3-CHLORO-4-FLUOROBENZYL ALCOHOL

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

Procedure: Sodium hydride (0.33 g) was added to a solution of the alcohol from Step 3 (2.0 g) in THF (50 mL) at 0° C. under N2. Stirring was continued for 5 minutes at 0° C. followed by 25 min at 25° C. The mixture was then cooled to 0° C. and p-toluenesulfonyl chloride (2.5 g) was added. Stirring was continued for 40 minutes at 0° C. followed by 2 hours at 25° C. The precipitated NaCl was allowed to settle and the supernatant solution (4.0 mL) of the title compound was used directly in the next step. followed by 25 min at 25° C Stirring was continued for 40 minutes at 0° C. followed by 2 hours at 25° C

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

Procedure: To a solution of LiAlH4 (2.2 g) in THF (100 mL) at 0° C. under nitrogen was added 3-chloro-4-fluorobenzoic acid (Aldrich; 10 g). After stirring for 1 hour at 0° C. the mixture was stirred for 1 hour at 25° C. followed by the addition of a further 1.0 g of LiAlH4. Stirring was continued for a further 12 hours at 25° C. after which time the mixture was cooled to 0° C. and quenched with H2O. The mixture was then acidified with 1N HCl (aq) and extracted with EtOAc. After washing with NaHCO3 (aq) and drying (MgSO4), the organic solution was evaporated to give the title compound as an oil. was stirred for 1 hour at 25° C. Stirring was continued for a further 12 hours at 25° C. after which time the mixture was cooled to 0° C. quenched with H2O extracted with EtOAc After washing with NaHCO3 (aq) drying (MgSO4) the organic solution was evaporated

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

Procedure: To a solution of LiAlH4 (2.2 g) in THF (100 mL) at 0° C. under nitrogen was added 3-chloro-4-fluorobenzoic acid (Aldrich; 10 g). After stirring for 1 hour at 0° C. the mixture was stirred for 1 hour at 25° C. followed by the addition of a further 1.0 g of LiAlH4. Stirring was continued for a further 12 hours at 25° C. after which time the mixture was cooled to 0° C. and quenched with H2O. The mixture was then acidified with 1N HCl (aq) and extracted with EtOAc. After washing with NaHCO3 (aq) and drying (MgSO4), the organic solution was evaporated to give the title compound as an oil. was stirred for 1 hour at 25° C. Stirring was continued for a further 12 hours at 25° C. after which time the mixture was cooled to 0° C. quenched with H2O extracted with EtOAc After washing with NaHCO3 (aq) drying (MgSO4) the organic solution was evaporated

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

Procedure: The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.

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

Procedure: The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C16H10ClFN4O, 329; Found, 329.

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

Procedure: The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chloro-4-fluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C16H10ClFN4O, 329. Found, 329.

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

Procedure: To a solution of (3-chloro-4-fluoro-phenyl)-methanol (4.3 g, 26.8 mmol) in DCM (20 mL) was added PBr3 (1 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour before it was quenched with satd. aq. NaHCO3 solution. The organic solution was washed with water, brine, dried over anhy. Na2SO4 and concentrated in vacuo to give the desired product (3.7 g, 61.9%). It was used directly in the next step, without further purification. was quenched with satd The organic solution was washed with water, brine dried over anhy Na2SO4 and concentrated in vacuo

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

Procedure: The compound of Example 131 was manufactured by the same method as in Example 95, by a similar method thereto or by a combination of such a method with a conventional method using 4-fluoro-3-chlorobenzenemethanol, 3-amino-1-methyl-1H-pyrazole and 4-chloro-6-hydroxy-quinazoline.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3-chloro-4-fluorophenyl)methanol (95 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through a plug of NH silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). Then the resulting solid was recrystallized from IPA-EtOAc to give the title compound (58.4 mg) as an off-white solid. washed with water and brine successively dried over MgSO4 filtered through a plug of NH silica gel concentrated in vacuo The residue was purified by silica gel column chromatography (hexane/EtOAc Then the resulting solid was recrystallized from IPA-EtOAc

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (3-chloro-4-fluorophenyl)methanol (95 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc, washed with water and brine successively, dried over MgSO4, filtered through a plug of NH silica gel, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH), followed by NH silica gel column chromatography (hexane/EtOAc). Then the resulting solid was recrystallized from IPA-EtOAc to give the title compound (58.4 mg) as an off-white solid. washed with water and brine successively dried over MgSO4 filtered through a plug of NH silica gel concentrated in vacuo The residue was purified by silica gel column chromatography (hexane/EtOAc Then the resulting solid was recrystallized from IPA-EtOAc

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

Procedure: The title compound was prepared by a procedure similar to that described for E1 starting from (3-chloro-4-fluorophenyl)methanol and 7-chloro-1,2-dimethyl-2,3-dihydro imidazo[1,2-c]pyrimidin5(1H)-one.

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

Procedure: The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-chloro-4-fluorophenyl)methanol.