3-prop-2-enoxybenzaldehyde

Conditions: temp:217.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 ml three-necked Morton flask equipped with mechanical stirrer, thermometer and reflux condenser was added 100 g of 3-allyloxybenzaldehyde (0.62 moles, 1 eq.) and 150 g of cis/trans decalin (1.5 vol). The mixture was purged with nitrogen and then heated to a reflux temperature of 217° C. The reaction was maintained at this reflux temperature for seven hours then cooled and 231 mL of toluene was added. The reaction mixture was then allowed to cool to room temperature. After stirring for 18 hours and further cooling to 0-5° C., reaction mixture was filtered and the cake washed with 200 mL of heptane. The wet cake was stirred in 200 mL of heptane for 1-2 hours at room temperature. After filtration and drying of the cake at 40° C., 54.27 g of crude 2-allyl-3-hydroxybenzaldehyde were obtained. This represents a recovery of 82% of the available 2-allyl product produced by the Claisen rearrangement. In a 500 ml three-necked Morton flask equipped with mechanical stirrer thermometer and reflux condenser The mixture was purged with nitrogen The reaction was maintained at this reflux temperature for seven hours then cooled 231 mL of toluene was added to cool to room temperature further cooling to 0-5° C. reaction mixture was filtered the cake washed with 200 mL of heptane The wet cake was stirred in 200 mL of heptane for 1-2 hours at room temperature After filtration drying of the cake at 40° C.

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

Procedure: In a 1 L round bottomed flask equipped with mechanical stirrer, reflux condenser and thermometer was added in sequence 400 mL ethanol, 59.63 g of 3-hydroxybenzaldehyde (0.49 moles, 1 eq.), 7.3 g of sodium iodide (48 mmol, 0.1 eq.), 120.98 g of allyl bromide (0.59 moles, 1.2 eq.) and 101.6 g of potassium carbonate (0.74 moles, 1.25 eq.). The reaction mixture was heated to reflux and heating continued for three hours. Heating was then discontinued and the reaction was allowed to cool to room temperature. The mixture was then filtered through a Hyflosupercel pad and ethanol was removed by rotary evaporation. The residual oil was then taken up in 500 mL of MTBE and the organic phase washed sequentially with 10% aqueous sodium hydroxide, water and brine. After drying over sodium sulfate, filtration and rotary evaporation of solvent 79.7 g of a yellow oil of 3-allyloxybenzaldehyde (quantitative yield) was obtained. In a 1 L round bottomed flask equipped with mechanical stirrer reflux condenser The reaction mixture was heated to reflux heating Heating The mixture was then filtered through a Hyflosupercel pad and ethanol was removed by rotary evaporation the organic phase washed sequentially with 10% aqueous sodium hydroxide, water and brine

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

Procedure: Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-prop-2-enoxybenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(3-prop-2-enoxyphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine. The crude product was purified by hplc eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents

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

Procedure: To a solution of 3-allyloxybenzaldehyde (7.2 g) in methanol (50 ml) at 0° C. was added sodium borohydride (1 g) in portions. The mixture was stirred for 30 minutes, evaporated dissolved in 5% acetic acid and extracted with diethyl ether (3×100 ml) , washed with water (2×100 ml), and sodium bicarbonate (2×100 ml), dried (magnesium sulphate), filtered and evaporated to give 3-allyloxybenzyl alcohol (7.26 g). evaporated dissolved in 5% acetic acid extracted with diethyl ether (3×100 ml) washed with water (2×100 ml), and sodium bicarbonate (2×100 ml) dried (magnesium sulphate) filtered evaporated

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

Procedure: To a solution of 3-allyloxybenzaldehyde (7.2 g) in methanol (50 ml) at 0° C. was added sodium borohydride (1 g) in portions. The mixture was stirred for 30 minutes, evaporated dissolved in 5% acetic acid and extracted with diethyl ether (3×100 ml) , washed with water (2×100 ml), and sodium bicarbonate (2×100 ml), dried (magnesium sulphate), filtered and evaporated to give 3-allyloxybenzyl alcohol (7.26 g). evaporated dissolved in 5% acetic acid extracted with diethyl ether (3×100 ml) washed with water (2×100 ml), and sodium bicarbonate (2×100 ml) dried (magnesium sulphate) filtered evaporated

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

Procedure: The product from Example 58A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.

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

Procedure: The product from Example 58A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.

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

Procedure: 3-Hydroxybenzaldehyde (1.00 g, 8.19 mmol) and allyl bromide (0.780 mL, 9.01 mmol) in N,N-dimethylacetamide (35 mL) was treated with Cs2CO3 (4.01 g, 12.3 mmol) and allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether (150 mL), washed with 1N HCl, saturated NaHCO3, brine, dried (MgSO4), filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent) to provide the title compound as a clear oil (1.19 g, 89%). washed with 1N HCl, saturated NaHCO3, brine dried (MgSO4) filtered the filtrate concentrated The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent)

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

Procedure: 3-Hydroxybenzaldehyde (1.00 g, 8.19 mmol) and allyl bromide (0.780 mL, 9.01 mmol) in N,N-dimethylacetamide (35 mL) was treated with Cs2CO3 (4.01 g, 12.3 mmol) and allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with diethyl ether (150 mL), washed with 1N HCl, saturated NaHCO3, brine, dried (MgSO4), filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent) to provide the title compound as a clear oil (1.19 g, 89%). washed with 1N HCl, saturated NaHCO3, brine dried (MgSO4) filtered the filtrate concentrated The residue was purified by flash chromatography (silica gel, using 7% ethyl acetate/hexanes as eluent)

Conditions: temp:217.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 ml three-necked Morton flask equipped with mechanical stirrer, thermometer and reflux condenser was added 100 g of 3-allyloxybenzaldehyde (0.62 moles, 1 eq.) and 150 g of cis/trans decalin (1.5 vol). The mixture was purged with nitrogen and then heated to a reflux temperature of 217° C. The reaction was maintained at this reflux temperature for seven hours then cooled and 231 mL of toluene was added. The reaction mixture was then allowed to cool to room temperature. After stirring for 18 hours and further cooling to 0-5° C., reaction mixture was filtered and the cake washed with 200 mL of heptane. The wet cake was stirred in 200 mL of heptane for 1-2 hours at room temperature. After filtration and drying of the cake at 40° C., 54.27 g of crude 2-allyl-3-hydroxybenzaldehyde were obtained. This represents a recovery of 82% of the available 2-allyl product produced by the Claisen rearrangement. In a 500 ml three-necked Morton flask equipped with mechanical stirrer thermometer and reflux condenser The mixture was purged with nitrogen The reaction was maintained at this reflux temperature for seven hours then cooled 231 mL of toluene was added to cool to room temperature further cooling to 0-5° C. reaction mixture was filtered the cake washed with 200 mL of heptane The wet cake was stirred in 200 mL of heptane for 1-2 hours at room temperature After filtration drying of the cake at 40° C.

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

Procedure: In a 1 L round bottomed flask equipped with mechanical stirrer, reflux condenser and thermometer was added in sequence 400 mL ethanol, 59.63 g of 3-hydroxybenzaldehyde (0.49 moles, 1 eq.), 7.3 g of sodium iodide (48 mmol, 0.1 eq.), 120.98 g of allyl bromide (0.59 moles, 1.2 eq.) and 101.6 g of potassium carbonate (0.74 moles, 1.25 eq.). The reaction mixture was heated to reflux and heating continued for three hours. Heating was then discontinued and the reaction was allowed to cool to room temperature. The mixture was then filtered through a Hyflosupercel pad and ethanol was removed by rotary evaporation. The residual oil was then taken up in 500 mL of MTBE and the organic phase washed sequentially with 10% aqueous sodium hydroxide, water and brine. After drying over sodium sulfate, filtration and rotary evaporation of solvent 79.7 g of a yellow oil of 3-allyloxybenzaldehyde (quantitative yield) was obtained. In a 1 L round bottomed flask equipped with mechanical stirrer reflux condenser The reaction mixture was heated to reflux heating Heating The mixture was then filtered through a Hyflosupercel pad and ethanol was removed by rotary evaporation the organic phase washed sequentially with 10% aqueous sodium hydroxide, water and brine