(4,4-difluorocyclohexyl)methanamine

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: 4-Bromo-2-bromomethyl-6-chlorobenzoic acid methyl ester (3.5 g, 9.35 mmol), (4,4-difluorocyclohexyl)methylamine (1.7 g, 11.39 mmol) and K2CO3 (3.15 g, 22.78 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2—SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford the title compound as a yellow foam (2.2 g, 45%), 1H NMR (300 MHz, CDCl3): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H), 2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H) The reaction was partitioned between ethyl acetate and water the organic layer was washed with brine dried over anhydrous Na2—SO4 The solvent was removed under reduced pressure the product was purified by column chromatography (10-25% EtOAc/Hexanes)

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

Procedure: 4-Bromo-2-bromomethyl-6-chlorobenzoic acid methyl ester (3.5 g, 9.35 mmol), (4,4-difluorocyclohexyl)methylamine (1.7 g, 11.39 mmol) and K2CO3 (3.15 g, 22.78 mmol) were stirred in toluene (10 mL) at 95° C. for 12 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2—SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (10-25% EtOAc/Hexanes) to afford the title compound as a yellow foam (2.2 g, 45%), 1H NMR (300 MHz, CDCl3): 7.58 (s, 1H), 7.50 (s, 1H), 4.36 (s, 2H), 3.48 (d, 2H), 2.10-2.14 (m, 2H), 1.64-1.82 (m, 5H), 1.35-1.447 (m, 2H) The reaction was partitioned between ethyl acetate and water the organic layer was washed with brine dried over anhydrous Na2—SO4 The solvent was removed under reduced pressure the product was purified by column chromatography (10-25% EtOAc/Hexanes)

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

Procedure: 4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H). Then, the reaction mixture was refluxed for 4 hours After filtration the product was extracted with dichloromethane from filtrate dried over anhydrous sodium sulphate filtered condensed

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

Procedure: 4,4-difluorocyclohexanecarboxamide (1.32 g, 8.10 mmol) was stirred in the solution of lithium borohydrate (1M, 30 ml) under nitrogen overnight. Then, the reaction mixture was refluxed for 4 hours. After cooled to room temperature, it was poured into ice-water slowly. After filtration, the product was extracted with dichloromethane from filtrate. Combined organic layers were water, brine, dried over anhydrous sodium sulphate, filtered and condensed to provide a 934 mg of colorless oil (82%). δ 2.53 (d, 2H), 1.98-2.09 (m, 2H), 1.73-1.82 (m, 6H), 1.17-1.29 (m, 3H). Then, the reaction mixture was refluxed for 4 hours After filtration the product was extracted with dichloromethane from filtrate dried over anhydrous sodium sulphate filtered condensed

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

Procedure: A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then condensed from toluene, and left under high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to give the title compound as its TFA salt. The solution was concentrated condensed from toluene filtered

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

Procedure: A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then condensed from toluene, and left under high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to give the title compound as its TFA salt. The solution was concentrated condensed from toluene filtered

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

Procedure: A solution of EXAMPLE 239A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then concentrated from toluene, and left on high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to provide the title compound as its trifluoroacetic acid salt. The solution was concentrated concentrated from toluene filtered

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

Procedure: A solution of EXAMPLE 239A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then concentrated from toluene, and left on high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to provide the title compound as its trifluoroacetic acid salt. The solution was concentrated concentrated from toluene filtered

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

Procedure: A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then condensed from toluene, and left under high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to give the title compound as its TFA salt. The solution was concentrated condensed from toluene filtered

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

Procedure: A solution of EXAMPLE 396A (3 g) in dichloromethane (35 mL), trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for 2 hours. The solution was concentrated, then condensed from toluene, and left under high vacuum for 24 hours. The semi-solid was taken up in ether/hexane and filtered to give the title compound as its TFA salt. The solution was concentrated condensed from toluene filtered