Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][NH:3]1.[CH:15]1([NH2:18])[CH2:17][CH2:16]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(#N)C.C(OCC)(=O)C>[CH:15]1([NH:18][C:12]([CH:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2](=[O:1])[NH:3][CH2:4]2)=[O:14])[CH2:17][CH2:16]1
Reactant: NC1CC1
Reactant: O=C(O)c1c[nH]c(=O)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1NCC(C(=O)NC2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.50 g (12.30 mmol) of methyl 1-oxo-1,2-dihydroisoquinoline-4-carboxylate and 1.30 g of 10% strength palladium on carbon were suspended in an autoclave, and the mixture was hydrogenated at 70° C. and 20 bar of hydrogen for 4 h. The autoclave was vented, after which the catalyst was filtered off and the solvent was removed under reduced pressure, and the crude product was purified by chromatography (ethyl acetate: n-heptane 2:1). This gave 2.28 g (88%) of the desired methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate. 1H-NMR (400 MHz, CDCl3 δ, ppm) 8.10 (d, 1H), 7.52 (t, 1H), 7.44 (t, 1H), 7.31 (d, 1H), 6.17 (br. s, 1H), 3.98 (dt, 1H), 3.88 (m, 1H), 3.29 (dd, 1H), 3.71 (s, 3H). 2.28 g (11.11 mmol) of methyl 1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxylate were dissolved in 20 ml of tetrahydrofuran, and 20 ml of 1 N aqueous sodium hydroxide solution were added. The solution was stirred at room temperature for 8 h, the solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and 1 N hydrochloric acid. The phases were separated, the organic phase was dried over magnesium sulphate and the solvent was removed under reduced pressure. In this manner, 2.12 g (94% of theory) of the desired 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were obtained. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 12.65 (br. s, 1H), 7.94 (d, 1H), 7.83 (d, 1H), 7.51 (t, 1H), 7.41-7.35 (m, 2H), 3.89 (t, 1H), 3.68-3.54 (m, 2H). 0.200 g (1.046 mmol) of 1-oxo-1,2-dihydroisoquinoline-4-carboxylic acid were dissolved in 10 ml of acetonitrile, and 0.109 ml (1.569 mmol) of cyclopropylamine, 0.170 g (1.255 mmol) of 1-hydroxy-1H-benzotriazole and 0.221 g (1.151 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The solution was stirred at room temperature for 8 h, diluted with ethyl acetate and the organic phase was extracted initially with saturated sodium bicarbonate solution and then with 1 N hydrochloric acid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].[F:15][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CCOC(C)=O>[F:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[NH:4][C:1](=[O:3])[CH3:2]
Reactant: F[B-](F)(F)F
Reactant: CC(=O)Nc1ccc2ccccc2c1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2ccccc2c1F
Temperature: 25 °C

Procedure:
A mixture of 1.95 g (10 mmol) of 2-acetylaminonaphthalene, and 7.1 g (20 mmol) of 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®) in 30 mL of CH2CN is heated to reflux under an atmosphere of nitrogen for 24 hours. After cooling to room temperature, 50 mL of EtOAc is added and the mixture is washed with H2O and dried over MgSO4. Evaporation of the solvents gives a syrup that is purified by flash chromatography on silica gel (25% EtOAc/hexane) to give 1-fluoro-2-acetylaminonaphthalene.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:19](Br)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].O>C1COCC1>[CH2:19]([CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CCCCCCBr
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCC1c2ccccc2-c2ccccc21
Temperature: -50 °C
Reaction time: 0.75 h
Yield: 75.9 %

Procedure:
To a solution of fluorene (33.2 g, 0.20 mol) in 300 mL THF at −78° C., n-butyllithium (2.5 M, 80 mL) was added dropwisely. The mixture was stirred at −50° C. for 45 minutes, and then cooled to −78° C. again and n-hexylbromide (33.0 g, 0.20 mol) in THF (25 mL) was added dropwise to the mixture. The solution was allowed to warm up to room temperature and stirred for 5 h. The mixture was then poured into water and extracted with ether. The organic extracts were washed with brine and dried over magnesium sulfate, and purified by silica gel column with hexane to give pure compound 2 (38 g, yield 76%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C@:11]12[CH2:28][CH2:27][C@H:26]3[C@@H:16]([CH2:17][CH2:18][C@@H:19]4[C@:24]3([CH3:25])[CH2:23][CH2:22][CH2:21][CH2:20]4)[C@@H:15]1[CH2:14][CH2:13][C@@H:12]2[NH2:29].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:29][C@H:12]2[CH2:13][CH2:14][C@H:15]3[C@H:16]4[C@H:26]([CH2:27][CH2:28][C@:11]23[CH3:10])[C@:24]2([CH3:25])[C@H:19]([CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:18][CH2:17]4)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](N)CC[C@@H]12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: C[C@]12CCCC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](NCc3ccc(Cl)cc3)CC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzaldehyde (0.464 g) , 5α-androstan-17β-amine (4.40 g) , glacial acetic acid (0.99 g), sodium cyanoborohydride (0.21 g) and tetrahydrofuran (5 ml) were added to methanol (11 ml). The resulting mixture was warmed to dissolve the solid in solution and allowed to stir overnight at room temperature. Excess solvent was removed under reduced pressure. Water was added and made basic (pH 9) with 50% aqueous NaOH. The mixture was extracted with ether and the organic layer became cloudy. Celite was used to filter the organic layer. The aqueous layer was washed with ether and the combined organic layers were dried (NaSO4), filtered and concentrated. The crude solid was mixed with 10 g of flash silica gel and dissolved in ethyl acetate. The solvent was removed and the silica was poured on top of the chromatographic column. The compound was eluted with 50% ethyl acetate-hexane. The title compound was obtained as a solid which was recrystallized from acetone (0.364 g) mp 101°-102° C. (PLA2, diabetes)
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(OC([NH:26][C@@H:27]([C:31]([C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)([CH3:33])[CH3:32])[C:28](O)=[O:29])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.O1CCOCC1>CN(C=O)C>[ClH:40].[ClH:1].[NH2:26][C@H:27]([C:31]([C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)([CH3:33])[CH3:32])[C:28]([N:6]1[CH2:7][CH2:8][N:3]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH2:4][CH2:5]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)c1ccc(Cl)cc1
Reactant: c1ccc2c(N3CCNCC3)ncnc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(c1ccc(Cl)cc1)[C@@H](N)C(=O)N1CCN(c2ncnc3ccccc23)CC1
Reaction time: 8 h
Yield: 145.6 %

Procedure:
The 4-piperazin-1-yl-quinazoline bis-hydrochloride (220 mg, 0.766 mmol), (S)-2-tert-butoxycarbonylamino-3-(4-chlorophenyl)-3-methyl-butyric acid (251 mg, 0.766 mmol, 1.0 equiv), 1-hydroxybenzotriazole (109 mg, 0.804 mmol, 1.05 equiv), and EDCI (154 mg, 0.804 mmol, 1.05 equiv) were dissolved/suspended in 6.0 mL of DMF. The mixture was treated with triethylamine (427 μL, 3.06 mmol) and allowed to stir overnight to completion. The reaction was partitioned between ethyl acetate and diluted NaHCO3 solution. The aqueous was extracted with ethyl acetate, and the organics were combined. The organic was washed with water, then brine, separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was eluted through a small plug of silica gel with ethyl acetate and concentrated in vacuo. The protected intermediate was immediately dissolved in 1 mL of dioxane and treated with 4M HCl in dioxane (1.92 mL, 7.66 mmol) at room temperature for four hours. The resulting precipitate was triturated with ether, then filtered to afford the (R)-2-amino-3-(4-chlorophenyl)-3-methyl-1-(4-quinazolin-4-yl-piperazin-1-yl)-butan-1-one bis-hydrochloride as a light-yellow solid (277 mg, 73%) upon drying under vacuum. 1H NMR (DMSO-d6, 400 MHz) δ 8.89 (s, 1H), 8.46 (brs, 3H), 8.17 (d, J=8.4 Hz, 1H), 8.06 (t, J=7.6 Hz, 1H), 7.97 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 4.53 (brs, 1H), 4.09 (m, 3H), 3.90 (m, 3H), 3.32 (m, 1H), 3.04 (t, J=9.2 Hz, 1H), 1.51 (s, 3H), 1.43 (s, 3H). LCMS (APCI+) m/z 424 [M+H]+; Rt=1.90 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12]CCO2)[S:5][C:6]=1[CH3:7].C([Li])CCC.[C:18](=[O:20])=[O:19].C(=O)([O-])O.[Na+]>O1CCCC1>[CH:8]([C:4]1[S:5][C:6]([CH3:7])=[C:2]([C:18]([OH:20])=[O:19])[CH:3]=1)=[O:12]
Reactant: O=C=O
Reactant: Cc1sc(C2OCCO2)cc1Br
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1sc(C=O)cc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 2-(4-bromo-5-methyl-2-thienyl)-1,3-dioxolane (5.0 g) in tetrahydrofuran (50 mL) was added dropwise n-butyl lithium (1.6M hexane solution, 12.5 mL) at −78° C. and, after the dropwise addition, the mixture was stirred for 1 hr. Carbon dioxide was blown into the reaction solution for 30 min. The reaction mixture was warmed to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was dissolved in tetrahydrofuran (50 mL), 1N hydrochloric acid (50 mL) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give 5-formyl-2-methylthiophene-3-carboxylic acid (1.2 g, yield 36%) as yellow crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). melting point 173° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]#[C:9][CH2:10][C:11]([CH2:22][CH2:23][CH2:24][CH:25]([O:31]C(=O)C)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])([S:17](OC)(=[O:19])=[O:18])C(OCC)=O)=[O:4].[Cl-].[Na+].[C:37](=O)=O>CCOCC.O.CS(C)=O>[CH3:37][S:17]([CH:11]([CH2:22][CH2:23][CH2:24][CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10][C:9]#[C:8][CH2:7][CH2:6][CH2:5][C:3]([OH:2])=[O:4])(=[O:19])=[O:18]
Reactant: CCCCCC(CCCC(CC#CCCCC(=O)OC)(C(=O)OCC)S(=O)(=O)OC)OC(C)=O
Reactant: O=C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOCC
Product: CCCCCC(O)CCCC(CC#CCCCC(=O)O)S(C)(=O)=O

Procedure:
A solution of ethyl 2-(6-methoxycarbonyl-2-hexyn-1-yl)-2-(4-acetoxynonyl)-2-(methoxysulfonyl)-acetate (48.8 g., 0.1 mole), water (3.6 g., 0.2 mole), and sodium chloride (6.5 g., 0.11 mole) in 120 ml. of dimethyl sulfoxide is heated at 130°-150° C. for 6 hours until evolution of carbon dioxide is completed. The mixture is cooled, treated with 400 ml. of water and the oily product taken up in ether, washed with water and dried over sodium sulfate. Evaporation of the ether in vacuo leaves the title compound as a yellow viscous oil.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17]([C:24]1[CH:32]=[CH:31][C:27](C(Cl)=O)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(OC2C=CC=CC=2)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>S(Cl)(Cl)=O.ClCCl.CCO>[O:17]([C:24]1[CH:25]=[CH:26][C:27]([C:12]([C:11]2[CH:15]=[CH:16][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:13])=[CH:31][CH:32]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1ccc(Oc2ccccc2)cc1
Yield: 64.4 %

Procedure:
DPBO was prepared according to the following protocol: 4-phenoxybenzoic acid (2.5 g, 11.7 mmol) was refluxed in thionyl chloride (50 ml) for 3 hours. The resulting mixture was allowed to cool and the solvent removed in vacuo to recover 4-phenoxybenzoyl chloride as a pale yellow oil (2.72 g, Yield=100%, λ max=1760 cm-1). The 4-phenoxybenzoyl chloride (2.72 g, 11.7 mmol) in dichloromethane (20 ml) was added to diphenylether (1.99 g, 11.7 mmol) in dichloromethane (30 ml) followed by aluminium trichloride (1.56 g, 11.7 mmol) and the resulting mixture refluxed for 3 hours. The refluxed mixture was poured onto ice-water (approximately 100 ml) and the resulting layers separated. The aqueous layer was extracted with ether (2×100 ml extractions) and the combined organics dried, filtered and evaporated to recover the 4,4'-bis(phenoxy)benzophenone (2.76 g, yield=64%) as a colourless solid [melting point=130 to 132° C., λ max (EtOH)=291 nm (ε=2.3×104) and δH 6.9 to 7.9 (18H, M, Ar H)].
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)(C)(C)C.FC1C=CC=C(F)C=1CC(O)=O.[N+](C1C=C([N+]([O-])=O)C=CC=1CC(O)=O)([O-])=O.C(OC1C=CC(CC(O)=O)=CC=1)C1C=CC=CC=1.ClC1C=C(CC(O)=O)C=CC=1OC.BrC1C=C(CC(O)=O)C=CC=1OC.[N+](C1C=C(CC(O)=O)C=CC=1OC)([O-])=O.COC1C=C(CC(O)=O)C=CC=1OC.COC1C(OC)=C(OC)C=CC=1CC(O)=O.C1OC2C=CC(CC(O)=O)=CC=2O1.C(OC1C=C(CC(O)=O)C=CC=1OCC)C.C1(C2C=CC=CC=2)C=CC(CC(O)=O)=CC=1.O(C1C=C(CC(O)=O)C=CC=1)C1C=CC=CC=1.C(NC1C=CC(CC(O)=O)=CC=1)=O.CN(C1C=CC(CC(O)=O)=CC=1)C>>[C:8]1([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Agent: CCOc1ccc(CC(=O)O)cc1OCC
Agent: CN(C)c1ccc(CC(=O)O)cc1
Agent: COc1ccc(CC(=O)O)c(OC)c1OC
Product: O=C(O)Cc1ccccc1

Procedure:
2-methyl- or 3-methyl- or 4-methylphenylacetic acid, 4-tert-butylphenylacetic acid; 2-chloro- or 3-chloro- or 4-chlorophenylacetic acid; 2,6-dichloro- or 3,4-dichlorophenylacetic acid; 2-fluoro- or 3-fluoro- or 4-fluorophenylacetic acid; 2,6-difluorophenylacetic acid; 2-nitro- or 3-nitro- or 4-nitrophenylacetic acid; 2,4-dinitrophenylacetic acid; 2-methoxy- or 3-methoxy- or 4-methoxyphenylacetic acid; 4-benzyloxyphenylacetic acid; 3-chloro-4-methoxyphenylacetic acid; 3-bromo-4-methoxyphenylacetic acid; 3-nitro-4-methoxyphenylacetic acid; 3,4-dimethoxyphenylacetic acid; 2,3,4-trimethoxyphenylacetic acid; 3,4-methylenedioxyphenylacetic acid; 3,4-diethoxyphenylacetic acid; 4-biphenylacetic acid; 3-phenoxyphenylacetic acid; 2-acetamino- or 3-acetamino- or 4-acetaminophenylacetic acid; 3-(N)-BOC-aminophenylacetic acid; 4-formylaminophenylacetic acid; 4-N,N-dimethylaminophenylacetic acid;
Reaction SMILES: [CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][NH:20][CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:17]=[CH:18][C:4]1=2)[CH3:2].Br[C:30]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:31]=1[CH:32]=[CH:33][CH:34]=[N:35]2.C(=O)([O-])[O-].[Cs+].[Cs+].[ClH:46]>C(O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O.C1(C)C=CC=CC=1>[ClH:46].[ClH:46].[ClH:46].[CH2:1]([N:3]1[C:9](=[O:10])[C:8]([CH3:12])([CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5]2[CH:15]=[C:16]([CH2:19][N:20]([CH2:21][CH2:22][C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:30]3[CH:39]=[CH:38][CH:37]=[C:36]4[C:31]=3[CH:32]=[CH:33][CH:34]=[N:35]4)[CH:17]=[CH:18][C:4]1=2)[CH3:2]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Reactant: Brc1cccc2ncccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)c3cccc4ncccc34)ccc21
Temperature: 130 °C
Reaction time: 1 h

Procedure:
1-Ethyl-3,3,5-trimethyl-7-{[N-(2-pyridin-3-ylethyl)amino]methyl}-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.45 g), 5-bromoquinoline(0.25 g), tris(dibenzylideneacetone)dipalladium(5.4 mg), xantphos(10 mg), and cesium carbonate (0.46 g) were added to toluene(9 ml), and the mixture was heated at 130° C. for 3 days. The reaction liquid was cooled to room temperature. Water was added to the reaction mixture, and stirred for 1 hour, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The filtrate was condensed under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: methanol=85:15). The purified product was condensed under reduced pressure. A 1N-hydrogen chloride in ethanol solution(1 ml) was added to a ethanol solution (5 ml) of the residue, and the liquid was stirred at room temperature, and concentrated under reduced pressure. Ethanol and ether were added to the residue. The precipitated insoluble matter was separated, washed with ether, and dried to give the title compound(0.20 g) as a yellow amorphous.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13](C)[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:11]([I:21])[CH:10]=1)(C)(C)C.C(Cl)[Cl:24]>C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]([I:21])[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([Cl:24])[CH:14]=1
Reactant: Cc1cc(CNC(=O)OC(C)(C)C)cc(I)c1NS(C)(=O)=O
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1c(Cl)cc(CN)cc1I
Reaction time: 12 h
Yield: 100 %

Procedure:
(3-Iodo-4-methanesulfonylamino-5-methylbenzyl)carbamic acid t-butyl ester (122.0 mg, 0.27 mmol) and CF3COOH (5˜6 drops) were added into methylene chloride. The mixture was stirred for 12 hrs. The mixture was concentrated in vacuo to yield brownish syrup (142.2 mg, 100%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:38](=[O:39])[C:37]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:36]2[C:35]1=[O:44])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>C(#N)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:34]1[C:35](=[O:44])[C:36]2=[CH:43][CH:42]=[CH:41][CH:40]=[C:37]2[C:38]1=[O:39])=[O:25])[CH3:28]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CSc2ccccc21
Reactant: CCOC(=O)C(Br)CCCCCN1C(=O)c2ccccc2C1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H](CCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Yield: 25.3 %

Procedure:
In 100 ml of acetonitrile are dissolved 2 g of tert-butyl 3(R)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate and 7.4 g of ethyl 2-bromo-7-phthalimidoheptanoate, and 0.85 g of triethylamine is added to the solution. After the mixture is heated at 80°-100° C. for 2 days, the mixture is concentrated under reduced pressure, diluted with 100 ml of water and extracted with 200 ml of ethyl acetate. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting oily substance is separated and purified by silicagel column chromatography (hexane:ethyl acetate=2:1) to give from the first fraction 1.0 g of tert-butyl 3(R)-[1(R)-ethoxycarbonyl-6-phthalimidohexyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]#[N:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C(N(CC)CC)C.[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][N:30]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][C:5]([C:14]#[N:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)[CH2:29]1
Reactant: N#Cc1cc(-c2ccccc2)c(F)cc1[N+](=O)[O-]
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN(C)[C@H]1CCN(c2cc([N+](=O)[O-])c(C#N)cc2-c2ccccc2)C1
Reaction time: 19 h
Yield: 94.8 %

Procedure:
6-Fluoro-4-nitrobiphenyl-3-carbonitrile (I-241) (6.0 g, 24.77 mmol) was dissolved in dimethyl sulfoxide (60 ml), and at room temperature, triethylamine (6.9 ml, 49.54 mmol) and (3S)-3-(dimethylamino)pyrrolidine (3.77 ml, 29.73 mmol) were added. After stirring at the same temperature for 19 hours, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was subjected to column chromatography with silica gel, and the fraction with chloroform:methanol=95:5 gave the entitled compound (7.90 g, 95%) as an orange powder.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.C(Cl)Cl.[C:12](O)(=[O:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CCCCCC.C(OCC)(=O)C.C(Cl)Cl.CC(C)=O>[O:8]=[C:4]1[CH2:5][CH2:6][CH2:7][C:2]([O:1][C:12](=[O:14])[CH3:13])=[CH:3]1
Reactant: CC(=O)O
Reactant: O=C1C=C(O)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(=O)OC1=CC(=O)CCC1

Procedure:
3-Hydroxy-cyclohex-2-enone (1.08 g, 9.64 mmol) was combined with methylene chloride (10 mL) in a 250 mL flask and acetic acid (1.4 eq, 13.75 mmol, 0.78 mL) was added to the mixture. The mixture was cooled in an ice bath and dicyclohexylcarbodiimide (1.3 eq, 12 mmol, 2.5 g) was added portionwise, followed by the addition of 4-(dimethylamino)pyridine (0.05 eq, 0.45 mmol, 50 mg). A sufficient amount of methylene chloride was added to ensure easy stirring and the reaction was monitored by TLC (silica gel, hexane-ethyl acetate-methylene chloride-acetone (3:3:3:1 v/v)), HPLC and LCMS and the intermediate acetic acid 3-oxo-cyclohex-1-enyl ester was formed. The mixture was stirred overnight at room temperature and then toluene (20 mL) was added. The mixture heated to 60° C. and after 72 hours the mixture was filtered, concentrated and purified by flash column chromatography to provide 2-acetyl-3-hydroxy-cyclohex-2-enone (1.19 g, 80%) as a colorless liquid. LCMS: MH+ 154.8.
Reaction SMILES: [CH2:1]([O:3][C@@H:4]1[C@@H:8]([CH2:9]O)[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5]1)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:40]=[N+:41]=[N-:42].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:40]([CH2:9][C@H:8]1[O:7][C@@H:6]([N:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[C:15](=[O:16])[NH:14][C:12]2=[O:13])[CH2:5][C@@H:4]1[O:3][CH2:1][CH3:2])=[N+:41]=[N-:42]
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CO
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.7 %

Procedure:
A mixture of 1.40 g of 2'-deoxy-3'-O-ethyl-5-ethyluridine, 1.3 g of triphenylphosphine, 1.59 g of sodium azide and 1.66 g of carbon tetrabromide in 19 ml of dimethylformamide was stirred at room temperature for 20 hours. 11 ml of methanol were added, the mixture was stirred for 30 minutes and then evaporated. The residue was suspended in 110 ml of water and extracted three times with 70 ml of ethyl acetate each time. The combined ethyl acetate extracts were evaporated and the residue was subject to flash chromatography on a column of silica gel using ethyl acetate/hexane (2:1) for the elution, there being obtained 1.26 g of 5'-azido-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine in the form of a colorless oil.