Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.[F:21][C:22]([F:32])([F:31])[C@H:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)[NH2:24]>>[F:32][C:22]([F:21])([F:31])[C@@H:23]([NH:24][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: N[C@@H](c1cccnc1)C(F)(F)F
Reactant: O=C(O)c1cc(OCc2ccc(F)cc2)c(Cl)cn1
Agent: Cl
Product: O=C(N[C@@H](c1cccnc1)C(F)(F)F)c1cc(OCc2ccc(F)cc2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 12d, using 5-chloro-4-(4-fluoro-benzyloxy)-pyridine-2-carboxylic acid and (αS)-α-(trifluoromethyl)-3-pyridinemethanamine hydrochloride (1:1) (CAN 749839-26-7) as starting materials and isolated (26 mg, 83%) as colorless oil; MS (ESI, m/z): 440.3 (MH+).
Reaction SMILES: [CH2:1]([CH:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:6]=O)[CH2:2][CH2:3][CH3:4].[CH2:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.C1COCC1.CCCCCC>[Si:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:6]=[CH2:21])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCC(C=O)CCCCCO[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=CC(CCCC)CCCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
2-Butyl-7-(tert-butyldimethylsilyloxy)heptanaI (6.01 g, 20 mmol) in 15 ml of anhydrous THF was added dropwise to a freshly prepared solution of methylidene(triphenyl)phosphorane (22 mmol in 125 ml of anhydrous THF/hexane at 0° C. over a period of 15 min. The mixture was warmed to room temperature, stirred for 8 h, and poured into 300 ml of ice/water and extracted (3×75 ml) with ether. The combined organic extracts were washed with water and dried over anhydrous MgSO4. Solvents were removed by evaporation and pentane (250 ml) was added to the red oily residue. The mixture was chilled to 0° C. and the precipitated Ph3PO removed by filtration The precipitate was washed with ice-cold pentane and the filtrate concentrated in vacuo. The crude product was purified by PMPLC yielding 4.06 g (68%) of 8-(tert-butyldimethylsilyloxy)-3-butyloct-1-ene.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=[O:7])[CH2:3]1.CO.Cl.[CH2:12](N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[O:1]=[C:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:12])=[O:7])[CH2:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CC(=O)C1

Procedure:
3-Oxocyclobutanecarboxylic acid 1 (350 g, 3.06 mol), methanol (190 mL, 4.69 mol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (885 g, 4.69 mol), 4-dimethylaminopyridine (37 g, 0.30 mol) and dichloromethane (6 L) were stirred at ambient temperature for 24 hours. After the completion of the reaction, it was taken in a separating funnel and washed with 1.5 N HCl solution (1 L), water (2 L×2) and brine (1 L×2). The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was taken to the next step without further purification. 1H NMR (300 MHz, CDCl3): δ 3.23-3.25 (m, 2H), 3.27-3.32 (m, 2H), 3.33-3.42 (m, 1H), 3.76 (s, 3H). GC-MS: [M]+ m/z=128.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3]1.[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:3]1
Reactant: COC(=O)c1cc(-c2ccccc2)nn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1nc(-c2ccccc2)cc1C(=O)O
Reaction time: 0.5 h
Yield: 28.5 %

Procedure:
Methyl 1-methyl-3-phenylpyrazole-5-carboxylate (3 g) was dissolved in a mixed solvent of ethanol (20 ml) and water (20 ml) and sodium hydroxide (0.7 g) was added. The mixture was stirred at a refluxing temperature for 30 min. Ethanol was evaporated and to the residue was added dilute hydrochloric acid. The obtained solid was recrystallized from aqueous methanol solution to give the title compound (0.8 g), melting point: 189° C.
Reaction SMILES: [CH2:1]([SH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:16]([Cl:17])=[CH:15][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:13][N:12]=1>[Cu]>[Cl:17][C:16]1[C:11]([S:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[N:12][CH:13]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:15]=1
Reactant: CCCCCCCCS
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [Cu]
Product: CCCCCCCCSc1ncc(C(F)(F)F)cc1Cl
Temperature: 185 °C
Reaction time: 4 h

Procedure:
At 23° C., 17.6 g (0.1166 mol) of n-octanethiol were added with stirring over a period of 5 minutes to a mixture of 25 g (0.1132 mol) of 97.8% pure 2,3-dichloro-5-trifluoromethylpyridine and 7 mg (0.1 mol %) of copper powder, and the mixture was stirred at 185° C. for 4 h. After cooling, the reaction mixture was partitioned between methylene chloride and water and the organic phase was dried and concentrated. 35.4 g (96.1% of theory) of the title compound of 24 n D
Reaction SMILES: [CH2:1]([C:3]1([CH2:7][OH:8])[CH2:6][O:5][CH2:4]1)[CH3:2].[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCN(CC)CC>CN(C1C=CN=CC=1)C>[CH3:16][C:15]1[CH:17]=[CH:18][C:12]([S:9]([O:8][CH2:7][C:3]2([CH2:1][CH3:2])[CH2:6][O:5][CH2:4]2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: CCC1(CO)COC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCC1(COS(=O)(=O)c2ccc(C)cc2)COC1
Yield: 91 %

Procedure:
This compound was synthesized as a colorless oil from (3-ethyloxetan-3-yl)methanol (122.4 mg, 1.05 mmol), TsCl (261.2 mg, 1.37 mmol), Et3N (159.4 mg, 1.58 mmol), and DMAP (128.8 mg, 1.05 mmol) in 91% yield by following general procedure 1.1: 1H NMR (400 MHz, CDCl3, δH) 7.80 (d, J=8.3 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 4.35 (d, J=6.3 Hz, 2H), 4.29 (d, J=6.3 Hz, 2H), 4.15 (s, 2H), 2.45 (s, 3H), 1.73 (q, J=7.5 Hz, 2H), 0.79 (t, J=7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3, OH) 145.35, 132.72, 130.21, 128.18, 71.97, 42.99, 26.26, 21.90, 8.05. ESI-MS: 271.1 (M+H+), 293.1 (M+Na+).
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[O:12]2)[CH2:8][CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH:6]1[CH2:11][CH2:10][C:9]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[O:12]2)[CH2:8][CH2:7]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OC(=O)c1ccccc12
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCC2(CC1)OC(=O)c1ccccc12
Temperature: 80 °C
Yield: 92.5 %

Procedure:
A mixture of 3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl methanesulfonate (120 mg, 0.40 mmol), sodium azide (263 mg, 4.05 mmol) in DMF (2.0 mL) was maintained at 80° C. overnight. After cooling, it was quenched with sat'd NH4Cl solution, then extracted with ethyl acetate. The extract was washed with water twice, brine once, and dried over anhydrous sodium sulfate. After filtration the filtrate was concentrated to yield 90 mg of 4′-azido-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (yield: 91%).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]1[NH:10][NH2:11].[C:12](OCC)(OCC)(OCC)[CH3:13]>C(O)CCC>[NH2:11][N:10]1[C:3]2=[N:4][C:5]([CH3:9])=[CH:6][C:7](=[O:8])[N:2]2[N:1]=[C:12]1[CH3:13]
Reactant: Cc1cc(=O)n(N)c(NN)n1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCCO
Product: Cc1cc(=O)n2nc(C)n(N)c2n1

Procedure:
A 3.0 g portion of 3-amino-2-hydrazino-6-methyl-4(3H)-pyrimidinone, 20 ml of triethyl orthoacetate and 100 ml of n-butanol was reacted as described in Example 1, giving 2.36 g of the desired intermediate, mp 287°-289° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C@@H:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1.C(N(CC)CC)C>C(#N)C>[C:1]([NH:5][C@@H:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:9]2([CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC[C@H](N)c3ccccc32)CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CCC2(CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −78° C., acetyl chloride (1 ml, 12 mmol) was added to a solution of the amine (B3) (3.2 g, 10 mmol) in dry acetonitrile (100 ml) followed by the dropwise addition of triethylamine. The reaction mixture was warmed to room temperature, stirred for 1 hour then concentrated. The residue was dissolved in ethyl acetate. The solution washed with saturated NaHCO3 and brine, dried and concentrated. The crude product was further purified by silica gel chromatography (CH2Cl2/CH3CN 9:1 to 7:3) to give (S)-tert-butyl 4-acetamido -3, 4-dihydro-2H-spiro[naphthalene-1,4′-piperidine]-1′-carboxylate (B4). LC-MS: m/e=359.3 (M+H), 303.3 (M+H−Me3CO). Rt=2.94 min. 1H-NMR (500 MHz, DMSO-d6): 8.17 (d, 1H), 7.36 (d, 1H), 7.22 (ddd, 1H), 7.14 (m, 2H), 4.95 (m, 1H), 3.86 (m, 2H), 2.97 (m, 2H), 2.01 (m, 1H), 1.85 (s, 3H), 1.80 (m, 4H), 1.61 (m 2H), 1.48 (d, 1H), 1.42 (s, 9H).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[C:9]2[CH:10]=[C:11]([S:14]([OH:17])(=O)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.CN(C)C=O>ClC(Cl)C>[Cl:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][S:5][C:9]=2[CH:10]=1)(=[O:17])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)(O)c1ccc2ncsc2c1
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2ncsc2c1
Reaction time: 1.5 h

Procedure:
Thionyl chloride (4 mL) was added to a suspension of the benzothiazole-6-sulfonic acid (0.60 g, 2.79 mmol) in dichloroethane (15 mL) and the reaction mixture was heated at reflux and dimethylformamide (5 mL) was added to the reaction mixture to yield a clear solution. After 1.5 hr. at reflux, the solvent was removed in vacuo and excess HCl and thionyl chloride was chased by evaporation with dichloroethane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([NH2:11])[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]([N:11]=[CH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:4]
Reactant: O=Cc1ccccn1
Reactant: COC(=O)c1cc(Cl)cn1N
Solvent: CO
Product: COC(=O)c1cc(Cl)cn1N=Cc1ccccn1

Procedure:
Prepared according to the imine formation condition used in Example 18 step b) from 1-amino-4-chloro-1H-pyrrole-2-carboxylic acid methyl ester and pyridine-2-carbaldehyde in refluxing methanol for 12 h. 1H NMR (CDCl3, δ in ppm): 8.67 (dt, 1H, J=1.3 Hz, 5.0 Hz), 8.48 (s, 1H), 8.21 (dt, 1H, J=1.1 Hz, 8.4 Hz), 7.79 (td, 1H, J=1.8 Hz, 7.8 Hz), 7.36 (m, 1H, J=1.0 Hz, 5.0 Hz, 7.6 Hz), 7.30 (d, 1H, J=2.2 Hz), 6.91 (d, 1H, J=1.8 Hz), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:10](=[O:12])[CH3:11])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1.[C:13](O)(=O)C>>[CH3:1][C:2]1([C:10]([OH:12])([CH3:13])[CH3:11])[CH:7]([CH3:8])[CH2:6][C:5]([CH3:9])=[CH:4][CH2:3]1
Reactant: CC(=O)C1(C)CC=C(C)CC1C
Reactant: CC(=O)O
Product: CC1=CCC(C)(C(C)(C)O)C(C)C1
Temperature: 0 °C

Procedure:
0.4 moles (66.4 g) 1-(1,4,6-trimethylcyclohex-3-en-1-yl)-ethan-1-one (as per Example 1) was then added dosewise at 70° C. to the reaction mixture according to (a). Then stirring was continued for another hour at 70° C. The reaction mixture was then cooled, poured on 300 g ice, and the precipitated magnesium salt was dissolved with 30 ml glacial acetic acid. Finally the phases were separated, the organic phase neutralized with sodium bicarbonate solution, the solvent drawn off and the residue subjected to fractional distillation. 30 g of the desired end product were obtained, corresponding to 40% of the theoretical amount.
Reaction SMILES: [C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH2:9])[CH3:8])(=[O:4])[CH:2]=[CH2:3].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C(#N)C>[C:1]([O:5][O:6][C:7]([CH2:10][CH3:11])([NH:9][C:15]([NH:14][CH2:12][CH3:13])=[O:16])[CH3:8])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCN=C=O
Reactant: C=CC(=O)OOC(C)(N)CC
Solvent: CC#N
Product: C=CC(=O)OOC(C)(CC)NC(=O)NCC
Reaction time: 24 h
Yield: 60.9 %

Procedure:
To a solution of 15.9 g of ethyl-β-amino-β-ethoxy acrylate in 30 ml of acetonitrile was added 7.1 g of ethyl isocyanate, and the resulting mixture was allowed to stand at room temperature for one day and one night. The acetonitrile was distilled away under reduced pressure. To the residue was added 100 ml of ether and the system then dried over anhydrous sodium sulfate. The ether was distilled away and the residue was distilled under reduced pressure. Thus, 14 g of ethyl-β-ethylureido-β-ethoxy acrylate of a boiling point of 127° to 130° C. was obtained.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].O.[BH4-].[Na+].Cl>O1CCCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(=O)O)s1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(CO)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 5-formylthiophene-2-carboxylic acid (2.000 g, 12.81 mmol) in tetrahydrofuran (25 ml) was added water (2.5 ml). Sodium borohydride (1.453 g, 38.42 mmol) was added by small portions, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was adjusted to pH about 8 by adding a small amount of 1M hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 2-2.5 by adding concentrated hydrochloric acid, and saturated with sodium chloride. The mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to dryness to give 5-(hydroxymethyl)thiophene-2-carboxylic acid (1.430 g, yield 70.6%) as a yellow solid.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.Cl.Cl.[N:24]1([C:30]2[N:31]=[CH:32][C:33]3[C:38]([CH:39]=2)=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.CCN(C(C)C)C(C)C>CN(C)C=O>[C:16]1([C:3]2[C:2]([N:27]3[CH2:26][CH2:25][N:24]([C:30]4[CH:39]=[CH:38][C:33]5[C:32](=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:31]=4)[CH2:29][CH2:28]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=3)[N:4]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: c1ccc2cc(N3CCNCC3)ncc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccc5ccccc5n4)CC3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv), 3-(piperazin-1-yl)isoquinoline dihydrochloride (250.8 mg, 0.88 mmol, 2.00 equiv), DIEA (170.3 mg, 1.32 mmol, 3.00 equiv), N,N-dimethylformamide (3 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 4×30 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 216.6 mg (crude) of methyl 3-(4-(isoquinolin-3-yl)piperazin-1-yl)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>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(O)C>[C:1]1([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1nccc2ccccc12
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nccc3ccccc23)cc1
Reaction time: 8 h
Yield: 43 %

Procedure:
In a 100 ml-three-necked flask, 3.04 g (24.9 mmole) of phenylboronic acid (made by Tokyo Kasei), 4.0 g of (25.0 mmole) of 1-chloroisoquinoline, 25 ml of toluene, 12.5 ml of ethanol and 25 ml of 2M-sodium carbonate aqueous solution were placed and stirred at room temperature under nitrogen stream, and 0.98 g (0.85 mmole) of tetrakis(triphenylphosphine)palladium (0) was added thereto. Thereafter, reflux under stirring was performed for 8 hours under nitrogen stream. After completion of the reaction, the reaction product was cooled and extracted by addition of cold water and toluene. The organic layer was washed with saline water and dried on magnesium sulfate, followed by removal of the solvent under a reduced pressure to provide dry solid. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to obtain 2.20 g (yield=43.0%) of 1-phenylisoquinoline. FIG. 7 shows a 1H-NMR spectrum of a solution of the compound in heavy chloroform.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][NH:18][C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:29])([CH3:28])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[C:15]([F:34])[CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:35]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][N:18]([C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24]([CH3:28])([CH3:29])[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)[C:42](=[O:43])[CH2:41][CH2:40][CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:15]([F:34])[CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc4c(c3)C(=O)OC(C)(C)O4)c(F)c2)cc1
Reactant: O=C(Cl)CCC1CCCC1
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)C(=O)OC(C)(C)O4)c(F)c2)cc1

Procedure:
The titled compound was prepared following the procedure B using 6-({4-[(4-butylphenyl)ethynyl]-2-fluorobenzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and 3-cyclopentylpropanoyl chloride as a colorless oil (73%). 1H NMR (CDCl3, 300 MHz) δ 7.69 (m, 1H), 7.43-7.30 (m, 3H), 7.28-7.20 (m, 1H), 7.19-7.03 (m, 4H), 6.92 (d, J=8.7 Hz, 1H), 4.87 (s, 2H), 2.61 (t, J=7.7 Hz, 2H), 2.06 (m, 2H), 1.73 (s, 6H), 7.70-1.26 (m, 13H), 1.00-0.85 (m, 5H). M+ (ESI): 582. HPLC, Rt: 6.63 min (Purity: 100%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[F:42][C:43]([F:55])([F:54])[C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>C(#N)C>[F:55][C:43]([F:42])([F:54])[C:44]1[CH:45]=[C:46]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:51])=[O:52])[CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3cccc(C(F)(F)F)c3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 58 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0298 g, 0.0646 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.388 mmol) and 3-trifluoromethylbenzenesulfonyl chloride (0.0310 mL, 0.194 mmol) to obtain 4-(3-trifluoromethylbenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0251 g, yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]1([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:36]2[CH2:35][CH2:34][N:33]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH2:38][CH2:37]2)=[O:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Reactant: COc1nc2ccccc2cc1NC(=O)Oc1ccccc1
Product: COc1nc2ccccc2cc1NC(=O)N1CCN(c2cccc3ccccc23)CC1
Yield: 68 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)carbamate and 1-(1-naphthyl)piperazine were reacted by the same way with the example 81 to obtain the titled compound.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])[CH3:2].S(OC)(O[CH3:13])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([CH:3]([CH2:7][CH3:8])[C:4]([O:6][CH3:13])=[O:5])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: CCC(CC)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC(CC)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.8 %

Procedure:
A mixture of 116 g (1 mol) of 2-ethylbutyric acid, 135 g (1.05 mol) of dimethyl sulfate, and 155 g (1.12 mol) of potassium carbonate in 500 ml of acetone was stirred at room temperature under nitrogen overnight, and then was allowed to reflux under nitrogen for 1 hour. The reaction mixture was cooled to room temperature, filtered, and the residual solid was washed with 500 ml of ether. The combined filtrate was concentrated in vacuo, the residue was redissolved in ether, the ether solution was washed successively with water and brine and then dried. The solvent was concentrated and the residual liquid was distilled to afford 70 g (53.8 %) of methyl 2-ethylbutyrate, b.p. 135°-137° C.
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.[C:32]([CH2:34][CH2:35][N:36]([CH3:41])[S:37](Cl)(=[O:39])=[O:38])#[N:33]>C1COCC1>[C:32]([CH2:34][CH2:35][N:36]([CH3:41])[S:37]([N:6]1[CH2:7][CH2:8][N:9]([C:14]2[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:10][C:11]21[CH2:12][CH2:13]2)(=[O:39])=[O:38])#[N:33]
Reactant: CN(CCC#N)S(=O)(=O)Cl
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(CCC#N)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Reaction time: 16 h

Procedure:
Intermediate 2 (0.05 mmol) was dissolved in THF (1.0 mL). Triethylamine (0.12 mmol) and 2-cyanoethyl(methyl)sulfamoyl chloride (0.06 mmol) was added. The reaction mixture was left at it for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.