1-(2-fluoroethyl)piperazine

Conditions: temp:0.00; pressure:0.00; stir:

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: 1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H). Reaction to stir overnight stopped bubbling Aqueous layer was then extracted with EtOAc (3×) Combined organic layers were dried over MgSO4 filtered concentrated in vacuo purified by flash chromatography

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1,1-dimethylethyl 4-(2-fluoroethyl)-1-piperazinecarboxylate was dissolved in 40 mL of MeOH and 40 mL 37% HCl. Reaction was stirred for 1 h. Carefully neutralized with solid K2CO3 and concentrated in vacuo being careful not to heat the H2O bath past 30° C. The resulting residue was taken up in diethyl ether and the solids were filtered and washed with diethyl ether and DCM several times. Filtrate was concentrated in vacuo, again being careful not to heat the H2O bath past 30° C., to give desired product 1-(2-fluoroethyl)piperazine (5.2 g, 73% over 2 steps) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.40-4.57 (m, 2H), 2.64-2.73 (m, 4H), 2.53-2.61 (m, 1H), 2.46-2.53 (m, 2H), 2.29-2.40 (m, 4H). Reaction concentrated in vacuo the solids were filtered washed with diethyl ether and DCM several times Filtrate was concentrated in vacuo to heat the H2O bath past 30° C.

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

Procedure: Treat a mixture of 3′,5′-dichloro-4′-[(R)-2-oxo-cis-1-(4-triisopropylsilanyloxy-cyclohexyl)-pyrrolidin-3-ylmethyl]-biphenyl-4-carboxylic acid (4 g, 5.46 mmol), 1-(2-fluoro-ethyl)-piperazine (2.97 g, 12.12 mmol) and diisopropylethylamine (3.13 g, 24.24 mmol) in 125 mL dichloromethane with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.1 g, 16.16 mmol) and stir at room temperature overnight. Dilute with 150 mL saturated sodium bicarbonate and separate layers. Wash the organic layer with 150 mL water then 100 mL brine. Extract the combined aqueous layers with 100 mL dichloromethane and combine with original organic layer. Dry over sodium sulfate, filter, concentrate, and purify via silica chromatography to give 4 g (67%) product as a foam: MS (m/z): 732 (M+). Treat separate layers Wash the organic layer with 150 mL water Extract the combined aqueous layers with 100 mL dichloromethane Dry over sodium sulfate filter concentrate purify via silica chromatography

Conditions: temp:0.00; pressure:0.00; stir:

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

Procedure: The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2-fluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=4.57 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=492.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.71 (m, 2H) 3.09-3.21 (m, 4H) 3.24-3.35 (m, 4H) 4.46 (t, J=4.89 Hz, 1H) 4.58 (t, J=4.89 Hz, 1H) 6.66 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.28-8.37 (m, 1H) 8.73 (d, J=1.95 Hz, 1H) 10.39 (br. s, 1H) 12.96-13.11 (m, 1H). to afford an off-white powder

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

Procedure: The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2-fluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=4.57 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=492.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.71 (m, 2H) 3.09-3.21 (m, 4H) 3.24-3.35 (m, 4H) 4.46 (t, J=4.89 Hz, 1H) 4.58 (t, J=4.89 Hz, 1H) 6.66 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.28-8.37 (m, 1H) 8.73 (d, J=1.95 Hz, 1H) 10.39 (br. s, 1H) 12.96-13.11 (m, 1H). to afford an off-white powder

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

Procedure: 1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H). Reaction to stir overnight stopped bubbling Aqueous layer was then extracted with EtOAc (3×) Combined organic layers were dried over MgSO4 filtered concentrated in vacuo purified by flash chromatography

Conditions: temp:30.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Crude 1,1-dimethylethyl 4-(2-fluoroethyl)-1-piperazinecarboxylate was dissolved in 40 mL of MeOH and 40 mL 37% HCl. Reaction was stirred for 1 h. Carefully neutralized with solid K2CO3 and concentrated in vacuo being careful not to heat the H2O bath past 30° C. The resulting residue was taken up in diethyl ether and the solids were filtered and washed with diethyl ether and DCM several times. Filtrate was concentrated in vacuo, again being careful not to heat the H2O bath past 30° C., to give desired product 1-(2-fluoroethyl)piperazine (5.2 g, 73% over 2 steps) which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.40-4.57 (m, 2H), 2.64-2.73 (m, 4H), 2.53-2.61 (m, 1H), 2.46-2.53 (m, 2H), 2.29-2.40 (m, 4H). Reaction concentrated in vacuo the solids were filtered washed with diethyl ether and DCM several times Filtrate was concentrated in vacuo to heat the H2O bath past 30° C.

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

Procedure: 1,1-Dimethylethyl 4-oxo-1-piperidinecarboxylate (15.7 g, 78.7 mmol) and 1-(2-fluoroethyl)piperazine (5.2 g, 39 mmol) were dissolved in 150 mL 1,2-DCE. HOAc (3.4 mL, 59 mmol) and TEA (5.5 mL, 39 mmol) were added followed by sodium triacetoxyborohydride (12.5 g, 59.0 mmol). The reaction was stirred for 3 h. TLC revealed the presence of starting material and so an additional 1.5 eq (12.5 g, 59.0 mmol) of sodium triacetoxyborohydride were added. Reaction was allowed to stir overnight. Saturated aqueous NaHCO3 solution was added carefully until the reaction stopped bubbling. Aqueous layer was then extracted with EtOAc (3×). Combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting crude product was adsorbed onto silica gel and purified by flash chromatography to give title compound of step C (10.2 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.39-4.57 (m, 2H), 3.90 (d, J=12.46 Hz, 2H), 2.61-2.73 (m, 2H), 2.47-2.61 (m, 2H), 2.36-2.47 (m, 8H), 2.24-2.35 (m, 1H), 1.69 (d, J=12.46 Hz, 2H), 1.37 (s, 9H), 1.14-1.26 (m, 2H). Reaction to stir overnight stopped bubbling Aqueous layer was then extracted with EtOAc (3×) Combined organic layers were dried over MgSO4 filtered concentrated in vacuo purified by flash chromatography