1-bromo-2,5-dichloro-3-fluorobenzene

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 160 mmol) and sodium methoxide (44.3 g, 820 mmol) were stirred in methanol (500 ml) at reflux for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried over Na2SO4 and evaporated to afford the title compound as a white solid (40 g). at reflux for 16 hours then quenched with water (500 ml) The mixture was extracted with diethyl ether (3×300 ml) dried over Na2SO4 evaporated

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

Procedure: 1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 160 mmol) and sodium methoxide (44.3 g, 820 mmol) were stirred in methanol (500 ml) at reflux for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried over Na2SO4 and evaporated to afford the title compound as a white solid (40 g). at reflux for 16 hours then quenched with water (500 ml) The mixture was extracted with diethyl ether (3×300 ml) dried over Na2SO4 evaporated

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

Procedure: Methanol (5 mL) was added to potassium tert-butoxide (3.94 g, 123 mmol) suspended in toluene/DMPU (3:1, 240 mL), and the mixture was placed in an oil bath at 80° C. under N2 with a reflux condenser for 25 minutes to obtain a solution. The solution was then allowed to cool to room temperature under N2, after which 1-bromo-2,5-dichloro-3-fluorobenzene (10 g, 41 mmol) was added dropwise to the solution and the resulting suspension was placed in an oil bath at 80° C. under N2. After 4 hours, the reaction mixture was allowed to cool to room temperature and was then diluted with hexanes (200 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with hexanes (200 mL). The combined organic portions were washed with water (3×300 mL), dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 7.20 (m, 1H), 6.80 (m, 1H), 3.90 (s, 3H). to obtain a solution the resulting suspension was placed in an oil bath at 80° C. under N2 After 4 hours to cool to room temperature The layers were separated the aqueous layer was extracted with hexanes (200 mL) The combined organic portions were washed with water (3×300 mL) dried (MgSO4) filtered concentrated

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

Procedure: Methanol (5 mL) was added to potassium tert-butoxide (3.94 g, 123 mmol) suspended in toluene/DMPU (3:1, 240 mL), and the mixture was placed in an oil bath at 80° C. under N2 with a reflux condenser for 25 minutes to obtain a solution. The solution was then allowed to cool to room temperature under N2, after which 1-bromo-2,5-dichloro-3-fluorobenzene (10 g, 41 mmol) was added dropwise to the solution and the resulting suspension was placed in an oil bath at 80° C. under N2. After 4 hours, the reaction mixture was allowed to cool to room temperature and was then diluted with hexanes (200 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with hexanes (200 mL). The combined organic portions were washed with water (3×300 mL), dried (MgSO4), filtered and concentrated to give the title compound. 1H NMR (CDCl3) δ 7.20 (m, 1H), 6.80 (m, 1H), 3.90 (s, 3H). to obtain a solution the resulting suspension was placed in an oil bath at 80° C. under N2 After 4 hours to cool to room temperature The layers were separated the aqueous layer was extracted with hexanes (200 mL) The combined organic portions were washed with water (3×300 mL) dried (MgSO4) filtered concentrated

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: 1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 0.16 mol) and sodium methoxide (44.3 g, 0.82 mol) were stirred in methanol (500 ml) at the reflux temperature for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried (Na2SO4) and evaporated to afford the product as a white solid (40 g) then quenched with water (500 ml) The mixture was extracted with diethyl ether (3×300 ml) dried (Na2SO4) evaporated

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 6-chloro-2-fluoro-3-methylphenol (3.3 g, 20.55 mmol) and 18-crown-6 (1.086 g, 4.11 mmol) were dissolved in dry DMSO (50 mL) and treated with 20% potassium t-butoxide in THF (11.50 g, 20.55 mmol) for 15 minutes at room temperature. 1-bromo-2,5-dichloro-3-fluorobenzene (7.21 g, 29.6 mmol) was added in one portion and the reaction mixture heated at 110° C. for 3 days at which time LC-MS indicated nearly complete consumption of phenol and formation of a major new product. Addition of water to the reaction mixture resulted in a brown gummy oil which was extracted with EtOAc. The organic phase was isolated, washed with brine four times, dried over MgSO4, filtered and concentrated to dryness to give a brown syrup. This material was filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM. The filtrate was concentrated to an amber oil and crystallized from EtOH and a few drops of water. This mixture was cooled in an ice bath, filtered, and the precipitate washed with three portions of cold EtOH to give 2-[(3-bromo-2,5-dichlorophenyl)oxy]-1-chloro-3-fluoro-4-methylbenzene (4.0 g, 10.40 mmol, 50.6% yield) as a cream solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (s, 1H), 7.29-7.47 (m, 2H), 6.81 (s, 1H), 2.29 (s, 3H). consumption of phenol and formation of a major new product Addition of water to the reaction mixture resulted in a brown gummy oil which was extracted with EtOAc The organic phase was isolated washed with brine four times dried over MgSO4 filtered concentrated to dryness to give a brown syrup This material was filtered through a plug of 45 g silica gel which was eluted with 500 mL DCM The filtrate was concentrated to an amber oil crystallized from EtOH and a few drops of water This mixture was cooled in an ice bath filtered the precipitate washed with three portions of cold EtOH

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

Procedure: The same method as in Example 3 was conducted using 2-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 44) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3-bromo-2,5-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound. to give the objective compound

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

Procedure: 1-Bromo-2,5-dichloro-3-fluorobenzene (40 g, 160 mmol) and sodium methoxide (44.3 g, 820 mmol) were stirred in methanol (500 ml) at reflux for 16 hours. The reaction was cooled to ambient temperature then quenched with water (500 ml). The mixture was extracted with diethyl ether (3×300 ml), dried over Na2SO4 and evaporated to afford the title compound as a white solid (40 g). at reflux for 16 hours then quenched with water (500 ml) The mixture was extracted with diethyl ether (3×300 ml) dried over Na2SO4 evaporated