5-fluoro-2-methylphenol

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

Procedure: A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to −30° C. to −40° C. and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SiO2 (5% ethyl acetate in hexanes) gave 0.58 g of the title product as bright yellow solid (68% yield). extracted with three 50 mL portions of dichloromethane The combined organic layers were washed with three 25 mL portions of water dried over sodium sulfate concentrated in vacuo to give a reddish crystalline solid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2-methylphenylamine (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0° C. for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130° C. over 10 minutes. After an additional 5 minutes at 130° C., the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10% aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HCl and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 mL portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99% yield). The mixture was cooled in an ice bath for 30 minutes After an additional 5 minutes at 130° C. to cool to room temperature was extracted with three 100 mL portions of dichloromethane The combined organic layers were washed with two 50 mL portions of water concentrated in vacuo The reddish oil was dissolved in 250 mL of diethyl ether washed with three 50 mL portions of 10% aqueous sodium hydroxide The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether extracted with three 100 mL portions of dichloromethane The combined dichloromethane layers were washed with two 50 mL portions of brine dried over sodium sulfate filtered concentrated in vacuo to give a light reddish liquid The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol (330 μL, 3.02 mmol), and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (80 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound mg) as a colorless solid. (Yield 92%) After cooling down partitioned The organic layer was washed with saturated brine (50 mL) dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound mg) as a colorless solid

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol (330 μL, 3.02 mmol), and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (80 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound mg) as a colorless solid. (Yield 92%) After cooling down partitioned The organic layer was washed with saturated brine (50 mL) dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound mg) as a colorless solid

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

Procedure: To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 5-fluoro-2-methylphenol (20 μL. 0.18 mmoL) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(5-fluoro-2-methyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (24 mg, 69%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.38 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.2 Hz, 2H), 7.52-7.65 (m, 3H), 7.16 (t, J=7.5 Hz, 1H), 6.92 (dd, J=11.3, 2.6 Hz, 1H), 6.67 (td, J=8.5, 2.7 Hz, 1H), 5.20 (s, 2H), 2.16 (s, 3H). evaporated to dryness The residue was purified by chromatography (66-75% EtOAc/hexanes)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol (330 μL, 3.02 mmol), and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (80 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (945 mg) as a colorless solid. (Yield 92%) After cooling down partitioned The organic layer was washed with saturated brine (50 mL) dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 7-bromo-8-chloromethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 7, 801 mg, 2.52 mmol), 5-fluoro-2-methylphenol (330 μL, 3.02 mmol), and potassium carbonate (524 mg, 3.79 mmol) was suspended in anhydrous N,N-dimethylformamide (10 mL) and stirred at 80° C. overnight. After cooling down, ethyl acetate (80 mL) and water (50 mL) were added to the reaction mixture and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (945 mg) as a colorless solid. (Yield 92%) After cooling down partitioned The organic layer was washed with saturated brine (50 mL) dried over anhydrous magnesium sulfate the solvent was removed under reduced pressure The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate)

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

Procedure: A stirred solution of 5-fluoro-2-methylphenol (640 mg, 5 mmol) in 20 mL of anhydrous acetonitrile was cooled to −30° C. to −40° C. and treated with nitronium tetrafluoroborate (740 mg, 5.5 mmol). After 45 minutes, the reaction mixture was diluted with 100 mL of cold water and extracted with three 50 mL portions of dichloromethane. The combined organic layers were washed with three 25 mL portions of water, dried over sodium sulfate, and concentrated in vacuo to give a reddish crystalline solid. Chromatography over SiO2 (5% ethyl acetate in hexanes) gave 0.58 g of the title product as bright yellow solid (68% yield). extracted with three 50 mL portions of dichloromethane The combined organic layers were washed with three 25 mL portions of water dried over sodium sulfate concentrated in vacuo to give a reddish crystalline solid

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2-methylphenylamine (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0° C. for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130° C. over 10 minutes. After an additional 5 minutes at 130° C., the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10% aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HCl and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 mL portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99% yield). The mixture was cooled in an ice bath for 30 minutes After an additional 5 minutes at 130° C. to cool to room temperature was extracted with three 100 mL portions of dichloromethane The combined organic layers were washed with two 50 mL portions of water concentrated in vacuo The reddish oil was dissolved in 250 mL of diethyl ether washed with three 50 mL portions of 10% aqueous sodium hydroxide The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether extracted with three 100 mL portions of dichloromethane The combined dichloromethane layers were washed with two 50 mL portions of brine dried over sodium sulfate filtered concentrated in vacuo to give a light reddish liquid The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes)

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 7 mL of a hot solution of concentrated sulfuric acid in 21 mL of water was added to 5-fluoro-2-methylphenylamine (5 g, 40 mmol). The mixture was cooled in an ice bath for 30 minutes and treated with a solution of sodium nitrite (3.38 g, 48 mmol) in 10 mL of water over a period of 10 minutes. After stirring at 0° C. for 45 minutes, the reaction was diluted with 20 mL of cold water and treated with 0.3 g of urea. The resulting mixture was added to a stirred solution of 11 mL of concentrated sulfuric acid in 10 mL of water containing 15 g of anhydrous sodium sulfate at 130° C. over 10 minutes. After an additional 5 minutes at 130° C., the reaction was allowed to cool to room temperature and was extracted with three 100 mL portions of dichloromethane. The combined organic layers were washed with two 50 mL portions of water and concentrated in vacuo. The reddish oil was dissolved in 250 mL of diethyl ether and washed with three 50 mL portions of 10% aqueous sodium hydroxide. The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether. The basic layer was acidified with 1 N aqueous HCl and extracted with three 100 mL portions of dichloromethane. The combined dichloromethane layers were washed with two 50 mL portions of brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a light reddish liquid. The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes) to give 5 g of 5-fluoro-2-methylphenol as a light brownish oil (99% yield). The mixture was cooled in an ice bath for 30 minutes After an additional 5 minutes at 130° C. to cool to room temperature was extracted with three 100 mL portions of dichloromethane The combined organic layers were washed with two 50 mL portions of water concentrated in vacuo The reddish oil was dissolved in 250 mL of diethyl ether washed with three 50 mL portions of 10% aqueous sodium hydroxide The combined aqueous sodium hydroxide extracts were washed with two 50 mL portions of diethyl ether extracted with three 100 mL portions of dichloromethane The combined dichloromethane layers were washed with two 50 mL portions of brine dried over sodium sulfate filtered concentrated in vacuo to give a light reddish liquid The crude was purified by chromatography on SiO2 (10% ethyl acetate in hexanes)

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

Procedure: A mixture of 7-bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 805 mg, 2.69 mmol), 5-fluoro-2-methylphenol (382 μL, 3.50 mmol), and tri-n-butylphosphine (874 μL, 3.50 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), 1,1′-(azodicarbonyl)dipiperidine (883 mg, 3.50 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. 5-Fluoro-2-methylphenol (382 μL, 3.50 mmol), tri-n-butylphosphine (874 μL, 3.50 mmol), and 1,1′-(azodicarbonyl)dipiperidine (890 mg, 3.53 mmol) were added thereto and it was furthermore stirred for 20 minutes. After hexane (15 mL) was added to the reaction mixture and the precipitated solids were filtered out, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (900 mg) as a colorless solid. (Yield 82%) it was furthermore stirred for 20 minutes the precipitated solids were filtered out the filtrate was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate)

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

Procedure: A mixture of 7-bromo-8-hydroxymethyl-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 1, 805 mg, 2.69 mmol), 5-fluoro-2-methylphenol (382 μL, 3.50 mmol), and tri-n-butylphosphine (874 μL, 3.50 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), 1,1′-(azodicarbonyl)dipiperidine (883 mg, 3.50 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. 5-Fluoro-2-methylphenol (382 μL, 3.50 mmol), tri-n-butylphosphine (874 μL, 3.50 mmol), and 1,1′-(azodicarbonyl)dipiperidine (890 mg, 3.53 mmol) were added thereto and it was furthermore stirred for 20 minutes. After hexane (15 mL) was added to the reaction mixture and the precipitated solids were filtered out, the filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (900 mg) as a colorless solid. (Yield 82%) it was furthermore stirred for 20 minutes the precipitated solids were filtered out the filtrate was concentrated under reduced pressure the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate)