ethyl 4-amino-3,5-dimethylbenzoate

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

Procedure: Ethyl 4-amino-3,5-dimethylbenzoate (2.0 g) was added to a tetrahydrofuran (THF) suspension of sodium hydride (0.82 g) in a nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. Subsequently, carbobenzoxychloride (4.4 ml) was added to the suspension and the mixture was stirred overnight. A small amount of water was added to the reaction solution and the mixture was poured into ice water, followed by extraction with ethyl acetate. Following washing and drying (with magnesium sulfate), the solvent was distilled off under vacuum. The resulting crystal was recovered by filtration in the presence of ethanol and dried under vacuum to yield the end product (3.2 g). the mixture was stirred overnight followed by extraction with ethyl acetate Following washing drying (with magnesium sulfate) the solvent was distilled off under vacuum The resulting crystal was recovered by filtration in the presence of ethanol dried under vacuum

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

Procedure: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (465 mg, 2.71 mmol) in THF (5 ml), CH2Cl2 (5 ml) and DMF (0.01 ml, 129.33 moles) is added dropwise oxalyl chloride (0.3 ml, 3.46 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure and the residue. To the residue CH2Cl2 (20 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (520 mg, 2.69 mmol) is added followed by N,N-dimethylpyridin-4-amine (15 mg, 122.78 moles) and Pyridine (0.66 ml, 8.16 mmoles). The cooling bath is removed and the clear yellow solution is allowed to warm to ambient temperature. After 1 hour, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel) using 0-50% ethyl acetate in hexanes to give the title compound as a solid (790 mg, 84%). Mass spectrum (m/z): 347.2 (M+1). reaction mixture the solvent is removed under reduced pressure To the residue CH2Cl2 (20 ml) is added reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 1 hour the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue is purified by flash chromatography (silica gel)

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

Procedure: To a solution of 5-bromo-2-methyl-benzoic acid (2.45 g, 11.16 mmol) in THF (10 ml), CH2Cl2 (10 ml) and DMF (20.00 μl, 258.65 moles) is added dropwise oxalyl chloride (1.16 ml, 13.39 mmoles) at 0° C. and the reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure. To the residue is added CH2Cl2 (40 ml) and the reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (2 g, 11.16 mmol) is added followed by N,N-dimethylpyridin-4-amine (13.63 mg, 0.11 mmoles) and pyridine (2.71 ml, 33.48 mmoles). The cooling bath is removed and the clear solution is allowed to warm to ambient temperature. After 2 hours, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 1N HCl, a saturated solution of sodium bicarbonate, and brine. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a light yellow solid (4.0 g; 95.5%). Mass spectrum (m/z): 376.0 (M+1). the solvent is removed under reduced pressure To the residue is added CH2Cl2 (40 ml) the reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 2 hours the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 1N HCl dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of 5-bromo-2-methyl-benzoic acid (1.35 g, 6.15 mmol) in THF (15 ml), CH2Cl2 (15 ml) and DMF (14.27 μl, 184.57 moles) is added dropwise oxalyl chloride (587.12 μl, 6.77 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure. To the residue CH2Cl2 (30 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (1.19 g, 6.15 mmol) is added followed by 4-pyridinamine, N,N-dimethyl-(37.58 mg, 307.61 mmoles) and pyridine (1.49 ml, 18.46 mmoles). The cooling bath is removed and the clear solution is allowed to warm to ambient temperature. After 5 hours, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 1N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is triturated with hexanes and the resulting solids were collected by filtration to give the title compound as a white solid (1.80 g; 75.2%). Mass spectrum (m/z): 390.2 (M+1). reaction mixture the solvent is removed under reduced pressure To the residue CH2Cl2 (30 ml) is added reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 5 hours the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 1N HCl, saturated solution of sodium bicarbonate, and brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The resulting residue is triturated with hexanes the resulting solids were collected by filtration

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

Procedure: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.78 g, 4.55 mmol) in CH2Cl2 (15 mL) at room temperature are added ethyl 4-amino-3,5-dimethyl-benzoate (0.878 g, 4.55 mmol) and N,N-diisopropylethylamine (1.98 ml, 11.36 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 3.25 ml, 5.46 mmol) is added via syringe. After 48 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification, the solid is triturated with 30% ethyl acetate in hexanes and filtered to give the title compound as a white powder (0.907 g, 57.5%). Mass spectrum (m/z): 347.2 (M+1). After 48 hours the solvent is removed under reduced pressure the residue is diluted with water extracted with ethyl acetate dried over magnesium sulfate filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel) After purification the solid is triturated with 30% ethyl acetate in hexanes filtered

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

Procedure: Ethyl 4-amino-3,5-dimethylbenzoate (2.0 g) was added to a tetrahydrofuran (THF) suspension of sodium hydride (0.82 g) in a nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. Subsequently, carbobenzoxychloride (4.4 ml) was added to the suspension and the mixture was stirred overnight. A small amount of water was added to the reaction solution and the mixture was poured into ice water, followed by extraction with ethyl acetate. Following washing and drying (with magnesium sulfate), the solvent was distilled off under vacuum. The resulting crystal was recovered by filtration in the presence of ethanol and dried under vacuum to yield the end product (3.2 g). the mixture was stirred overnight followed by extraction with ethyl acetate Following washing drying (with magnesium sulfate) the solvent was distilled off under vacuum The resulting crystal was recovered by filtration in the presence of ethanol dried under vacuum

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

Procedure: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (465 mg, 2.71 mmol) in THF (5 ml), CH2Cl2 (5 ml) and DMF (0.01 ml, 129.33 moles) is added dropwise oxalyl chloride (0.3 ml, 3.46 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure and the residue. To the residue CH2Cl2 (20 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (520 mg, 2.69 mmol) is added followed by N,N-dimethylpyridin-4-amine (15 mg, 122.78 moles) and Pyridine (0.66 ml, 8.16 mmoles). The cooling bath is removed and the clear yellow solution is allowed to warm to ambient temperature. After 1 hour, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel) using 0-50% ethyl acetate in hexanes to give the title compound as a solid (790 mg, 84%). Mass spectrum (m/z): 347.2 (M+1). reaction mixture the solvent is removed under reduced pressure To the residue CH2Cl2 (20 ml) is added reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 1 hour the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue is purified by flash chromatography (silica gel)

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

Procedure: To a solution of 5-bromo-2-methyl-benzoic acid (2.45 g, 11.16 mmol) in THF (10 ml), CH2Cl2 (10 ml) and DMF (20.00 μl, 258.65 moles) is added dropwise oxalyl chloride (1.16 ml, 13.39 mmoles) at 0° C. and the reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure. To the residue is added CH2Cl2 (40 ml) and the reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (2 g, 11.16 mmol) is added followed by N,N-dimethylpyridin-4-amine (13.63 mg, 0.11 mmoles) and pyridine (2.71 ml, 33.48 mmoles). The cooling bath is removed and the clear solution is allowed to warm to ambient temperature. After 2 hours, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 1N HCl, a saturated solution of sodium bicarbonate, and brine. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a light yellow solid (4.0 g; 95.5%). Mass spectrum (m/z): 376.0 (M+1). the solvent is removed under reduced pressure To the residue is added CH2Cl2 (40 ml) the reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 2 hours the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 1N HCl dried over anhydrous Na2SO4 filtered concentrated under reduced pressure

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

Procedure: To a solution of 5-bromo-2-methyl-benzoic acid (1.35 g, 6.15 mmol) in THF (15 ml), CH2Cl2 (15 ml) and DMF (14.27 μl, 184.57 moles) is added dropwise oxalyl chloride (587.12 μl, 6.77 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure. To the residue CH2Cl2 (30 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (1.19 g, 6.15 mmol) is added followed by 4-pyridinamine, N,N-dimethyl-(37.58 mg, 307.61 mmoles) and pyridine (1.49 ml, 18.46 mmoles). The cooling bath is removed and the clear solution is allowed to warm to ambient temperature. After 5 hours, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 1N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is triturated with hexanes and the resulting solids were collected by filtration to give the title compound as a white solid (1.80 g; 75.2%). Mass spectrum (m/z): 390.2 (M+1). reaction mixture the solvent is removed under reduced pressure To the residue CH2Cl2 (30 ml) is added reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 5 hours the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 1N HCl, saturated solution of sodium bicarbonate, and brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The resulting residue is triturated with hexanes the resulting solids were collected by filtration

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

Procedure: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.78 g, 4.55 mmol) in CH2Cl2 (15 mL) at room temperature are added ethyl 4-amino-3,5-dimethyl-benzoate (0.878 g, 4.55 mmol) and N,N-diisopropylethylamine (1.98 ml, 11.36 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 3.25 ml, 5.46 mmol) is added via syringe. After 48 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes. After purification, the solid is triturated with 30% ethyl acetate in hexanes and filtered to give the title compound as a white powder (0.907 g, 57.5%). Mass spectrum (m/z): 347.2 (M+1). After 48 hours the solvent is removed under reduced pressure the residue is diluted with water extracted with ethyl acetate dried over magnesium sulfate filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel) After purification the solid is triturated with 30% ethyl acetate in hexanes filtered

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

Procedure: To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (465 mg, 2.71 mmol) in THF (5 ml), CH2Cl2 (5 ml) and DMF (0.01 ml, 129.33 μmoles) is added dropwise oxalyl chloride (0.3 ml, 3.46 mmoles) at 0° C. and reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure and the residue. To the residue CH2Cl2 (20 ml) is added and reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (520 mg, 2.69 mmol) is added followed by N,N-dimethylpyridin-4-amine (15 mg, 122.78 μmoles) and Pyridine (0.66 ml, 8.16 mmoles). The cooling bath is removed and the clear yellow solution is allowed to warm to ambient temperature. After 1 hour, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by flash chromatography (silica gel) using 0-50% ethyl acetate in hexanes to give the title compound as a solid (790 mg, 84%). Mass spectrum (m/z): 347.2 (M+1). reaction mixture the solvent is removed under reduced pressure To the residue CH2Cl2 (20 ml) is added reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 1 hour the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 0.5N HCl, saturated solution of sodium bicarbonate, and brine dried over anhydrous Na2SO4 filtered concentrated under reduced pressure The residue is purified by flash chromatography (silica gel)

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

Procedure: To a solution of 5-bromo-2-methyl-benzoic acid (2.45 g, 11.16 mmol) in THF (10 ml), CH2Cl2 (10 ml) and DMF (20.00 μl, 258.65 μmoles) is added dropwise oxalyl chloride (1.16 ml, 13.39 mmoles) at 0° C. and the reaction mixture is slowly allowed to warm to ambient temperature. After 2 hours, the solvent is removed under reduced pressure. To the residue is added CH2Cl2 (40 ml) and the reaction mixture is cooled to 0° C., then ethyl 4-amino-3,5-dimethyl-benzoate (2 g, 11.16 mmol) is added followed by N,N-dimethylpyridin-4-amine (13.63 mg, 0.11 mmoles) and pyridine (2.71 ml, 33.48 mmoles). The cooling bath is removed and the clear solution is allowed to warm to ambient temperature. After 2 hours, the solvent is removed and the reaction mixture is diluted with ethyl acetate and washed with 1N HCl, a saturated solution of sodium bicarbonate, and brine. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound as a light yellow solid (4.0 g; 95.5%). Mass spectrum (m/z): 376.0 (M+1). the solvent is removed under reduced pressure To the residue is added CH2Cl2 (40 ml) the reaction mixture is cooled to 0° C. The cooling bath is removed to warm to ambient temperature After 2 hours the solvent is removed the reaction mixture is diluted with ethyl acetate washed with 1N HCl dried over anhydrous Na2SO4 filtered concentrated under reduced pressure