(2,4-dichlorophenyl)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:

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=25/75) was prepared as white crystals in 72.4% 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-dichlorobenzyl alcohol.

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

Procedure: The title compound was prepared as white crystals in 76.5% 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-dichlorobenzyl alcohol.

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

Procedure: The title compound was prepared as white crystals in 76.5% 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-dichlorobenzyl alcohol.

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

Procedure: To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran in 25 ml of diethyl ether were added 1.06 g of 2,4-dichlorobenzyl alcohol, followed by a catalytic amount (2-3 drops) of phosphorus oxytrichloride. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added to the mixture, which was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel as in Example 1(a), to give 1.82 g of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the lesser polarity), 144 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the greater polarity) and 200 mg of a cis/trans mixture. was then concentrated by evaporation under reduced pressure The residue was purified by column chromatography through silica gel as in Example 1(a)

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

Procedure: To a solution of 1.34 g of 2-tosyloxymethyl-3,4-dihydro-2H-pyran in 25 ml of diethyl ether were added 1.06 g of 2,4-dichlorobenzyl alcohol, followed by a catalytic amount (2-3 drops) of phosphorus oxytrichloride. The mixture was then stirred at room temperature for 4 days, after which 3 drops of triethylamine were added to the mixture, which was then concentrated by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel as in Example 1(a), to give 1.82 g of trans-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the lesser polarity), 144 mg of cis-6-(2,4-dichlorobenzyloxy)-2-tosyloxymethyltetrahydropyran (having the greater polarity) and 200 mg of a cis/trans mixture. was then concentrated by evaporation under reduced pressure The residue was purified by column chromatography through silica gel as in Example 1(a)

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

Procedure: A suspension of (2,4-dichlorophenyl)methanol (4.10 g, 23.2 mmol), 2-chloro-4-iodopyridine (5.05 g, 21.1 mmol), Cs2CO3 (8.94 g, 27.4 mmol), CuI (4.01 g, 21.1 mmol) and 1,10-phenanthroline (760 mg, 4.22 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 (6.13 g, 79.5 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. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded 1.36 g (24%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.16 (br s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.1, 1H), 7.50 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.91 (dd, J=7.5, 2.7 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.10 (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:105.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A suspension of (2,4-dichlorophenyl)methanol (4.10 g, 23.2 mmol), 2-chloro-4-iodopyridine (5.05 g, 21.1 mmol), Cs2CO3 (8.94 g, 27.4 mmol), CuI (4.01 g, 21.1 mmol) and 1,10-phenanthroline (760 mg, 4.22 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 (6.13 g, 79.5 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. Flash chromatography on silica gel ((1:1 EtOAc/hexanes)/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) afforded 1.36 g (24%) of the title compound as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 11.16 (br s, 1H), 7.71 (d, J=2.1 Hz, 1H), 7.61 (d, J=8.1, 1H), 7.50 (dd, J=8.4, 2.1 Hz, 1H), 7.26 (d, J=7.2 Hz, 1H), 5.91 (dd, J=7.5, 2.7 Hz, 1H), 5.81 (d, J=2.4 Hz, 1H), 5.10 (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