Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)N[CH2:11][CH:12]1[CH2:17][CH:16]2[CH2:18][CH:14]([C:15]2([CH3:20])[CH3:19])[C:13]1=[CH2:21])C1C=CC=CC=1.[CH2:23]([SiH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24].[CH2:30]([N:32](CC)CC)C>C(Cl)Cl.[Pd](Cl)Cl>[CH3:20][C:15]1([CH3:19])[CH:14]2[CH2:18][CH:16]1[CH2:17][CH:12]([CH2:11][CH2:30][NH2:32])[C:13]2=[CH2:21].[CH2:23]([SiH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH3:24]
Reactant: CCN(CC)CC
Reactant: C=C1C(CNC(=O)OCc2ccccc2)CC2CC1C2(C)C
Agent: Cl[Pd]Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: C=C1C(CCN)CC2CC1C2(C)C
Reaction time: 1 h

Procedure:
(6,6-Dimethyl-2-methylene-bicyclo[3.1.1]hept-3-ylmethyl)-carbamic acid benzyl ester (988 mg, 3.30 mmol) was dissolved in CH2Cl2 (20 ml) under an atmosphere of dry N2. To this solution was added triethylsilane (2.10 ml, 13.2 mmol), triethylamine (330 μl, 2.37 mmol) and palladium(II) chloride (165 mg). The reaction was then heated to reflux and stirred at this temperature for one hour. The reaction was then quenched with the addition of saturated ammonium chloride solution (3.0 ml). The reaction is then partitioned between CH2Cl2 and 0.1 N NaOH. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated under vacuum to give the titled compound along with unreacted triethylsilane: C.I. m/z 166 [M+1].
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:30][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[CH:8][CH:9]=1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(Cc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Cc2ccc(Cl)cc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 78.6 %

Procedure:
To a solution of 4-(4-chloro-benzyl)-phenol (1.1 g, 5 mmol) in DMF (15 mL) at 0-5° C. was added 60% NaH (0.4 g, 10 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (2.14 g, 6 mmol) in DMF (5 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to it and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (1.58 g, 78%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].[N:35]1([CH2:40][CH2:41]O)[CH:39]=[CH:38][N:37]=[CH:36]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:35]1([CH2:40][CH2:41][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[CH:20]=[N:21]3)=[CH:16][C:15]=2[O:33][CH3:34])[CH:39]=[CH:38][N:37]=[CH:36]1
Reactant: OCCn1ccnc1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCn1ccnc1
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 79.9 %

Procedure:
Diethyl azodicarboxylate (435 mg, 2.5 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (612 mg, 2 mmol), (prepared as described for the starting material in Example 85), 2-(imidazol-1-yl)ethanol (280 mg, 2.5 mmol), (J. Med. Chem. 1993, 25 4052-4060), and triphenylphosphine (655 mg, 2.5 mmol) in methylene chloride (10 ml) at 5° C. The mixture was stirred for 10 minutes at 5° C. and then 1 hour at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/methanol (95/5) to give 7-(2-(imidazol-1-yl)ethoxy)-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (640 mg, 80%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH:21]=[CH2:22]>>[CH2:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:25][CH2:24]1)[CH:21]=[CH2:22]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: C=CCN1CCNCC1
Product: C=CCN1CCN(c2ncc3c(=O)c(C(=O)OCC)cn(CC)c3n2)CC1
Yield: 79 %

Procedure:
2-(4'-Allyl-piperazino)-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine is prepared, in a yield of 79%, by condensing 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine with 1-allyl-piperazine, as indicated in the preceding Examples. It is a solid which melts in two stages; melting point 131°C, solidification, followed by melting point 143°C [after recrystallization from a mixture of benzene (1 volume) and isopropyl ether (1 volume)].
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:19][C:20](=[O:30])[NH:21][C:22]2[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([Cl:29])[CH:23]=2)[C:9]1=[O:31])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:28][C:26]1[CH:27]=[C:22]([NH:21][C:20]([CH2:19][N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17](=[O:18])[N:8]([CH2:7][C:6]([OH:32])=[O:5])[C:9]2=[O:31])=[O:30])[CH:23]=[C:24]([Cl:29])[N:25]=1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottomed flask is charged with {1-[(2,6-Dichloro-pyridin-4-ylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-acetic acid tert-butyl ester (50.9 mg, 0.106 mmol) is treated with DCM (1.5 ml) and TFA (1.5 ml). The reaction mixture is stirred at RT for 2 hours and then concentrated in vacuo. The residue is taken up in a minimal amount of DCM and concentrated in vacuo. This process is repeated twice with EtOAc, and twice with MeOH to give the title compound, [M+H]+ 422
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:19]=2)[CH:10]([CH3:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2C)cc1
Temperature: 100 °C

Procedure:
A suspension of 6 g (0.0205 mol) of 4-tert-butyloxycarbonyl-1-(4-hydroxyphenyl)-2-methylpiperazine, 2.4 ml (0.0246 mol) of methyl bromoacetate and 3.4 g (0.0246 mol) of potassium carbonate in 50 ml of dimethylformamide is heated at 100° C. for 6 hours and, after cooling, concentrated to dryness in vacuo. The residue is partitioned between ethyl acetate and water and the aqueous phase is extracted once more with ethyl acetate. The combined ethyl acetate extracts are concentrated to dryness in vacuo. The residue is purified by means of chromatography on a silica gel column, ethyl acetate/cyclohexane being used as eluent. After evaporation, the residue is crystallized from ether/petroleum ether.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][CH2:15][CH2:16][OH:17])=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1>C(O)(=O)C>[Br:1][C:9]1[CH:10]=[N:11][C:12]2[C:7]([C:8]=1[NH:14][CH2:15][CH2:16][OH:17])=[CH:6][CH:5]=[C:4]([Cl:3])[CH:13]=2
Reactant: BrBr
Reactant: OCCNc1ccnc2cc(Cl)ccc12
Solvent: CC(=O)O
Product: OCCNc1c(Br)cnc2cc(Cl)ccc12
Reaction time: 8 h

Procedure:
Bromine (4.3 g) was added dropwise to a solution of 7-chloro-N-(2-hydroxyethyl)-4-quinolinamine (6 g) in 60 ml of acetic acid. The mixture was stirred overnight and the solid separated by filtration. This solid was dispensed in 100 ml of water and the mixture made alkaline (pH=8) with a sodium bicarbonate solution. After two hours of stirring, the product was filtered and recrystallized twice from isopropanol and from ethanol. The yield was 3.5 g, mp 169°-170° C.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([CH:14]=O)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[N+](=[C:20](P(OC)(OC)=O)C(OC)=O)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[Br:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6]3[N:7]=[C:8]([C:14]#[CH:20])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: COC(=O)C(=[N+]=[N-])P(=O)(OC)OC
Reactant: O=Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1nc2c(s1)CCOc1cc(Br)ccc1-2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carbaldehyde (0.688 g, 2.2 mmol) was dissolved in methanol (8 mL) and methyl 2-diazo-2-(dimethoxyphosphoryl)acetate (0.923 g, 4.44 mmol) was added followed by potassium carbonate (0.613 g, 4.44 mmol). The resulting mixture was stirred 12 h at ambient temperature and quenched by the addition of sat. NH4Cl aqueous solution and stirred 5 min. Diluted with H2O and EtOAc, extracted the aqueous layer with EtOAc (2×) and the combined organic portions were washed with brine. Dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by ISCO chromatography (24 g column, 0-25% EtOAc/heptane) to provide 8-Bromo-2-ethynyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene as an oil (0.26 g, 38% yield). 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J=8.5, 1H), 7.31-7.18 (m, 2H), 4.37 (t, J=5.1, 2H), 3.49 (s, 1H), 3.33 (t, J=5.1, 2H)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[C:33]([Br:34])=[CH:32][C:31]([C:35](=[O:37])[CH3:36])=[CH:30][C:29]=1[Br:38]>C(#N)C>[Br:34][C:33]1[CH:32]=[C:31]([C:35](=[O:37])[CH3:36])[CH:30]=[C:29]([Br:38])[C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N:12]1[CH2:11][CH2:10][CH:9]([C:6]2[C:5]3[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:14][CH2:13]1
Reactant: CC(=O)c1cc(Br)c(OCCCBr)c(Br)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(Br)c(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c(Br)c1
Yield: 58.7 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (2.0 g, 9.0 mmoles), K2CO3 (1.3 g), and 1-[4-(3-bromopropoxy)-3,5-dibromophenyl]ethanone (2.65 g, 9.0 mmoles) and acetonitrile (50 ml) was heated at reflux for 3 hr. At the end of the reaction, the solvent was evaporated and the residue was extracted into dichloromethane (150 ml). The insolubles were filtered off. The dichloromethane solution was concentrated down to an oil. The purification was done by flash chromatography on a silica gel column (SiO2, 47 g; eluted with dichloromethane, 300 ml; 1% methanol in dichloromethane, 600 ml). The material thus purified as a colorless oil, solidified on standing. Recrystallization from ethanol gave 1-[3,5-dibromo-4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]propoxy]phenyl]ethanone as white crystals (2.93 g, 57%), m.p.=102°-103° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:25](O)[CH2:26][CH2:27][OH:28]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:28][CH2:27][CH2:26][CH2:25][O:12]1
Reactant: OCCCO
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1Nc2ccc(Cl)cc2C12OCCCO2
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of 5-chloroisatin (5.00 g, 27.5 mmol), p-toluenesulfonic acid monohydrate (1.05 g, 5.5 mmol, 0.2 mole %) and 1,3 propanediol (6.04 mL, 83 mmol, 3 eq) in benzene (535 mL) was refluxed with a Dean Stark Trap for 7.5 hr. After cooling to room temperature the solution was decanted from the reaction mixture and concentrated The residue was washed with sat. aq. NaHCO3 (2×), brine (1×), dried over Na2SO4, filtered and concentrated. The crude product was purified on Biotage KP silica gel eluting with 70/30 Petroleum ether/EtOAc to give the title compound as a pale yellow solid (4.77 g, 72.5% ). A portion was dried at 42° C. in vacuo to give the analytically pure sample. Anal: Calc'd for C11H10ClNO3: C, 55.13; H, 4.21; N, 5.84. Found: C, 55.31; H, 4.34; N, 5.78. NMR (300 Mz, DMSO-d6): consistent. IR: consistent. MS: (ES−) m/z 238 [M−H]; one Cl pattern observed, consistent. m.p.: 184-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH2:15][S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1)[C:7]([C:23]([O:25]CC)=[O:24])=[C:6]2[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([CH2:15][S:16][C:17]1[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=1)[C:7]([C:23]([OH:25])=[O:24])=[C:6]2[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1
Reactant: CCOC(=O)c1c(CSc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2c(C(=O)O)c(CSc3nccn3C)nc3cc(OC)c(OC)cc23)cc1OC
Yield: 52.8 %

Procedure:
A mixture of ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol-2-yl)thiomethyl]-quinoline-3-carboxylate (0.6 g), 2N sodium hydroxide (1.7 ml) and ethanol (12 ml) was refluxed for 6 hours. The reaction mixture was concentrated in vacuo. The residue was diluted with water, washed with ethyl acetate, made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated in vacua to give crystals. The crystals were recrystallized from ethanol-ethyl ether to give 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methylimidazol-2-yl)thiomethyl]-quinoline-3-carboxylic acid (0.3 g, 53%) as colorless prisms. mp. 213°-214° C.
Reaction SMILES: [C:1]1([C:7](=[O:11])[CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OC(C)C)(C)C>CO>[C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCC(=O)c1ccccc1
Solvent: CO
Solvent: CC(C)OC(C)C
Product: OCC[C@H](O)c1ccccc1
Temperature: 50 °C
Reaction time: 22 h
Yield: 2396.7 %

Procedure:
In a 200 ml stainless steel-made autoclave were charged 426.5 mg of [RuI(p-cymene)(R)-Tol-BINAP]I3 prepared in Example 2, the diisopropyl ether solution of 3-phenyl-3-oxopropanal prepared in Reference Example 2, 100 ml of methanol, and 2.0 ml of degassed purified water in a nitrogen atmosphere, followed by stirring the mixture at 50° C. for 22 hours under a hydrogen pressure of 50 atm. The reaction mixture was concentrated and subjected to silica gel column chromatography (eluent: hexane/isopropanol=9/l by volume) to eliminate the complex. The obtained hydrogenation product was dissolved in a 6-fold amount of diisopropyl ether by heating and allowed to stand at 0° C. for 24 hours. The resulting precipitate was collected by filtration and dried (room temperature, 1 mmHg), and 10.5 g of (1S)-phenyl-1,3-propanediol was obtained as a colorless crystal (percent yield: 45%).
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)[CH2:3][C:4](=[O:6])[CH3:5]>C1(C)C=CC=CC=1>[F:18][C:16]([F:17])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5])=[CH:11][CH:12]=1
Reactant: CC(=O)CC(O)CCSc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccc(C(F)(F)F)cc1

Procedure:
0.5 Gram of 4-hydroxy-6-(4-trifluoromethylphenylthio)-2-hexanone was dissolved in 10 ml of toluene, and 0.26 g of Nafion® was added thereto. The resulting mixture was refluxed for 6 hours with stirring, allowed to cool and then treated in the same manner as in Production example 34. Thus, 6-(4-trifluoromethylphenylthio)-3-hexen-2-one was obtained (purity: 78.0%).
Reaction SMILES: [OH2:1].NN.[C:4]1(=O)[N:8]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:7](=O)[C:6]2=CC=CC=[C:5]12>C(O)C>[NH2:8][CH2:7][CH2:6][CH2:5][O:1][C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][CH:10]=[C:9]2[N:8]2[CH2:4][CH2:5][CH2:6][CH2:7]2)=[CH:14][CH:15]=1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1c1cccc2ccccc12
Agent: NN
Solvent: CCO
Product: NCCCOc1ccc2cccc(N3CCCC3)c2c1

Procedure:
85% hydrazine hydrate (9.6 ml) is added to a stirred solution of the phthalimido naphthalene prepared as described in the previous step (about 50 g) in absolute ethanol (about 500 ml). The reaction mixture is heated at reflux for about 3 hours and allowed to cool. The resulting precipitate is removed by filtration and washed with absolute ethanol. The filtrate is evaporated in vacuo and the residue triturated with 5% aqueous hydrochloric acid. The aqueous suspension is filtered and the solid washed with 5% hydrochloric acid. The filtrate is made strongly alkaline with 50% sodium hydroxide solution, resulting in an oily precipitate which is extracted into diethyl ether. The ether extract is washed with saturated sodium chloride solution, dried, filtered and the filtrate evaporated in vacuo, yielding the desired amine as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](O)=O)=O)(C)(C)C.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[NH2:26]>>[F:25][C:21]1[C:20]2[N:26]=[C:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[NH:18][C:19]=2[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(F)c1N
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Product: Fc1cccc2[nH]c(CC3CCCCN3)nc12
Yield: 61.6 %

Procedure:
(RS)-2-Carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (1.93 g) was heated with 1,2-diamino-3-fluorobenzene (1.00 g) (Kirk, K. L, J. Org. Chem., 1969, 34, 384) as described in Description 18 to afford the title compound (1.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13]Cl)[C:6]=2[CH:15]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:27]3[CH2:26][CH2:25][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=4)[CH2:29][CH2:28]3)[C:6]=2[CH:15]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: ClCCCCn1nnc2ccc(Cl)cc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CCCCn3nnc4ccc(Cl)cc43)CC2)c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-chloro-1-(4-chlorobutyl)-1H-benzotriazole (8.75 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.5 g compound (I-54) with a yield of 64.7%. ESI-MS [M+H]+: m/z 437.2.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].C(O[CH:32]1[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1)C>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][CH:32]3[CH2:33][CH2:34][C:35](=[O:37])[NH:36]3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC1CCC(=O)N1
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCC(=O)N4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 90.8 %

Procedure:
Adenosine 2',3',5'-triacetate (2.0 g) and 5-ethoxy-2-pyrrolidinone (1.2 g) were stirred in N,N-dimethylformamide (10 ml) at 130° C. overnight. The reaction mixture was distilled to remove the N,N-dimethylformamide and the residue was subjected to silica gel column chromatography using chloroformacetone (5:3) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give N6 -(5-oxo-2-pyrrolidinyl)adenosine 2',3',5'-triacetate as an oil (2.2 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[CH:9]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[F:18])=[CH2:10].C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][CH2:2][C:3]([C:4]1[CH2:10][CH:9]([C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[O:6][N:5]=1)=[O:8]
Reactant: C=Cc1c(F)cccc1F
Reactant: O=C(CCl)C(Cl)=NO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O=C(CCl)C1=NOC(c2c(F)cccc2F)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.2 %

Procedure:
To a stirred solution of 3-chloro-N-hydroxy-2-oxopropanimidoyl chloride (0.89 g, 5.71 mmol) in acetonitrile (20 mL) was added 2-ethenyl-1,3-difluorobenzene (1.0 g, 7.14 mmol) and sodium bicarbonate (1.8 g, 2.14 mmol) at room temperature. The reaction mixture was stirred at room temperature for 12 h, concentrated in under reduced pressure and the resulting material was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was separated, washed with saturated aqueous sodium chloride solution and concentrated in under reduced pressure. The resulting material was triturated with petroleum ether and filtered to provide the title product as white solid (1.1 g) melting at 82.1-83.4° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)([Cl:14])=O>CN(C)C=O.C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: O=S(Cl)Cl
Reactant: C=Cc1ccc(C(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
While 16.6 g of p-vinylbenzoic acid (manufactured by Wako Pure Chemical Industries, Ltd.), 80 ml of toluene, two drops of N,N-dimethylformamide were stirred at room temperature, 9.7 ml of thionyl chloride (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto, which was heated and stirred at 60° C. for 2 hours. The inside of the reaction system was cooled to 40° C., toluene and an excessive amount of thionyl chloride were removed under reduced pressure, and p-vinyl benzoic acid chloride was obtained. While 22.5 g of 2-aminoanthraquinone (manufactured by Tokyo Chemical Industry Co., Ltd.) and 110 ml of pyridine were stirred on ice, p-vinyl benzoic acid chloride was slowly added dropwise thereto. After stirring the mixture on ice for 30 minutes, the temperature was increased to 60° C. and the mixture was heat while stirring for 3 hours. Thereafter, the mixture was cooled to room temperature and water was added thereto. The resulting coarse crystals were filtrated and washed with water and methanol, and then 500 ml of methanol was added to the collected coarse crystals, and then heated while stirring at 60° C. Thereafter, the resultant crystals were separated by filtration, washed with methanol and dried. Thus, 20.1 g of M-19 was obtained (yield: 70%).