(4R)-4-propan-2-yl-1,3-oxazolidin-2-one

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cooled (−10° C.) solution of 8-(4-fluoro-3-methylphenyl)octanoic acid (0.486 g, 1.926 mmol) in 15 mL of THF, were added stepwise triethylamine (0.69 mL, 4.952 mmol) and pivaloyl chloride (0.23 mL, 1.889 mmol). The reaction mixture was stirred at −10° C. for 1 h and then LiCl (0.080 g, 1.889 mmol) and (R)-4-iso-propyloxazolidin-2-one (0.237 g, 1.834 mmol) were added stepwise. After being warmed slowly to room temperature and stirred for overnight, the reaction mixture was diluted with ethyl acetate (80 mL) and washed with saturated NaHCO3 solution and brine. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes to give the title compound as colorless oil (0.547 g, 82% yield). GC-MS: tR=6.9 min; m/z 363 (M+). After being warmed slowly to room temperature stirred for overnight washed with saturated NaHCO3 solution and brine The organic layer was dried (Na2SO4) filtered concentrated under reduced pressure The product was isolated by Flash column chromatography (silica gel column) eluting with 0-100% dichloromethane/hexanes

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

Procedure: A solution of 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide (84 mg, 0.25 mmol), (R)-4-isopropyloxazolidin-2-one (32 mg, 0.25 mmol), N,N-dimethylethane-1,2-diamine (2 mg, 0.025 mmol), copper(I) iodide (5 mg, 0.025 mmol) and potassium carbonate (121 mg, 0.88 mmol) in dioxane (1 ml) was stirred at 110° C. overnight. Concentration and reverse phase chromatography provided the title compound. 1H NMR (400 MHz, methanol-d4) δ ppm 9.13 (t, J=5.3 Hz, 1H), 8.74 (d, J=5.5 Hz, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.62 (d, J=4.1 Hz, 1H), 7.47 (d, J=7.0 Hz, 1H), 6.77 (d, J=4.2 Hz, 1H), 4.72 (s, 2H), 4.61-4.42 (m, 3H), 2.46 (ddd, J=10.2, 6.9, 3.5 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H); (APCI(+)) m/e 385 (M+H)+. Concentration

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

Procedure: A solution of 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide (84 mg, 0.25 mmol), (R)-4-isopropyloxazolidin-2-one (32 mg, 0.25 mmol), N,N-dimethylethane-1,2-diamine (2 mg, 0.025 mmol), copper(I) iodide (5 mg, 0.025 mmol) and potassium carbonate (121 mg, 0.88 mmol) in dioxane (1 ml) was stirred at 110° C. overnight. Concentration and reverse phase chromatography provided the title compound. 1H NMR (400 MHz, methanol-d4) δ ppm 9.13 (t, J=5.3 Hz, 1H), 8.74 (d, J=5.5 Hz, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.79 (s, 1H), 7.62 (d, J=4.1 Hz, 1H), 7.47 (d, J=7.0 Hz, 1H), 6.77 (d, J=4.2 Hz, 1H), 4.72 (s, 2H), 4.61-4.42 (m, 3H), 2.46 (ddd, J=10.2, 6.9, 3.5 Hz, 1H), 1.00 (d, J=7.0 Hz, 3H), 0.85 (d, J=6.8 Hz, 3H); (APCI(+)) m/e 385 (M+H)+. Concentration

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 27.2 g (168.7 mmol) of the compound from Example V are dissolved in 400 ml of toluene and stirred under reflux in an oil bath at 150° C. while passing in nitrogen.

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 27.2 g (168.7 mmol) of the compound from Example V are dissolved in 400 ml of toluene and stirred under reflux in an oil bath at 150° C. while passing in nitrogen.

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

Procedure: A solution of (E) 3-[6-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-(S), 4-dimethylhexanoyl)-4-(R)-isopropyl-2-oxazolidinone (1.3 g) and p-toluenesulphonic acid (0.6 g) in methanol (25 ml) was left at room temperature for 24 hours. The solution was diluted with methylene chloride and washed with dilute aqueous sodium bicarbonate and water, then dried and evaporated. The residue was chromatographed on silica gel, eluting with 99.2:0.8 methylene chloride methanol, to give (E) 3-[6-(1,3-dihydro-6-methoxy-4-hydroxy-7-methyl-3-oxoisobenzofuran-5-yl)]-2-(S), 4-dimethylhexanoyl)-4-(R) -isopropyl-2-oxazolidinone, mp 127°-128-C (hexane/methylene chloride). washed with dilute aqueous sodium bicarbonate and water dried evaporated The residue was chromatographed on silica gel eluting with 99.2:0.8 methylene chloride methanol

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 27.2 g (168.7 mmol) of the compound from Example V are dissolved in 400 ml of toluene and stirred under reflux in an oil bath at 150° C. while passing in nitrogen.

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H). to slowly warm to room temperature stirred for 3 days was then quenched with saturated ammonium chloride The aqueous layer was extracted with ethyl acetate (2×) dried over anhydrous sodium sulfate filtered the volatiles were removed in vacuo The residue was purified by silica gel chromatography eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H). to slowly warm to room temperature stirred for 3 days was then quenched with saturated ammonium chloride The aqueous layer was extracted with ethyl acetate (2×) dried over anhydrous sodium sulfate filtered the volatiles were removed in vacuo The residue was purified by silica gel chromatography eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H). to slowly warm to room temperature stirred for 3 days was then quenched with saturated ammonium chloride The aqueous layer was extracted with ethyl acetate (2×) dried over anhydrous sodium sulfate filtered the volatiles were removed in vacuo The residue was purified by silica gel chromatography eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A cooled (−20° C.) solution of tiglic acid (2.005 g, 20.031 mmol) in anhydrous tetrahydrofuran (50 mL) was sequentially treated with triethylamine (6.1 mL, 44.068 mmol) and dropwise pivaloyl chloride (2.7 mL, 22.034 mmol). After stirring at −20° C. for 30 min, lithium chloride (1.019 g, 24.037 mmol) and (R)-(+)-4-isopropyl-2-oxazolidinone (2.587 g, 20.031 mmol) were added. The reaction mixture was allowed to slowly warm to room temperature, stirred for 3 days and was then quenched with saturated ammonium chloride. The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1 to afford the title compound (3.307 g, 78%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 0.92 (d, J=6.9 Hz, 3H), 0.94 (d, J=7.1 Hz, 3H), 1.83 (d, J=6.9 Hz, 3H), 1.93 (s, 3H), 2.38 (d of heptet, J=6.9, 4.2 Hz, 1H), 4.19 (dd, J=8.9, 4.6 Hz, 1H), 4.33 (app t, J=8.9 Hz, 1H), 4.49-4.58 (m, 1H), 6.23 (q, J=7.1 Hz, 1H). to slowly warm to room temperature stirred for 3 days was then quenched with saturated ammonium chloride The aqueous layer was extracted with ethyl acetate (2×) dried over anhydrous sodium sulfate filtered the volatiles were removed in vacuo The residue was purified by silica gel chromatography eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 4:1

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 27.2 g (168.7 mmol) of the compound from Example V are dissolved in 400 ml of toluene and stirred under reflux in an oil bath at 150° C. while passing in nitrogen.