4-(2,2,2-trifluoroethoxymethyl)piperidine;hydrochloride

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

Procedure: A solution of 4M hydrogen chloride in 1,4-dioxane (2.48 mL, 9.93 mmol) was added to tert-butyl 4-[(2,2,2-trifluoroethoxy)methyl]piperidine-1-carboxylate (Intermediate 180, 0.289 g, 0.993 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (0.136 g, 59%). Method B HPLC-MS: MH+ (HCl salt) requires m/z=198 Found: m/z=198, Rt=0.72 min. before being evaporated to dryness

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

Procedure: To 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) in DMF (2 mL) was added DIPEA (93.6 μL, 0.537 mmol) at the mixture was stirred at room temperature for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method C, to afford the title compound (10.8 mg, 8.9%). the mixture was stirred at room temperature for 18 h The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h The reaction mixture was concentrated under reduced pressure dissolved in EtOAc washed with water The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by preparative HPLC, Method C

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

Procedure: 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) at room temperature and the mixture was stirred for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A, to afford the title compound (22.1 mg, 18%). stirred at room temperature for 2 h The reaction mixture was concentrated under reduced pressure dissolved in water extracted with EtOAc The combined organic extracts was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A

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

Procedure: A solution of 4M hydrogen chloride in 1,4-dioxane (2.48 mL, 9.93 mmol) was added to tert-butyl 4-[(2,2,2-trifluoroethoxy)methyl]piperidine-1-carboxylate (Intermediate 180, 0.289 g, 0.993 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (0.136 g, 59%). Method B HPLC-MS: MH+ (HCl salt) requires m/z=198 Found: m/z=198, Rt=0.72 min. before being evaporated to dryness

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

Procedure: To 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) in DMF (2 mL) was added DIPEA (93.6 μL, 0.537 mmol) at the mixture was stirred at room temperature for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method C, to afford the title compound (10.8 mg, 8.9%). the mixture was stirred at room temperature for 18 h The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h The reaction mixture was concentrated under reduced pressure dissolved in EtOAc washed with water The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by preparative HPLC, Method C

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

Procedure: 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) at room temperature and the mixture was stirred for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A, to afford the title compound (22.1 mg, 18%). stirred at room temperature for 2 h The reaction mixture was concentrated under reduced pressure dissolved in water extracted with EtOAc The combined organic extracts was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A

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

Procedure: 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) at room temperature and the mixture was stirred for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A, to afford the title compound (22.1 mg, 18%). stirred at room temperature for 2 h The reaction mixture was concentrated under reduced pressure dissolved in water extracted with EtOAc The combined organic extracts was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A

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

Procedure: A solution of 4M hydrogen chloride in 1,4-dioxane (2.48 mL, 9.93 mmol) was added to tert-butyl 4-[(2,2,2-trifluoroethoxy)methyl]piperidine-1-carboxylate (Intermediate 180, 0.289 g, 0.993 mmol) and the mixture was stirred at room temperature for 18 h before being evaporated to dryness to provide the title compound (0.136 g, 59%). Method B HPLC-MS: MH+ (HCl salt) requires m/z=198 Found: m/z=198, Rt=0.72 min. before being evaporated to dryness

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

Procedure: To 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (Intermediate 134, 0.100 g, 0.268 mmol) in DMF (2 mL) was added DIPEA (93.6 μL, 0.537 mmol) at the mixture was stirred at room temperature for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.063 g, 0.268 mmol) was added and the mixture was stirred at room temperature for 18 h. The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h. The reaction mixture was concentrated under reduced pressure, dissolved in EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC, Method C, to afford the title compound (10.8 mg, 8.9%). the mixture was stirred at room temperature for 18 h The reaction mixture was then heated to 50 C for 18 h and to 70 C for 36 h The reaction mixture was concentrated under reduced pressure dissolved in EtOAc washed with water The organic layer was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by preparative HPLC, Method C

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

Procedure: 2-N-methyl-2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 60, 0.110 g, 0.285 mmol) was added to a mixture of potassium carbonate (0.071 g, 0.518 mmol) in DMF (2 mL) at room temperature and the mixture was stirred for 5 min. 4-[(2,2,2-trifluoroethoxy)methyl]piperidine hydrochloride (Intermediate 179, 0.060 g, 0.259 mmol) was added to the reaction mixture and stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, dissolved in water and extracted with EtOAc. The combined organic extracts was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A, to afford the title compound (22.1 mg, 18%). stirred at room temperature for 2 h The reaction mixture was concentrated under reduced pressure dissolved in water extracted with EtOAc The combined organic extracts was dried over anhydrous sodium sulfate filtered concentrated under reduced pressure The crude compound was purified by FCC (EtOAc:heptane 1:1) and preparative HPLC, Method A