Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][N:12]1[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=O)=[O:21].[CH2:28]1[C:36]2[C:31](=[CH:32]C=CC=2)[CH2:30][N:29]1C(NC1C=CC(C(O)=O)=CC=1)=O>>[CH3:30][CH:31]([CH3:32])[CH2:36][CH2:28][NH:29][C:25](=[O:27])[CH2:24][CH2:23][NH:22][C:20]([N:12]1[CH2:11][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:21]
Reactant: O=C(O)CCNC(=O)N1Cc2ccccc2C1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Agent: NCCCc1ccccc1
Product: CC(C)CCNC(=O)CCNC(=O)N1Cc2ccccc2C1

Procedure:
The title compound was prepared as described in Example 1C, substituting 1,3-methylbutan-1-amine for 3-phenylpropan-1-amine and 3-(isoindoline-2-carboxamido)propanoic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.76-7.81 (m, 1H), 7.25-7.34 (m, 4H), 6.31-6.36 (m, 1H), 4.56 (s, 4H), 3.23-3.31 (m, 2H), 3.02-3.09 (m, 2H), 2.27 (t, J=7.0 Hz, 2H), 1.46-1.62 (m, 1H), 1.27 (q, J=7.1 Hz, 2H), 0.84 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 304 (M+H)+.
Reaction SMILES: OC(C(F)(F)F)=O.[Cl:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]1[C:18]([NH2:26])=[N:19][NH:20][C:21]=1[C:22]([F:25])([F:24])[F:23].O=[C:28]([CH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[CH2:29][C:30](OCC)=[O:31]>C(O)(=O)C>[Cl:8][C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16][C:17]1[C:21]([C:22]([F:25])([F:23])[F:24])=[N:20][N:19]2[C:30]([OH:31])=[CH:29][C:28]([CH:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:26][C:18]=12
Reactant: Nc1n[nH]c(C(F)(F)F)c1Cc1cccc(Cl)c1Cl
Reactant: CCOC(=O)CC(=O)C1CCOCC1
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Product: Oc1cc(C2CCOCC2)nc2c(Cc3cccc(Cl)c3Cl)c(C(F)(F)F)nn12
Reaction time: 8 h

Procedure:
To a suspension of 4-[(2,3-dichlorophenyl)methyl]-5-(trifluoromethyl)-1H-pyrazol-3-amine TFA salt (201 mg, 0.48 mmol) in acetic acid (2 mL) was added ethyl 3-oxo-3-(tetrahydro-2H-pyran-4-yl)propanoate (100 mg, 0.50 mmol). The reaction vessel was sealed, stirred and irradiated (microwave) at 140° C. for 40 minutes. The reaction mixture was cooled and diluted with acetic acid (5 mL). It was stood still overnight. The precipitate was collected, washed with acetic acid (2 mL), then with cooled methanol (2 mL) and dried to give crude product. The crude material was purified by reverse-phase HPLC to provide titled compound. (16 mg, 7.5%); LC/MS: MS (ES+) m/e 446 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.75-1.77 (m, 4H) 2.82 (s, 1H) 3.38-3.41 (m, 2H) 3.96 (dd, J=10.99, 2.91 Hz, 2H) 4.21 (s, 2H) 5.84 (s, 1H) 6.77-6.83 (m, 1H) 7.25 (t, J=7.96 Hz, 1H) 7.54 (dd, J=7.96, 1.39 Hz, 1H) 12.22 (s, 1H).
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[CH:13]=[N:14][C:15]([O:19][CH3:20])=[C:16]([CH3:18])[CH:17]=2)[CH2:6]1)=[O:4].C(O)(=O)C.[CH:25]([NH2:27])=[NH:26].C[O-].[Na+].C(O)(=O)C>CO.C(Cl)Cl>[CH3:20][O:19][C:15]1[N:14]=[CH:13][C:12]([N:7]2[CH2:8][CH2:9][C:10]3[N:26]=[CH:25][N:27]=[C:3]([OH:4])[C:5]=3[CH2:6]2)=[CH:17][C:16]=1[CH3:18]
Reactant: COC(=O)C1CN(c2cnc(OC)c(C)c2)CCC1=O
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COc1ncc(N2CCc3ncnc(O)c3C2)cc1C
Temperature: 90 °C
Yield: 76.1 %

Procedure:
A mixture of 6′-methoxy-5′-methyl-4-oxo-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-3-carboxylic acid methyl ester (900 mg, 3.23 mmol), formamidine acetate (521 mg, 4.85 mmol), sodium methoxide (5.4 Molar) in methanol (2.395 mL, 12.94 mmol) and methanol (4 mL) was heated to 90° C. for 3 h. The mixture was allowed to cool down to rt, diluted in CH2Cl2, neutralized with acetic acid (0.741 mL, 12.94 mmol) and quenched with H2O. The layers were separated and aqueous was washed twice with CH2Cl2, organics were combined, washed with brine, dried over sodium sulfate, filtered and evaporated to give a yellow solid. The solid was triturated in ethylacetate to yield 6-(6-methoxy-5-methyl-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-ol (669 mg, yield 76%) as a white powder. 1H-NMR (400 MHz, DMSO-d6, 298K) δ ppm 2.14 (s, 3H) 2.72 (t, 2H) 3.39 (t, 2H) 3.81 (s, 3H) 3.90 (s, 2H) 7.42 (d, 1H) 7.67 (d, 1H) 8.07 (s, 1H) 12.46 (br.s., 1H). LCMS: [M+H]+=273.1, Rt(3)=1.30 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.[CH2:10]([O:12][C:13](=[O:15])C)C.C(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:9][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[OH:8])[NH:1][C:13](=[O:15])[O:12][CH3:10]
Reactant: CCOC(C)=O
Reactant: Nc1ccc(O)c(Cl)c1
Agent: O=C(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)Nc1ccc(O)c(Cl)c1
Temperature: 40 °C
Reaction time: 48 h

Procedure:
Powdered 4-amino-2-chlorophenol (210 grams, 1.46 moles) is added to a dry ethylacetate solution (2100 ml.) of phosgene (210 grams, 2.05 moles) and the mixture is stirred at 0°C. to 10°C. Slowly the reaction mixture is raised to reflux temperature after 1 hour. Further phosgene (20 grams) is passed through the solution during a one-half hour period, then the mixture is heated under reflux during another 30 minute period, cooled to 40°C., and rapidly filtered. The filtrate is evaporated under reduced pressure to a volume of 900 ml. An infrared spectrum of this oil has a peak at 2260 cm.-1 (N=C=O). The isocyanate solution is added to methanol (1.8 liters) with stirring, and the reaction is brought to reflux for 16 hours, then set aside at 20°C. for 48 hours. Evaporation of the reaction mixture affords a viscous oil. Addition of benzene (2 × 300 ml.) followed by evaporation causes the oil to solidify. The crude solid is vacuum dried, melting point 96°C. to 98°C., 250.5 grams (86%). Crystallization of a 5 gram sample from benzene (trace n-hexane) affords crystals, melting point 104°C. to 105°C., 2.76 grams (47%).
Reaction SMILES: O.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]([OH:9])[CH3:8].BrCl.C(O)C1[O:17]C=CC=1>O1CCCC1>[CH3:8][C:7]1[O:9][CH:6]=[CH:5][C:4](=[O:17])[C:3]=1[OH:2]
Reactant: OCc1ccco1
Reactant: CC(O)c1ccco1
Agent: ClBr
Solvent: O
Solvent: C1CCOC1
Product: Cc1occc(=O)c1O
Temperature: 0 °C

Procedure:
To a 3-neck round bottom flask is charged a solution of 50 ml of water and 20 ml of tetrahydrofuran and the solution is cooled to 0° C. An addition funnel is charged with a solution of 1(2-furyl)-1-ethanol (0.89 mole) in 25 ml of tetrahydrofuran and this solution is added dropwise to the reaction flask while BrCl (0.30 mole) is added via a gas inlet tube. The rate of addition is such that all the furfuryl alcohol is added in the first 1.3-1.5 equivalents of BrCl while maintaining the temperature below 30° C. The reaction mixture is heated to reflux and the tetrahydrofuran removed by distillation. When the temperature reaches 105° C., a condensor is attached and the reaction mixture heated under reflux for about 2 hours. The reaction mixture is cooled and maltol isolated by the method of Example 1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].Cl.[N:9]([O-])=[O:10].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O>[N:9]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7])=[O:10]
Reactant: OC[C@@H]1CCCN1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=NN1CCC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h
Yield: 95.9 %

Procedure:
To a stirred mixture of (S)-(+)-2-pyrrolidinemethanol (6.52 g, 64.4 mmol) in THF (120 mL) and 3N hydrochloric acid (33 mL, 99 mmol) at 3° C. was added dropwise a solution of sodium nitrite (5.80 g, 84 mmol) in water (25 mL) over 20 minutes. The reaction mixture was warmed to room temperature and stirred for 15 hours. After being basified with aqueous sodium carbonate, the mixture was extracted with EtOAc twice, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, EtOAc) to give the title compound (8.04 g, 96% yield) as a liquid. 1H NMR (300 MHz, CDCl3) δ 4.53-4.31 (m, 1H), 4.30-4.27 (m, 1H), 4.02-3.93 (m, 2H), 3.70-3.52 (m, 2H), 2.23-1.89 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 63.4, 62.6, 45.9, 26.2, 20.5, LRMS (API-TIS) m/z 131 (MH+).
Reaction SMILES: COC1C=C(C=CC=1)C([Cl:17])C1C2C(=CC=CC=2)C=CC=1.O[CH:22]([C:30]1[CH:42]=[CH:41][C:33]([C:34]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1>>[Cl:17][CH:22]([C:30]1[CH:42]=[CH:41][C:33]([C:34]([N:36]([CH2:39][CH3:40])[CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1
Reactant: CCN(CC)C(=O)c1ccc(C(O)c2ccc(Cl)cc2)cc1
Reactant: COc1cccc(C(Cl)c2cccc3ccccc23)c1
Product: CCN(CC)C(=O)c1ccc(C(Cl)c2ccc(Cl)cc2)cc1

Procedure:
The compound 32 was prepared by following the synthesis procedure as described for compound 2, but substituting compound 1 for compound 31.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([NH2:22])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.[Cl:23][C:24]1[N:29]=[C:28](Cl)[N:27]=[C:26]([O:31][CH3:32])[N:25]=1>CO>[Cl:23][C:24]1[N:25]=[C:26]([O:31][CH3:32])[N:27]=[C:28]([NH:22][C:12]2[CH:13]=[CH:14][C:15]([N:16]3[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]3)=[C:10]([O:9][CH3:8])[CH:11]=2)[N:29]=1
Reactant: COc1nc(Cl)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1nc(Cl)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.23 ml, 1.62 mmol) was added to a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (300 mg, 1.48 mmol) in 5 ml of methanol. The mixture was cooled in an ice-bath and 2,4-dichloro-6-methoxy-[1,3,5]triazine (266 mg, 1.48 mmol) added portionwise. The mixture was stirred for 1 hour at 0° C. The resulting precipitate was removed by filtration and dried to give the title compound as a slightly brownish solid (317 mg, 62%).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:22].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Compound 5c (680 mg, 2.20 mmol) and carbon tetrabromide (947 mg, 2.86 mg) were dissolved in dichloromethane (20 ml). The solution was cooled down to 0° C. with an ice bath and pyridine (2.0 ml) was added followed by triphenylphosphine (749 mg, 0.286 mmol). The solution was stirred at 0° C. for half an hour and at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford compound 6c (680 mg, 79.6%): 1H NMR δ 3.79 (m, 4H), 3.66 (m, 8H), 3.56 (t, 2H), 3.47 (t, 2H), 0.89 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]2=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][CH:25]([CH3:27])[CH3:26].O>CN(C=O)C>[CH2:24]([N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CBr
Reactant: O=[N+]([O-])c1ccc2[nH]c3c(c2c1)CCCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c2c(c3cc([N+](=O)[O-])ccc31)CCCC2
Temperature: 70 °C
Reaction time: 14 h
Yield: 93.7 %

Procedure:
To a solution of 6-nitro-2,3,4,9-tetrahydro-1H-carbazole (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 mmol) in DMF (8 mL) was added 1-bromo-2-methylpropane (0.314 mL, 2.89 mmol), and the mixture was stirred at 70° C. for 14 hr. The reaction mixture was cooled, and to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 55% ethyl acetate/hexane) to give 9-isobutyl-6-nitro-2,3,4,9-tetrahydro-1H-carbazole (296 mg, 1.087 mmol, 94%) as a yellow powder.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[C:15](=[C:16]([CH2:21]Cl)[CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1.O>CS(C)=O>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([CH2:21][C:1]#[N:2])[C:15]=3[CH:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: Cc1ccc(-c2nccc3c(CCl)cccc23)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(-c2nccc3c(CC#N)cccc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
Sodium cyanide (1.89 g) was dissolved in 100 ml of dimethylsulfoxide, and 8.6 g of 1-(4-methylphenyl)-5-chloromethylisoquinoline was added. At room temperature, the mixture was stirred for 1 hour. After the reaction, the reaction mixture was poured into water, extracted with ether, washed in water, and dried. The solvent was distilled off. The residue was recrystallized from ether to afford 7 g of 1-(4-methylphenyl)isoquinoline-5-acetonitrile as prisms having a melting point of 101.7° to 102.1° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[CH:59]1[C:71]2[NH:70][C:69]3[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=3)[C:63]=2[C:62]([C:72]2[CH:73]=[CH:74][C:75]([CH2:78][OH:79])=[N:76][CH:77]=2)=[CH:61][CH:60]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:10][C:4]1[CH:3]=[C:2]([N:70]2[C:71]3[CH:59]=[CH:60][CH:61]=[C:62]([C:72]4[CH:77]=[N:76][C:75]([CH2:78][OH:79])=[CH:74][CH:73]=4)[C:63]=3[C:64]3[C:69]2=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: OCc1ccc(-c2cccc3[nH]c4ccccc4c23)cn1
Reactant: N#Cc1ccc(Br)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: N#Cc1ccc(-n2c3ccccc3c3c(-c4ccc(CO)nc4)cccc32)cc1F
Temperature: 25 °C
Yield: 15.7 %

Procedure:
0.34 g of 4-bromo-2-fluorobenzonitrile, 1.4 g of caesium carbonate, 0.08 g of (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) and 25 mg of palladium acetate are successively added, under argon, to a solution of 0.31 g of [5-(9H-carbazol-4-yl)pyridin-2-yl]methanol in 15 ml of dioxane. The reaction mixture is refluxed for 4 hours, cooled to ambient temperature, filtered through celite and concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a mixture of cyclohexane and ethyl acetate (85/15 by volume), so as to give 70 mg of 2-fluoro-4-{4-[6-(hydroxymethyl)pyridin-3-yl]-9H-carbazol-9-yl}benzonitrile in the form of a yellow solid, the characteristics of which are the following:
Reaction SMILES: [NH2:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)[CH2:3][OH:4].C(N(CC)CC)C.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27](Cl)=O>O1CCCC1>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:26]=1[C:27]1[O:4][CH2:3][CH:2]([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=2)[N:1]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC(C)(C)c1ccc(OCC(N)CO)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(OCC2COC(c3c(F)cccc3F)=N2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 76.1 %

Procedure:
To a mixture of 1.46 g (6.54 mmol.) of 2-amino-3-[4-(1,1-dimethylethyl)phenoxy]propanol, 0.86 g (8.50 mmol.) of triethylamine and 20 ml of anhydrous tetrahydrofuran, there was added dropwise a solution of 1.15 g (6.54 mmol.) of 2,6-difluorobenzoylchloride in 10 ml of anhydrous tetrahydrofuran with stirring at a temperature of from 5° C. to 10° C. for 5 minutes. After addition, the reaction mixture was stirred at room temperature for one hour. After the reaction was completed, the resultant mixture was concentrated under reduced pressure. To the residue, there was added 20 ml of benzene and 10 ml of thionyl chloride and the reaction mixture was refluxed by heating with stirring for 3 hours. Then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 20 ml of ethanol and further added dropwise 1.4 ml of a 5N aqueous solution of sodium hydroxide with stirring at a temperature of 60° C. for 5 minutes. The reaction mixture was then stirred at the same temperature for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. To the residue, there was added 100 ml of ethyl acetate. The mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 1.72 g of 2-(2,6-diflurophenyl)-4-{[4-(1,1-dimethylethyl)phenoxy]methyl}-2-oxazoline as a colorless oily substance (nD 19.1 1.5391).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][N:6]([C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)[CH2:5][CH2:4][O:3]1.N([O-])=O.[Na+].[OH-].[Na+].[BrH:21]>O>[Br:21][C:11]1[CH:13]=[CH:14][C:8]([N:6]2[CH2:5][CH2:4][O:3][CH:2]([CH3:1])[CH2:7]2)=[CH:9][CH:10]=1
Reactant: CC1CN(c2ccc(N)cc2)CCO1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CN(c2ccc(Br)cc2)CCO1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(2-methylmorpholino)aniline (7.21 g, 37.5 mmol) in 100 mL HBr in water (40%), a solution of NaNO2 (2.59 g, 37.5 mmol) in 15 mL water was added slowly at −10° C.˜0° C. The mixture was stirred for 30 minutes and was added dropwise to a solution of CuBr (2.96 g, 20.6 mmol) in 30 mL HBr in water (40%). The resulting mixture was stirred and heated at 60° C. for 2 hours. Then the reaction solution was adjusted by 2N NaOH solution to pH>7. Extracted by EA, the combined organic phase was washed with brine, dried and concentrated to give crude product as black oil. MS (m/z): 256 (M+H)+; 258 (M+3)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[F:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:14]2[CH:13]=[CH:12][C:11]([N+:17]([O-:19])=[O:18])=[C:10]([F:9])[CH:15]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2ccc([N+](=O)[O-])c(F)c2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
N-Ethylpiperazine (4.8 mL, 37.7 mmol, 1.2 equiv) is added to a mixture of 2,4-difluoronitrobenzene (5 g, 31.4 mmol) and potassium carbonate (8.7 g, 62.9 mmol, 2 equiv) in DMF (50 mL). The reaction mixture is stirred at 100° C. for 6 h, allowed to cool to RT, diluted with H2O and extracted with EtOAc. The organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography (DCM/MeOH+1% NH3aq, 95:5) to provide the title compound as a yellow oil: ES-MS: 254.1 [MH]+; TLC: Rf=0.67 (DCM/MeOH+1% NH3aq, 95:5).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:15]=2)[C:10]([C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([F:29])[CH:23]=2)=[O:19])=[C:9]1[CH:30]([CH3:32])[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2c(C(=O)NCc3ccc(F)c(F)c3)c(C(C)C)n(Cc3ccccc3)c2c1

Procedure:
Following General Procedure A, 1-benzyl-N-(3,4-difluorobenzyl)-6-hydroxy-2-isopropyl-1H-indole-3-carboxamide (Compound 8, 10.7 mg, 0.025 mmol) in DMF (1.0 ml) was reacted with K2CO3 (10.0 mg, 0.074 mmol) and 1-iodohexane (18.0 μl, 0.12 mmol) to yield the title compound as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:11][C:12]1[C:13]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:21][CH:20]=2)=[N:14][CH:15]=[C:16]([OH:18])[CH:17]=1>N1C=CC=CC=1>[C:1]([O:18][C:16]1[CH:17]=[C:12]([F:11])[C:13]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:23][CH:24]=2)=[N:14][CH:15]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(-c2ncc(O)cc2F)cc1
Reactant: CCCCCCCC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCCCOc1ccc(-c2ncc(OC(=O)CCCCCCC)cc2F)cc1
Temperature: 0 °C
Yield: 64.3 %

Procedure:
1.2 ml (7.1 mmol) of octanoyl chloride are added dropwise at O° C. to 1.5 g (4.7 mmol) of 3-fluoro-5-hydroxy-2-(4octyloxyphenyl)pyridine in 20 ml of pyridine and the mixture is stirred at 0° C. for 3 hours, subsequently poured into ice-water and filtered and the residue is purified by chromatography (silica gel/hexane: ethyl acetate 9:1) and by recrystallization from acetonitrile, giving 1.34 g of 3-fluoro-2-(4-octyloxyphenyl)pyridin-5-yl octanoate. ##STR20##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>O>[C:23]([N:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)(=[O:25])[CH3:24]
Reactant: COc1ccc(C2CCCNC2)cc1OC
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2CCCN(C(C)=O)C2)cc1OC
Temperature: 20 °C

Procedure:
A mixture of 8 g of 3-(3',4'-dimethoxyphenyl)-piperidine, 80 ml of benzene and 3.6 ml of acetic acid anhydride was stirred at 20° C for an hour and was then diluted with 100 ml of water. 500 ml of an aqueous solution saturated with sodium bicarbonate were added thereto and the mixture was stirred for an hour and then was decanted. The aqueous phase was re-extracted with ethyl acetate and the organic phases were washed with water, dried and evaporated to dryness. The residue was chromatographed over silica gel and was eluted with a 6-3-1 cyclohexane-chloroform-triethylamine mixture to obtain 6.75 g of N-acetyl-3-(3',4'-dimethoxyphenyl)-piperidine.