3,5-difluoro-N-methylaniline

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

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

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: A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide. To the solution of LiAlH4 (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na2SO4), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil. quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml) The reaction mixture was filtered extracted with EtOAc Organics were dried (Na2SO4) concentrated

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

Procedure: 3,5-difluoro-N-methylaniline (222 mg, 1.55 mmol), 8-(1-bromoethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one hydrobromide (200 mg, 0.39 mmol) and potassium iodide (64.3 mg, 0.39 mmol) in CHCl3 (0.8 mL) and MeOH (0.2 mL) were stirred at 20° C. for 25 hrs. The reaction mixture was concentrated to dryness, diluted with DCM (30 mL), washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product. Purification was done by flash chromatography on silica gel eluting with 2 to 4% MeOH in DCM. The solvent was evaporated to dryness to afford a foam which was dissolved in acetonitrile-water and concentrated under vacuum to give 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (115 mg, 60%) as a white solid. Mass Spectrum: M+H+ 498. NMR is Spectrum (DMSOd6): 1.56 (d, 3H), 1.78-1.93 (m, 4H), 2.62 (s, 3H), 3.23-3.29 (m, 2H), 3.35-3.56 (m, 10H), 5.55 (s, 1H), 5.59 (q, 1H), 6.40 (t, 1H), 6.53 (d, 2H), 7.79 (d, 1H), 8.01 (d, 1H). The reaction mixture was concentrated to dryness diluted with DCM (30 mL) washed with water, brine dried over magnesium sulfate concentrated to afford the crude product Purification The solvent was evaporated to dryness to afford a foam which concentrated under vacuum

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

Procedure: 3,5-difluoro-N-methylaniline (222 mg, 1.55 mmol), 8-(1-bromoethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one hydrobromide (200 mg, 0.39 mmol) and potassium iodide (64.3 mg, 0.39 mmol) in CHCl3 (0.8 mL) and MeOH (0.2 mL) were stirred at 20° C. for 25 hrs. The reaction mixture was concentrated to dryness, diluted with DCM (30 mL), washed with water, brine, dried over magnesium sulfate and concentrated to afford the crude product. Purification was done by flash chromatography on silica gel eluting with 2 to 4% MeOH in DCM. The solvent was evaporated to dryness to afford a foam which was dissolved in acetonitrile-water and concentrated under vacuum to give 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-6-(pyrrolidine-1-carbonyl)-4H-chromen-4-one (115 mg, 60%) as a white solid. Mass Spectrum: M+H+ 498. NMR is Spectrum (DMSOd6): 1.56 (d, 3H), 1.78-1.93 (m, 4H), 2.62 (s, 3H), 3.23-3.29 (m, 2H), 3.35-3.56 (m, 10H), 5.55 (s, 1H), 5.59 (q, 1H), 6.40 (t, 1H), 6.53 (d, 2H), 7.79 (d, 1H), 8.01 (d, 1H). The reaction mixture was concentrated to dryness diluted with DCM (30 mL) washed with water, brine dried over magnesium sulfate concentrated to afford the crude product Purification The solvent was evaporated to dryness to afford a foam which concentrated under vacuum

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

Procedure: Potassium iodide (1.521 g, 9.16 mmol) was added to a suspension of methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.3 g, 8.33 mmol, as described in Example 2.00) and 3,5-difluoro-N-methylaniline (3.58 g, 24.99 mmol) in CHCl3 (16 mL) and MeOH (4 mL). The mixture was stirred at RT over the weekend. The reaction mixture was concentrated to dryness and the resulting dark oil was triturated with diethyl ether to give a solid which was collected by filtration. This solid was suspended in water and pH was adjusted to 6-7 with 2N NaOH. The crude product was filtered and washed with ether, dried and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.1 g, 81%) as a white solid. Mass Spectrum: M+H+ 459. The reaction mixture was concentrated to dryness the resulting dark oil was triturated with diethyl ether to give a solid which was collected by filtration The crude product was filtered washed with ether dried purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

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

Procedure: Potassium iodide (1.521 g, 9.16 mmol) was added to a suspension of methyl 8-(1-bromoethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.3 g, 8.33 mmol, as described in Example 2.00) and 3,5-difluoro-N-methylaniline (3.58 g, 24.99 mmol) in CHCl3 (16 mL) and MeOH (4 mL). The mixture was stirred at RT over the weekend. The reaction mixture was concentrated to dryness and the resulting dark oil was triturated with diethyl ether to give a solid which was collected by filtration. This solid was suspended in water and pH was adjusted to 6-7 with 2N NaOH. The crude product was filtered and washed with ether, dried and purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford methyl 8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (3.1 g, 81%) as a white solid. Mass Spectrum: M+H+ 459. The reaction mixture was concentrated to dryness the resulting dark oil was triturated with diethyl ether to give a solid which was collected by filtration The crude product was filtered washed with ether dried purified by flash chromatography on silica gel eluting with 0 to 10% MeOH in DCM The solvent was evaporated to dryness

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

Procedure: A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide. To the solution of LiAlH4 (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na2SO4), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil. quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml) The reaction mixture was filtered extracted with EtOAc Organics were dried (Na2SO4) concentrated

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

Procedure: A solution of 3,5-difluoroaniline (5.0 g, 38.7 mmol) in HCOOH (15 mL) was heated to reflux for 4 h. The mixture was poured into ice-water and stirred for 0.5 h. The white solid was collected by filtration, and dried under vacuum to give 4.8 g (79%) of crude N-(3,5-difluorophenyl)formamide. To the solution of LiAlH4 (3.0 g, 78.9 mmol) in dry THF (50 mL) was added a solution of N-(3,5-difluorophenyl)formamide (4.8 g, 30.6 mmol) in dry THF (50 mL) at r.t. The mixture was stirred overnight and then quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml). The reaction mixture was filtered and extracted with EtOAc. Organics were dried (Na2SO4), and concentrated to give 3.8 g (86%) of the title compound as a pale brown oil. quenched with addition of water (3.0 mL), aqueous 10% NaOH (3.0 mL), and water (9.0 ml) The reaction mixture was filtered extracted with EtOAc Organics were dried (Na2SO4) concentrated

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