Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][C:2]1[C:3]2[C:8]([C:9]([Li])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.Cl[Si:18]([Cl:21])([CH3:20])[CH3:19]>C(OCC)C>[Cl:21][Si:18]([CH3:20])([CH3:19])[C:2]1[C:3]2[C:8]([C:9]([Si:18]([Cl:21])([CH3:20])[CH3:19])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: [Li]c1c2ccccc2c([Li])c2ccccc12
Reactant: C[Si](C)(Cl)Cl
Solvent: CCOCC
Product: C[Si](C)(Cl)c1c2ccccc2c([Si](C)(C)Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 44 h
Yield: 13 %

Procedure:
The obtained solution of 9,10-dilithioanthracene was dropped into a solution prepared from 61.4 g (0.476 mol) of dichlorodimethylsilane and 40 ml of dried diethyl ether as a solvent, in a 1L-volume flask for 2 hours using a separating funnel. After the solution was stirred for 44 hours at room temperature and salt yielded by reaction was removed by means of filtration, the remaining filtrate was concentrated to remove the solvent of the filtrate using an evaporator. The residue was recrystallized in n-pentane to obtain 5.6 g (yield: 13%) of yellow 9,10-bis(chlorodimethylsilyl)anthracene.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[C:28](#[N:31])[CH:29]=[CH2:30]>>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([CH2:30][CH2:29][C:28]#[N:31])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: C=CC#N
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(CCC#N)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
A mixture of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (75 mg, 0.207 mmol) and acrylonitrile (75 μL, 1.14 mmol) in IMS (3 mL) was stirred in a sealed tube at 70° C. for 3 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined, concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM), followed by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-60% 0.1% NH4OH in acetonitrile/water) and finally loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The ammonia fractions were combined and concentrated in vacuo affording 126 as a white solid (28 mg, 33%). LCMS: RT 1.67 min [M+H]+ 416.1. 1H NMR (CDCl3, 400 MHz): δ 8.52 (1H, s), 7.96 (1H, s), 7.80-7.73 (1H, m), 7.65-7.59 (1H, m), 7.26-7.08 (3H, m), 5.29 (1H, bs), 4.69-4.57 (1H, m), 3.09 (1H, bd, J=11.28 Hz), 2.90 (1H, d, J=11.11 Hz), 2.76-2.60 (3H, m), 2.37-2.25 (3H, m), 2.30-2.30 (1H, m), 1.98-1.66 (7H, m)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1.C(=O)(O)[O-].[Na+].ClCCl.[C:44](OC(=O)C)(=[O:46])[CH3:45]>O>[C:44]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:26])[Cl:27])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 83.7 %

Procedure:
3-(4-(3(S)-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyl-oxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) was dissolved in water (5 ml) and treated with aqueous sodium bicarbonate solution (5 ml) and dichloromethane (10 ml) in an ice-bath. Acetic anhydride (216 mg, 2 mM) was added, the mixture stirred 18 hours, allowing the temperature to rise to ambient, followed by addition of a further portion of acetic anhydride (216 mg), and a further period of 10 hours stirring. The organic phase was separated, washed with aqueous sodium dihydrogen phosphate (2%, 2×15 ml), brine (10 ml), and dried (magnesium sulfate). Evaporation gave the desired product (338 mg).
Reaction SMILES: N[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2NC)=[C:4](CC)[N:3]=1.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].CO>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18]([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:17]1
Reactant: CCc1nc(N)nc2c1ncn2NC
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [N-]=[N+]=[N-]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3cncnc32)C[C@@H]1F
Temperature: 45 °C
Reaction time: 168 h
Yield: 42 %

Procedure:
2-Amino-6-ethylmethylamino-9H-purine (0.5 g, 2.6 mmoles) and 2',3'-dide-oxy-3'-fluorouridine (0.5 g, 2.2 mmoles) were suspended in potassium phosphate buffer (50 ml, 10 mM), pH 7.0, containing potassium azide 0.04%. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphory-lase (10,000 I.U.) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added to the reaction and the suspension was stirred at 45° C. After 7 days, MeOH (170 ml) was added to the reaction. The reaction was applied to a column containing AG1-X2 (OH- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:acetone (92:8). Product containing fractions were again pooled, concentrated, and flash chromatographed on silica gel (2.5×20 cm) with dichloromethane:meth-anol (95:5). Solvent was removed and lyophilization yielded 9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofura-nosyl)-9H-purine (0.22 g, 32%): mp 89°-9° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28](=[O:39])OC2C=CC([N+]([O-])=O)=CC=2)([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.Cl.[F:41][C:42]1([F:48])[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:27][C:28]([NH:47][CH:44]2[CH2:45][CH2:46][C:42]([F:48])([F:41])[CH2:43]2)=[O:39])([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:19]=[C:18]([F:26])[CH:17]=2)[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:6][CH:7]=1
Reactant: NC1CCC(F)(F)C1
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NC1CCC(F)(F)C1)N[C@@](Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45 %

Procedure:
To a crude solution of (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethylcarbamate in DCM (1 mL) (29 mg, 0.053 mmol) was added 3,3-difluorocyclopentanamine hydrochloride (17 mg, 0.106 mmol). The reaction mixture was stirred at room temperature for 2 h and the solution turned yellow. The solution was diluted with CH2Cl2 (1 mL) and washed with 1N NaOH (3×1 mL), dried over Na2SO4, and concentrated. The yellow residue was purified by flash chromatography (4 g SiO2, 0-40% EtOAc/hexane) to furnish 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethyl)-3-(3,3-difluorocyclopentyl)urea as a white solid (13 mg, 45%). LCMS: 4.06 min [M+1] 542.2 (4 min gradient, MeOH/H2O 0.1% NH4OAc) LC/MS: [M+H]=542.2 1H NMR (CDCl3, 400 MHz): 8.26 (m, 1H), 7.67 (dd, J=2 Hz, J=4 Hz, 1H), 7.52 (br, 1H), 7.38 (m, 1H), 7.22 (m, 1H), 7.18-7.08 (m, 5H), 6.57 (m, 2H), 4.50 (d, J=8 Hz, 1H), 4.46 (dd, J=4 Hz, J=8 Hz, 1H), 4.25 (m, 1H), 3.55 (d, J=12 Hz, 1H), 2.65-1.54 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[C:29]([C:34]5[NH:35][C:36]([CH:39]6[CH2:43][CH2:42][CH2:41][N:40]6[C:44](=[O:54])[CH:45]([NH:49][C:50]([O:52][CH3:53])=[O:51])[CH:46]([CH3:48])[CH3:47])=[N:37][CH:38]=5)[CH:30]=4)[CH:25]=3)=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.[ClH:55]>CO.CCOCC>[ClH:55].[ClH:55].[ClH:55].[CH3:53][O:52][C:50](=[O:51])[NH:49][CH:45]([C:44]([N:40]1[CH2:41][CH2:42][CH2:43][CH:39]1[C:36]1[NH:35][C:34]([C:29]2[CH:28]=[CH:27][C:26]3[C:31](=[CH:32][CH:33]=[C:24]([C:21]4[CH:22]=[CH:23][C:18]([C:15]5[NH:14][C:13]([CH:9]6[CH2:10][CH2:11][CH2:12][NH:8]6)=[N:17][CH:16]=5)=[CH:19][CH:20]=4)[CH:25]=3)[CH:30]=2)=[CH:38][N:37]=1)=[O:54])[CH:46]([CH3:48])[CH3:47]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CCCN6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a slurry of 2-{5-[4-(6-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.14 mmol) in MeOH (0.15 mL) was added HCl in dioxanes (4 M, 0.7 mL). The resulting solution was stirred at room temperature for 1 hour and diluted with Et2O. The resulting precipitate was filtered and dried to provide {2-Methyl-1-[2-(5-{6-[4-(2-pyrrolidin-2-yl-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-propyl}-carbamic acid methyl ester trihydrochloric acid salt (0.09 g, 87%) as a white powder. LCMS-ESI+: calc'd for C37H41N7O3: 631.3 (M+). Found: 632.7 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CO>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:24](=[O:25])[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[F:21])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccccc1F
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4ccccc4F)c3C2=O)C(=O)N1
Yield: 94.9 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and 2-fluorobenzoyl chloride (1.0 mL, 8.4 mmol) in THF (40 mL) was heated to reflux for 15 h. To the mixture was added methanol, (10 mL) to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-fluoro-benzamide as a white solid (1.5 g, 93% yield): mp, 300-302° C.; 1H NMR (DMSO-d6) δ 2.05-2.12 (m, 1H, CHH), 2.45-2.65 (m, 2H, CH2), 2.83-2.97 (m, 1H, CHH), 5.18 (dd, J=5.5, 12.9 Hz, 1H, NCH), 7.40-7.49 (m, 2H, Ar), 7.67-7.76 (m, 2H, Ar), 7.88-7.98 (m, 1H, Ar), 8.01-8.05 (m, 1H, Ar), 8.76 (d, J=8.4 Hz, 1H Ar), 10.56 (d, JN-F=10 Hz, 1H, NH), 11.17 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.92, 48.97, 116.48, 116.97 (d, JC-F=14 Hz), 118.82, 120.87 (d, JC-F=12 Hz), 125.32 (d, JC-F=1.5 Hz), 125.74, 131.32, 131.39, 134.88 (d, JC-F=9 Hz), 136.22, 136.48, 159.75 (d, JC-F=252 Hz), 161.76 (d, JC-F=7 Hz), 166.58, 168.04, 169.70, 172.71; Anal. Calcd for C20H14N3O5F: C, 60.76; H, 3.57; N, 10.63; F, 4.81. Found: C, 60.70; H, 3.64; N, 10.64; F. 4.91.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.Cl[CH2:11][C:12]1[C:13]([O:18][CH3:19])=[N:14][CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:19][O:18][C:13]1[C:12]([CH2:11][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COc1ncccc1CCl
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
8.2 g of 4-piperidineethanol, 10.0 g of 3-(chloromethyl)-2-methoxypyridine and 17.5 g of potassium carbonate were suspended in 65 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound as a yellow oil (quantitatively).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[Cu].C1(C)C=CC=CC=1>[C:8]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Ic1ccccc1
Reactant: Nc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 129.3 %

Procedure:
That is, in a two-neck flask of 500 ml in volume, 152.0 g anhydrous sodium carbonate (1.10 mol) and 9.5 g powdery copper (0.15 mol) were added and then heated for 2 hours while stirring to uniform. Subsequently, after cooling to room temperature, the solution was added with 67.6 g of an aniline compound (0.5 mol) represented by the formula (49) described below and 305.9 g of iodobenzene (1.5 mol) and then heated again to 220° C. to allow the reaction for 2.5 hours. After that, the solution was cooled to room temperature and then added with 100 ml toluene, followed by filtration. The resulting residue was dissolved in toluene and dried over activated clay. After that, the residue was dissolved in toluene and then added with methanol to crystallization. Then, the residue was dissolved in toluene again and added with methanol to crystalline and the resulting residue was followed by filtration and dried to form crystal. Subsequently, the resulting crystal was purified through silica gel column chromatography (developing solvent: chloroform/hexane solvent), thereby obtaining 79.3 g of a triphenylamine derivative compound represented by the general formula (50) (yields: 55.2%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:33]1[CH2:32][CH2:31][N:30]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=3)[CH2:35][CH2:34]1)=[O:19])=[N:5]2
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3nc4cc(F)ccc4nc3OC)CC2)c1
Yield: 72 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 72%). MS(ESI) m/z 442 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])[CH:10]=[CH:11][CH:12]=1>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([CH2:6][C:5]([OH:44])=[O:4])[CH:8]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:33])([F:32])[F:34])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cccc(CC(=O)OC)c2)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2cccc(CC(=O)O)c2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.065 mL, 0.065 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-((E)-4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butenyl)-phenyl]-propyl}-2′-methyl-biphenyl-3-yl)acetic acid methyl ester (Example 71-(1); 12.8 mg, 0.022 mmol) in methanol-tetrahydrofuran (1:1, 1 mL), and the mixture was stirred at 60° C. for one hour. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=8:3, saturated with water) to give the target compound as a colorless oil (12.1 mg, 97%).
Reaction SMILES: [NH2:1][C@H:2]([CH3:21])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[N:5]1.[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27]1[CH:31]=[C:30]([C:32](O)=[O:33])[NH:29][N:28]=1>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@H:2]([NH:1][C:32]([C:30]3[NH:29][N:28]=[C:27]([C:23]4[O:22][CH:26]=[CH:25][CH:24]=4)[CH:31]=3)=[O:33])[CH3:21])[N:5]=2)=[CH:10][C:11]=1[C:17]([F:20])([F:19])[F:18])#[N:14]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)NC(=O)c1cc(-c2ccco2)n[nH]1
Yield: 74.5 %

Procedure:
(The title compound was prepared from (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)benzonitrile (0.080 g, 0.272 mg) and 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.053 g, 0.299 mmol) using the method of Example 34(d) affording 0.092 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 4.30-4.39 (m, 2H), 4.42-4.51 (m, 1H), 6.61 (m, 1H), 7.03 (d, 1H), 7.76 (m, 1H), 7.86 (d, 1H), 8.17 (d, 1H), 8.27 (m, 2H), 8.34-8.36 (m, 1H), 13.69 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][OH:24])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[OH:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C@@H:9]1[C@@:13]([CH2:23][O:24][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=2)(=[O:42])=[O:41])([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:12][C@@H:11]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@@H:10]1[O:33][S:40]([C:37]1[CH:38]=[CH:39][C:34]([CH3:44])=[CH:35][CH:36]=1)(=[O:42])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccn([C@@H]2O[C@](CO)(COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@]2(COCc3ccccc3)O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OS(=O)(=O)c3ccc(C)cc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 2 h
Yield: 78 %

Procedure:
To a stirred solution of 1-(3,5-di-O-benzyl-4-C-hydroxymethyl-β-D-ribofuranosyl)uracil 41 (3.55 g, 7.81 mmol) in dichloromethane (50 cm3) were added DMAP (3.82 g) and p-toluenesulphonyl chloride (4.47 g, 23.5 mmol) at room temperature. Stirring was continued for 2 h, and dichloromethane (100 cm3) was added. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate (2×75 cm3) and dried (Na2SO4). The organic phase was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (99.5:0.5, v/v) as eluent to give nucleoside 75 (4.65g, 78%) as a white solid material. δH (CDCl3) 8.49 (1H, br s, NH), 7.67 (1H, d, J 8.3, 6-H), 7.51-7.03 (18H, m, Bn, Ts), 6.0 (1H, d, J 7.6, 1′-H), 5.05 (1H, m, 2′-H), 4.91 (2H, m, 5-H, Bn), 4.56 (2H, m, Bn), 4.42 (1H, d, J 10.4, Bn), 4.31 (1H, d, J 4.9, 3′-H), 4.05 (2H, m, 1″-H), 3.75-3.64 (2H, m, 5′-H), 2.41 (3H, s, CH3), 2.34 (3H, s, CH3). δC (CDCl3) 162.2 (C-4), 149.5 (C-2), 146.0, 145.3 (Ts), 139.0 (C-6), 136.7, 131.9, 130.0, 129.9, 128.9, 128.7, 128.5, 128.4, 128.3, 128.2, 128.0, 127.6 (Bn, Ts) 102.7 (C-5), 85.5 (1′-C), 84.4 (4′-C), 79.2, 78.3, 75.1, 74.3, 72.4, 69.1 (Bn, 3′-C, 2′-C, 5′-C, 1″-C ), 21.7, 21.6 (Ts). FAB-MS m/z 763. Found: C, 61.2; H, 4.4; N, 3.3; C38H38N2O11S2 requires C, 59.8; H,5.0; N,3.6.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:7]1=[O:23])[NH2:5].[CH2:25]([O:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:24])[CH:4]([CH:6]1[CH2:10][C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[O:21][CH3:22])[C:7]1=[O:23])[NH:5][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33]([O:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:34]
Reactant: COC(=O)C(N)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 50 h

Procedure:
In 20 ml of dimethylformamide were dissolved 1 g of 2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl] glycine methyl ester and 1.5 g of N-hydroxysuccinimide ester of benzyloxycarbonyl-L-alanine, and the solution was stirred at room temperature for 50 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate, washed with 2 N hydrochloric acid and saturated sodium hydrogen carbonate, and dried over sodium sulfate and concentrated under reduced pressure. To the residue was added petroleum ether to give benzyloxycarbonyl-L-alanyl-2-[1-(2,4-dimethoxybenzyl)-2,5-dioxopyrrolidin-3-yl] glycine methyl ester as a white powder. This powder was dissolved in a mixture of 50 ml of methanol and 10 ml of acetic acid and stirred with 500 ml of palladium black in a stream of hydrogen at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dried in a desiccator overnight and dissolved in 50 ml of methanol. With adjusting pH to 9-10 with 1 N sodium hydroxide, the solution was stirred at room temperature for 3 hours. This reaction mixture was adjusted to pH 5 and concentrated under reduced pressure. The residue was dried in a desiccator overnight, dissolved in 10 ml of a 30% solution of hydrogen bromide in acetic acid, and stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and adjusted to pH 4 with saturated sodium hydrogen carbonate. It was chromatographed on a column (200 ml) of MCI gel CHP-20P, and water to 50% aqueous methanol-water gradient elution was carried out. The eluate was concentrated under reduced pressure and lyophilized to give L-alanyl-2-(2,5-dioxopyrrolidin-3-yl)glycine as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:37]5[CH:38]=[CH:39][CH:40]=[C:41]([F:42])[C:36]=5[Cl:35])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5Cl)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 2-chloro-3-fluoro-phenylboronic acid.