(2,4-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:; See reaction.notes.procedure_details.

Procedure: DE-A 2,333,849 discloses that 2,4-difluorobenzaldehyde can be converted into 2,4-difluorobenzyl alcohol in a yield of 68.6% by hydrogenation over Raney nickel. Disadvantages of this process are not only the large amount of catalyst (31 g per mol) and the large amount of a solvent (1100 ml per mole) but also the unsatisfactory yield of 68.6%. These factors result in an unsatisfactory space-time yield. The aldehyde used was obtained here from the difficult-to-obtain 2,4-difluorotoluene by side-chain chlorination and subsequent hydrolysis. These factors result in an unsatisfactory space-time yield

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

Procedure: The title compound (trans) was prepared as a white powder in 63.8% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-methylcyclopropylmethyl)pyrrolo[2,3-d]pyridazine and 2,4-difluorobenzyl alcohol.

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

Procedure: The title compound (cis/trans=18/82) was prepared as a pale yellow powder in 43.1% 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=21/79) and 2,4-difluorobenzyl alcohol.

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

Procedure: The title compound (cis/trans=18/82) was prepared as a pale yellow powder in 43.1% 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=21/79) and 2,4-difluorobenzyl alcohol.

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

Procedure: The title compound was prepared as a white powder in 26.6% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-difluorobenzyl alcohol.

Conditions: temp:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (2,4-difluorophenyl)methanol (4.86 g, 33.7 mmol), 2-chloro-4-iodopyridine (7.35 g, 30.7 mmol), Cs2CO3 (14.3 g, 43.8 mmol), CuI (5.83 g, 30.7 mmol) and 1,10-phenanthroline (1.11 g, 6.14 mmol) in toluene (20 mL) was degassed by bubbling N2 through the suspension for 15 min. The suspension was put under N2, and heated at 105° C. for 18 h. The suspension was cooled, EtOAc (50 mL) was added, and the resulting suspension was passed through a plug of SiO2. The resulting solution was concentrated under reduced pressure. Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid. A suspension of the white solid and NH4OAc (8.21 g, 107 mmol) in 1:1 HCO2H/H2O (40 mL) was heated at reflux with stirring for 4 d. The solution was cooled and concentrated under reduced pressure. The resulting residue was made basic with saturated NaHCO3 solution, and the resulting suspension was filtered. The solid was washed with H2O and dried under reduced pressure to afford 3.16 g (44%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.14 (br s, 1H), 7.62 (br dd, J=15.3, 8.7 Hz, 1H), 7.33 (ddd, J=10.5, 10.5, 2.4 Hz, 1H), 7.25 (d, J=7.2 Hz, 1H), 7.12 (ddd, J=8.4, 8.4, 1.8 Hz, 1H), 5.91-5.82 (m, 2H), 5.06 (s, 2H). was degassed by bubbling N2 through the suspension for 15 min The suspension was cooled EtOAc (50 mL) was added The resulting solution was concentrated under reduced pressure Flash chromatography on silica gel (hexanes/(1:1 EtOAc/hexanes), 100:0 to 0:100) afforded a white solid was heated at reflux The solution was cooled concentrated under reduced pressure the resulting suspension was filtered The solid was washed with H2O dried under reduced pressure

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 (2,4-difluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.78-6.86 (2H, m), 7.33 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.39-7.45 (1H, m), 7.51 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.62 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10F2N4O, 313; Found, 313.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (0.1 g, 60%, 2.5 mmol) is added to a solution of 2,4-difluorobenzyl alcohol (0.28 ml, 2.5 mmol) in sulfolane (5 ml) at 50° C. After 1 hour at 50° C., 4-cyano-2,6-bis(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (1 g, 2.3 mmol) (from Example 2) is added to the reaction mixture. The mixture is heated to 90° C. overnight. After cooling, the reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed 6 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v) and washing of the product with diisopropyl ether yields the title compound (0.2 g, 21% yield) of melting point 109° C. After cooling filtered through a bed of silica gel The filtrate is washed 6 times with water The organic layer is dried with anhydrous magnesium sulfate filtered evaporated in vacuo Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v) washing of the product with diisopropyl ether

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Sodium hydride (0.1 g, 60%, 2.5 mmol) is added to a solution of 2,4-difluorobenzyl alcohol (0.28 ml, 2.5 mmol) in sulfolane (5 ml) at 50° C. After 1 hour at 50° C., 4-cyano-2,6-bis(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine (1 g, 2.3 mmol) (from Example 2) is added to the reaction mixture. The mixture is heated to 90° C. overnight. After cooling, the reaction mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed 6 times with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v) and washing of the product with diisopropyl ether yields the title compound (0.2 g, 21% yield) of melting point 109° C. After cooling filtered through a bed of silica gel The filtrate is washed 6 times with water The organic layer is dried with anhydrous magnesium sulfate filtered evaporated in vacuo Purification by flash chromatography (silica gel: pentane/ethyl acetate 8/2 v/v) washing of the product with diisopropyl ether

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 (2,4-difluorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.19 (2H, s), 5.74 (1H, d, J=2.0 Hz), 6.78-6.86 (2H, m), 7.33 (1H, dd, J=1.2 Hz, J=4.8 Hz), 7.39-7.45 (1H, m), 7.51 (1H, d, J=1.6 Hz), 7.94 (1H, s), 8.62 (1H, d, J=4.8 Hz). [M+H] Calc'd for C16H10F2N4O, 313. Found, 313.