Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([O:27]C)=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:10][CH:9]=1)[CH2:2][CH3:3].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]3[S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][C:19]([C:25]([OH:27])=[O:26])=[CH:18][C:17]=3[CH:29]=2)=[CH:30][CH:31]=1)[CH2:2][CH3:3]
Reactant: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(Oc2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 65 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
To methyl 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.40 g) dissolved in THF (12 ml)/methanol (6.0 ml) was added a 1 N aqueous solution (2.7 ml) of sodium hydroxide, and the resulting mixture was stirred at 65° C. for 16 hours. After cooling to the room temperature, the reaction mixture was concentrated under reduced pressure to remove a half of the solvent. A 1 N aqueous solution of sodium hydroxide (3.0 ml) was added to the resulting mixture, which was washed with ethyl acetate. After being adjusted to pH=about 5, the resulting aqueous layer was extracted with ethyl acetate and the extract was washed with an aqueous saturated solution of sodium chloride and was then dried with magnesium sulfate. After evaporation to remove the solvent, the resulting residue was washed with hexane/ethyl acetate (=8/1) to obtain 7-[4-(2-propoxyethoxy)phenoxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (0.25 g).
Reaction SMILES: Br[CH2:2][CH2:3][Cl:4].C([O-])([O-])=O.[K+].[K+].[F:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[CH:16][C:17]=1[F:18]>CN(C=O)C.CC(=O)OCC>[Cl:4][CH2:3][CH2:2][S:19][C:14]1[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=1
Reactant: Fc1ccc(S)cc1F
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Fc1ccc(SCCCl)cc1F
Reaction time: 16 h
Yield: 94.2 %

Procedure:
5.7 ml (68.4 mmol) of 1-bromo-2-chloroethane and 1.9 g (13.7 mmol) of K2CO3 were added to a solution of 2.0 g (13.7 mmol) of 3,4-difluorothiophenol in DMF (20 ml). Stirring was then carried out for 5 h at 60° C. and for 16 h at RT. The mixture was then diluted with EA (50 ml) and washed in succession with 1 M aq. Na2CO3 solution and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. There were obtained as residue 2.7 g (12.9 mmol, 95%) of (2-chloroethyl)-(3,4-difluorophenyl)sulfane, which was reacted further without additional purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].Cl[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([C:34]([F:37])([F:36])[F:35])=[CH:27][N:26]=1.Cl>COCCOC.C1(C)C=CC=CC=1>[CH2:8]([O:7][C:5]([CH:4]([C:3]([O:16][CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[C:25]1[C:30]([N+:31]([O-:33])=[O:32])=[CH:29][C:28]([C:34]([F:35])([F:36])[F:37])=[CH:27][N:26]=1)=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C(C(=O)OCc1ccccc1)c1ncc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a dry flask was placed sodium hydride as a 60% suspension in oil (800 mg, 2.0 mmol). Most of the oil was removed by washing twice with hexanes. The remaining solid sodium hydride was then suspended in dry 1,2-dimethoxyethane (DME) (20 mL). A solution of dibenzyl malonate (5.0 mL, 2.0 mmol) in DME (15 mL) was then added dropwise with stirring. The mixture was stirred at room temperature for 0.5 hr after which a solution of 2-chloro-3-nitro-5-trifluoromethyl pyridine (2.3 g, 10.2 mmol) in DME (15 mL) was added. Stirring at room temperature was continued overnight and the reaction mixture was poured into ice/water. Following acidification to pH 3 with 1N HCl solution, the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo to leave an oil. This was subjected to flash chromatography on silica gel using toluene as eluant. All fractions containing the desired product were combined and concentrated to leave a tan solid; 3.8 g (79%): mp 82°-84° C.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2.C(C1[O:19][CH2:18]1)Cl>[Na]>[OH:3][CH:1]([CH2:18][OH:19])[CH2:2][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: Oc1cccc2cccnc12
Reactant: ClCC1CO1
Reactant: CCO
Agent: [Na]
Product: OCC(O)COc1cccc2cccnc12

Procedure:
To 100 ml of ethanol in which 2,5 g of sodium metal had been dissolved was added 15 g of 8-hydroxyquinoline. 12 g of epichlorohydrin was then added to the resulting solution and the mixture was refluxed for 8 hours while stirring. After completion of the reaction, the precipitated material was removed by filtration, and the mother liquor was concentrated to dryness. The resulting residue was recrystallized from ethanol-water to give 16 g of 8-(2,3-dihydroxy)propoxyquinoline as colorless needle-like crystals having a melting point of 193° - 194° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>ClCCl>[ClH:16].[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([Cl:16])=[O:13])=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: O=C(Cl)c1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To 4-quinolinecarboxylic acid (5.0 g, 29.1 mmol) at 0° C. under argon was added thionyl chloride (20.0 ml, 0.27 mol). The reaction mixture was slowly warmed to room temperature and stirred for 1 hour. Dichloromethane (100 ml) was added and the reaction mixture was refluxed for 3 hours. The solvents were removed by distillation and the residue was dried at 130° C. in high vacuum to afford 5.8 g (87%) of 4-quinolinecarboxylic acid chloride hydrochloride as a green crystals, m.p. 249°-251° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1.[CH:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>O1CCCC1>[C:9]([C:2]1[S:3][CH:4]=[C:5]([CH:7]=[O:8])[CH:6]=1)#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1csc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cc(C=O)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-bromo-4-thiophenecarboxaldehyde (45.3 g), 1-dodecyne (43.4 g), and triethylamine (99 ml), in dry tetrahydrofuran (250 ml) was chilled to 5° C. and degassed under nitrogen. bis(Triphenylphosphine)palladium(II)chloride (1.66 g) and copper(I)iodide (0.23 g) were added to the reaction mixture. The mixture was degassed and stirred overnight, under nitrogen, as it was allowed to warm to room temperature. The precipitate was filtered off, washed with ethyl acetate, and the filtrate was evaporated. Ethyl acetate was added to the residue. The solution was washed with brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated. The residue was chromatographed through a silica gel pad eluting with heptane/1% ethyl acetate. The appropriate fractions were collected and evaporated. The residue and that from a similar reaction on a 0.05 mole scale were combined and distilled to give 30.7 g (79.5%), bp 181-185° C. @ 0.35 mm Hg.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].Cl.CCN(C(C)C)C(C)C>C(O)C>[CH2:17]([O:19][C:20]([C:22]1([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:24][N:25]([C:2]2[N:11]=[C:10]([OH:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Reactant: COc1cc2nc(Cl)nc(O)c2cc1OC
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCN(c2nc(O)c3cc(OC)c(OC)cc3n2)CC1
Yield: 84.2 %

Procedure:
A mixture of 1.2 g (5 mmol) 2-Chloro-6,7-dimethoxy-quinazolin-4-ol (commercially available), 2.26 g (8 mmol) 4-Benzyl-piperidine-4-carboxylic acid ethyl ester; hydrochloride and 1.93 g (15 mmol) DIPEA in 80 mL ethanol was heated to reflux for 62 h. The mixture was concentrated, the precipitate filtered off and washed with ethanol and diethyl ether. The residue was dried. 1.9 g (87%) of the title compound was isolated as white solid. MS (m/e): 452.2 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=O)[CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CO.O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH3:15])[C@H:9]1[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[C@H]1OCCN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.7 %

Procedure:
To a solution of (2R,3S)-benzyl 4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (15.7 g, 46.1 mmol) in THF (60 mL) was added a solution of borane in THF (1 mol/L, 69.2 mL) dropwise over a period of 1 hour at −10° C. under N2. After the end of addition, the mixture was warmed to 25° C. and stirred for 16 hours, then cooled to −10° C. And to the mixture was added methanol slowly until gas evolution was ceased, then added water (10 mL). The mixture was concentrated in vacuo and the residue was dissolved in EtOAc (150 mL). The organic layer was washed with aqueous NaOH solution (2 mol/L, 50 mL×2) and brine (50 mL×2). The organic phase was concentrated in vacuo to give the title compound as colorless oil (13 g, 86.7%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].O1CCOCC1.[OH-].[Na+].Cl>O>[CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1nc(Cl)c(CC(=O)O)c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
128 mg of the product of Example 16 were introduced into 2.56 ml of dioxane and 0.52 ml of 2N sodium hydroxide and the mixture was stirred at ambient temperature for 16 hours, then diluted with 10 ml of water, neutralized with 0.52 ml of 2N hydrochloric acid and evaporated to dryness under reduced pressure to obtain 135 mg of crude product which was crystallized from ethyl acetate and hexane to obtain 85 mg of the expected product melting at 180° C.
Reaction SMILES: [CH:1](O)=O.[NH:4]([C:6]1[S:7][C:8]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([CH3:16])[C:9]=2[N:10]=1)[NH2:5]>O>[CH3:16][C:11]1[C:9]2[N:10]3[CH:1]=[N:5][N:4]=[C:6]3[S:7][C:8]=2[CH:14]=[CH:13][C:12]=1[CH3:15]
Reactant: Cc1ccc2sc(NN)nc2c1C
Reactant: O=CO
Solvent: O
Product: Cc1ccc2sc3nncn3c2c1C
Temperature: 25 °C

Procedure:
A solution of 12 milliliters of formic acid (97-100 percent) and 3.5 grams of 2-hydrazino-4,5-dimethylbenzothiazole was refluxed for 24 hours with stirring. The reaction mixture was then cooled to room temperature and poured into water. The 5,6-dimethyl-s-triazole(3,4-b)benzothiazole compound precipitated and was separated by filtration, 2.6 grams, m.p. 226-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[I:12]N1C(=O)CCC1=O>CC(O)=O>[Cl:1][C:2]1[C:3]([I:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7]
Reactant: Nc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(I)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 5-chloro-2-nitroaniline (25 g, 145 mmol) in AcOH (250 mL) was added N-iodosuccinimide (32.6 g 145 mmol). The mixture was stirred overnight at 50° C., cooled down to rt and filtered. The solid residue was washed with AcOH, water, saturated aqueous NaHCO3 and water, and then dried to afford the desired product 16-1 as a brown solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:18][C:19]3[CH:39]=[CH:38][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([O:35]C)=[O:34])=[C:27]([CH3:37])[CH:26]=4)=[CH:21][C:20]=3[O:40][CH:41]([CH3:43])[CH3:42])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:9]([CH2:18][C:19]3[CH:39]=[CH:38][C:22]([CH2:23][O:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:37])[CH:26]=4)=[CH:21][C:20]=3[O:40][CH:41]([CH3:43])[CH3:42])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(Cn3nc(-c4ccccc4)cc3-c3ccccc3)c(OC(C)C)c2)ccc1CCC(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a mixed solution of methyl 3-[4-({4-[(3,5-diphenyl-1H-pyrazol-1-yl)methyl]-3-isopropoxybenzyl}oxy)-2-methylphenyl]propanoate (0.20 g, 0.35 mmol) in methanol (2 mL) and tetrahydrofuran (4 mL) was added 1 N aqueous sodium hydroxide solution (0.70 mL, 0.70 mmol), and the mixture was stirred at 50° C. for 2 hr. The reaction mixture was neutralized with 1 N hydrochloric acid, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (gradient cycle A). The obtained oil was diluted with ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate, and the mixture washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (0.15 g, yield 77%) as a colorless oil. MS (ESI+): 561 (M+H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([CH:10]([OH:12])[CH3:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC=CC=1>[O-2].[O-2].[Mn+4].O>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:7]([C:10]([CH3:11])=[O:12])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCc1ncc(C(C)=O)n1Cc1ccccc1Cl
Reaction time: 17 h
Yield: 59.2 %

Procedure:
A mixture of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(α-hydroxy)ethyl-1H-imidazole (1.07 g, 3.65 mmol), activated manganese dioxide (6 g). and toluene (75 mL) was heated at 90° to 100° C. under a slight vacuum with a Dean Stark water separator for 17 hours. The inorganics were filtered, the concentrated filtrate was applied to a flash silica gel column and the product was eluted with 3:7 hexane/ethyl acetate to give 0.628 g (59%) of [2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]methyl ketone.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:19][CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CS(C)=O.CO.O>[CH:20]([CH2:19][N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Reactant: ClCC=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: O=c1c2ccccc2n(CC=Cc2ccccc2)c2ccccc12
Temperature: 45 °C
Reaction time: 5 h

Procedure:
15 g of 9(10H)acridone (manufactured by Wako Pure Chemical Industries, Ltd.) and 3.4 g of sodium hydroxide (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved in 84 g of dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.), and the solution was heated to 45° C. 17.6 parts of CMS-P (manufactured by Seimi Chemical Co., Ltd.; chloromethylstyrene) was added dropwise to the solution, and the mixture was subjected to heating and stirring for further 5 hours at 50° C. This reaction liquid was poured under stirring into a mixed solution of 30 g of distilled water and 30 g of methanol (manufactured by Wako Pure Chemical Industries, Ltd.), and the resulting precipitate was separated by filtration and washed with 300 g of a solution prepared by mixing equal amounts by weight of distilled water and methanol. The resulting solids were dried under reduced pressure, and thus 17.5 g of 10-[(styrenyl)methyl]-9-acridanone was obtained as pale yellow solids. 175 g of N-methylpyrrolidone (manufactured by Wako Pure Chemical Industries, Ltd.) was added to 17.5 g of 10-[(styrenyl)methyl]-9-acridanone and 60.9 g of thioglycerol (manufactured by Sigma-Aldrich Co.), and the mixture was heated to 65° C. and stirred for 30 minutes under a nitrogen atmosphere. Subsequently, 0.14 g of V-65 (trade name, manufactured by Wako Pure Chemical Industries, Ltd.; 2,2′-azobis(2,4-dimethylvaleronitrile) was added thereto, and the mixture was stirred for 2 hours. 500 g of a mixed solvent of water/methanol (mixture at a weight ratio of 1:1) was added to the reaction solution, and the crystals crystallized out therefrom were separated by filtration and were washed using 100 g of methanol. The obtained solids were dried under reduced pressure, and 22.0 g of M-1 was obtained as pale yellow solids.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[C:15]1([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].CO>C(OCC)(=O)C>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(C(c2ccccc2)c2ccccc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(diphenylmethyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 81% overall yield. mp 160°-161°. FDMS m/e=441 (M+ of free base). α[D]589 =-8.71 (c=0.89, methanol).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[CH:11]=[CH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:12]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([Cl:8])[C:2]=1[Cl:1])[CH:11]=[CH2:10]
Reactant: Oc1cccc(Cl)c1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc(Cl)c1Cl
Temperature: 0 °C

Procedure:
A mixture of 2,3-dichlorophenol (35.5 g., 0.22 mole), allyl bromide (29.4 g., 0.24 mole) and potassium carbonate (33 g., 0.24 mole) in dimethylformamide (200 ml.) is vigorously stirred and heated at 55°-60° C. for 1 hour, poured into ice water, extracted with ether, washed with water and dried over magnesium sulfate. Evaporation of the ether leaves 2,3-dichlorophenyl allyl ether which is subjected to a Claisen rearrangement by heating at 250° C. for 10 minutes. Distillation gives 36 g. of 2,3-dichloro-6-allylphenol which boils at 132°-134°/13 mm.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]([NH:12][C:13]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([Cl:46])[CH:42]=4)[CH:37]=3)(=[O:35])=[O:34])[CH2:29][C:28]2=[O:47])[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C.C(O)C>[CH2:2]([O:9][C:10]([NH:12][C:13]1([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([S:33]([C:36]3[CH:45]=[CH:44][C:43]4[C:38](=[CH:39][CH:40]=[C:41]([Cl:46])[CH:42]=4)[CH:37]=3)(=[O:34])=[O:35])[CH2:29][C:28]2=[O:47])[CH2:18][CH2:17][N:16]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:15][CH2:14]1)=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)(NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NC1(CN2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2=O)CCN(c2ccncc2)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A 4N hydrochloric acid solution in ethyl acetate (50 ml) and ethanol (10 ml) was added to 1-[4-benzyloxycarbonylamino-1-(tert-butoxycarbonyl)-4-piperidylmethyl]-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (7.42 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 4-chloropyridine hydrochloride (1.80 g), triethylamine(6.97 ml) and ethanol (100 ml) were added to the residue, and the mixture was heated at 150° C. for 5 hours in a sealed tube. After cooling, the reaction mixture was diluted with ethyl acetate, and washed with water. The ethyl acetate layer was dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel chromatography (ethyl acetate-ethyl acetate/methanol=8/1) to obtain the title compound (3.58 g, 55%) as powders.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][C:7]2[CH:8]=[C:9]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:10]=[C:11]3[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]=1[C:12]=23)=O.[CH2:27]([Sn](CCCC)(CCCC)C=C)CCC>CN(C)C=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>[C:23]([O:22][C:20](=[O:21])[NH:19][C:9]1[CH:10]=[C:11]2[C:17](=[O:18])[NH:16][N:15]=[CH:14][C:13]3=[C:5]([CH:3]=[CH2:27])[NH:6][C:7]([CH:8]=1)=[C:12]23)([CH3:25])([CH3:26])[CH3:24]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Yield: 83.5 %

Procedure:
Under an argon atmosphere, Intermediate 147(d) of Example 147 (0.250 g, 0.661 mmol), tributyl-vinyl-tin (0.420 g, 1.32 mmol) and tetrakis(triphenylphosphine)palladium(0) (38 mg, 0.033 mmol) in anhydrous N,N-dimethylformamide (5 mL) were heated at 85° C. for 16 hours. The reaction was filtered through a thin pack of diatomaceous earth, and the filtrate concentrated in vacuo. Silica gel chromatography (eluted with 1:4 ethyl acetate:dichloromethane) afforded the title compound (0.18 g, 0.552 mmol) as a yellow powder in 84% yield.