Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([CH:9]=O)=[CH:3][CH:2]=1.[CH:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16])([CH3:13])[CH3:12].C(O)(=O)C>ClCCl>[CH:21]([C:17]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:11]([CH3:13])[CH3:12])[C:15]=1[N:16]1[CH2:7][C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[CH2:9]1)([CH3:23])[CH3:22]
Reactant: O=Cc1ccccc1C=O
Reactant: CC(C)c1cccc(C(C)C)c1N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)c1cccc(C(C)C)c1N1Cc2ccccc2C1

Procedure:
0.5 g of o-phthalaldehyde and 0.661 g of 2,6-diisopropylaniline were dissolved in 20 ml of dichloromethane, 1 ml of acetic acid was added thereto, and the mixture was reacted at room temperature for 25 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(O)(=O)/C=C/C(O)=O.C([O-])(=O)/C=C/C([O-])=O>O1CCCC1.C(O)(C)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:18])[CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCC2CCNCC2)cc1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])/C=C/C(=O)[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: O
Product: COc1ccc(C(O)CCC2CCNCC2)cc1
Temperature: 5 °C
Yield: 75.9 %

Procedure:
To a suspension of 10.2 g of 1-(4-methoxyphenyl) 3-(4-piperidyl) 1-propanone in 130 ml of dry tetrahydrofurane, maintained at 5° C. and under a nitrogen atmosphere, 2.8 g of lithium aluminum hydride are added in small portions. When the addition is complete, the reaction mixture is heated to 60° C. over five hours, then cooled to 0° C. Then, while maintaining this temperature, 25.2 ml of water are added very slowly. The mineral products are filtered and washed twice with 50 ml of hot methylenechloride. The collected organic solutions are concentrated by evaporation of the solvent. The oil obtained is dissolved in 150 ml of isopropanol and treated with 7.4 g of fumaric acid. In this manner, 7.8 g of 1-(4-methoxyphenyl) 3-(4-piperidyl) 1-propanol in the form of its fumarate are obtained.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[I-:11].[Na+]>CC(=O)CC>[I:11][CH2:2][CH2:3][CH2:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: [I-]
Reactant: C[Si](C)(C)C#CCCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: C[Si](C)(C)C#CCCCI
Yield: 93.8 %

Procedure:
A mixture of 5-chloro-1-trimethylsilylpent-1-yne (13.5 g) and sodium iodide (29 g) in butanone (100 ml) was heated at reflux for 10 hours. After this time the solvent was removed in vacuo and the residue partitioned between diethyl ether and water. The organic phase was separated, washed with water and brine before drying over anhydrous magnesium sulphate. The solvent was removed under reduced pressure to leave 5-iodo-1-trimethylsilylpent-1-yne as a colourless oil (19.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:17][S:18]([C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][N:22]=1)(=[O:20])=[O:19].CS(C1C2C(=CN=CC=2)NN=1)(=O)=O>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH:11]3[CH2:14][O:13][CH2:12]3)[C:7]([CH2:9][N:23]3[C:24]4[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:21]([S:18]([CH3:17])(=[O:19])=[O:20])=[N:22]3)=[N:8][C:4]=2[CH:3]=1
Reactant: ClCc1nc2cc(Cl)ccc2n1C1COC1
Reactant: CS(=O)(=O)c1n[nH]c2ccccc12
Agent: CS(=O)(=O)c1n[nH]c2cnccc12
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2C2COC2)c2ccccc12

Procedure:
The title compound was prepared in analogy to Example 2-1 by using 5-chloro-2-chloromethyl-1-oxetan-3-yl-1H-benzoimidazole and 3-methanesulfonyl-1H-indazole instead of 5-chloro-2-chloromethyl-1-((S)-1,1-dioxo-tetrahydro-1λ6-thiophen-3-yl)-1H-benzoimidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14])[CH:9]=2)[NH:4][N:3]=1.[NH2:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][C:21]#[N:22].C(N(CC)CC)C>CC(O)C>[CH3:16][C:15]1[NH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[C:20]([C:21]#[N:22])[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])[C:12]=1[C:13]#[N:14]
Reactant: N#CC=C(N)C(F)(F)F
Reactant: CC(=O)/C(C#N)=C/c1ccc2[nH]nc(C)c2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3[nH]nc(C)c3c2)C(C#N)=C(C(F)(F)F)N1

Procedure:
A suspension of 5.4 g (24.0 mmol) (2E)-2-[(3-methyl-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 2A) and 13.05 g (95.9 mmol) 3-amino-4,4,4-trifluorobut-2-enenitrile [preparation: A. W. Lutz, U.S. Pat. No. 3,635,977; C. G. Krespan, J. Org. Chem. 34, 42 (1969)] in 2-propanol (27 ml) and triethylamine (0.33 ml) was stirred at reflux temperature for 15 h. After cooling, the precipitate was collected by filtration, washed twice with cold 2-propanol and dried under high vacuum to yield 5.98 g (72% of th.) of the racemic title compound as a tan solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][N:30]3C2CCCCO2)[CH3:24])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25][C:26]2[N:34]=[CH:33][N:32]=[C:31]3[C:27]=2[N:28]=[CH:29][NH:30]3)[CH3:24])[CH2:9]1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-3-(2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}benzoimidazol-1-yl)piperidine-1-carboxylic acid tertbutyl ester (2.27 g, 4.15 mmol) in DCM (25 mL) was added TFA (15 mL) and the mixture was stirred at RT for 1 h. Volatiles were removed under reduced pressure and the resulting residue was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with a 1:1 mixture MeOH:DCM and the product was eluted with 2M NH3/MeOH (100 mL) in DCM (150 mL). The product containing fractions were combined and concentrated in vacuo affording [(S)-1-((R)-1-Piperidin-3-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine as a pale yellow solid (1.53 g, quantitative). LCMS: RT 1.63 min [M+H]+ 363.2.
Reaction SMILES: C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.C(O)(C)C.CC(C)([O-])C.[K+].[Cl:37][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=1)=[O:40]>C(O)(C)C>[Cl:37][CH2:38][CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[CH:42]=1)[OH:40]
Reactant: Cc1cccc(C(=O)CCl)c1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)O
Product: Cc1cccc(C(O)CCl)c1
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A solution of di-μ-chlorodichlorobis(pentamethylcyclopentadienyl)dirhodium (III) (3.1 mg, 0.005 mmol) and (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (7.3 mg, 0.02 mmol) in isopropyl alcohol (5.0 ml) was heated at 80° C. for 20 minutes while stirring. After cooling the solution to room temperature, a 0.1 M potassium tert-butoxide isopropyl alcohol solution (0.5 ml, 0.05 mmol) and an isopropyl alcohol solution (4.5 ml) of 2-chloro-3′-methylacetophenone (168.6 mg, 1.0 mmol) as a reaction substrate were added thereto, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to give a desired compound, (+)-2-chloro-1-(3′-methylphenyl)ethanol (158.6 mg; yield: 93.0%; optical purity: 95.6% ee).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31]([C:38](O)=[O:39])=[CH:30][CH:29]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:38]([C:31]5[C:32]6[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=6)[N:28]=[CH:29][CH:30]=5)=[O:39])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccnc2ccccc12
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccnc2ccccc12

Procedure:
The title compound, white solid (104 mg, 86%), MS (ISP) m/z=486.5 [(M+H)+], mp 210° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and quinoline-4-carboxylic acid.
Reaction SMILES: ClCCl.[C:4]1([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][NH:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(N(CC)CC)C>[C:4]1([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12][N:11]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cl
Reactant: c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2ccccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 130 ml dichloromethane solution containing 6.28 g of 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 3.34 g of triethylamine, 3.1 ml of ethyl chloroformate was added dropwise under ice-cooling, followed by stirring at room temperature overnight. The reaction solution was washed successively with water, 1N hydrochloric acid, water and brine and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, thereby 10.58 g of ethyl 1-phenyl-1,2,3,4-tetrahydro-2-isoquinolinecarboxylate was obtained as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[C:8](O)=[N:9][C:10]([CH3:14])=[N:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:8]1[C:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)=[C:12]([CH3:13])[N:11]=[C:10]([CH3:14])[N:9]=1
Reactant: Cc1nc(C)c(Cc2ccc(F)cc2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc(C)c(Cc2ccc(F)cc2)c(Cl)n1
Yield: 67 %

Procedure:
A solution of 5-(4-fluorobenzyl)-2,6-dimethylpyrimidin-4-ol (730 mg, 3.14 mmol) in phosphorus oxychloride (10 mL) was stirred at 60° C. for 90 min. The reaction mixture was concentrated and ethyl acetate (50 mL) was added to the residue. The organic solution was washed with saturated sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL), dried over sodium sulfate, filtered and concentrated. Column chromatography of the residue on silica (5-40% ethyl acetate in hexanes) afforded 4-chloro-5-(4-fluorobenzyl)-2,6-dimethylpyrimidine (527 mg, 67% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): 7.21 (m, 2H), 6.98 (m, 2H), 4.12 (s, 2H), 2.67 (s, 3H), 2.45 (s, 3H); MS (EI) for C13H12ClFN2: 250 (M+).
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[C:14](=[O:17])[CH2:15][CH2:16][N:9]3[C:10]=2[C:2]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=13.C([Li])CCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[C:23]([C:15]1[C:14](=[O:17])[C:11]2[CH:12]=[CH:13][CH:1]=[C:2]3[C:10]=2[N:9]([CH:16]=1)[C:8]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CCn2c3ccccc3c3cccc1c32
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1cn2c3ccccc3c3cccc(c1=O)c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 14 %

Procedure:
5,6-dihydro-4H-pyrido[3,2,1-jk]carbazole-4-one (4 g) prepared by the procedure described in J.O.C., 24, 324 (1959) was dissolved in anhydrous tetrahydrofuran (160 ml). n-butyl lithium (solution in hexane, 15 ml) was added dropwise to the solution cooled in an acetone-dry ice bath, and the mixture was stirred for 30 minutes. Benzaldehyde (2 ml) dissolved in anhydrous tetrahydrofuran (80 ml) was gradually added dropwise to the solution cooled in an acetone-dry ice bath, and the mixture was stirred for 90 minutes. Saturated aqueous solution of ammonium chloride of an adequate amount was added to the reaction mixture, and the mixture was heated to room temperature, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: hexane/ethyl acetate=5:1) to obtain the title compound (852 mg, 14%).
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:12]=[CH:11][O:10][CH:9]=1)[CH:2]=[CH2:3].[CH2:13]=O>C(O)(=O)C>[CH2:1]([N:4]1[CH2:5][CH2:6][CH2:7][C:8]2[CH:12]=[CH:11][O:10][C:9]=2[CH2:13]1)[CH:2]=[CH2:3]
Reactant: C=CCNCCCc1ccoc1
Reactant: C=O
Solvent: CC(=O)O
Product: C=CCN1CCCc2ccoc2C1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 1.803 g (10.912 mmol) of N-allyl-3-(3-furyl)propylamine in 50 ml of acetic acid, 1.06 g (13.1 mmol) of 37% aqueous formaldehyde was added, followed by stirring at 100° C. for 1 hour. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide, and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12]CC)=O)(C(C)(C)C)(C)C.[NH2:19][C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=1>>[OH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:19][C:20]1[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][N:21]=1)=[O:12]
Reactant: Cc1cnc(N)cn1
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Product: CCCCC(O)C(=O)Nc1cnc(C)cn1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}hexanoate and 2-amino-5-methylpyrazine, 1H NMR (300 MHz, CDCl3) δ 9.46 (s, 1H), 8.98 (br s, 1H), 8.12 (s, 1H), 4.32 (m, 1H), 2.98 (d, 1H), 2.54 (s, 3H), 1.96 (m, 1H), 1.78 (m, 1H), 1.44 (m, 4H), 0.93 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:28])=O.C([BH3-])#N.[Na+]>[OH-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:19][CH2:20][N:21]([CH:26]([CH3:28])[CH3:25])[CH2:22][CH2:23]2)=[N:6][CH:7]=1
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Product: CC(C)N1CCC(CNc2ccccc2C(=O)Nc2ccc(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (0.152 g, 0.4 mmol) in methanolacetic acid (95:5) (5 mL) was treated with acetone (5 mL) and sodium cyanoborohydride (0.111 g, 1.8 mmol). The reaction mixture was stirred at room temperature for 24 h, then it was diluted with 1 N NaOH until pH 13 and extracted with dichloromethane. The organic extracts were combined, dried with MgSO4, filtered and concentrated in vacuo to provide the title compound (0.158 g, 92%). The crude material was triturated in dichloromethane-hexanes, giving a white powder which was filtered and dried under vacuum at 60° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([OH:31])[CH2:27][CH2:28][C:29]#[CH:30].Cl>N1CCCCC1.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.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:30]#[C:29][CH2:28][CH2:27][CH2:26][OH:31])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Reactant: C#CCCCO
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCCc2cc(C#CCCCO)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To 850 mg (2.2 mmol) 6-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester in 5 ml piperidine, 128.0 mg (0.1 mmol) tetrakis(triphenylphosphine)palladium followed by 21.0 mg (0.1 mmol) copper iodide were added. The solution was evaporated and flushed with argon prior to the addition of 210 μl (2.2 mmol) 4-pentynol at 80° C. over a period of 45 min. Further 0.2 ml (2.1 mmol) 4-pentynol were added and the solution was stirred for 2 h. The mixture was added to ice water, acidified with 2M HCl and extracted with ether. The combined organic phases were washed with water and dried over Na2SO4. Purification by column chromatography with CH2Cl2/MeOH 30:1 yielded 650 mg (92%) 6-(5-Hydroxy-pent-1-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as light brown oil, MS: 316 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[C:15]([F:17])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CC(O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([C:13]2[CH:12]=[C:11]([F:10])[CH:16]=[C:15]([F:17])[CH:14]=2)=[C:3]([F:9])[CH:4]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: Oc1ccc(Br)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: Oc1ccc(-c2cc(F)cc(F)c2)c(F)c1
Temperature: 25 °C
Yield: 74 %

Procedure:
4-Bromo-3-fluorophenol (T-1) (50.0 g), 3,5-difluorophenylboronic acid (45.5 g), potassium carbonate (72.4 g), Pd(Ph3P)2Cl2 (5.52 g) and 2-propanol (500 ml) were put in a reaction vessel and heated to reflux for 5 hours under an atmosphere of nitrogen. After the reaction solution had been cooled to 25° C., it was poured into water (500 ml) and mixed with it. Toluene (500 ml) was added to the solution to separate organic and aqueous phases, and extraction was carried out. The combined organic phase was washed with water and dried over anhydrous magnesium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified with a fractional operation by means of column chromatography (silica gel; toluene). The product was further purified by recrystallization from a mixed solvent of heptane/Solmix A-11 and dried, giving 4-hydroxy-2,3′,5′-trifluoro-1,1′-biphenyl (T-2) (43.4 g). The yield based on the compound (T-1) was 74%.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH2:19][CH2:20][CH3:21])=[C:7]([CH:13]=[CH:14][C:15]=1[C:16](=[O:18])[CH3:17])[O:8][CH2:9][CH2:10][CH2:11]Br)(=[O:3])[CH3:2].Cl.[Br:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][C:38]=1[OH:39])[C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[O:28].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:4][C:5]1[C:6]([CH2:19][CH2:20][CH3:21])=[C:7]([CH:13]=[CH:14][C:15]=1[C:16](=[O:18])[CH3:17])[O:8][CH2:9][CH2:10][CH2:11][O:39][C:38]1[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[O:28])=[CH:25][C:24]=1[Br:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1OC(C)=O
Reactant: CN(C)CCCOC(=O)c1ccc(O)c(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)OCCCN(C)C)cc2Br)ccc(C(C)=O)c1OC(C)=O
Yield: 69.5 %

Procedure:
In dimethylformamide (30 ml), 3-(3-acetoxy-4-acetyl-2-propylphenoxy)propylbromide (1.6 g) was allowed to react with 3-dimethylaminopropyl 3-bromo-4-hydroxybenzoate.hydrochloride (1.7 g), potassium iodide (0.83 g) and potassium carbonate (0.7 g) at 60°-70° C. for 6 hours with stirring. Insoluble materials were filtered off, and the filtrate was concentrated. The resulting syrup was purified by means of a flash chromatography using silica-gel to give 3-dimethylaminopropyl 4-[3-(3-acetoxy-4-acetyl-2-propylphenoxy)propoxy]-3-bromobenzoate (1.8 g). The product was dissolved in ether, to which was added equivalent oxalic acid (250 mg) to give crystalline oxalate (1.8 g), m.p. 141°-142° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[C:34]([CH3:35])=[C:33]([CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[C:34]([CH3:35])=[C:33]([CH3:36])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: Cc1ccnc(C(=O)CBr)c1C
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2nccc(C)c2C)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-3,4-dimethylpyridine hydrobromide*.
Reaction SMILES: CO[C:3](=[O:19])[CH2:4][C@H:5]([OH:18])[CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O.C(OC(=O)C[C@H](O)CI)C.C(OC(=O)C[C@H]1CO1)C.C(O)(=O)[C@H](CC(O)=O)O.[CH2:48]([NH2:51])[C:49]#[CH:50]>>[OH:18][C@@H:5]1[CH2:6][N:51]([CH2:48][C:49]#[CH:50])[C:3](=[O:19])[CH2:4]1
Reactant: C#CCN
Reactant: COC(=O)C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)C[C@H](O)CI
Agent: CCOC(=O)C[C@H]1CO1
Agent: O=C(O)C[C@H](O)C(=O)O
Product: C#CCN1C[C@@H](O)CC1=O

Procedure:
In accordance with Scheme I, (S)-3-hydroxy-4-[[(4-methylphenyl)sulfonyl]oxy]butanoic acid methyl ester 2, (S)-3-hydroxy-4-iodobutanoic acid ethyl ester 3 and (S)-oxiraneacetic acid ethyl ester 4 are prepared from (S)-malic acid 1 using previously described methods [S. Saito et. al. Chem. Lett. 1389, (1984) and M. Larcheveque et. al. Tetrahedron Lett. 1781, 28 (1987)]. The esters 2, 3 and 4 are individually reacted with propargylamine in an alcohol solvent at temperatures ranging from room temperature to the reflux temperature of the solvent, preferably in the presence of an alkali metal carbonate, to produce (S)-4-hyroxy-1-(2-propynyl)-2-pyrrolidinone 5. Compound 5 is then reacted with an aryl or a (C1 -C6) carboxylic acid anhydride such as acetic anhydride in the presence of pyridine and preferably dimethylaminopyridine in an ether or a chlorohydrocarbon solvent, such as dichloromethane, to give the intermediate of general formula 6, for example, (S)-4-(acetyloxy)-1-(2-propynyl)-2 -pyrrolidinone.