methyl 2,2,2-trimethoxyacetate

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

Procedure: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-7-amino-8-hydroxyquinoline (6 g, 30.8 mol) and methyl trimethoxyacetate (16.3 g, 123.2 mol) was heated at 100° C. overnight. The reaction was cooled in an ice bath and filtered. The precipitate was dissolved in acetone (250 ml). The resulting solution was treated with charcoal at reflux, filtered through a pad of silica gel and celite and partially concentrated. Crystals formed which were filtered and dried giving 4.1 g (51% yield) of solid. M.P. 217°-218° C. The reaction was cooled in an ice bath filtered The precipitate was dissolved in acetone (250 ml) The resulting solution was treated with charcoal at reflux filtered through a pad of silica gel and celite partially concentrated Crystals formed which were filtered dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-7-amino-8-hydroxyquinoline (6 g, 30.8 mol) and methyl trimethoxyacetate (16.3 g, 123.2 mol) was heated at 100° C. overnight. The reaction was cooled in an ice bath and filtered. The precipitate was dissolved in acetone (250 ml). The resulting solution was treated with charcoal at reflux, filtered through a pad of silica gel and celite and partially concentrated. Crystals formed which were filtered and dried giving 4.1 g (51% yield) of solid. M.P. 217°-218° C. The reaction was cooled in an ice bath filtered The precipitate was dissolved in acetone (250 ml) The resulting solution was treated with charcoal at reflux filtered through a pad of silica gel and celite partially concentrated Crystals formed which were filtered dried

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

Procedure: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-7-amino-8-hydroxyquinoline (6 g, 30.8 mol) and methyl trimethoxyacetate (16.3 g, 123.2 mol) was heated at 100° C. overnight. The reaction was cooled in an ice bath and filtered. The precipitate was dissolved in acetone (250 ml). The resulting solution was treated with charcoal at reflux, filtered through a pad of silica gel and celite and partially concentrated. Crystals formed which were filtered and dried giving 4.1 g (51% yield) of solid. M.P. 217°-218° C. The reaction was cooled in an ice bath filtered The precipitate was dissolved in acetone (250 ml) The resulting solution was treated with charcoal at reflux filtered through a pad of silica gel and celite partially concentrated Crystals formed which were filtered dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 5-chloro-7-amino-8-hydroxyquinoline (6 g, 30.8 mol) and methyl trimethoxyacetate (16.3 g, 123.2 mol) was heated at 100° C. overnight. The reaction was cooled in an ice bath and filtered. The precipitate was dissolved in acetone (250 ml). The resulting solution was treated with charcoal at reflux, filtered through a pad of silica gel and celite and partially concentrated. Crystals formed which were filtered and dried giving 4.1 g (51% yield) of solid. M.P. 217°-218° C. The reaction was cooled in an ice bath filtered The precipitate was dissolved in acetone (250 ml) The resulting solution was treated with charcoal at reflux filtered through a pad of silica gel and celite partially concentrated Crystals formed which were filtered dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-aminobenzene-1,3-diol hydrochloride (i in Scheme 1) (0.50 g, 3.1 mmol) and sodium hydrogen carbonate (2.5 mg) in methyl trimethoxyacetate (2 mL) was stirred at 100° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1) to afford methyl 6-hydroxybenzo[d]oxazole-2-carboxylate as a white solid (0.49 g, 82%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.26 (s, 1H), 7.70 (m, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 3.92 (s, 3H) ppm; MS (ESI): 194.3 (M+1). concentrated under reduced pressure The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-aminobenzene-1,3-diol hydrochloride (i in Scheme 1) (0.50 g, 3.1 mmol) and sodium hydrogen carbonate (2.5 mg) in methyl trimethoxyacetate (2 mL) was stirred at 100° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1) to afford methyl 6-hydroxybenzo[d]oxazole-2-carboxylate as a white solid (0.49 g, 82%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.26 (s, 1H), 7.70 (m, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 3.92 (s, 3H) ppm; MS (ESI): 194.3 (M+1). concentrated under reduced pressure The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1)

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-aminobenzene-1,3-diol hydrochloride (i in Scheme 1) (0.50 g, 3.1 mmol) and sodium hydrogen carbonate (2.5 mg) in methyl trimethoxyacetate (2 mL) was stirred at 100° C. overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1) to afford methyl 6-hydroxybenzo[d]oxazole-2-carboxylate as a white solid (0.49 g, 82%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.26 (s, 1H), 7.70 (m, 1H), 7.12 (m, 1H), 6.95 (m, 1H), 3.92 (s, 3H) ppm; MS (ESI): 194.3 (M+1). concentrated under reduced pressure The residue obtained was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=9/1)

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

Procedure: A 500 mL round bottom flask was charged with methyl 2,2-dichloro-2-methoxyacetate (50 g, 248.5 mmol, 1 equiv). This was cooled to 0° C. with an ice bath at which point anhydrous methanol (34.33 g, 745.7 mmol, 44 mL, 3 equiv) was added with stirring over the course of 5 minutes. The mixture was then immediately diluted with anhydrous diethyl ether (150 mL). While maintaining the reaction at 0° C. with an external ice bath, anhydrous pyridine (49.10 g, 621.4 mmol, 50.20 mL, 2.5 equiv) was added via a pressure equalizing addition funnel over 1 hour. The reaction mixture was then rapidly stirred for an additional 30 minutes at 0° C. The stirring was then stopped and the mixture allowed to stand at room temperature for 72 hours where upon long white needles were formed in solution. The resulting mixture was filtered through a medium porosity glass frit, and the recovered solids were washed with diethyl ether. The filtrate was then concentrated by rotary evaporation under reduced pressure to yield a pale yellow oil. This oil was subsequently cooled to 0° C. with an ice bath. The oil was then rapidly stirred, and pyrrolidine (25 mL) was added in a drop wise fashion, by means of a pressure equalizing addition funnel, over a period of 20 minutes. The solution rapidly turned yellowish-orange in color. Upon completion of addition of the pyrrolidine, the mixture was stirred for an additional 30 minutes at 0° C., and then subjected to a reduced pressure distillation collecting unreacted pyrrolidine and ethanol at 40 Torr and 28° C. followed by the desired material, methyl 2,2,2-trimethoxyacetate (44 g, 80% yield) at 2 Torr and 58° C., as a colorless liquid. was added While maintaining the reaction at 0° C. with an external ice bath addition funnel over 1 hour The reaction mixture was then rapidly stirred for an additional 30 minutes at 0° C to stand at room temperature for 72 hours where upon long white needles were formed in solution The resulting mixture was filtered through a medium porosity glass frit the recovered solids were washed with diethyl ether The filtrate was then concentrated by rotary evaporation under reduced pressure to yield a pale yellow oil The oil was then rapidly stirred addition funnel over a period of 20 minutes the mixture was stirred for an additional 30 minutes at 0° C. subjected to a reduced pressure distillation collecting unreacted pyrrolidine and ethanol at 40 Torr and 28° C.

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

Procedure: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH

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

Procedure: A solution of 2-amino-6-fluorophenol (14) (254 mg, 2 mmol) and methyl 2,2,2-trimethoxyacetate (15) (328 mg, 2 mmol) in 3 ml MeOH was heated in micro wave reactor at 140° C. for 1 h. After cooling down to r.t. crystals formed. Filtration followed by washing with MeOH furnished 208 mg of methyl 7-fluorobenzoxazole-2-carboxylate (16) as brown needles. Yield: 53.3%. LC-MS: calculated M=195.15; observed M=195.96. formed Filtration by washing with MeOH