(S)-N-[3-(3-Fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 108 (20.0 g, 52.8 mmol, prepared as described in Example 1, above) in anhydrous 1,4-dioxane (130 mL) was treated with 4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (10.2 g, 11.6 mL, 80.0 mmol, 1.5 equiv) and triethylamine (16.0 g, 22.4 mL, 158.4 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) (Pd(dppf)2Cl2, 1.32 g, 1.6 mmol, 0.03 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 7 h. When HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being treated with water (100 mL) and ethyl acetate (100 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl (50 mL), dried over MgSO4, and concentrated in vacuo. The residual brown oil was further dried in vacuo to afford the desired (5S)—N-{3-[3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}acetamide 123 (18.8 g, 94%) as brown solids. This product was directly used in subsequent reactions without further purification. C18H24BFN2O5, HPLC/MS (ESI) m/e 379 (M++H). The resulting reaction mixture was degassed three times under a steady stream of argon The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 7 h before being treated with water (100 mL) and ethyl acetate (100 mL) The two layers were separated the aqueous layer was extracted with ethyl acetate (2×50 mL) The combined organic extracts were washed with water (2×50 mL) and saturated aqueous NaCl (50 mL) dried over MgSO4 concentrated in vacuo The residual brown oil was further dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of aryl boronic acid 120 (25.0 g, 64.30 mmol, 1.45 equiv) in a mixture of toluene (120 mL), EtOH (40 mL), and water (40 mL) was treated with (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 108 (16.80 g, 44.44 mmol, prepared as described in Example 1, above) and solid K2CO3 (18.40 g, 133.4 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before being treated with Pd(PPh3)4 (2.57 g, 2.23 mmol, 0.05 equiv). The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 8 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being poured into water (300 mL) and ethyl acetate (EtOAc, 300 mL). The two layers were separated, and the organic phase was washed with water (60 mL) and saturated aqueous NaCl (2×50 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The product was recrystallized from EtOAc/hexanes and dried in vacuo to afford the desired (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(3-fluoro-propyl)-carbamic acid tert-butyl ester 121 (21.2 g, 61.5% yield for three steps) as an off-white powder. The resulting reaction mixture was degassed three times under a steady stream of argon The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 8 h before being poured into water (300 mL) and ethyl acetate (EtOAc, 300 mL) The two layers were separated the organic phase was washed with water (60 mL) and saturated aqueous NaCl (2×50 mL) dried over anhydrous Na2SO4 concentrated in vacuo The product was recrystallized from EtOAc/hexanes dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of aryl boronic acid 120 (2.50 g, 8.03 mmol) in a mixture of toluene (24 mL), EtOH (8 mL), and water (8 mL) was treated with aryl iodide 108 (2.53 g, 6.7 mmol, 0.83 equiv) and solid K2CO3 (2.80 g, 20.1 mmol, 3.0 equiv) at room temperature. The resulting reaction mixture was degassed three times under a steady stream of argon before tetrakis(triphenylphosphine)palladium (0) (Pd(PPh3)4, 387 mg, 0.335 mmol, 0.05 equiv) was added. The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 8 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was cooled to room temperature before being poured into water (60 mL) and EtOAc (60 mL). The two layers were separated, and the organic phase was washed with water (30 mL) and saturated aqueous NaCl (2×30 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The product was then recrystallized from EtOAc/hexanes and dried in vacuo to afford the desired (5S)-{4′-[5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2′-fluoro-biphenyl-4-ylmethyl}-(3-fluoro-propyl)-carbamic acid tert-butyl ester 121 (1.3 g, 30%) as an off-white powder. The resulting reaction mixture was added The resulting reaction mixture was degassed three times under a steady stream of argon before being warmed to reflux for 8 h before being poured into water (60 mL) and EtOAc (60 mL) The two layers were separated the organic phase was washed with water (30 mL) and saturated aqueous NaCl (2×30 mL) dried over anhydrous Na2SO4 concentrated in vacuo The product was then recrystallized from EtOAc/hexanes dried in vacuo

Conditions: temp:2.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of amine 107 (16.0 g, 47.6 mmol) in CH2Cl2 (150 mL) was treated with TEA (9.62 g, 13.2 mL, 95.2 mmol, 2.0 equiv) at 25° C., and the resulting reaction mixture was cooled to 0-5° C. before being treated with acetic anhydride (Ac2O, 7.29 g, 6.75 mL, 71.4 mmol, 1.5 equiv) and 4-N,N-dimethylaminopyridine (DMAP, 58 mg, 0.5 mmol, 0.01 equiv) at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was quenched with H2O (100 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5S)—N-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-acetamide 108 (17.36 g, 96.5% yield) as a white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 1.63 (s, 3H, NHCOCH3), 3.25 (t, 2H, J=5.4 Hz), 3.56 (dd, 1H, J=6.4, 9.2 Hz), 3.95 (t, 1H, J=9.1 Hz), 4.58 (m, 1H), 5.16 (t, 1H, J=5.7 Hz, OH), 7.02 (dd, 1H, J=2.4, 8.2 Hz), 7.38 (dd, 1H, J=2.4, 10.8 Hz), 7.66 (t, 1H, J=7.5, 8.4 Hz), 8.08 (t, 1H, J=5.8 Hz, NHCOCH3). C12H12FIN2O3, LCMS (EI) m/e 379 (M++H). the resulting reaction mixture The resulting reaction mixture the reaction mixture was quenched with H2O (100 mL) The two layers were separated the aqueous layer was extracted with CH2Cl2 (2×50 mL) The combined organic extracts were washed with H2O (2×100 mL) and saturated aqueous NaCl (100 mL) dried over MgSO4 concentrated in vacuo The residue was further dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-(−)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C. is degassed heated up to reflux refluxed for seven hours The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) the layers are separated The aqueous phase is extracted with ethyl acetate (2×30 mL) the combined organic phase is washed with saline (40 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure triturated with diethyl ether The resultant precipitate is filtered

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-(−)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C. is degassed heated up to reflux refluxed for seven hours The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) the layers are separated The aqueous phase is extracted with ethyl acetate (2×30 mL) the combined organic phase is washed with saline (40 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure triturated with diethyl ether The resultant precipitate is filtered

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of (S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide described above (4.200 g, 11.11 mmol) and trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (4.150 g, 13.88 mmol) in 1,4-dioxane (50 mL) was degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.545 g, 0.78 mmol) was added, the reaction again degassed, and then the mixture was brought to reflux under nitrogen. After 3 h TLC revealed some of the iodide still remained. Additional tin reagent (0.400 g, 1.34 mmol) and palladium catalyst (0.100 g, 0.14 mmol) were added and the mixture refluxed for 4 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 20% methanol/chloroform, filtered through Celite and concentrated in vacuo. The crude solids were triturated with dichloromethane/diethyl ether, the solids filtered, washed with diethyl ether and dried in vacuo to give 4.200 g (98%) of the title compound. The following characteristics were noted: was degassed the reaction again degassed to reflux under nitrogen the mixture refluxed for 4 h concentrated under reduced pressure The residue was dissolved in 20% methanol/chloroform filtered through Celite concentrated in vacuo The crude solids were triturated with dichloromethane/diethyl ether the solids filtered washed with diethyl ether dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A slurry of (S)-N-[[3-(3-fluoro-4-iodophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide described above (4.200 g, 11.11 mmol) and trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (4.150 g, 13.88 mmol) in 1,4-dioxane (50 mL) was degassed by repeated evacuation and filling with nitrogen. Bis(triphenylphosphine)palladium(II) chloride (0.545 g, 0.78 mmol) was added, the reaction again degassed, and then the mixture was brought to reflux under nitrogen. After 3 h TLC revealed some of the iodide still remained. Additional tin reagent (0.400 g, 1.34 mmol) and palladium catalyst (0.100 g, 0.14 mmol) were added and the mixture refluxed for 4 h. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in 20% methanol/chloroform, filtered through Celite and concentrated in vacuo. The crude solids were triturated with dichloromethane/diethyl ether, the solids filtered, washed with diethyl ether and dried in vacuo to give 4.200 g (98%) of the title compound. The following characteristics were noted: was degassed the reaction again degassed to reflux under nitrogen the mixture refluxed for 4 h concentrated under reduced pressure The residue was dissolved in 20% methanol/chloroform filtered through Celite concentrated in vacuo The crude solids were triturated with dichloromethane/diethyl ether the solids filtered washed with diethyl ether dried in vacuo

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of (S)-(-)-N-[[3-[4-iodo-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (5.45 g), vinyltributyltin (5.48 g) and bis(triphenylphosphine)palladium(II) chloride (303 mg) in 1,4-dioxane (72 mL) under N2 is degassed, heated up to reflux, refluxed for seven hours, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) and the layers are separated. The aqueous phase is extracted with ethyl acetate (2×30 mL), and the combined organic phase is washed with saline (40 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and triturated with diethyl ether. The resultant precipitate is filtered to give the title compound, mp 165-166° C. is degassed heated up to reflux refluxed for seven hours The mixture is then diluted with ethyl acetate (40 mL) and water (50 mL) the layers are separated The aqueous phase is extracted with ethyl acetate (2×30 mL) the combined organic phase is washed with saline (40 mL) dried over anhydrous magnesium sulfate concentrated under reduced pressure triturated with diethyl ether The resultant precipitate is filtered

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-{[(5S)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (273 mg, 0.72 mM), {3-[5-(trimethylstannyl)thien-2-yl]-4,5-dihydroisoxazol-5-yl}methanol (250 mg, 0.72 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (75 mg, 0.072 mM) and tri-2-furylphosphine (34 mg, 0.145 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 16 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (180 mg). The solids were degassed Anhydrous dioxane (5 ml) was added The reaction mixture was cooled the solvent was evaporated The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-({3-[4-(Trimethylstannyl)phenyl]-4,5-dihydroisoxazol-5-yl}methyl)-1H-1,2,3-triazole (0.62 g, 1.58 mmol), N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.5 g, 1.32 mmol) and tri-2-furylphosphine (0.08 g, 0.34 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris(dibenzylideneacetone)palladium (0) (0.16 g, 0.18 mmol) was added and the solution was degassed three times. The solution was stirred and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.20 g desired product. degassed three times the solution was degassed three times The mixture was concentrated in vacuo purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-({3-[4-(Trimethylstannyl)phenyl]-4,5-dihydroisoxazol-5-yl}methyl)-1H-1,2,3-triazole (0.62 g, 1.58 mmol), N-{[(5S)-3-(3-fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl}acetamide (0.5 g, 1.32 mmol) and tri-2-furylphosphine (0.08 g, 0.34 mmol) were dissolved in 1,4-dioxane (6 ml) and degassed three times. Tris(dibenzylideneacetone)palladium (0) (0.16 g, 0.18 mmol) was added and the solution was degassed three times. The solution was stirred and heated to 90° C. for 18 hours. The mixture was concentrated in vacuo and then purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent giving 0.20 g desired product. degassed three times the solution was degassed three times The mixture was concentrated in vacuo purified by silica flash chromatography with 5-10% methanol in dichloromethane as eluent