2,2,2-trifluoroethylhydrazine;hydrochloride

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

Procedure: The title compound was prepared as TFA salt according to procedure for Example 69A-69F, substituting (±)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate for (R)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate and isopropylhydrazine for (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 315 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.51 (dd, J=6.71, 3.66 Hz, 6H), 1.71-1.95 (m, 3H), 2.05-2.25 (m, 2H), 2.24-2.37 (m, 1H), 2.41-2.56 (m, 2H), 2.69-2.78 (m, 1H), 2.77-2.89 (m, 1H), 2.90-3.03 (m, 1H), 2.96 (s, 3H), 3.29-3.44 (m, 2H), 3.77-3.96 (m, 1H), 4.73-4.91 (m, 2H).

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

Procedure: To a solution of Example 69A (3.0 g, 11 mmol) in ethanol (10 mL) was added (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt (2.3 g, 11 mmol) and triethylamine (1.84 mL, 13.2 mmol) at rt. The solution was heated under reflux for 4 h. After cooling, the reaction mixture was concentrated and the residue was separated by flash chromatography to give Example 69B. Yield: 3.5 g (88%). MS (DCI): m/z 369 (M+H)+. The solution was heated under reflux for 4 h After cooling the reaction mixture was concentrated the residue was separated by flash chromatography to give Example 69B

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

Procedure: The title compound was prepared as TFA salt according to procedure for Example 69A-69F, substituting (±)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate for (R)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate and ethylhydrazine for (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 301 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.42 (t, J=7.36 Hz, 2H), 1.75-1.91 (m, 4H), 2.02-2.26 (m, 2H), 2.23-2.37 (m, 1H), 2.52 (t, J=5.68 Hz, 2H), 2.59-2.77 (m, 1H), 2.77-2.89 (m, 1H), 2.88-3.03 (m, 1H), 2.96 (s, 3H), 3.26-3.41 (m, 1H), 3.75-3.93 (m, 1H), 4.30 (q, J=7.36 Hz, 2H), 4.96 (t, J=8.29 Hz, 1H).

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

Procedure: The title compound was prepared as TFA salt according to procedure for Example 69A-69F, substituting (±)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate for (R)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate and ethylhydrazine for (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 301 (M+H)+; 1H NMR (400 MHz, CD3OD): δ 1.42 (t, J=7.36 Hz, 2H), 1.75-1.91 (m, 4H), 2.02-2.26 (m, 2H), 2.23-2.37 (m, 1H), 2.52 (t, J=5.68 Hz, 2H), 2.59-2.77 (m, 1H), 2.77-2.89 (m, 1H), 2.88-3.03 (m, 1H), 2.96 (s, 3H), 3.26-3.41 (m, 1H), 3.75-3.93 (m, 1H), 4.30 (q, J=7.36 Hz, 2H), 4.96 (t, J=8.29 Hz, 1H).

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

Procedure: Alternatively, and following the procedure for 184, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by treatment of trifluoroethylhydrazine hydrochloride in acetic acid to provide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m, 7H)

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

Procedure: Alternatively, and following the procedure for 184, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by treatment of trifluoroethylhydrazine hydrochloride in acetic acid to provide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m, 7H)

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

Procedure: Alternatively, and following the procedure for 184, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by treatment of trifluoroethylhydrazine hydrochloride in acetic acid to provide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m, 7H)

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

Procedure: Alternatively, and following the procedure for 184, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by treatment of trifluoroethylhydrazine hydrochloride in acetic acid to provide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m, 7H)

Conditions: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 12-chloro-4-iodo-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1 (14),2,4,10,12-pentaene (1.60 g, 4.60 mmol) and acetamidine hydrochloride (481 g, 5.06 mmol), Et3N (4.00 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 532 mg, 0.920 mmol), and Pd(OAc)2 (103 mg, 0.460 mmol) in DMF (20.0 mL) was heated under carbon monoxide atmosphere at 40° C. for 3 h. After cooling to room temperature, a solution of (2,2,2-trifluoroethyl)hydrazine hydrochloride (800 mg, 5.32 mmol) in acetic acid (15.0 mL) was added. The resultant mixture was further heated at 65° C. for 3 h. After concentratin, the residue was extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3 to give 12-chloro-4-[3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6,13-triazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene (1.35 mg, 76% yield) as pale yellow solid. LCMS (ESI) m/z: 385.1 [M+H+]. After cooling to room temperature the residue was extracted with ethyl acetate washed with brine dried over MgSO4 filtered evaporated The crude product was purified by reverse phase Combiflash eluting with a 0-40% gradient of CH3CN in 0.5% NH4HCO3

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

Procedure: Alternatively, and following the procedure for 184, methyl 2-carbamoyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylate was reacted with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by treatment of trifluoroethylhydrazine hydrochloride in acetic acid to provide 185 (65% yield). 1H NMR (400 MHz, DMSO) δ 8.51 (d, J=8.4, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 7.71 (dd, J=8.4, 1.7, 1H), 7.58 (d, J=1.6, 1H), 5.89 (q, J=8.8, 2H), 4.65-4.45 (m, 5H), 3.87 (s, 3H), 3.58-3.37 (m, 7H)

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

Procedure: The title compound was prepared as TFA salt according to procedure for Example 69A-69F, substituting (±)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate for (R)-1-benzyl 2-methyl pyrrolidine-1,2-dicarboxylate and isopropylhydrazine for (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt. MS (DCI): m/z 315 (M+H)+; 1H NMR (500 MHz, CD3OD): δ 1.51 (dd, J=6.71, 3.66 Hz, 6H), 1.71-1.95 (m, 3H), 2.05-2.25 (m, 2H), 2.24-2.37 (m, 1H), 2.41-2.56 (m, 2H), 2.69-2.78 (m, 1H), 2.77-2.89 (m, 1H), 2.90-3.03 (m, 1H), 2.96 (s, 3H), 3.29-3.44 (m, 2H), 3.77-3.96 (m, 1H), 4.73-4.91 (m, 2H).

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

Procedure: To a solution of Example 69A (3.0 g, 11 mmol) in ethanol (10 mL) was added (2,2,2-Trifluoro-ethyl)-hydrazine HCl salt (2.3 g, 11 mmol) and triethylamine (1.84 mL, 13.2 mmol) at rt. The solution was heated under reflux for 4 h. After cooling, the reaction mixture was concentrated and the residue was separated by flash chromatography to give Example 69B. Yield: 3.5 g (88%). MS (DCI): m/z 369 (M+H)+. The solution was heated under reflux for 4 h After cooling the reaction mixture was concentrated the residue was separated by flash chromatography to give Example 69B