(3,5-difluorophenyl)methanol

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: The title compound (cis/trans=29/71) was prepared as a white powder in 41.6% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 3,5-difluorobenzyl alcohol.

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

Procedure: The title compound (cis/trans=29/71) was prepared as a white powder in 41.6% yield in a similar procedure to that described in Example 1 by using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrolo[2,3-d]pyridazine (cis/trans=24/76) and 3,5-difluorobenzyl alcohol.

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

Procedure: The title compound or its salt was prepared by a procedure similar to that described for E2 starting from (3,5-difluorophenyl)methanol and 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one.

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

Procedure: 3,5-Difluorobenzyl alcohol (227.5 μL, 2.01 mmol) was dissolved into 15 mL of anhydrous tetrahydrofuran and treated with sodium hydride (80.3 mg, 60% dispersion in mineral oil, 2.01 mmol). This was stirred under nitrogen for 15 minutes at ambient temperature, then the reaction was treated with 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1a) (500 mg, 1.67 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford 605.2 mg of the title product (I-1b). After cooling to room temperature extracted with ethyl acetate (2×50 mL) The combined organic extracts were washed with brine (20 mL) dried over sodium sulfate filtered concentrated The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes)

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

Procedure: Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 3,5-difluorobenzyl alcohol and phosgene (20% in toluene). Prepared

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 2 ml microwave vial was added EXAMPLE 3C (50 mg), 3,5-difluorophenyl)methanol (30.7 mg), 1,1′-carbonyldiimidazole (34.5 mg), 4-(dimethylamino)pyridine (2 mg), and acetonitrile (1065 μl). The mixture was heated in a Biotage Initiator 2 monomode microwave reactor at 150° C. for 25 minutes. Into the vial was added another portion of 1,1′-carbonyldiimidazole (34.5 mg) and the mixture was diluted with 1-methyl-2-pyrrolidinone (900 μl) then heated in an oil bath at 70° C. for 5 hours. To the vial was added (3,5-difluorophenyl)methanol (30.7 mg) and the mixture was heated at 70° C. for 18 hours. The mixture was cooled and phosgene (112 μl) in toluene was added and reaction was stirred at room temperature for 1 week. The mixture was filtered and purified using reverse phase HPLC with 0.1% ammonium hydroxide dissolved in the acetonitrile/water as the mobile phase. MS (ESI(+)) m/e 629 (M+H)+; 1H-NMR (500 MHz, methanol-d4) □ 8.62 (bs, 1H), 7.98 (d, 1H), 7.72-7.76 (m, 1H), 7.67-7.72 (m, 3H), 7.56 (td, 3H), 7.52 (d, 2H), 7.45 (t, 1H), 7.32 (d, 1H), 7.30 (dt, 1H), 7.20 (d, 1H), 6.69 (d, 1H), 5.19 (s, 2H), 3.87-3.94 (m, 4H), 3.33 (s, 4H). the mixture was heated at 70° C. for 18 hours The mixture was cooled reaction The mixture was filtered purified dissolved in the acetonitrile/water as the mobile phase

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 2 ml microwave vial was added EXAMPLE 3C (50 mg), 3,5-difluorophenyl)methanol (30.7 mg), 1,1′-carbonyldiimidazole (34.5 mg), 4-(dimethylamino)pyridine (2 mg), and acetonitrile (1065 μl). The mixture was heated in a Biotage Initiator 2 monomode microwave reactor at 150° C. for 25 minutes. Into the vial was added another portion of 1,1′-carbonyldiimidazole (34.5 mg) and the mixture was diluted with 1-methyl-2-pyrrolidinone (900 μl) then heated in an oil bath at 70° C. for 5 hours. To the vial was added (3,5-difluorophenyl)methanol (30.7 mg) and the mixture was heated at 70° C. for 18 hours. The mixture was cooled and phosgene (112 μl) in toluene was added and reaction was stirred at room temperature for 1 week. The mixture was filtered and purified using reverse phase HPLC with 0.1% ammonium hydroxide dissolved in the acetonitrile/water as the mobile phase. MS (ESI(+)) m/e 629 (M+H)+; 1H-NMR (500 MHz, methanol-d4) □ 8.62 (bs, 1H), 7.98 (d, 1H), 7.72-7.76 (m, 1H), 7.67-7.72 (m, 3H), 7.56 (td, 3H), 7.52 (d, 2H), 7.45 (t, 1H), 7.32 (d, 1H), 7.30 (dt, 1H), 7.20 (d, 1H), 6.69 (d, 1H), 5.19 (s, 2H), 3.87-3.94 (m, 4H), 3.33 (s, 4H). the mixture was heated at 70° C. for 18 hours The mixture was cooled reaction The mixture was filtered purified dissolved in the acetonitrile/water as the mobile phase

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

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

Procedure: 3,5-Difluorobenzyl alcohol (227.5 μL, 2.01 mmol) was dissolved into 15 mL of anhydrous tetrahydrofuran and treated with sodium hydride (80.3 mg, 60% dispersion in mineral oil, 2.01 mmol). This was stirred under nitrogen for 15 minutes at ambient temperature, then the reaction was treated with 4-(2-chloro-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (I-1a) (500 mg, 1.67 mmol) in one portion. The resultant mixture was refluxed under nitrogen for 4 hours. After cooling to room temperature, the reaction was poured into water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (20 mL), then dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes) to afford 605.2 mg of the title product (I-1b). After cooling to room temperature extracted with ethyl acetate (2×50 mL) The combined organic extracts were washed with brine (20 mL) dried over sodium sulfate filtered concentrated The residue was purified by column chromatography (silica gel, 1:1 ethyl acetate:hexanes)