1-(bromomethyl)-2-(difluoromethoxy)benzene

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

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

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one (25 mg, 0.08 mmol), 1-(bromomethyl)-2-(difluoromethoxy)benzene (28 mg, 0.12 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in DMF (900 uL) was heated to 80° C. for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (22 mg, 58%) as a white solid. LCMS (M+H)+=476. The mixture was filtered the filter cake was washed with ACN (500 uL) the filtrate was purified by prep-HPLC

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

Procedure: In a similar manner as described for example B18, 207.7 mg of 2-(difluoromethoxy)benzyl bromide, 200 mg of methyl 3-hydroxy-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate, 110.9 mg of potassium carbonate in 6 ml anhydrous DMF yield the title compound.

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

Procedure: 207.7 mg of 2-(difluoromethoxy)benzyl bromide is added to a mixture of 200 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 110.9 mg of potassium carbonate in 6 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Additional 207.7 mg of 2-(Difluoromethoxy)benzyl bromide and 110.9 mg of potassium carbonate are added and the mixture is stirred at 75° C. for 3 h. Ice water is added to the mixture at room temperature and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and purified by flash column chromatography (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v)) to yield the title compound. the mixture is stirred at 75° C. for 3 h the organic phase is extracted with dichloromethane The organic phase is poured on a phase separator the solvent is removed under vacuum The residue is dissolved in ethyl acetate purified by flash column chromatography (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v))

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

Procedure: 207.7 mg of 2-(difluoromethoxy)benzyl bromide is added to a mixture of 200 mg of methyl 3-hydroxy-5-(3H-imidazo[4,5-c]pyridin-3-yl)thiophene-2-carboxylate and 110.9 mg of potassium carbonate in 6 ml anhydrous DMF. The mixture is stirred for 14 h at room temperature. Additional 207.7 mg of 2-(Difluoromethoxy)benzyl bromide and 110.9 mg of potassium carbonate are added and the mixture is stirred at 75° C. for 3 h. Ice water is added to the mixture at room temperature and the organic phase is extracted with dichloromethane. The organic phase is poured on a phase separator and the solvent is removed under vacuum. The residue is dissolved in ethyl acetate and purified by flash column chromatography (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v)) to yield the title compound. the mixture is stirred at 75° C. for 3 h the organic phase is extracted with dichloromethane The organic phase is poured on a phase separator the solvent is removed under vacuum The residue is dissolved in ethyl acetate purified by flash column chromatography (eluent: hexane/ethyl acetate 1/1 (v/v) to 0/100 (v/v))

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

Procedure: N-Benzyl-2-(2-difluoromethoxy-benzyl)-morpholin-3-one was prepared as described for example 70, intermediate (b), but using 4-benzylmorpholine-3-one and 2-difluoromethoxybenzyl bromide and was isolated as a pale yellow oil. was isolated as a pale yellow oil

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

Procedure: 4-Morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyric acid (1.27 g, 4.64 mmol) was dissolved in 50 mL dry EtOH and set to stir at room temperature. NaOH pellets (556 mg, 13.92 mmol) were added in one portion, and the reaction mixture was allowed to stir for 10 min. 2-(Difluoromethoxy)-benzyl bromide (1.00 g, 4.219 mmol) was then added, and the reaction mixture was allowed to stir at ambient temperature for 20 h. Upon completion (LCMS), the reaction mixture was diluted with water and the pH was lowered to ˜2. The reaction mixture was then washed 3× with EtOAc. The organic phase was concentrated in vacuo and then diluted with 100 mL aqueous MeOH. Oxone (1.58 g, 2.43 mmol) was added in one portion and the reaction was stirred at room temperature for 4 h. Conversion of sulfide to sulfone was monitored via LCMS. Upon completion, reaction was quenched by the addition of sodium thiosulfate. Salts were filtered, and the reaction mixture was washed 3× with ethyl acetate and dried over sodium sulfate. The organics were evaporated by vacuum under reduced pressure. Product was purified via HPLC. Yield: 195 mg, 19.0%. m/z (LCMS) M+ 422.1. Rf=2.42. δH 12.6 (1H, br s), 7.6–7.2 (4H, m), 7.19 (1H, s) 4.5 (2H, s), 3.5 (4H, m), 3.5 (1H, m), 3.4 (4H, m), 3.2 (2H, d), 2.75 (2H, d). were added in one portion to stir for 10 min to stir at ambient temperature for 20 h The reaction mixture was then washed 3× with EtOAc The organic phase was concentrated in vacuo diluted with 100 mL aqueous MeOH the reaction was stirred at room temperature for 4 h Upon completion, reaction was quenched by the addition of sodium thiosulfate Salts were filtered the reaction mixture was washed 3× with ethyl acetate dried over sodium sulfate The organics were evaporated by vacuum under reduced pressure Product was purified via HPLC

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A capped mixture of 4-(3-hydroxy-5-methylsulfonylphenyl)-6-methylfuro[2,3-c]pyridin-7-one (25 mg, 0.08 mmol), 1-(bromomethyl)-2-(difluoromethoxy)benzene (28 mg, 0.12 mmol), and Cs2CO3 (50 mg, 0.15 mmol) in DMF (900 uL) was heated to 80° C. for 3 h. The mixture was filtered and the filter cake was washed with ACN (500 uL), the filtrate was purified by prep-HPLC to afford the title compound (22 mg, 58%) as a white solid. LCMS (M+H)+=476. The mixture was filtered the filter cake was washed with ACN (500 uL) the filtrate was purified by prep-HPLC