(4S)-5,5-dimethyl-4-phenyl-1,3-oxazolidin-2-one

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A butyllithium solution (9.7 M in hexanes, 7.64 mL, 74 mmol) was added drop-wise to a solution of C3 (13.5 g, 70.6 mmol) in tetrahydrofuran (800 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., A solution of C6 (21.3 g, 78 mmol) in tetrahydrofuran (50 mL) was then added slowly, and the reaction was stirred at −78° C. for 30 minutes and then at 25° C. for about 3 hours. The reaction mixture was then poured into phosphate buffer (pH 7) and extracted with ethyl acetate (2×). The organic extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a minimal volume. The resultant residue was then precipitated by addition of 1 liter of hexanes. The solid white product was collected by filtration, and the filtrate was concentrated. The resultant residue was purified by silica gel chromatography (gradient: 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate), to provide C7 as a white solid. Yield: 22.8 g, 75 LCMS m/z 430.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 0.85 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.57 (3H, s), 4.36 (2H, apparent s, actual AB quartet, J=12.3 Hz), 5.21 (1H, s), 5.21 (1H, q, J=6.6 Hz), 7.23 (2H, m), 7.38 (8H, m), 7.61 (4H, m). the reaction was stirred at −78° C. for 30 minutes at 25° C. for about 3 hours extracted with ethyl acetate (2×) The organic extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution dried over sodium sulfate concentrated to a minimal volume The resultant residue was then precipitated by addition of 1 liter of hexanes The solid white product was collected by filtration the filtrate was concentrated The resultant residue was purified by silica gel chromatography (gradient: 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A butyllithium solution (9.7 M in hexanes, 7.64 mL, 74 mmol) was added drop-wise to a solution of C3 (13.5 g, 70.6 mmol) in tetrahydrofuran (800 mL) at −78° C., and the mixture was stirred for 30 minutes at −78° C., A solution of C6 (21.3 g, 78 mmol) in tetrahydrofuran (50 mL) was then added slowly, and the reaction was stirred at −78° C. for 30 minutes and then at 25° C. for about 3 hours. The reaction mixture was then poured into phosphate buffer (pH 7) and extracted with ethyl acetate (2×). The organic extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated to a minimal volume. The resultant residue was then precipitated by addition of 1 liter of hexanes. The solid white product was collected by filtration, and the filtrate was concentrated. The resultant residue was purified by silica gel chromatography (gradient: 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate), to provide C7 as a white solid. Yield: 22.8 g, 75 LCMS m/z 430.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 0.85 (3H, s), 1.35 (3H, d, J=6.6 Hz), 1.57 (3H, s), 4.36 (2H, apparent s, actual AB quartet, J=12.3 Hz), 5.21 (1H, s), 5.21 (1H, q, J=6.6 Hz), 7.23 (2H, m), 7.38 (8H, m), 7.61 (4H, m). the reaction was stirred at −78° C. for 30 minutes at 25° C. for about 3 hours extracted with ethyl acetate (2×) The organic extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution dried over sodium sulfate concentrated to a minimal volume The resultant residue was then precipitated by addition of 1 liter of hexanes The solid white product was collected by filtration the filtrate was concentrated The resultant residue was purified by silica gel chromatography (gradient: 9:1 hexanes:ethyl acetate to 6:4 hexanes:ethyl acetate)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of C2 (38.8 g, 235 mmol) in dichloromethane (1000 mL) was treated with carbonyldiimidazole (45.6 g, 281 mmol) and heated at reflux for 2 hours. The reaction mixture was cooled to 25° C., quenched with 1 N hydrochloric acid (560 mL), and extracted with dichloromethane (3×). The combined organic extracts were dried over sodium sulfate and concentrated, and the resultant residue was purified by trituration with 4:1 hexanes: ethyl acetate, followed by chromatography on silica gel (gradient: 9:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide C3 as a white solid. Yield: 24.7 g, 55%. MS (APCI) m/z 192.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 0.91 (3H, s), 1.58 (3H, s), 4.62 (1H, s), 5.53-5.60 (1H, br s), 7.20-7.39 (5H, m). heated at reflux for 2 hours quenched with 1 N hydrochloric acid (560 mL) extracted with dichloromethane (3×) The combined organic extracts were dried over sodium sulfate concentrated the resultant residue was purified by trituration with 4:1 hexanes

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

Procedure: The compound was synthesized starting from (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.25 g, 1.31 mmol), 4-bromobenzene-1,2-diamine (0.245 g, 1.31 mmol), copper(I) iodide (0.025 g, 0.13 mmol), potassium carbonate (0.362 g, 2.62 mmol), cyclohexane-1,2-diamine (0.015 mL, 0.13 mmol), 5N HCl (6.5 mL), formic acid (0.648 mL) as described in method 5 step D The compound was synthesized

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.100 g, 0.523 mmol), methyl 4-bromo-2-methylbenzoate (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.132 g, 0.575 mmol), tribasic potassium phosphate (0.555 g, 2.61 mmol) and dioxane (3.50 mL). The mixture was purged with argon and then copper (I) iodide (0.100 g, 0.523 mmol) and N,N′-dimethylethylenediamine (0.113 mL, 1.046 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 140° C. for 1 hour in a microwave. The reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford an orange brown solid. The solid thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoate (0.159 g, 0.468 mmol, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (s, 3H), 1.63 (s, 3H), 2.43 (s, 3H), 3.75 (s, 3H), 5.52 (s, 1H), 7.03-7.46 (m, 6H), 7.50 (d, J=2.35 Hz, 1H), 7.75 (d, J=8.71 Hz, 1H). m/z (ESI) 340 (M+H)+. The mixture was purged with argon The system was purged with argon the tube was sealed The reaction mixture was filtered through Celite® brand filter aid the filtrate was concentrated to afford an orange brown solid The solid thus obtained was purified

Conditions: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A microwave vial was charged with (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.100 g, 0.523 mmol), methyl 4-bromo-2-methylbenzoate (commercially available from Sigma-Aldrich, Milwaukee, Wis., 0.132 g, 0.575 mmol), tribasic potassium phosphate (0.555 g, 2.61 mmol) and dioxane (3.50 mL). The mixture was purged with argon and then copper (I) iodide (0.100 g, 0.523 mmol) and N,N′-dimethylethylenediamine (0.113 mL, 1.046 mmol) were added. The system was purged with argon, the tube was sealed, and the reaction mixture was heated at 140° C. for 1 hour in a microwave. The reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford an orange brown solid. The solid thus obtained was purified using column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-50% EtOAc-hexane) to afford (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)-2-methylbenzoate (0.159 g, 0.468 mmol, 90% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90 (s, 3H), 1.63 (s, 3H), 2.43 (s, 3H), 3.75 (s, 3H), 5.52 (s, 1H), 7.03-7.46 (m, 6H), 7.50 (d, J=2.35 Hz, 1H), 7.75 (d, J=8.71 Hz, 1H). m/z (ESI) 340 (M+H)+. The mixture was purged with argon The system was purged with argon the tube was sealed The reaction mixture was filtered through Celite® brand filter aid the filtrate was concentrated to afford an orange brown solid The solid thus obtained was purified

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

Procedure: To a microwave vial were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (1 g, 5.23 mmol), 2-chloro-4-iodopyridine (1.878 g, 7.84 mmol) (commercially available from Frontier Scientific, Inc., Logan Utah), and dioxane (10.46 mL). Tribasic potassium phosphate (5.55 g, 26.1 mmol) and copper (I) iodide (0.996 g, 5.23 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) were then added to the vial. The vessel was purged with argon and then N,N′-dimethylethylenediamine (1.126 mL, 10.46 mmol, commercially available from Sigma-Aldrich, Milwaukee, Wis.) was added. The vessel was then irradiated at 140° C. for 40 minutes, and LC-MS indicated complete conversion to the desired product. After cooling to room temperature, the reaction mixture was passed through a syringe filtered, and the material thus obtained was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 10% MeOH in DCM, to provide (S)-3-(2-chloropyridin-4-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one. m/z (ESI) 303.3 (M+H)+. ) were then added to the vial The vessel was purged with argon ) was added The vessel was then irradiated at 140° C. for 40 minutes the reaction mixture was passed through a syringe filtered the material thus obtained was absorbed onto a plug of silica gel purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g) eluting with a gradient of 0% to 10% MeOH in DCM

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

Procedure: The title compound was prepared as described in General Scheme A substituting (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (commercially available from Astatech Inc., Bristol, Pa.). The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM, concentrated, and purified (ISCO: 5 g cartridge, 12 g column, 0 to 35 to 100%, 90/10 DCM-MeOH in DCM). Fractions with product were repurified (ISCO: 5 g cartridge, 12 g column, 0 to 100% EtOAc-heptanes) giving (S)-5,5-dimethyl-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-phenyloxazolidin-2-one (79.7 mg, 0.237 mmol, 53.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.80 (m, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.53-7.56 (m, 1H), 7.36 (m, 6H), 5.49 (s, 1H), 3.30 (s, 2H), 2.73-2.88 (m, 2H), 1.62 (s, 3H), 0.90 (s, 3H). m/z (ESI) 337.2 (M+H)+. The title compound was prepared The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM concentrated purified (ISCO: 5 g cartridge, 12 g column, 0 to 35 to 100%, 90/10 DCM-MeOH in DCM) Fractions with product were repurified (ISCO: 5 g cartridge, 12 g column, 0 to 100% EtOAc-heptanes)

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

Procedure: The title compound was prepared as described in General Scheme A substituting (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) and 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (commercially available from Astatech Inc., Bristol, Pa.). The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM, concentrated, and purified (ISCO: 5 g cartridge, 12 g column, 0 to 35 to 100%, 90/10 DCM-MeOH in DCM). Fractions with product were repurified (ISCO: 5 g cartridge, 12 g column, 0 to 100% EtOAc-heptanes) giving (S)-5,5-dimethyl-3-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-phenyloxazolidin-2-one (79.7 mg, 0.237 mmol, 53.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.76-7.80 (m, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.53-7.56 (m, 1H), 7.36 (m, 6H), 5.49 (s, 1H), 3.30 (s, 2H), 2.73-2.88 (m, 2H), 1.62 (s, 3H), 0.90 (s, 3H). m/z (ESI) 337.2 (M+H)+. The title compound was prepared The final reaction mixture was filtered through Celite® brand filter aid with MeOH and DCM concentrated purified (ISCO: 5 g cartridge, 12 g column, 0 to 35 to 100%, 90/10 DCM-MeOH in DCM) Fractions with product were repurified (ISCO: 5 g cartridge, 12 g column, 0 to 100% EtOAc-heptanes)

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

Procedure: To a round bottom flask were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.750 g, 3.92 mmol), 2-fluoro-5-iodopyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.749 g, 7.84 mmol), and dioxane (15.69 mL). Tribasic potassium phosphate (4.16 g, 19.61 mmol) was then added to the mixture. The vessel was purged with nitrogen followed by the addition of N,N′-dimethylethylenediamine (0.844 mL, 7.84 mmol) and copper (I) iodide (0.747 g, 3.92 mmol). The vessel was heated to reflux overnight providing an orange suspension. To the mixture was added water (˜10 mL), and the resulting slurry was filtered through Celite® brand filter aid. The yellow filtrate was transferred to a separatory funnel, diluted with water and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The residue was purified with a 50 g SNAP column (Biotage) ramping EtOAc in heptane (0-35%, then isocratic at 35%) to elute (S)-3-(6-fluoropyridin-3-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.815 g, 2.85 mmol, 72.6% yield) which was obtained as a white solid upon drying. 1H NMR (400 MHz, CDCl3) δ=8.21 (ddd, J=3.0, 6.8, 9.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.41-7.34 (m, 3H), 7.20-7.16 (m, 2H), 6.88 (ddd, J=0.6, 3.5, 8.9 Hz, 1H), 5.00 (s, 1H), 1.71 (s, 3H), 1.04 (s, 3H). m/z (ESI) 287.1 (M+H)+. The vessel was purged with nitrogen The vessel was heated to reflux overnight providing an orange suspension the resulting slurry was filtered through Celite® brand filter aid The yellow filtrate was transferred to a separatory funnel diluted with water extracted with EtOAc (2×) The combined organic layers were dried with Na2SO4 filtered dried under reduced pressure The residue was purified with a 50 g SNAP column (Biotage)

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

Procedure: To a round bottom flask were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (0.750 g, 3.92 mmol), 2-fluoro-5-iodopyridine (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.749 g, 7.84 mmol), and dioxane (15.69 mL). Tribasic potassium phosphate (4.16 g, 19.61 mmol) was then added to the mixture. The vessel was purged with nitrogen followed by the addition of N,N′-dimethylethylenediamine (0.844 mL, 7.84 mmol) and copper (I) iodide (0.747 g, 3.92 mmol). The vessel was heated to reflux overnight providing an orange suspension. To the mixture was added water (˜10 mL), and the resulting slurry was filtered through Celite® brand filter aid. The yellow filtrate was transferred to a separatory funnel, diluted with water and extracted with EtOAc (2×). The combined organic layers were dried with Na2SO4, filtered, and dried under reduced pressure. The residue was purified with a 50 g SNAP column (Biotage) ramping EtOAc in heptane (0-35%, then isocratic at 35%) to elute (S)-3-(6-fluoropyridin-3-yl)-5,5-dimethyl-4-phenyloxazolidin-2-one (0.815 g, 2.85 mmol, 72.6% yield) which was obtained as a white solid upon drying. 1H NMR (400 MHz, CDCl3) δ=8.21 (ddd, J=3.0, 6.8, 9.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.41-7.34 (m, 3H), 7.20-7.16 (m, 2H), 6.88 (ddd, J=0.6, 3.5, 8.9 Hz, 1H), 5.00 (s, 1H), 1.71 (s, 3H), 1.04 (s, 3H). m/z (ESI) 287.1 (M+H)+. The vessel was purged with nitrogen The vessel was heated to reflux overnight providing an orange suspension the resulting slurry was filtered through Celite® brand filter aid The yellow filtrate was transferred to a separatory funnel diluted with water extracted with EtOAc (2×) The combined organic layers were dried with Na2SO4 filtered dried under reduced pressure The residue was purified with a 50 g SNAP column (Biotage)

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

Procedure: To a round bottom flask were added (S)-5,5-dimethyl-4-phenyloxazolidin-2-one (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (1.717 g, 8.98 mmol), methyl 4-iodobenzoate (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (2.353 g, 8.98 mmol), and dioxane (90 mL). Tribasic potassium phosphate (9.53 g, 44.9 mmol), and copper (I) iodide (1.710 g, 8.98 mmol) were then added to the flask. The vessel was purged with nitrogen and N,N′-dimethylethylenediamine (1.933 mL, 17.96 mmol) was added. The suspension was heated at reflux overnight yielding a tan suspension. The mixture was filtered through Celite® brand filter aid, and the filtrate was dried under reduced pressure providing (S)-methyl 4-(5,5-dimethyl-2-oxo-4-phenyloxazolidin-3-yl)benzoate (2.72 g, 8.36 mmol, 93% yield) as a light green oil which was used in the next step. 1H NMR (400 MHz, CDCl3) δ=7.94-7.90 (m, 2H), 7.55-7.51 (m, 2H), 7.39-7.32 (m, 3H), 7.21-7.16 (m, 2H), 5.04 (s, 1H), 3.86 (s, 3H), 1.70 (s, 3H), 1.02 (s, 3H). was added The suspension was heated at reflux overnight yielding a tan suspension The mixture was filtered through Celite® brand filter aid the filtrate was dried under reduced pressure