 mmol). The reaction was stirred (0° C.) for 4 h and then warmed to rt. The mixture was quenched with the addition of ice water (1 mL). The layers were separated and the organic layer was dried (Na2SO4) and evaporated. The residue was dissolved in DMF (1 mL) and potassium carbonate (85 mg, 0.62 mmol) and piperidine (18 μL, 0.22 mol) were added to the mixture. The reaction was stirred (60° C.) for 17 h and then cooled to rt. The mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The layers were separated and the aqueous was further extracted with ethyl acetate (2×10 mL). The combined organics were dried (Na2SO4) and evaporated. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water to obtain 4 mg (5%) of the desired product. 1H NMR (300 MHz, CD3CN) δ 7.86 (s, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.32 (m, 4 H), 7.12-7.09 (m, 1 H), 7.09-7.06 (m, 1 H), 7.04-7.00 (s, 1 H), 6.56 (s, 1 H), 5.17 (s, 2 H), 2.96 (t, 2 H), 2.47-2.27 (m, 6 H), 1.83-1.73 (m, 2 H), 1.63-1.1.51 (m, 6 H), 1.48-1.40 (m, 2 H); ES-MS m/z 456.3 [M+H]+, HPLC RT (min) 2.29.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[N:6][C:7]=1[CH3:8].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.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>[CH3:8][C:7]1[N:6]=[C:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:4]=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH3:23]
Reactant: Cc1ccccc1B(O)O
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1Br
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: O
Solvent: C1COCCO1
Product: Cc1ccccc1-c1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)nc1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A 40 mL vial was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4[(5-bromo-6-methylpyridin-2-yl)methyl]piperazine-1-carboxylate (1.00 g, 2.70 mmol, 1.00 equiv), (2-methylphenyl)boronic acid (0.730 g, 5.40 mmol, 2.00 equiv), tetrakis(triphenylphosphine)palladium (0.310 g, 0.270 mmol, 0.10 equiv), potassium carbonate (1.15 g, 8.32 mmol, 3.08 equiv), dioxane (15 mL), water (3 mL). The resulting solution was stirred overnight at 80° C. and diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (2×20 mL) and the organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (60/40) to provide 1.00 g (92% yield) of tert-butyl 4-[[6-methyl-5-(2-methylphenyl)pyridin-2-yl]methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 382 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[C:16]3[C:17]4([CH2:20][O:21][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:19][CH2:18]4)=[N:8][CH:9]=1)([O-])=O.O.[Cl-].[NH4+]>O1CCCC1>[C:17]12([C:16]3[C:11]([O:10][C:7]4[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)=[CH:12][CH:13]=[CH:14][C:15]=3[O:21][CH2:20]1)[CH2:19][CH2:18]2
Reactant: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of 5-nitro-2-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)pyridine (Intermediate 86, 99 mg) in tetrahydrofuran (5 ml)/water (2.5 ml) iron (97 mg, 1.741 mmol) and then ammonium chloride (93 mg, 1.741 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The catalyst was filtered off and the residue was diluted with an aqueous saturated solution of NaHCO3 (5 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane/ethyl acetate 8:2 to cyclohexane/ethyl acetate 1:1 as eluents affording the title compound as a light yellow solid (85 mg).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[Cl:10][C:11]1[N:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([N:21]3[CH:25]([O:26][C:27](OC4C=CC=CC=4)=[O:28])[C:24]4[S:36][CH2:37][CH2:38][O:39][C:23]=4[C:22]3=[O:40])=[N:18]2)=[CH:13][CH:12]=1.C(OC(C)C)(C)C>C(#N)C>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([C:27]([O:26][CH:25]2[N:21]([C:17]3[CH:16]=[CH:15][C:14]4[C:19](=[N:20][C:11]([Cl:10])=[CH:12][CH:13]=4)[N:18]=3)[C:22](=[O:40])[C:23]3[O:39][CH2:38][CH2:37][S:36][C:24]2=3)=[O:28])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: O=C(Oc1ccccc1)OC1C2=C(OCCS2)C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: C=CCN1CCNCC1
Solvent: CC(C)OC(C)C
Solvent: CC#N
Product: C=CCN1CCN(C(=O)OC2C3=C(OCCS3)C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Reaction time: 29 h
Yield: 63.5 %

Procedure:
1-Allylpiperazine (6.3 g.) is added to a suspension of 6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-5-phenoxycarbonyloxy-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (4.56 g.) in acetonitrile (25 cc.). The temperature of the reaction mixture rises to about 25° C. After 29 hours, diisopropyl ether (50 cc.) is added and the insoluble product is filtered off and washed with diisopropyl ether (2 × 15 cc.). After drying, 5-(4-allylpiperazine-1-yl)carbonyloxy-6-(7-chloro-1,8-naphthyridin-2-yl)-7-oxo-2,3,6,7-tetrahydro-5H-1,4-oxathiino[2,3-c]pyrrole (3.1 g.), melting at 254° C., is obtained.
Reaction SMILES: C1(CO[C:6]([S:8][CH:9]2[N:12]([C:13](=[C:22]([OH:25])CBr)[C:14]([O:16][CH2:17][C:18]([Cl:21])([Cl:20])[Cl:19])=[O:15])[C:11](=[O:26])[CH:10]2[NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=O)CC1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:30]([CH2:29][C:28]([NH:27][CH:10]1[C:11](=[O:26])[N:12]2[CH:13]([C:14]([O:16][CH2:17][C:18]([Cl:19])([Cl:21])[Cl:20])=[O:15])[C:22](=[O:25])[CH2:6][S:8][C@H:9]12)=[O:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N(C(C(=O)OCC(Cl)(Cl)Cl)=C(O)CBr)C1SC(=O)OCC1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)C(=O)CS[C@H]12
Reaction time: 1 h
Yield: 124.7 %

Procedure:
To a stirred solution of 2,2,2-trichloroethyl α-[4-cyclopropylmethoxycarbonylthio-3-phenoxyacetamido-2-oxo-azetidine-1yl]-α-(2-bromo-1-hydroxyethylidene)acetate (330 mg) in methylene chloride (6 ml) is added aluminum chloride (330 mg) at room temperature, and the mixture is stirred for 60 minutes. The reaction mixture is poured into ice cold diluted hydrochloric acid, and is extracted with ethyl acetate. The extract solution is washed with diluted hydrochloric acid and water, dried, and evaporated to give 2,2,2-trichloroethyl 7-phenoxyacetamido-3-oxocepham-4-carboxylate (300 mg). Foam. IR: νmaxCHC13 3420, 1780, 1685 cm-1. NMR: δCDC13 3.37s2H, 4.53s2H, 4.85s2H, 5.07d(4)1H, 5.20-5.73m2H, 6.8-7.7m6H.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13](Br)[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4].[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>C1(C)C=CC=CC=1.CO>[CH3:1][O:2][C:3]([C:5]1[N:9]2[CH:10]=[C:11]([CH3:15])[N:12]=[C:13]([C:22]3[CH:21]=[CH:20][C:19]([Cl:18])=[CH:24][C:23]=3[Cl:25])[C:8]2=[N:7][C:6]=1[CH2:16][CH3:17])=[O:4]
Reactant: CCc1nc2c(Br)nc(C)cn2c1C(=O)OC
Reactant: OB(O)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCc1nc2c(-c3ccc(Cl)cc3Cl)nc(C)cn2c1C(=O)OC
Yield: 107.4 %

Procedure:
8-Bromo-2-ethyl-6-methylimidazo[1,2-a]pyrazine-3-carboxylic acid methyl ester (0.30 g, 1.0 mmol) was dissolved in a mixed solvent of toluene (5.6 mL) and methanol (1.4 mL). Then 2,4-dichlorobenzeneboronic acid (0.382 g, 2.0 mmol) and tetrakistriphenylphosphine palladium complex (116 mg, 0.1 mmol) were added thereto, and the mixture was heated under reflux for 4 hours under nitrogen atmosphere. After the reaction mixture was allowed to cool, the solvent was removed. Then the residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give the title compound (391 mg) as white crystals.
Reaction SMILES: C(O[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[CH2:6][N:5]=1)C.Cl.[CH3:15][NH2:16]>C(O)C>[ClH:13].[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([CH2:6][NH:5][C:4]2=[N:16][CH3:15])=[CH:8][CH:9]=1
Reactant: CCOC1=NCc2ccc(Cl)cc21
Reactant: CN
Agent: Cl
Solvent: CCO
Product: CN=C1NCc2ccc(Cl)cc21
Yield: 148.4 %

Procedure:
A suspension of 110.5 g of 1-ethoxy-6-chloro-3H-isoindole and 41.9 g of methylamine hydrochloride in 1,100 ml of ethanol was heated to boiling under reflux for 4 hours under argon, whereupon it was cooled to 2°, the separated crystals were filtered off under suction and recrystallized from ethanol. There are obtained 91.0g of 6-chloro-1-(methylimino)isoindoline hydrochloride as white crystals with a m.p. of >250°.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].[O:16]=[C:17]1[C:22]2=[CH:23][NH:24][C:25]([CH:26]=O)=[C:21]2[CH2:20][CH2:19][NH:18]1.N1CCCCC1>C(O)C>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:26][C:25]1[NH:24][CH:23]=[C:22]2[C:21]=1[CH2:20][CH2:19][NH:18][C:17]2=[O:16])(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C
Yield: 44.8 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid methylamide (66 mg, 0.3 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (50 mg, 0.3 mmol) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 50 mg (45%) of the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH:23]=O.[Cl-].[NH4+]>ClCCl>[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH:23]=[N:2][OH:3]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: NO
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CC=NO
Yield: 85.1 %

Procedure:
Hydroxylamine hydrochloride (5.74 g, 82.6 mmol) and triethylamine (31.4 mL, 225 mmol) were sequentially added to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (14.2 g, 75.1 mmol) in dichloromethane. The resultant suspension was stirred at room temperature for several hours and adjusted to pH 6 with the addition of saturated aqueous ammonium chloride. The aqueous layer was then separated and extracted with several portions of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a vacuum filter funnel (silica gel, eluting with 3% to 5% methanol in dichloromethane). The product was then dissolved in dichloromethane, and the solution was washed with 1 N hydrochloric acid. The aqueous layer was extracted a few times with dichloromethane, and the combined organic fractions were dried over magnesium sulfate, filtered, and concentrated to provide 13.05 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethanal oxime as a white solid.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl[C:29]1[N:34]=[CH:33][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[C:1]12([C:11]3[CH:12]=[C:13]([C:29]4[N:30]=[CH:31][C:32](/[CH:35]=[CH:36]/[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:33][N:34]=4)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CCOC(=O)/C=C/c1cnc(Cl)nc1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCOC(=O)/C=C/c1cnc(-c2ccc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)c2)nc1
Temperature: 25 °C
Yield: 96.9 %

Procedure:
To a solution of 3-(1-adamantyl)-4-benzyloxyphenylboronic acid (Zhang Y. et al., Blood, 2002; 100:2917-2925, Dawson M. I. et al., J. Med. Chem., 2004; 47:3518-3536) (3.62 g, 10.0 mmol) and ethyl (2E)-3-(2-chloro-5-pyrimidinyl)-2-propenoate (1.76 g, 8.30 mmol) in dimethoxyethane (50 mL) was added under argon tetrakis(triphenylphosphine)-palladium (1.15 g, 1.00 mmol) and 2 M aqueous Na2CO3 (10 mL). The reaction mixture was heated at reflux for 18 h, cooled to room temperature, diluted with ethyl acetate, washed (water and brine) and dried. After solvent removal at reduced pressure, the residue was chromatographed (9% to 14% ethyl acetate/hexane) to give 3.98 g (96%) of ethyl(E)-3-[2-(3-(1-adamantyl)-4-benzyloxyphenyl)-5-pyrimidinyl]-2-propenoate as a yellow solid, mp 164-167° C. IR 2903, 1710, 1432, 1225 cm−1; 1H NMR δ (CDCl3) 1.40 (t, J=7.2 Hz, 3H, OCH2CH3), 1.77 (bs, 6H, AdCH2), 2.11 (bs, 3H, AdCH), 2.26 (bs, 6H, AdCH2), 4.33 (q, J=7.2 Hz, 2H, OCH2CH3), 5.24 (s, 2H, CH2), 6.59 (d, J=16.2 Hz, 1H, CH═CHCO), 7.08 (d, J=8.7 Hz, 1H, 5-ArH), 7.35-7.58 (m, 5H, C6H5), 7.65 (d, J=16.2 Hz, 1H, CH═CHCO), 8.33 (dd, J=8.7 Hz, 2.1 Hz, 1H, 6-ArH), 8.47 (d, J=2.1 Hz, 1H, 2-ArH), 8.91 ppm (s, 2H, 4-PyrH, 6-PyrH). HRMS calcd C32H34N2O3 [M+H]+ 495.2642. found 495.2636.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16]=1[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:6]=[CH:5]2.O[CH:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1.O>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([O:1][CH:28]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH:11]=[CH:10]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCOC(=O)C(O)Cc1ccccc1
Reactant: CCCCC(=O)c1c(-c2ccc3cc(O)ccc3c2)oc2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3cc(OC(Cc4ccccc4)C(=O)OCC)ccc3c2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To an ice-cooled mixture of 1-[2-(6-hydroxy-2-naphthyl)-1-benzofuran-3-yl]-1-pentanone (0.620 g, 1.80 mmol), ethyl 2-hydroxy-3-phenylpropanoate (0.528 g, 2.72 mmol), triphenylphosphine (0.710 g, 2.71 mmol) in benzene (30 mL) was added, dropwise, diisopropyl azodicarboxylate (0.53 mL, 2.7 mmol) in benzene (5 mL). The mixture was stirred at room temperature for 45 minutes, poured into excess water and extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (Biotage apparatus) using 100% hexane and 2-3.5% ethyl acetate in hexane as eluants. The title compound was obtained as a thick yellow oil (0.670 g). Mass spectrum (+ESI, [M+H]+) m/z 521.5; 1HNMR (500 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (t, 2H, J=7.8 Hz), 7.95 (d, 1H, J=8.6 Hz), 7.8 (dd, 1H, J=8.6 Hz and 1.7 Hz), 7.7 (d, 1H, J=8.1 Hz), 7.25-7.45 (m, 9H), 5.35 (t, 2H, J=6.5 Hz), 4.05-4.15 (m, 3H), 2.7 (t, 2H, J=7.3 Hz), 1.5-1.55 (m, 2H), 1.1-1.2 (m, 2H), and 0.7 ppm (t, 3H, J=7.4 Hz).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].C(#N)C>ClCCl>[CH3:10][C@@H:11]([CH2:12][CH3:13])[CH2:14][O:2][C:1]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: CC[C@H](C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC[C@H](C)COc1ccc(O)cc1
Yield: 47.9 %

Procedure:
A reaction mixture of hydroquinone (18.2 grams); (S)-(+)-1-bromo-2-methylbutane (4.55 grams); anhydrous potassium carbonate (23 grams); and acetonitrile (250 mls.) was allowed to reflux for 40 hours. Flash chromatography using dichloromethane eluant yielded 2.6 grams (48%) of white crystals exhibiting a Fisher-Johns melting point of 44°-45° C. and having the structure ##STR24## confirmed by TLC, NMR, IR and mass spectral analyses.