1-bromo-2-ethoxy-4-fluorobenzene

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-bromo-2-ethoxy-4-fluorobenzene (2.0 g) in DMF (20 mL) was added sodium methanethiolate (1.66 g). The mixture was stirred for 2 h at 65° C. The mixture was cooled to room temperature and ethyl iodide (1.3 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.65 g of the title compound. The mixture was cooled to room temperature The mixture was stirred at room temperature for 1 h the mixture was extracted with ethyl acetate The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

Procedure: To a stirred solution of 2-bromo-5-fluorophenol (5.0 g) in DMF (30 mL) was added potassium carbonate (10.8 g) and iodoethane (6.12 g). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and hexane (3:1). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 5.06 g of the title compound as a crude product, that was used for the next step without purification. The solvent was removed in vacuum Water was added the mixture was extracted with a mixture of ethyl acetate and hexane (3:1) The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

Procedure: To a stirred solution of 2-bromo-5-fluorophenol (5.0 g) in DMF (30 mL) was added potassium carbonate (10.8 g) and iodoethane (6.12 g). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and hexane (3:1). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 5.06 g of the title compound as a crude product, that was used for the next step without purification. The solvent was removed in vacuum Water was added the mixture was extracted with a mixture of ethyl acetate and hexane (3:1) The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

Procedure: Making Grignard reagent: A solution of 2-ethoxy-4-fluorophenyl bromide (30 g, 138 mmol) in THF (140 ml) was added dropwisely into a stirred mixture of magnesium flake and catalytically amount of iodine under nitrogen. The result mixture was heated to reflux for 15 minutes and cooled to room temperature (Grignard reagent). In a separated flask, 6-chloro-2-methyl-4H-benzo[d][1,3]oxazin-4-one (25 g, 128 mmole) was dissolved into THF (200 ml) and stirred under nitrogen. The Grignard reagent was transferred slowly into the flask during 30 minutes. The reaction temperature was kept below 55° C. during addition. The result mixture was stirred for further 2 hours under nitrogen. The reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml). The reaction was extracted into MTBE (500 ml). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated on a rotary evaporator to solid. The solid was sonicated for 5 minutes in ethyl acetate (250 ml) and filtered. The filtrate was concentrated on a rotary evaporator to about 70 ml and cooled at −20° C. for 4 hours. During this time, crystallized product came out and was collected by filtration (25 g, yield: 58%). 1H NMR (CDCl3): 11.2 (br, 1H), 8.73 (d, J=22 Hz, 1H), 7.49 (dd, J=24 Hz, 7 Hz, 1H), 7.38 (d, J=6 Hz, 1H), 7.2 (m, 1H), 7.07 (dd, J=20 Hz, 8 Hz, 1H), 6.93 (m, 1H), 3.97 (q, J=17 Hz, 2H), 2.27 (s, 1H), 1.13 (tr, J=17 Hz, 3H). The result mixture was heated to reflux for 15 minutes The reaction temperature was kept below 55° C. during addition The result mixture was stirred for further 2 hours under nitrogen The reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml) The reaction was extracted into MTBE (500 ml) The organic layer was washed with brine dried (Na2SO4) filtered concentrated on a rotary evaporator to solid The solid was sonicated for 5 minutes in ethyl acetate (250 ml) filtered The filtrate was concentrated on a rotary evaporator to about 70 ml During this time, crystallized product was collected by filtration (25 g, yield: 58%)

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred solution of 1-bromo-2-ethoxy-4-fluorobenzene (2.0 g) in DMF (20 mL) was added sodium methanethiolate (1.66 g). The mixture was stirred for 2 h at 65° C. The mixture was cooled to room temperature and ethyl iodide (1.3 mL) was added. The mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Silica gel chromatography gave 1.65 g of the title compound. The mixture was cooled to room temperature The mixture was stirred at room temperature for 1 h the mixture was extracted with ethyl acetate The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

Procedure: To a stirred solution of 2-bromo-5-fluorophenol (5.0 g) in DMF (30 mL) was added potassium carbonate (10.8 g) and iodoethane (6.12 g). The mixture was stirred at room temperature for 16 h. The solvent was removed in vacuum. Water was added and the mixture was extracted with a mixture of ethyl acetate and hexane (3:1). The organic phase was washed with saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum, to give 5.06 g of the title compound as a crude product, that was used for the next step without purification. The solvent was removed in vacuum Water was added the mixture was extracted with a mixture of ethyl acetate and hexane (3:1) The organic phase was washed with saturated sodium chloride solution dried (sodium sulfate) the solvent was removed in vacuum

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

Procedure: Making Grignard reagent: A solution of 2-ethoxy-4-fluorophenyl bromide (30 g, 138 mmol) in THF (140 ml) was added dropwisely into a stirred mixture of magnesium flake and catalytically amount of iodine under nitrogen. The result mixture was heated to reflux for 15 minutes and cooled to room temperature (Grignard reagent). In a separated flask, 6-chloro-2-methyl-4H-benzo[d][1,3]oxazin-4-one (25 g, 128 mmole) was dissolved into THF (200 ml) and stirred under nitrogen. The Grignard reagent was transferred slowly into the flask during 30 minutes. The reaction temperature was kept below 55° C. during addition. The result mixture was stirred for further 2 hours under nitrogen. The reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml). The reaction was extracted into MTBE (500 ml). The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated on a rotary evaporator to solid. The solid was sonicated for 5 minutes in ethyl acetate (250 ml) and filtered. The filtrate was concentrated on a rotary evaporator to about 70 ml and cooled at −20° C. for 4 hours. During this time, crystallized product came out and was collected by filtration (25 g, yield: 58%). 1H NMR (CDCl3): 11.2 (br, 1H), 8.73 (d, J=22 Hz, 1H), 7.49 (dd, J=24 Hz, 7 Hz, 1H), 7.38 (d, J=6 Hz, 1H), 7.2 (m, 1H), 7.07 (dd, J=20 Hz, 8 Hz, 1H), 6.93 (m, 1H), 3.97 (q, J=17 Hz, 2H), 2.27 (s, 1H), 1.13 (tr, J=17 Hz, 3H). The result mixture was heated to reflux for 15 minutes The reaction temperature was kept below 55° C. during addition The result mixture was stirred for further 2 hours under nitrogen The reaction was quenched by slowly addition of aqueous solution of ammonium chloride (30 g/300 ml) The reaction was extracted into MTBE (500 ml) The organic layer was washed with brine dried (Na2SO4) filtered concentrated on a rotary evaporator to solid The solid was sonicated for 5 minutes in ethyl acetate (250 ml) filtered The filtrate was concentrated on a rotary evaporator to about 70 ml During this time, crystallized product was collected by filtration (25 g, yield: 58%)