3,5-dichlorobenzonitrile

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: step 1—A 100 mL round bottom flask was charged under a stream of nitrogen with 3,5-dichlorobenzonitrile (7.0 g, 40.69 mmol) and anhydrous DMF (75 mL). To the solution was added sodium methoxide (2.26 g, 44.76 mmol) and resulting solution was stirred further at RT for 24 h. When the reaction was complete, aqueous 10% HCl added dropwise to the reaction vessel. The crude mixture was extracted with EtOAc and sequentially washed with aqueous acid, water and brine. The EtOAc extracts were dried (Na2SO4), filtered and the solvent was removed in vacuo to afford a crude solid which was recrystallized from hexane/acetone to afford 5.9 g (86%) of 5-chloro-3-methoxy-benzonitrile. resulting solution The crude mixture was extracted with EtOAc sequentially washed with aqueous acid, water and brine The EtOAc extracts were dried (Na2SO4) filtered the solvent was removed in vacuo to afford a crude solid which was recrystallized from hexane/acetone

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

Procedure: step 1—A 100 ml round bottom flask was charged under a stream of nitrogen with 3,5-dichlorobenzonitrile (R-3a,7.0 g, 40.69 mmol) and anhydrous DMF (75 mL). To the solution was added sodium methoxide (2.26 g, 44.76 mmol) and resulting solution was stirred further at RT for 24 h. When the reaction was complete, aqueous 10% HCl added dropwise to the reaction vessel. The crude mixture was extracted with EtOAc and sequentially washed with aqueous acid, water and brine. The EtOAc extracts were dried (Na2SO4), filtered and the solvent was removed in vacuo to afford a crude solid which was recrystallized from hexane/acetone to afford 5.9 g (86%) of 5-chloro-3-methoxy-benzonitrile. resulting solution The crude mixture was extracted with EtOAc sequentially washed with aqueous acid, water and brine The EtOAc extracts were dried (Na2SO4) filtered the solvent was removed in vacuo to afford a crude solid which was recrystallized from hexane/acetone

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

Procedure: To a 250 mL round bottom flask charged with 3,5-dichlorobenzonitrile (130a, 7.31 g; 34.90 mmol) and maintained under an argon atmosphere was added DMF (70 mL). The flask was cooled to 0° C. and powdered sodium methoxide (1.88 g; 34.90 mmol) was added in two portions 15 m apart. The homogeneous mixture was allowed to warm to room temperature and stirred for 24 h. The solution was cooled to 0° C. and aqueous 10% HCl (20 mL) was added dropwise via an addition funnel after which the reaction was warmed to RT. The mixture was extracted with EtOAc and the combined extracts washed sequentially with water and brine. The organic phase was dried (Na2SO4), filtered, and volatile solvents were removed in vacuo. The resulting solid was recrystallized from hexanes to afford 3-chloro-5-methoxybenzonitrile (130b, 4.2 g; 72%). maintained under an argon atmosphere to warm to room temperature The solution was cooled to 0° C. was warmed to RT The mixture was extracted with EtOAc the combined extracts washed sequentially with water and brine The organic phase was dried (Na2SO4) filtered volatile solvents were removed in vacuo The resulting solid was recrystallized from hexanes

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

Procedure: To a 250 mL round bottom flask charged with 3,5-dichlorobenzonitrile (130a, 7.31 g; 34.90 mmol) and maintained under an argon atmosphere was added DMF (70 mL). The flask was cooled to 0° C. and powdered sodium methoxide (1.88 g; 34.90 mmol) was added in two portions 15 m apart. The homogeneous mixture was allowed to warm to room temperature and stirred for 24 h. The solution was cooled to 0° C. and aqueous 10% HCl (20 mL) was added dropwise via an addition funnel after which the reaction was warmed to RT. The mixture was extracted with EtOAc and the combined extracts washed sequentially with water and brine. The organic phase was dried (Na2SO4), filtered, and volatile solvents were removed in vacuo. The resulting solid was recrystallized from hexanes to afford 3-chloro-5-methoxybenzonitrile (130b, 4.2 g; 72%). maintained under an argon atmosphere to warm to room temperature The solution was cooled to 0° C. was warmed to RT The mixture was extracted with EtOAc the combined extracts washed sequentially with water and brine The organic phase was dried (Na2SO4) filtered volatile solvents were removed in vacuo The resulting solid was recrystallized from hexanes

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: The requisite phenols utilized in the condensation with 15 or 18b were prepared as depicted in SCHEME 3. Dibromofluorobenzene (20a) was treated with sodium methoxide resulting in displacement of the fluorine substituent to afford 20b. Monometallation and formylation of the resulting lithium salt with DMF afforded 21. Conversion of the formyl group into a difluoromethyl group was effected with DAST. Demethylation of the methyl ether afforded the requisite phenol 23. 3-Chloro-5-hydroxy-benzonitrile (24c) was prepared form 3,5-dichloro-benzonitrile by displacement of a chlorine substitutent with sodium methoxide and demethylation of the resulting ether to afford 24c.

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

Procedure: The requisite phenols utilized in the condensation with 15 or 18b were prepared as depicted in SCHEME 3. Dibromofluorobenzene (20a) was treated with sodium methoxide resulting in displacement of the fluorine substituent to afford 20b. Monometallation and formylation of the resulting lithium salt with DMF afforded 21. Conversion of the formyl group into a difluoromethyl group was effected with DAST. Demethylation of the methyl ether afforded the requisite phenol 23. 3-Chloro-5-hydroxy-benzonitrile (24c) was prepared form 3,5-dichloro-benzonitrile by displacement of a chlorine substitutent with sodium methoxide and demethylation of the resulting ether to afford 24c.

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

Procedure: The requisite phenols utilized in the condensation with 15 or 18b were prepared as depicted in SCHEME 3. Dibromofluorobenzene (20a) was treated with sodium methoxide resulting in displacement of the fluorine substituent to afford 20b. Monometallation and formylation of the resulting lithium salt with DMF afforded 21. Conversion of the formyl group into a difluoromethyl group was effected with DAST. Demethylation of the methyl ether afforded the requisite phenol 23. 3-Chloro-5-hydroxy-benzonitrile (24c) was prepared form 3,5-dichloro-benzonitrile by displacement of a chlorine substitutent with sodium methoxide and demethylation of the resulting ether to afford 24c.

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

Procedure: 3,5-Dichlorobenzonitrile (52.93 g, 307.7 mmol) was dissolved in anhydrous DMF (300 mL) and cooled to 0° C. in an ice bath. Sodium methoxide (18.28 g, 338.5 mmol) was added as a solid and the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was poured into a mixture of 10% HCl and ice. The solid that formed was filtered, washed with water, and dried overnight. The solid was dissolved in EtOAc and DCM and filtered to remove insoluble material. The solution was washed with water, dried over MgSO4, filtered and evaporated to afford the title compound (46.48 g, 90%) as a solid. 1H NMR (400 MHz, CDCl3): δ ppm 7.20 (t, 1H), 7.10 (t, 1H), 7.03 (dd, 1H), 3.82 (s, 3H). to warm to RT The solid that formed was filtered washed with water dried overnight The solid was dissolved in EtOAc DCM and filtered to remove insoluble material The solution was washed with water dried over MgSO4 filtered evaporated