3,5-dichloro-4-(2,4-difluorophenyl)benzaldehyde

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

Procedure: To a solution of 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid (27 mg, 0.087 mmol) (from Example 5-1, Step 4) and 2,6-dichloro-2′,4′-difluorobiphenyl-4-carboxaldehyde (20 mg, 0.070 mmol) (from Step 3) in DMF (2 mL) in a 20 mL scintillation vial was added acetic acid (13 uL, 0.209 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 20 hours and then was filtered to remove the resin and washed with acetonitrile/water. The mixture was acidified with TFA and used directly for reverse phase (C-18) HPLC chromatography (10-55% acetonitrile/water gradient, 0.1% TFA) to afford the desired title compound (27 mg) as a solid TFA salt. The TFA salt was converted to the title compound hydrochloride salt by taking up in DCM and addition of excess 2M hydrogen chloride in ether and evaporation (twice) followed by trituration with ether to give the HCl salt (24 mg) as a white solid. was filtered to remove the resin washed with acetonitrile/water

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

Procedure: To a solution of 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid (27 mg, 0.087 mmol) (from Example 5-1, Step 4) and 2,6-dichloro-2′,4′-difluorobiphenyl-4-carboxaldehyde (20 mg, 0.070 mmol) (from Step 3) in DMF (2 mL) in a 20 mL scintillation vial was added acetic acid (13 uL, 0.209 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 20 hours and then was filtered to remove the resin and washed with acetonitrile/water. The mixture was acidified with TFA and used directly for reverse phase (C-18) HPLC chromatography (10-55% acetonitrile/water gradient, 0.1% TFA) to afford the desired title compound (27 mg) as a solid TFA salt. The TFA salt was converted to the title compound hydrochloride salt by taking up in DCM and addition of excess 2M hydrogen chloride in ether and evaporation (twice) followed by trituration with ether to give the HCl salt (24 mg) as a white solid. was filtered to remove the resin washed with acetonitrile/water

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

Procedure: To a solution of 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid (27 mg, 0.087 mmol) (from Example 5-1, Step 4) and 2,6-dichloro-2′,4′-difluorobiphenyl-4-carboxaldehyde (20 mg, 0.070 mmol) (from Step 3) in DMF (2 mL) in a 20 mL scintillation vial was added acetic acid (13 uL, 0.209 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 20 hours and then was filtered to remove the resin and washed with acetonitrile/water. The mixture was acidified with TFA and used directly for reverse phase (C-18) HPLC chromatography (10-55% acetonitrile/water gradient, 0.1% TFA) to afford the desired title compound (27 mg) as a solid TFA salt. The TFA salt was converted to the title compound hydrochloride salt by taking up in DCM and addition of excess 2M hydrogen chloride in ether and evaporation (twice) followed by trituration with ether to give the HCl salt (24 mg) as a white solid. was filtered to remove the resin washed with acetonitrile/water

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

Procedure: To a solution of 4-(2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl)benzoic acid (27 mg, 0.087 mmol) (from Example 5-1, Step 4) and 2,6-dichloro-2′,4′-difluorobiphenyl-4-carboxaldehyde (20 mg, 0.070 mmol) (from Step 3) in DMF (2 mL) in a 20 mL scintillation vial was added acetic acid (13 uL, 0.209 mmol) and MP-cyanoborohydride resin (56 mg, 0.140 mmol, 2.49 mmol/g). The mixture was shaken at room temperature for 20 hours and then was filtered to remove the resin and washed with acetonitrile/water. The mixture was acidified with TFA and used directly for reverse phase (C-18) HPLC chromatography (10-55% acetonitrile/water gradient, 0.1% TFA) to afford the desired title compound (27 mg) as a solid TFA salt. The TFA salt was converted to the title compound hydrochloride salt by taking up in DCM and addition of excess 2M hydrogen chloride in ether and evaporation (twice) followed by trituration with ether to give the HCl salt (24 mg) as a white solid. was filtered to remove the resin washed with acetonitrile/water