Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH3:6][O:7][C:8]([NH:10][CH:11]([CH:75]([CH3:77])[CH3:76])[C:12]([N:14]1[CH:18]([C:19]2[N:20](COCC[Si](C)(C)C)[CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]#[C:31][C:32]4[CH:37]=[CH:36][C:35]([C:38]5[N:39]=[C:40]([CH:51]6[CH2:55][CH2:54][CH2:53][N:52]6[C:56](=[O:66])[CH:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[CH:58]([CH3:60])[CH3:59])[N:41](COCC[Si](C)(C)C)[CH:42]=5)=[CH:34][CH:33]=4)=[CH:26][CH:25]=3)[N:23]=2)[CH2:17][NH:16][CH2:15]1)=[O:13])=[O:9].CN1CCOCC1>ClCCl.CN(C)C=O.O.C(O)(C(F)(F)F)=O.C(#N)C>[CH3:5][O:4][C:2]([N:16]1[CH2:17][CH:18]([C:19]2[NH:20][CH:21]=[C:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]#[C:31][C:32]4[CH:33]=[CH:34][C:35]([C:38]5[N:39]=[C:40]([CH:51]6[CH2:55][CH2:54][CH2:53][N:52]6[C:56](=[O:66])[CH:57]([NH:61][C:62]([O:64][CH3:65])=[O:63])[CH:58]([CH3:60])[CH3:59])[NH:41][CH:42]=5)=[CH:36][CH:37]=4)=[CH:28][CH:29]=3)[N:23]=2)[N:14]([C:12](=[O:13])[CH:11]([NH:10][C:8]([O:7][CH3:6])=[O:9])[CH:75]([CH3:76])[CH3:77])[CH2:15]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4cn(COCC[Si](C)(C)C)c(C5CNCN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)cn1COCC[Si](C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(C#Cc3ccc(-c4c[nH]c(C5CN(C(=O)OC)CN5C(=O)C(NC(=O)OC)C(C)C)n4)cc3)cc2)c[nH]1)C(C)C
Yield: 18.9 %

Procedure:
Methyl chloroformate (15 μL, 0.19 mmol) was added to a solution of 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1-(2-trimethylsilanyl-ethoxymethyl)-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazole (97 mg, 0.09 mmol), and 4-methylmorpholine (40 μL, 0.36 mmol) in dichloromethane (3 mL). After 30 minutes the solvent was removed under reduced pressure and azeotroped with toluene. The residue was taken up in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. After 16 hours the volatiles were removed under reduced pressure and the residue was taken up in tetrahydrofuran (4 mL) and methanol (2 mL). An aqueous solution of sodium hydroxide (2 N, 1 mL) was added. After 30 min the organic solvents were removed under reduced pressure and the resulting precipitate was isolated by filtration. The solid was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 3′-(2-methoxycarbonylamino-3-methyl-butyryl)-4-[4-(4-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-2′,3′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-1′-carboxylic acid methyl ester (14.1 mg, 0.017 mmol, 10%).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[OH:27][C@@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cccnc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(-c2cccnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 36 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and pyridin-3-ylboronic acid to afford a yellow solid. UPLC-MS (condition 1) tR=1.82 min, m/z=445.1 [M+H]+, m/z=443.2 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.67-1.77 (m, 1H) 1.83 (dd, J=8.80, 4.40 Hz, 1H) 2.87 (d, J=11.49 Hz, 1H) 3.14-3.26 (m, 2H) 3.39-3.45 (m, 1H) 4.18 (d, J=2.45 Hz, 1H) 4.83 (br. s, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.50 (dd, J=7.70, 4.77 Hz, 1H) 7.78-7.90 (m, 3H) 8.03 (d, J=2.20 Hz, 1H) 8.55-8.61 (m, 1H) 8.65 (d, J=1.71 Hz, 1H) 8.77 (d, J=2.45 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:13]([OH:20])[CH2:14][NH:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][C:31]=1[C:40]#[N:41].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[O:1]1[CH:5]2[O:6][CH2:7][CH2:8][CH:4]2[CH:3]([O:9][C:10](=[O:28])[NH:11][CH:12]([CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]([OH:20])[CH2:14][N:15]([S:36]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[C:31]([C:40]#[N:41])[CH:32]=2)(=[O:37])=[O:38])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:2]1
Reactant: CC(C)CNCC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CN(CC(O)C(Cc1ccccc1)NC(=O)OC1COC2OCCC12)S(=O)(=O)c1ccc(F)c(C#N)c1
Yield: 92 %

Procedure:
To a solution of (1-benzyl-2-hydroxy-3-isobutylamino-propyl)-carbamic acid hexahydro-furo[2,3-b]furan-3-yl ester 19 in CH2C12 (4 mL) was added 4-fluoro-3-cyanobenzenesulfonyl chloride (92 mg, 0.42 mmol) followed by NaHCO3 (40 mg) and satd. NaHCO3 (0.4 mL) and stirred at RT for 1 h. The reaction mixture was diluted with ethyl acetate (25 mL) and washed with water, brine and dried with Na2SO4 and concentrated to furnish crude product (240 mg). The crude product was purified by column chromatography using 1/1 ethyl acetate/hexane to provide 200 mg product (92% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][O:25]C3CCCCO3)=[O:23])=[CH:16][C:15]=2[CH3:32])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[ClH:35]>CO>[ClH:35].[ClH:35].[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:24][OH:25])=[O:23])=[CH:16][C:15]=2[CH3:32])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(/C=C/C(=O)NOC2CCCCO2)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Agent: Cl
Solvent: CO
Product: Cc1cc(/C=C/C(=O)NO)cnc1N[C@@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (306 mg) in MeOH (5.6 mL) was added hydrogen chloride methanol reagent 10 (1.4 mL, Tokyo Kasei), and the mixture was stirred at ambient temperature for 2 hours. To the reaction mixture was added Men and the solvent was removed in vacuo. Obtained colorless solid was triturated with Men to give (2E)-3-(6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-methyl-3-pyridyl)-N-hydroxyacrylamide dihydrochloride (202.1 mg) as colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29]#[N:30])[C:16]([CH2:31][CH3:32])=[C:15]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[O-].[K+]>C1COCC1>[CH2:1]([O:8][C:9]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[C:22]3[C:29]#[N:30])[C:16]([CH2:31][CH3:32])=[C:15]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1c(-c2ccc3c(c2)c(C#N)cn3C)nc(OCc2ccccc2)c(C(=O)O)c1OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of methyl 2,4-bis(benzyloxy)-6-(3-cyano-1-methyl-1H-indol-5-yl)-5-ethylnicotinate (130 mg, 0.24 mmol) in THF (2.5 mL) was added potassium trimethylsilanolate (80 mg, 0.62 mmol, 2.6 eq) at room temperature. Then the reaction mixture was heated to 60° C. and stirred for 8 h. Upon completion of the reaction, the solvents were removed under reduced pressure. The reaction was acidified with 1N HCl (1 mL) and then the reaction mixture was extracted with CH2Cl2 (3×20 mL). The solvent was removed to give a crude product which was purified by flash column chromatography (0-15% EtOAc in CH2Cl2) to afford the title compound (99 mg, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17](F)=[CH:18][N:19]=1)[C:5]([C:7](=[CH:13][N:14]([CH3:16])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].Cl.[CH3:22][N:23]1[CH2:26]C(N)[CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][N:19]=1)[N:14]([CH:16]1[CH2:24][N:23]([CH3:26])[CH2:22]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)ncc1F
Reactant: CN1CC(N)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CN(C)C2)c2cnc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 163.8 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 66, 0.690 g, 2 mmol, 1 equiv.) in THF (7 mL) was added 1-methylazetidin-3-amine HCl (245 mg, 2 mmol, 1 equiv.) and potassium carbonate (276 mg, 2 mmol, 1 equiv.). This reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and re-suspended in DMF (7 mL). Potassium carbonate (553 mg, 4 mmol, 2 equiv.) was added, and the reaction mixture was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and quenched with water. 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-(1-methylazetidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (1.2 g, ≧99%). Calcd for C15H16BrN3O3 [M+H]+: 367.91.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][CH3:27])=[CH:4][CH2:3]1.C[C:30]1(C)[C:39]2C=CC(C#CC3C=CC(C(OCC)=O)=CC=3)=C[C:34]=2C(=O)[CH2:32][CH2:31]1>>[CH3:28][C:2]1([CH3:1])[C:11]2[CH:10]=[CH:9][C:8]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)=[CH:7][C:6]=2[C:5]([S:25][CH2:26][C:27]2[CH:34]=[CH:39][CH:30]=[CH:31][CH:32]=2)=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCC)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCc2ccccc2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoate (Compound 151), 500 mg (1.44 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]benzoate (Compound 2) was converted into the title compound (colorless crystals, recrystallized from methyl alcohol) using 268 mg (1.42 mmol) of titanium tetrachloride, 184 mg (1.49 mmol) of benzyl mercaptan and 271 mg (2.82 mmol) of triethylamine.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][CH3:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.CS[C:21]1[NH:22][CH:23]=[C:24]([CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)[C:25](=[O:27])[N:26]=1>C(O)C>[F:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([CH3:16])[C:21]3[NH:22][CH:23]=[C:24]([CH2:28][C:29]4[CH:30]=[N:31][CH:32]=[N:33][CH:34]=4)[C:25](=[O:27])[N:26]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CNCCc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CSc1nc(=O)c(Cc2cncnc2)c[nH]1
Solvent: CCO
Product: CN(CCc1ccc(Oc2ccc(F)cc2)cc1)c1nc(=O)c(Cc2cncnc2)c[nH]1
Temperature: 125 °C
Reaction time: 16 h
Yield: 51.2 %

Procedure:
2-[4-(4-fluoro-phenoxy)-phenyl]-ethyl-methyl amine (0.204 mmol, 1 eq) and 2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.082 mmol, 0.4 eq) were dissolved in dry ethanol (200 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-10% in 30CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(4-fluoro-phenoxy)phenyl]-ethyl-methyl-amino}-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.042 mmol, yield: 20%, HPLC-MS/UV: [M+H]=432.14; rt: 10.14 mins; purity: 97%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.89 (t, J=7.17, 2H), 3.59 (s, 2H), 3.69-3.77 (m, 2H), 6.86-7.05 (m, 5H), 7.10-7.18 (m, 2H), 7.23-7.30 (m, 2H), 7.69 (s, 1H), 8.61 (s, 1H), 9.02-9.05 (m, 1H), 9.95 (br.s., 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[N:16]1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:12])([F:13])[F:14])=[O:38])=[CH:4][C:3]=1[N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])=[N:16]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C)cc1SCC(F)(F)F
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2C)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
0.3 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-5-methyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of chloroform, and 0.16g of m-chloroperbenzoic acid (purity: 75%) was slowly added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (ethyl acetate:hexane=1:2) to obtain 0.30 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-5-methyl-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]1[CH2:8][NH:7][C:6](=[O:9])[NH:5][C:4]1=[O:10].II.S(=O)(=O)(O)O.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.CS(C)=O>[F:11][C:2]([F:1])([F:12])[C:3]1[C:4](=[O:10])[NH:5][C:6](=[O:9])[NH:7][CH:8]=1
Reactant: O=C1NCC(C(F)(F)F)C(=O)N1
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=c1[nH]cc(C(F)(F)F)c(=O)[nH]1
Temperature: 117 °C
Reaction time: 9 h
Yield: 72.8 %

Procedure:
In 24.7 ml of dimethylformamide, 10 g of 5-trifluoromethyl-5,6-dihydrouracil is dissolved, and 12.8 g of dimethylsulfoxide, 1.4 g of iodine and 0.54 g of concentrated sulfuric acid were added to obtain a uniform solution. The obtained solution was stirred at 117° C. for 9 hours. The resultant was cooled to room temperature and 70 g of 3% aqueous sodium sulfite was added to reduce iodine. The resulting mixture was concentrated under reduced pressure. Water was added to the residue and the residue was extracted three times with ethyl acetate. The ethyl acetate layer was concentrated and the residue was recrystallized from 40 ml of water to obtain 7.2 g (73%) of 5-trifluoromethyluracil in the form of white needle-shaped crystals.
Reaction SMILES: C(P(CCCC)CCCC)CCC.[C:14]([O:17][C@H:18]1[C@@H:44]2[O:45][C@@H:43]2[C@@:42]2([CH3:46])[C:20](=[CH:21][C@@H:22](OC(OC)=O)[C@@H:23]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:47])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[CH:28]([CH:30]2[O:35][CH2:34][C:33]([CH3:37])([CH3:36])[CH2:32][O:31]2)[CH3:29])[CH2:19]1)(=[O:16])[CH3:15]>O1CCOCC1>[C:14]([O:17][C@H:18]1[C@@H:44]2[O:45][C@@H:43]2[C@@:42]2([CH3:46])[C:20](=[CH:21][CH:22]=[C:23]3[C@@H:41]2[CH2:40][CH2:39][C@@:38]2([CH3:47])[C@H:24]3[CH2:25][CH2:26][C@@H:27]2[CH:28]([CH:30]2[O:31][CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][O:35]2)[CH3:29])[CH2:19]1)(=[O:16])[CH3:15]
Reactant: COC(=O)O[C@@H]1C=C2C[C@@H](OC(C)=O)[C@@H]3O[C@@H]3[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(C)C4OCC(C)(C)CO4)CC[C@H]3[C@H]12
Agent: CCCCP(CCCC)CCCC
Solvent: C1COCCO1
Product: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.3 %

Procedure:
A mixture of 10.3 mg (0.00997 mmole) of tris(dibenzylideneacetone)dipalladium(chloroform), 19.9 μl (0.0798 mmole) of tributylphosphine and 5 ml of dry 1,4-dioxane was stirred in an atmosphere of argon gas at room temperature for 10 minutes. To this mixture was added a solution of 43.6 mg (0.0798 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate in 2 ml of dry 1,4-dioxane, and the mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and filtered through a glass filter with the aid of Florisil. The filtrate was concentrated under reduced pressure and the concentrate was purified by silica gel chromatography (eluent: ether-hexane=1:10, v/v) to give 17.4 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate. In addition, 15.3 mg of the starting compound 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate was recovered. The yield of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregna-5,7-dien-3β-yl acetate was 71% based on consumed 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-methoxycarbonyloxypregn-5-en-3β-yl acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[N+:9]=2[O-])[CH:4]=1.C1(C)C=CC(S([Cl:24])(=O)=O)=CC=1>ClC(Cl)C>[Cl:24][CH2:14][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=1
Reactant: COc1ccc2c(ccc(C)[n+]2[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(Cl)Cl
Product: COc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Yield: 34.1 %

Procedure:
6-Methoxyquinaldine N-Oxide (6.94 g, 36.71 mmol) was added to a stirring solution of p-toluenesulfonylchloride (7.0 g, 36.84 mmol) in dichloroethane (100 mL). The reaction was heated to 100° C. overnight, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4, and evaporated under reduced pressure. The crude solid was purified by HPLC to afford 2.6 g (37%) of chloride.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=1[Cl:16].[OH-].[Na+]>C1COCC1>[NH2:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][NH2:13])=[CH:10][C:9]=1[Cl:16]
Reactant: N#Cc1ccc(N)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.9 %

Procedure:
To lithium aluminum hydride (2.11 g, 55.6 mmol) in dry THF (50 mL) was added dropwise 4-amino-3-chlorobenzonitrile (3.29 g, 21.6 mmol) in THF (40 mL). The mixture was stirred at RT for 16 hours. Then, 6.0 mL of 1.0 N NaOH solution was added dropwise and the reaction mixture was stirred for 20 min. The solid was filtered off and washed with THF for three times. The solvent was removed by rotavap to give 4-amino-3-chlorobenzylamine as an oily liquid (3.04 g, 90%). 1H NMR (500 MHz, CD3OD): δ 7.18 (d, J=2Hz, 1H), 7.00 (dd, J=8Hz, 2Hz, 1H), 6.78 (d, J=8Hz, 1H), 3.61 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].[H][H]>[Pd].C(O)C>[NH2:1][C:2]1[N:10]=[C:9]([CH2:11][CH2:12][CH:13]([OH:15])[CH3:14])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: [H][H]
Reactant: CC(O)C#Cc1nc(N)c2ncn(C)c2n1
Agent: [Pd]
Solvent: CCO
Product: CC(O)CCc1nc(N)c2ncn(C)c2n1

Procedure:
4-(6-Amino-9-methyl-9H-purin-2-yl)but-3-yn-2-ol (1.5 g, 6.88 mmol) was placed in an autoclave with ethanol (30 ml) and palladium 10% on graphite (0.350 g, 20% in weight) was added. The mixture was stirred overnight under 4 atm of hydrogen at 50° C. The catalyst was filtered off through Celite and the resulting solution was evaporated under reduced pressure, to give a residue that was used without any further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24]C)=[O:23])=[CH:20][CH:19]=2)=[O:15])[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][C:14]([CH2:16][NH:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=2)=[O:15])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(NCC(=O)C=Cc2cc(C(C)C)c(C(C)C)o2)cc1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)c1cc(C=CC(=O)CNc2ccc(C(=O)O)cc2)oc1C(C)C
Yield: 96 %

Procedure:
The ester obtained above (68 mg, 0.314 μmol) was hydrolyzed with lithium hydroxide in a conventional manner, and the residue was recrystallized to obtain the title compound (27, 63 mg, 96%) as colorless prisms.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([CH3:16])[CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([CH2:16][Br:17])[CH:15]=1)[O:5][Si:6]([C:9]([CH3:11])([CH3:12])[CH3:10])([CH3:7])[CH3:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(CBr)c1

Procedure:
(3-Bromo-5-methyl-phenoxy)-tert-butyldimethylsilane (3.32 mmol) [prepared according to the procedure of J. E. Baldwin et al, Tetrahedron, 1991, 47(29), 5603], N-bromosuccinimide (3.65 mmol), and benzoyl peroxide (0.332 mmol) were dissolved in dichloromethane (10 mL) and the reaction mixture irradiated for 4 hours. Diluted with dichloromethane and washed with water, dried over magnesium sulfate and concentrated to dryness. The crude material was purified by column chromatography on silica gel with 10% ethyl acetate/cyclohexane to give (3-bromo-5-bromomethyl-phenoxy)-tert -butyldimethylsilane as a colorless oil. This material was subjected to the conditions described in the first part of EXAMPLE 1A, but using (3-bromo-5-bromomethyl-phenoxy)-tert-butyldimethylsilane in place of 3-bromobenzylbromide, to give 3-bromo-N,N-(bis-tert-butoxycarbonyl)-5-(tert-butyldimethylsilyloxy)benzylamine as a colorless oil. MS (EI) 516 and 518 (M++H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2([C:10]3[CH:15]=[CH:14][C:13]([C@@:16]4([CH2:22][OH:23])[O:20][C:19](=[O:21])[NH:18][CH2:17]4)=[CH:12][CH:11]=3)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4][O:3]1.C(N(CC)CC)C.[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[CH3:1][C:2]1([C:7]2([C:10]3[CH:11]=[CH:12][C:13]([C@@:16]4([CH2:22][O:23][S:37]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)(=[O:39])=[O:38])[O:20][C:19](=[O:21])[NH:18][CH2:17]4)=[CH:14][CH:15]=3)[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC1(C2(c3ccc([C@]4(CO)CNC(=O)O4)cc3)CC2)OCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C2(c3ccc([C@]4(COS(=O)(=O)c5ccccc5)CNC(=O)O4)cc3)CC2)OCCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5(R)-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-hydroxymethyloxazolidin-2-one (2.55 g) and triethylamine (1.7 mL) in tetrahydrofuran (20 mL) was added benzenesulfonyl chloride (1.2 mL) at 0° C., the mixture was stirred at room temperature overnight, and heated at 40° C. for 10 hours. After dilution with water, the mixture was extracted with tetrahydrofuran. The organic extracts were washed with 1 N hydrochloric acid, saturated sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=1:1) of the residue gave 5(R)-[4-(1-(2-methyl-1,3-dioxolan-2-yl)cyclopropan-1-yl)phenyl]-5-phenylsulfonyloxymethyloxazolidin-2-one (3.05 g).