Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:34])([F:33])[CH2:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([O:24][CH2:23][C:22]([F:21])([F:33])[F:34])[CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(OCC(F)(F)F)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OCC(F)(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with 3-(2,2,2-trifluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 424.43 g/mol.
Reaction SMILES: CO[C:3]1[CH:31]=CC(CS[C@@H]2CN(C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H](C(O)=O)C2)=C[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.FC(F)(F)C(O)=O.[N+](C1C=CC(COC(N=C(NC(OCC2C=CC([N+]([O-])=O)=CC=2)=O)NC[CH2:66][C:67]([NH:69][CH:70]2[CH2:73]N[CH2:71]2)=O)=O)=CC=1)([O-])=O>C(#N)C>[CH:3]([N:69]([CH2:67][CH3:66])[CH:70]([CH3:71])[CH3:73])([CH3:31])[CH3:4]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(CCNC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC1CNC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (909 mg) in anhydrous acetonitrile (13 ml), N,N-carbonyldiimidazole (346 mg) was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, N,N-diisopropylethylamine (338 μl) and a solution of the compound (1.68 g), which had been obtained in (2), in anhydrous acetonitrile (15 ml) were added and the mixture was stirred overnight at room temperature. Dichloromethane was added to the reaction mixture. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate-methanol), whereby 1.88 g of the title target compound were obtained as a colorless amorphous substance.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1)=O.CC(C[AlH]CC(C)C)C>ClCCl.CCCCCC>[OH:2][CH2:3][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1
Reactant: COC(=O)c1coc2ccccc12
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: ClCCl
Product: OCc1coc2ccccc12
Temperature: 25 °C
Yield: 81.2 %

Procedure:
To a stirring solution of 650 mg (3.69 mmol) of Benzofuran-3-carboxylic acid methyl ester, prepared as in Intermediate 18, in 25 mL dichloromethane at -78° C. is added dropwise over 5 min a solution of 9.22 mL (9.22 mmol, 2.5 equiv) of a 1.0M solution of DIBAL-H in hexane. The resulting solution is allowed to slowly warm to RT over a 4 h period then quenched by careful addition of 5 mL of H2O. The reaction mixture is poured into 100 mL of EtOAc and extracted with 1N HCl (1×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using hexane/EtOAc 4/1 as eluent afforded 444 mg of the title compound as a pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ7.66 (d, 1H), 7.60 (s, 1H), 7.49 (d, 1H), 7.29 (m, 2H), 4.82 (d, 2H), 1.70 (m, 1H); Rf =0.17 in hexane/EtOAc 5/1.
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:12](C(OOCC)=O)=[O:13])[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:12](=[O:13])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=1)[C:6]([O:8][CH:9]([CH3:10])[CH3:11])=[O:7]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)C)=C1SCS1
Product: CC(C)OC(=O)C(C(=O)Nc1ccc(C(F)(F)F)cc1)=C1SCS1

Procedure:
Following the procedure of Example 18, the titled compound was prepared as a white solid (67%) from isopropyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and 4-aminobenzotrifluoride.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:24])=[C:21]([CH:23]=1)[NH2:22]>>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([F:24])=[C:21]([NH:22][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[CH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:23]=1
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1cc(Cl)ccc1F
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cc(Cl)ccc1F
Yield: 71.2 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (2.0 g, 9.65 mmol) and 5-chloro-2-fluoroaniline (1.26 g, 8.69 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (2.07 g, 64%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=3)[CH:16]=[CH:17][CH:18]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][NH:28]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH2:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][N:28]1[CH2:25][C:21]1[CH:20]=[C:19]([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[N:3]=[C:2]([CH3:1])[CH:11]=3)[CH:14]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1cc(Nc2cccc(-c3cccc(C=O)c3)c2)c2ccccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Cc1cc(Nc2cccc(-c3cccc(CN4CCc5ccccc5C4)c3)c2)c2ccccc2n1
Reaction time: 19 h
Yield: 54.7 %

Procedure:
To a solution of 73 (102 mg, 0.301 mmol) in dichloroethane (3.0 mL) under N2 was added 40 (0.04 mL, 0.315 mmol). The reaction was stirred for 24 minutes before the sequential addition of NaBH(OAc)3 (94 mg, 0.444 mmol) and AcOH (0.02 mL, 0.349 mmol). The reaction was stirred for 19 hours and then extracted with ethyl acetate (2×30 mL). The ethyl acetate extracts were washed with 2 N NaOH (aq. 15 mL), brine (15 mL), dried (MgSO4), and concentrated. The residue was chromatographed on silica gel (dichloromethane to 30:1 to 20:1 dichloromethane/methanol) to give the desired product as a yellow solid (75 mg, 55%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([CH:17]3[C:25]4[C:20](=[C:21]([OH:26])[CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:35][CH2:36][OH:37]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12](=[O:27])[N:13]([CH:17]3[C:25]4[C:20](=[C:21]([O:26][CH2:35][CH2:36][OH:37])[CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)[CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)c1cccn(C2CCc3c(O)cccc32)c1=O
Reactant: OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Br)cc1)c1cccn(C2CCc3c(OCCO)cccc32)c1=O
Yield: 60 %

Procedure:
To a solution of N-(4-bromophenyl)-1-(4-hydroxy-2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (30 mg, 0.071 mmol) in DMF (0.2 mL) was added K2CO3 (30 mg, 0.22 mmol) and 2-chloroethanol (9.3 uL, 0.14 mmol). The reaction mixture was heated at 70 C overnight. It was filtered and purified by prep HPLC to afford N-(4-bromophenyl)-1-(4-(2-hydroxyethoxy)-2,3-dihydro-1H-inden-1-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (20 mg, 60%). Retention time (min)=7.588, method [7], MS (ESI) 469.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.20 (s, 1H), 8.57 (dd, J=2.1 Hz, 6.9 Hz, 1H), 7.65 (d, J=9.0 Hz, 2H), 7.44 (d, J=9.0 Hz, 2H), 7.15-7.30 (overlap with CDCl3, 2H), 6.83 (d, J=8.1 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 6.58 (dd, J=5.4 Hz, 8.4 Hz, 1H), 6.39 (t, J=6.9 Hz, 1H), 4.14 (m, 2H), 4.00 (m, 2H), 2.78-3.15 (m, 3H), 1.90-2.10 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[CH:11][C:10]=1[O:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[N+:30]([O-])([OH:32])=[O:31]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:21][CH3:22])=[CH:11][C:12]([C:15]2([C:19]#[N:20])[CH2:18][CH2:17][CH2:16]2)=[C:13]([N+:30]([O-:32])=[O:31])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C2(C#N)CCC2)ccc1OCc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: COc1cc(C2(C#N)CCC2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
A solution of 1-(4-(benzyloxy)-3-methoxyphenyl)cyclobutanecarbonitrile (5 g, 17.04 mmol), from Step 1, in acetic acid (20 mL)/acetic anhydride (20 mL) was cooled in an ice bath to 0° C. and treated slowly with 65% nitric acid (2.54 mL, 34.1 mmol). The reaction was stirred at 0° C. for 20 min, poured into ice and extracted with EtOAc. Organic layer was washed with saturated aqueous NaHCO3 and water. Organic layer was dried (MgSO4), filtered and concentrated. Purification by flash chromatography (silica gel, 5-50% EtOAc/hexane) afforded 1-(4-(benzyloxy)-5-methoxy-2-nitrophenyl)cyclobutanecarbonitrile (5.29 g, 92%). MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16].[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20]>O1CCOCC1.C(O)C>[C:18]([OH:23])(=[O:22])[C:19]([OH:21])=[O:20].[CH2:13]([NH:17][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=C(O)C(=O)O
Solvent: C1COCCO1
Solvent: CCO
Product: CCCCNCC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
18 g of D-glucose are suspended in 200 ml of dioxane and 100 ml of ethanol, and 7.3 g of butylamine are added. The mixture is warmed to 70° C. and, after 10 minutes, 9.0 g anhydrous oxalic acid is added. The temperature is maintained for 4 hours. After cooling to room temperature, the product crystallizes out. The solid is filtered off with suction, rinsed five times with 50 ml of ethanol each time and dried in vacuo.
Reaction SMILES: [O:1]1CCCC1.[CH2:6]([O:13][C:14](=[O:27])[NH:15][C@H:16]1[C@H:23]2[C@H:19]([O:20][C:21]([CH3:25])([CH3:24])[O:22]2)[C:18](=[CH2:26])[CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].OO>O>[CH2:6]([O:13][C:14](=[O:27])[NH:15][C@H:16]1[C@H:23]2[C@H:19]([O:20][C:21]([CH3:24])([CH3:25])[O:22]2)[C@H:18]([CH2:26][OH:1])[CH2:17]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: C=C1C[C@@H](NC(=O)OCc2ccccc2)[C@@H]2OC(C)(C)O[C@H]12
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)O[C@@H]2[C@H](CO)C[C@@H](NC(=O)OCc3ccccc3)[C@@H]2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
Borane-THF complex in tetrahydrofuran (1M, 0.99 mL, 0.99 mmol) was added to a 0° C. solution of benzyl((3aS,4R,6aR)-2,2-dimethyl-6-methylenetetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (0.150 g, 0.494 mmol) in tetrahydrofuran (10 mL, 0.1 mol). Some bubbling initially observed, the mixture stirred at room temperature for 1 hour. The reaction was quenched via the addition of aqueous sodium hydroxide (4M, 1.24 mL, 0.00494 mol) and hydrogen peroxide 35% (35%, 0.425 ml, 4.94 mmol) were added and reaction stirred at room temperature for 2.5 hours. Water (5 ml) added to the reaction and the aqueous was extracted with ether (3×50 mls). The combined organics were dried with MgSO4 and purified by FC (Hex/EtOAc 1:1) to yield benzyl((3aS,4R,6S,6aR)-6-(hydroxymethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)carbamate (0.070 g, 44%) as a thick colorless oil: MS (ESI+) for C17H23NO5 m/z 344.2 [M+Na]+; MS (ESI−) for C17H23NO5 m/z 320.3 [M−H]−;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[S:10][CH:9]=2)=[CH:3][CH:2]=1.[H-].[Na+].S(OCC)(O[CH2:23][CH3:24])(=O)=O>CN(C)C=O>[CH2:23]([N:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][CH:9]=1)[CH3:24]
Reactant: CCOS(=O)(=O)OCC
Reactant: c1cnc2scc(Nc3ccncc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1ccncc1)c1csc2ncccc12
Temperature: 0 °C
Yield: 46.7 %

Procedure:
A solution of 3-(4-pyridinylamino)thieno[2,3-b]pyridine (4 g) in 25 mL of dimethylformamide was added to an ice-cooled suspension of sodium hydride (60% oil dispersion, 0.8 g, washed with heptane) in 5 mL of dimethylformamide. After anion formation was completed a solution of diethyl sulfate (3 g) in 5 mL of dimethylformamide was added. After one hour the reaction mixture was poured into ice-water and extracted with ethyl acetate. The organic extract was washed with water and saturated sodium chloride, and then was dried (anhydrous magnesium sulfate), filtered and evaporated to 5 g of an oil. Elution through silica with 10% methanol in ethyl acetate via flash column chromatography afforded 2.1 g of a solid. Recrystallization from acetonitrile afforded 1.4 g of crystals, m.p. 123°-125° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]=[O:18]>C(Cl)Cl>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([NH:13][C:17](=[O:18])[NH:16][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(=O)CCN=C=O
Reactant: CCCCCCCCc1ccc(N)cc1
Solvent: ClCCl
Product: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Yield: 87.8 %

Procedure:
To 4-n-octylaniline (0.1 g; 0.49 mmol) ethyl 3-isocyanatopropionate (0.08 g; 0.54 mmol) was added at room temperature. The resulting mixture was diluted to 1 ml with CH2Cl2, refluxed for 30 min and evaporated to dryness. The residue was treated with Et2O (5 ml) and the solid formed was filtered off and dried to give the title compound (0.15 g; 87%), as colourless crystals. 1H-NMR (CDCl3) 7.22-7.07 (m, 4H); 6.34 (broad s, 1H); 5.34 (m, 1H); 4.15-4.07 (m, 2H); 3.54-3.46 (m, 2H); 2.73 (m, 4H); 2.57-2.51 (m, 4H); 1.58 (m, 2H); 1.27-1.19 (m, 13H); 0.86 (m, 3H).
Reaction SMILES: [Si:1]([O:8][CH:9]([C:22]1[O:23][CH:24]=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]C(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:42])(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Si:1]([O:8][CH:9]([C:22]1[O:23][C:24]([F:42])=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncco1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1ncc(F)o1
Temperature: -78 °C
Reaction time: 2 h
Yield: 22 %

Procedure:
2-(1-(tert-Butyldimethylsilyloxy)-7-phenylheptyl)oxazole (135 mg, 0.361 mmol) was dissolved in anhydrous THF (5 mL), cooled to −78° C. and t-BuLi (1.7 M in pentane, 1.3 equiv) was added dropwise under Ar. The reaction mixture was stirred for 2 h at −40° C., and N-fluorobenzenesulfonimide (1.5 equiv) was added in one portion. The reaction mixture was warmed to room temperature, diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude aryl fluoride, which was purified by flash chromatography (0-2% EtOAc/hexanes) to afford the title compound as a clear oil (31 mg, 22%): 1H NMR (CDCl3, 500 MHz) 7.37-7.34 (m, 2H), 7.27-7.24 (m, 3H), 6.36 (d, 1H, J=9.0 Hz), 4.71 (t, 1H, J=7.2 Hz), 2.68 (t, 2H, J=7.8 Hz), 1.94-1.86 (m, 2H), 1.71-1.66 (m, 2H), 1.51-1.43 (m, 6H), 0.96 (s, 9H), 0.16 (s, 3H), 0.07 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 158.6 (d, J=292 Hz), 143.2, 128.8, 128.7, 126.0, 99.1 (d, J=12.8 Hz), 69.2, 36.4, 36.3, 31.8, 29.5, 29.5, 26.1, 25.4, 18.6, −4.7, −4.8.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:29])([F:28])[F:27])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[CH3:30][C:31]([O:34][C:35]([N:37]([CH2:39][C:40](O)=[O:41])[CH3:38])=[O:36])([CH3:33])[CH3:32]>C(Cl)Cl>[O:8]=[C:6]1[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]([F:28])([F:27])[F:29])[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4][C@H:3]([CH2:2][O:1][C:40](=[O:41])[CH2:39][N:37]([C:35]([O:34][C:31]([CH3:32])([CH3:30])[CH3:33])=[O:36])[CH3:38])[O:7]1
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CN(CC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
The 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (800 mg, 1.98 mmol) obtained in step B of Example 1-14 was dissolved in methylene chloride (10 ml). Thereafter, Boc-sar-OH (449 mg, 2.37 mmol), N,N-dimethylaminopyridine (73 mg, 0.59 mmol), and WSCI (493 mg, 2.57 mmol) were added at 0° C. to the solution. The obtained mixture was stirred at a room temperature for 15 hours. Thereafter, the reaction mixture was concentrated under reduced pressure, and the obtained residue was then purified by silica gel chromatography (methylene chloride:methanol=20:1), so as to obtain N-tert-butoxycarbonyl-N-methylaminoacetic acid (R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethyl ester (1.14 g, 100%) in the form of a colorless foaming substance.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].C([Li])CCC.CN([CH:27]=[O:28])C>C1COCC1>[CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[C:9]([CH:27]=[O:28])[N:8]=[C:7]1[Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])(=[O:4])=[O:5]
Reactant: CN(C)C=O
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(C=O)nc1[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred, cooled (−78° C.) solution of 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide (1.02 g; CAS 129378-52-5) in THF (20 ml) under an argon atmosphere was added dropwise butyl lithium (3.3 ml; 1.6 M solution in hexanes) over a period of 10 minutes. After 30 minutes of stirring, DMF (1.3 ml) was added over a period of 5 minutes and the mixture (clear light yellow solution) was stirred at −78° C. for another 2 hours. The mixture was quenched with saturated aqueous NH4Cl and diluted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated to give 2-(tert-butyl-dimethyl-silanyl)-4-formyl-imidazole-1-sulfonic acid dimethylamide (1.22 g) as viscous orange oil which was used in the next reaction step without further purification. MS (ISP): 318.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH:18]([CH3:20])[CH3:19])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:22]1([CH2:28][C:29]([N:31]=[C:32]=[S:33])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:32]([NH:31][C:29](=[O:30])[CH2:28][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[S:33])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[N:17]([CH:18]([CH3:19])[CH3:20])[CH:16]=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CC(C)n1ccc2ncnc(Oc3ccc(N)cc3F)c21
Solvent: C1CCOC1
Product: CC(C)n1ccc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c21
Reaction time: 3 h
Yield: 24.7 %

Procedure:
To a suspension of 248 (10 mg, 0.035 mmol) in THF (1 mL) was added 2-phenylacetyl isothiocyanate (0.007 mL, 0.038 mmol). The reaction mixture was stirred for 3 hours, concentrated under reduced pressure and the residue was purified by flash chromatography, eluent EtOAc/hexane (1:1) and preparative HPLC (C-18 Aquasyl column, gradient: 60% to 95% MeOH in water, 45 min), to afford title compound 249 (4 mg, 26% yield) as a white solid. 1HNMR: (CD3OD) δ (ppm): 8.35(s, 1H), 8.03 (d, J=12.4 Hz, 1H), 7.96(d, J=3.13 Hz, 1H), 7.44-7.26(m, 6H), 6.69 (d, J=3.13 Hz, 1 H), 5.29 (quintuplet, J=6.65 Hz, 1H), 3.75(s, 2H), 3.60 (d, J=10.96 Hz, 3H), 1.63(d, J=6.65 Hz, 6H). MS (m/z): 464.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)([O:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CC#N
Product: CCOC(=O)CO[C@@](C)(c1cccc(Cl)c1)[C@@H]1CCCNC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-tert-butyl 3-((R)-1-(3-chlorophenyl)-1-(2-ethoxy-2-oxoethoxy)ethyl)piperidine-1-carboxylate (0.0580 g, 0.136 mmol), 2 NHCl (50 mL), and CH3CN (50 mL) was vigorously stirred at rt for 24 h. After the reaction mixture was evaporated under reduced pressure, the crude product ethyl 2-((R)-1-(3-chlorophenyl)-1-((R)-piperidin-3-yl)ethoxy)acetate was directly used in the next step without further purification. MS ESI +ve m/z 328 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][S:7](Cl)(=[O:9])=[O:8])=[O:5])[CH3:2].C[Si](C)(C)[NH:13][Si](C)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH2:6][S:7]([NH2:13])(=[O:9])=[O:8])=[O:5])[CH3:2]
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC(=O)CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CS(N)(=O)=O

Procedure:
A solution of 54.6 g (0.29 mole) ethoxy carbonyl methanesulfonyl chloride in 250 ml methylene chloride is stirred at 0° under a nitrogen atmosphere while 46.8 g (0.29 mole) hexamethyldisilazane is added dropwise. The resulting cloudy solution is allowed to warm to 25° over one hour and then evaporated in vacuo to an oil which crystallizes: yield of the title product is 48.4 g (100%), mp 63°-67°; lit.1 mp 67°-68°, lit2 mp 66°-68°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]1.[CH3:17][NH2:18]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[O:6][CH:7]1[CH2:10][N:9]([C:11]([NH:18][CH3:17])=[O:12])[CH2:8]1
Reactant: CN
Reactant: COc1cccc(OC2CN(C(=O)Cl)C2)c1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)N1CC(Oc2cccc(OC)c2)C1
Reaction time: 16 h
Yield: 20.7 %

Procedure:
A solution of 4.8 g (0.02 mole) of 3-(3-methoxyphenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine and stirred for 16 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated was extracted into methylene chloride (2×50 ml). The extracts were dried by passing through Whatman phase separating paper and concentrated in vacuo (3.85 g). The residue was purified by chromatography on two 4 mm (silica gel) chromatotron plates by eluting with an ethyl acetate/methylene chloride gradient to give 0.98 g (21%) of tan solid. Recrystallization from benzene with a trace of ligroin yielded 600 mg of tan crystalline powder, m.p. 109°-111° C.