Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]([C@H:12]2[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]2[O:18][CH3:19])[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH2:26][CH2:27]Br)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([N:7]([C@H:12]2[CH2:17][CH2:16][N:15]([CH:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:27])[CH2:14][C@H:13]2[O:18][CH3:19])[C:8](=[O:11])[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)[C@H]1CCNC[C@H]1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(=O)N(c1ccccc1)[C@H]1CCN(C(C)c2ccccc2)C[C@H]1OC
Yield: 61.8 %

Procedure:
cis-N-Phenyl-N-(3-methoxy-4-piperidinyl)propanamide (8, 0.5 g, 1.9 mmol) from Example 6, phenylethyl bromide (0.40 g, 2.2 mmol) and 2.76 g (19 mmol) of potassium carbonate in 100 ml of acetonitrile were heated to reflux overnight. The reaction solution was concentrated under vacuum and the crude residue was purified by chromatography (silica gel; ethyl acetate) to yield 0.43 g (62%, Rf 0.326) of pure cis-N-phenyl-N-(1-phenylethyl-3-methoxy-4-piperidinyl)propanamide (I).
Reaction SMILES: [C:1]1([CH:11]([CH2:16][C:17]([OH:19])=[O:18])[CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:20](O)CC(C)C.CC(C)=O.O>>[CH3:20][O:14][C:13](=[O:15])[CH2:12][C@H:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CC(CC(=O)O)c1cccc2ccccc12
Reactant: CC(C)CCO
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@@H](CC(=O)O)c1cccc2ccccc12

Procedure:
Formula C16H16O4. Yield 62%; TLC (isoamyl alcohol-acetone-H2O 5:2:2) Rf. 0.65 (N.B.: 3-(1-naphthyl) glutaric acid has Rf. 0.52 in the same eluent).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][C@H:14]2[C@H:18]([CH3:19])[CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[NH:27]([C:29]([O:31]CC)=O)N.C1CCN2C(=[N:38]CCC2)CC1>CN1CCCC1=O>[CH3:19][C@H:18]1[C@H:14]([O:13][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]3[NH:27][C:29](=[O:31])[NH:38][N:2]=3)[N:4]=2)[CH2:15][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:17]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: CCOC(=O)NN
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(C#N)cc2ccccc12
Solvent: CN1CCCC1=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Oc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 170 °C
Yield: 140.7 %

Procedure:
A mixture of tert-butyl trans-3-((3-cyanoisoquinolin-1-yl)oxy)-4-methylpyrrolidine-1-carboxylate (790 mg, 2.235 mmol), ethyl hydrazinecarboxylate (1164 mg, 11.18 mmol) and DBU (168 μL, 1.118 mmol) in N-methyl-2-pyrrolidinone (5.6 mL) and under a nitrogen atmosphere was heated at 170° C. in a sealed vial for 16 hours. The reaction mixture was allowed to cool to RT and was poured onto ice water, forming a pale yellow precipitate. After the ice melted (total volume was 100 mL) the solid was filtered and dried to give the title compound as a pale yellow solid (647 mg, 70.3%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.12 (d, 3H), 1.40 (d, 9H), 3.11 (d, 1H), 3.70 (dd, 2H), 3.86-4.04 (m, 2H), 5.70-5.80 (1H, m), 7.68 (t, 1H), 7.81 (t, 1H), 7.98 (s, 1H), 8.02 (d, 1H), 8.18 (d, 1H), 11.79 (s, 1H), 12.03 (d, 1H); ESI-MS m/z [M+H-Boc]+ 312.7.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:21][CH2:22][Br:23])=[CH:15][CH:14]=1>>[Br-:23].[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:20][CH2:21][CH2:22][N+:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[OH:1])[CH:7]=2)=[CH:17][CH:18]=1
Reactant: Fc1ccc(C(CCCBr)c2ccc(F)cc2)cc1
Reactant: Oc1cccc2cnccc12
Product: Oc1cccc2c[n+](CCCC(c3ccc(F)cc3)c3ccc(F)cc3)ccc12
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-hydroxyisoquinoline (4.56 g, 31.41 mmol) and 4,4-bis(4-fluorophenyl)butyl bromide (11.40 g, 35.06 mmol. Prepared according to the procedure of Miroslav Rajsner, et al., Czech. Collect. Czech. Chem. Commun., 1978;43:1760) in 100 mL of anhydrous DMF was stirred at 80° C. overnight. The reaction mixture was cooled to 0° C. Ethyl acetate (400 mL) was added to precipitate product. The solid was collected by filtration and washed with ethyl acetate (2×100 mL). The solid was air-dried to give 10.74 g of product as an off-white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:21]=[C:9]2[NH:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][C:13](=[O:14])[N:8]2[N:7]=1)=[O:5])C.[OH-].[K+].Cl>C(O)C.O1CCOCC1.C(OCC)(=O)C>[O:14]=[C:13]1[N:8]2[N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:21]=[C:9]2[NH:10][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:12]1
Reactant: CCOC(=O)c1cc2[nH]c(-c3ccccc3)cc(=O)n2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1cc2[nH]c(-c3ccccc3)cc(=O)n2n1

Procedure:
To a solution of 50 mg (0.18 mmol) of 7-oxo-5-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid ethyl ester in 4 mL of ethanol (EtOH) was added 26 mg (0.40 mmol) of potassium hydroxide (KOH) and the resulting mixture was heated at reflux for 60 h. The reaction mixture was then acidified with 4 M HCl in dioxane solution, and diluted with ethyl acetate. The organic extract was washed with water and brine, dried over sodium sulfate, and concentrated to give desired 7-oxo-5-phenyl-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid as indicated by 1H NMR; LC-MS—calcd for C13H9N3O3 [M++H]+: 256.06, found: 256.1. This corresponds to entry 619.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[N:14][CH:13]=[CH:12][N:11]3[C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23](S(C)(=O)=O)[N:22]=2)=[CH:4][CH:3]=1.[NH2:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:15]([O:16][CH:17]([CH3:19])[CH3:18])=[N:14][CH:13]=[CH:12][N:11]3[C:20]=2[C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])[N:22]=2)=[CH:4][CH:3]=1
Reactant: CC(C)Oc1nccn2c(-c3ccnc(S(C)(=O)=O)n3)c(-c3ccc(F)cc3)nc12
Reactant: CC(C)(CN)CO
Solvent: CC#N
Product: CC(C)Oc1nccn2c(-c3ccnc(NCC(C)(C)CO)n3)c(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 65.4 %

Procedure:
A suspension of 2-(4-fluorophenyl)-8-isopropoxy-3-(2-methanesulfonylpyrimidin-4-yl)-imidazo[1,2-a]pyrazine (0.16 g, 0.37 mmol) and 3-amino-2,2-dimethylpropan-1-ol (TCI-US, 0.208 g, 0.74 mmol) in ACN (5 mL) was heated at about 80° C. overnight to give a clear solution. The reaction mixture was cooled to ambient temperature, the volatiles were evaporated, and the resulting residue was dissolved in DCM and washed with water. The organic phase was dried over MgSO4, filtered, and evaporated to give a white solid that was triturated with heptane to afford 0.109 g (64.7%) the title compound as a white solid: LC/MS (Table 1, Method g) Rt=3.01 min; MS m/z: 494.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][N:6]=1.[C:10]1([S-:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na+].CC(C)=O.[OH-].[Na+]>O>[C:10]1([S:16][C:2]2[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][N:6]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)c1cnc(Cl)s1
Reactant: [S-]c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1cnc(Sc2ccccc2)s1
Reaction time: 3 h

Procedure:
1-(2-Chloro-thiazol-5-yl)-ethanone (221 mg, 1.37 mmol) and sodium benzenethiolate (226 mg, 1.71 mmol) were added to acetone (20 mL) and stirred for 3 h. The suspension was poured into water (100 mL) containing 2 M aqueous NaOH (10 mL) and extracted with DCM (3×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated to give the product. Yield=314 mg, 97%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24]([NH2:26])=[O:25])=[N:4][C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].N[C:28]1C(C(OCC)=O)=NC(C2C=CC=C(O)C=2)=NC=1NC1C=CC=CC=1OC.N>CO>[OH:23][C:19]1[CH:18]=[C:17]([C:5]2[N:6]=[C:7]3[C:2]([N:1]=[CH:28][N:8]3[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:3]([C:24]([NH2:26])=[O:25])[N:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)nc(C(N)=O)c1N
Reactant: CCOC(=O)c1nc(-c2cccc(O)c2)nc(Nc2ccccc2OC)c1N
Agent: N
Solvent: CO
Product: COc1ccccc1-n1cnc2c(C(N)=O)nc(-c3cccc(O)c3)nc21
Temperature: 25 °C
Yield: 99 %

Procedure:
5-Amino-2-(3-hydroxyphenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxamide. A solution of ethyl 5-amino-2-(3-hydroxyphenyl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate. (57.8 mg, 0.152 mmol) in anhydrous methanol (5 mL) was chilled to −78° C. The solution was then saturated with ammonia gas. The reaction vessel was sealed at −78° C. and allowed to warm to room temperature. After 18 h the reaction was chilled to −78° C. and opened to atmosphere. The volatiles were evaporated and the resulting material was purified by column chromatography (SiO2, 2% to 5% methanol in methylene chloride) to provide the title compound in 98.3% purity (53 mg, 0.151 mmol, 99% yield). 1H NMR (400 MHz, CD3OD) δ 8.41 (m, 1H), 7.79 (dt, J=8.00, 1.20, 1H), 7.73 (m, 1H), 7.21 (t, J=8.00, 1H), 7.06 (m, 3H), 6.79 (ddd, J=8.00, 2.54, 0.98, 1H), 3.94 (s, 3H); MS (ESI) m/z 352.2 [M+1]+; mp: 230-231° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=4)=[O:19])=[CH:13][C:12]=3[CH:29]=2)=[CH:4][CH:3]=1.CN([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1)C.CS(Cl)(=O)=O.N1CCCCC1>O1CCCC1.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[S:17][CH2:16][CH2:15][C:14]([C:18]([NH:20][C:21]4[CH:22]=[CH:23][C:24]([CH2:27][N:34]5[CH2:35][CH2:36][CH2:37][CH2:38][CH2:33]5)=[CH:25][CH:26]=4)=[O:19])=[CH:13][C:12]=3[CH:29]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCS3)cc1
Reactant: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1CCNCC1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCCCC4)cc2)CCS3)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 7-(4-methylphenyl)-N-(4-hydroxymethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (0.2 g), triethylamine (0.21 ml) and dimethylaminopyridine (catalytic amount) in tetrahydrofuran (10 ml) was dropwise added methane-sulfonylchloride (0.06 ml) under ice-cooling, and the mixture was stirred for 10 minutes. To the mixture was added piperidine (0.15 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 7-(4-methylphenyl)-N-(4-piperidinomethylphenyl)-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 93) (0.19 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])[N:12]([C:14](OC(C)(C)C)=O)[CH:13]=2)[O:3]1.Cl.[H-].[Na+].CI>C(Cl)Cl.O1CCOCC1>[CH3:14][N:12]1[CH:13]=[C:9]([B:4]2[O:3][C:2]([CH3:1])([CH3:31])[C:6]([CH3:8])([CH3:7])[O:5]2)[CH:10]=[C:11]1[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CI
Product: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Benzyl 1-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1,2-dicarboxylate (0.5 g) was dissolved in CH2Cl2 (1 mL) and then 4 N HCl in dioxane (1 mL) was added. The reaction was stirred at room temperature for 1 hour. The solvent was removed under vacuum. The residue was redissolved in DMF (4 mL). To the resulting solution was added NaH (60% dispersion in mineral oil, 0.08 g, 2.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. Methyl iodide (0.11 mL, 2.0 mmol) was added and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with sat. NH4Cl solution and then diluted with EtOAc. After separation of layers, the organic phase was washed with water (twice) and brine; dried over Na2SO4. The solvent was removed to provide the desired crude product which was used in the next step without further purification. LCMS calculated for C19H25BNO4 (M+H)+: m/z=342.2. found: 342.2.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[S:12]([N:15]([C:19]1[CH:23]=[CH:22][S:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25])[CH2:16][O:17][CH3:18])(=[O:14])=[O:13].[C:28]1(/[CH:34]=[CH:35]/B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>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.O.C(O)C>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([S:12]([N:15]([C:19]2[CH:23]=[CH:22][S:21][C:20]=2[C:24]([O:26][CH3:27])=[O:25])[CH2:16][O:17][CH3:18])(=[O:14])=[O:13])=[C:2]([CH:35]=[CH:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1Br
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COCN(c1ccsc1C(=O)OC)S(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A 2.5-5.0 mL microwave reaction tube was successively charged with 6 (200.0 mg, 0.43 mmol), trans-2-phenylvinylboronic acid (96.0 mg; 0.65 mmol), cesium carbonate (420.0 mg; 1.30 mmol), tetrakis(triphenylphosphine)palladium(0) (25.0 mg; 0.022 mmol), toluene (1.3 mL), ethanol (1.3 mL) and water (1.3 mL). The reaction tube was purged with nitrogen and subjected to the following microwave conditions: Temperature=140° C.; Power=250 W; Time=15 minutes; Cooling On; Absorption Very High. The reaction mixture was allowed to cool to room temperature and then was diluted with ethyl acetate (15 mL) and washed with aqueous hydrochloric acid (3×10 mL; 2N). The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude dark oil residue was purified by automated silica gel column chromatography (Biotage®) eluting with ethyl acetate/hexanes (0 to 30% v/v over 400 mL gradient elution) to give the title product as a white solid (134 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[OH:14])[N:10]=[C:9]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:8]=[C:7]2[N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[C:36](=[O:37])[C:35]3[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=3)[N:29]([CH3:39])[C:28]2=[O:40])[CH2:23][CH2:22]1)[CH3:2].[CH2:41](I)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([O:14][C:13]1[CH:12]=[C:11]2[C:6]([C:7]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:36](=[O:37])[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([CH3:38])[CH:34]=5)[N:29]([CH3:39])[C:28]4=[O:40])[CH2:23][CH2:22]3)=[N:8][C:9]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:10]2)=[CH:5][C:4]=1[O:3][CH2:1][CH3:2])[CH2:42][CH2:43][CH3:44]
Reactant: CCOc1cc2c(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)nc(N3CCOCC3)nc2cc1O
Reactant: CCCCI
Product: CCCCOc1cc2nc(N3CCOCC3)nc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OCC
Yield: 39 %

Procedure:
The same procedure as in Example 48 was repeated, using 335 mg (0.61 mmol) of Compound 47 obtained in Example 47, except that butyl iodide was used in place of methyl iodide, to give 144 mg (yield: 39%) of Compound 51 as white crystals.
Reaction SMILES: [H][H].[C@@H:3]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH2:5][CH2:4]1.C[OH:21]>C(N(CC)CC)C.[C].[Pd]>[C@@H:3]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH2:5][C@H:4]1[OH:21]
Reactant: CO
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Product: OC[C@@H]1C[C@@H](O)[C@H](n2cnc3c(O)ncnc32)O1
Temperature: 25 °C

Procedure:
Br--AcO--HxR, 415 mg (1.0 mmol), was dissolved in 30 ml of methanol containing 0.24 ml of triethylamine and 170 mg of 10% palladium carbon was added to the solution. While stirring the mixture at room temperature, hydrogen gas was passed in a flow rate of 40 ml/min. After the palladium carbon was filtered off, the filtrate was washed with ethanol and the solvent was distilled off under reduced pressure. The residue was dissolved in 8 ml of methanol and 0.54 ml of 28% sodium methoxide (methanolic solution) was added to the solution. The mixture was stirred at room temperature for 30 minutes. The reaction solution was quantitatively determined by HPLC, where 63.7 mg (0.27 mmoles) of 2',3'-dideoxyinosine and 93.2 mg (0.37 mmoles) of 3'-deoxyinosine were produced in yields of 7% and 37%, respectively. 300 MHz nuclear magnetic resonance spectra of the purified and isolated 2',3'-dideoxyinosine and 3'-deoxyinosine supported the structures of the products.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH2:12])[CH2:6]1)=[O:4].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:49][C:50]1[S:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:55]([C:53]2[S:54][C:50]([Cl:49])=[CH:51][CH:52]=2)=[O:56])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CC(O)C(CN)C1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Yield: 32 %

Procedure:
To a stirred suspension of the crude (1SR,3SR,4RS)-3-aminomethyl-4-hydroxy-cyclopentanecarboxylic acid methyl ester (189 mg) at r.t. in DMF (5 ml) under an argon atmosphere were added N-ethyldiisopropylamine (0.74 ml), BOP (531 mg) and 5-chloro-2-thiophenecarboxylic acid (195 mg). The reaction mixture was stirred over night, then diluted with EtOAc and washed with H2O. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried (MgSO4), filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 93:7) to give (1SR,3SR,4RS)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester (111 mg) as light brown gum. MS: 318.0 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][OH:13])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:13][CH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([CH3:1])=[O:3])=[CH:6][CH:7]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Oc1ccc(CCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(CCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
55 g (0.305 mole) 2-(4-methylcarbonyloxyphenyl)-1-ethanol and 34.4 g (0.341 mole) triethylamine in 300 ml dichloromethane were cooled on an ice bath. 38.5 g (0.336 mole) methanesulfonyl chloride was slowly added. The ice bath was removed and the mixture was stirred for 3 hours at room temperature. Water was added and the phases were separated. The organic phase was washed with saturated sodium hydrogen bicarbonate and brine, dried (magnesium sulfate), filtered and evaporated in vacuo to give 76.6 g (yield 97%) of 4-(methylcarbonyloxy)phenethyl methanesulfonate.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.C([O-])([O-])=O.[K+].[K+].[OH:24][CH2:25][CH2:26][N:27]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:28](=[O:33])[CH2:29][CH2:30][CH2:31]Cl>C(Cl)(Cl)Cl>[OH:24][CH2:25][CH2:26][N:27]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C:28]([CH2:29][CH2:30][CH2:31][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2)=[O:33]
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Reactant: O=C(CCCCl)N(CCO)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=C(CCCOc1ccc2[nH]c(=O)ccc2c1)N(CCO)C1CCCCC1
Yield: 12.5 %

Procedure:
Into 50 ml of dimethylformamide were added 1.73 g of 6-hydroxycarbostyril, 1.8 g of K2CO3 and 0.5 g of KI. The mixture was heating at 60°-70° C. under stirring, then 3.2 g of N-(2-hydroxyethyl)-N-(4-chlorobutyryl)cyclohexylamine was added dropwise gradually thereto. After the addition operation, the reaction mixture was further stirred at the same temperature for 4 hours. Then the solvent was removed by distillation and the residue thus obtained was dissolved in 200 ml of chloroform and the chloroform layer was washed with a diluted hydrochloric acid, 1% Na OH aqueous solution and water in this order, then dried with anhydrous sodium sulfate. The drying agent was removed by filtration, and the mother liquid was concentrated, then the residue thus obtained was crystallized with petroleum ether. The crystals thus obtained was recrystallized from chloroform-petroleum ether to obtain 0.5 g of 6-{3-[N-(2-hydroxyethyl)-N-cyclohexylaminocarbonyl]propoxy}carbostyril. Melting point: 165°-166° C.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1>>[OH:47][C:44]1[CH:45]=[CH:46][C:41]([CH2:40][CH2:39][NH:38][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:42][CH:43]=1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: NCCc1ccc(O)cc1
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NCCc4ccc(O)cc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and 4-(2-aminoethyl)-phenol. Purification was performed using HPLC with a normal phase column. Elution with a mixture of etoxynonafluorobutane and methanol gave the title compound in 90% yield, m.p. 190-194° C. MS [(+)ESI, m/z]: 572 [M+H]+