2,4-difluoro-6-methoxybenzonitrile

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

Procedure: 2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid. were charged to a round-bottom flask reaction extracted thrice with ethyl acetate The organic solutions were dried (MgSO4) evaporated the residue was purified by dry flash chromatography (DCM eluent)

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

Procedure: 2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid. were charged to a round-bottom flask reaction extracted thrice with ethyl acetate The organic solutions were dried (MgSO4) evaporated the residue was purified by dry flash chromatography (DCM eluent)

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

Procedure: 2,4-Difluoro-6-methoxybenzonitrile (for a preparation see Intermediate 48) (29.2 g, 0.17 mol) was suspended in n-butanol (250 mL) and hydrazine hydrate (16.6 mL, 0.34 mol) was added. The suspension was heated at 110° C. for 19 h, then 115° C. for 4 h. The reaction was allowed to cool and a solid formed overnight. The solid was collected by filtration, and washed with n-butanol. Solid is mainly an aryl hydrazine by-product (uncyclised or regioisomer). The filtrate was concentrated and azeotroped with toluene to give 15.6 g of crude product (84% by LCMS). The crude product was taken up in ˜400 mL water, ˜5 mL AcOH and ˜350 mL ethyl acetate and any insoluble material was discarded. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was taken up in hot ethyl acetate (75 mL, 55° C.) and heptane was added (20 mL). The solid was collected by filtration, washed with heptane. This was repeated twice to give the title compound (6.7 g, 21%) as a purple solid. to cool a solid formed overnight The solid was collected by filtration washed with n-butanol The filtrate was concentrated azeotroped with toluene to give 15.6 g of crude product (84% by LCMS) The organic layer was washed with water dried (MgSO4) evaporated was taken up in hot ethyl acetate (75 mL, 55° C.) heptane was added (20 mL) The solid was collected by filtration washed with heptane

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

Procedure: 2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid. were charged to a round-bottom flask reaction extracted thrice with ethyl acetate The organic solutions were dried (MgSO4) evaporated the residue was purified by dry flash chromatography (DCM eluent)

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

Procedure: 2,4-Difluoro-6-methoxybenzonitrile (for a preparation see Intermediate 48) (29.2 g, 0.17 mol) was suspended in n-butanol (250 mL) and hydrazine hydrate (16.6 mL, 0.34 mol) was added. The suspension was heated at 110° C. for 19 h, then 115° C. for 4 h. The reaction was allowed to cool and a solid formed overnight. The solid was collected by filtration, and washed with n-butanol. Solid is mainly an aryl hydrazine by-product (uncyclised or regioisomer). The filtrate was concentrated and azeotroped with toluene to give 15.6 g of crude product (84% by LCMS). The crude product was taken up in ˜400 mL water, ˜5 mL AcOH and ˜350 mL ethyl acetate and any insoluble material was discarded. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was taken up in hot ethyl acetate (75 mL, 55° C.) and heptane was added (20 mL). The solid was collected by filtration, washed with heptane. This was repeated twice to give the title compound (6.7 g, 21%) as a purple solid. to cool a solid formed overnight The solid was collected by filtration washed with n-butanol The filtrate was concentrated azeotroped with toluene to give 15.6 g of crude product (84% by LCMS) The organic layer was washed with water dried (MgSO4) evaporated was taken up in hot ethyl acetate (75 mL, 55° C.) heptane was added (20 mL) The solid was collected by filtration washed with heptane

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

Procedure: 2,4-Difluoro-6-methoxybenzonitrile (for a preparation see Intermediate 48) (29.2 g, 0.17 mol) was suspended in n-butanol (250 mL) and hydrazine hydrate (16.6 mL, 0.34 mol) was added. The suspension was heated at 110° C. for 19 h, then 115° C. for 4 h. The reaction was allowed to cool and a solid formed overnight. The solid was collected by filtration, and washed with n-butanol. Solid is mainly an aryl hydrazine by-product (uncyclised or regioisomer). The filtrate was concentrated and azeotroped with toluene to give 15.6 g of crude product (84% by LCMS). The crude product was taken up in ˜400 mL water, ˜5 mL AcOH and ˜350 mL ethyl acetate and any insoluble material was discarded. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was taken up in hot ethyl acetate (75 mL, 55° C.) and heptane was added (20 mL). The solid was collected by filtration, washed with heptane. This was repeated twice to give the title compound (6.7 g, 21%) as a purple solid. to cool a solid formed overnight The solid was collected by filtration washed with n-butanol The filtrate was concentrated azeotroped with toluene to give 15.6 g of crude product (84% by LCMS) The organic layer was washed with water dried (MgSO4) evaporated was taken up in hot ethyl acetate (75 mL, 55° C.) heptane was added (20 mL) The solid was collected by filtration washed with heptane