tert-butyl-dimethyl-piperidin-4-yloxysilane

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

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-[[5-bromo-2-(trifluoromethyl)benzoyl]amino]-3,5-dimethyl-benzoate (0.10 g, 232.44 μmol), tert-butyl-dimethyl-(4-piperidyloxy)silane (55.08 mg, 255.68 μmol, see preparation 3) and Cs2CO3 (227.2 mg, 697.32 μmol) in 1,4-dioxane (2.5 ml) is added Pd2(dba)3 (21.28 mg, 23.24 μmol) followed by 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (9.54 mg, 23.24 μmol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 120° C. After 8 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrates are dried over sodium sulfate, filtered, and concentrated under reduced pressure and purified by flash chromatography (neutral alumina) using of 15%-85% ethyl acetate in hexanes as eluent to afford the title compound as a pale yellow oil (0.10 g, 80%). Mass spectrum (m/z): 565.4 (M+1). The reaction mixture is purged with nitrogen for 5 minutes the reaction is cooled to ambient temperature filtered through Celite™ washed with EtOAc The combined filtrates are dried over sodium sulfate filtered concentrated under reduced pressure purified by flash chromatography (neutral alumina)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(3-bromo-1-naphthamido)-2,4-dimethylbenzoate (0.48 g, 0.0011 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.75 g, 0.0034 mol, see preparation 3) and Cs2CO3 (1.00 g, 0.0033 mol) in 1,4-dioxane (8 ml) is added Pd2(dba)3 (0.10 g, 0.00011 mol) followed by S-Phos (0.045 g, 0.00011 mol). The reaction mixture is purged with nitrogen for 5 minutes and then stirred at 80° C. The reaction mixture is purged with nitrogen for 5 minutes

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(2-chloroquinoline-4-carboxamido)-2,4-dimethylbenzoate (0.54 g, 0.00146 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.63 g, 0.00293 mol, see preparation 3) and Cs2CO3 (1.43 g, 0.0044 mol) in 1,4-dioxane (8 ml) is added Pd2(dba)3 (0.134 g, 0.000146 mol) followed by S-Phos (0.060 g, 0.000146 mol). The reaction mixture is purged with nitrogen for 5 minutes and then stirred at 80° C. After 16 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a black semi-solid (1.31 g, 60%, crude). Mass spectrum (m/z): 548.2 (M+1). The reaction mixture is purged with nitrogen for 5 minutes the reaction is cooled to ambient temperature filtered through Celite™ washed with EtOAc dried over sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-(2-chloroquinoline-4-carboxamido)-3,5-dimethylbenzoate, (0.50 g, 0.00135 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.32 g, 0.0015 mol, see preparation 3) and Cs2CO3 (1.77 g, 0.0054 mol) in 1,4-dioxane (5 ml) is added Pd2(dba)3 (0.124 g, 0.000135 mol) followed by S-Phos (0.060 g, 0.000135 mol). The reaction mixture is purged with nitrogen for 5 minutes and then stirred at 80° C. After 4 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (0.21 g, 28%). Mass spectrum (m/z): 548.2 (M+1). The reaction mixture is purged with nitrogen for 5 minutes the reaction is cooled to ambient temperature filtered through Celite™ washed with EtOAc dried over sodium sulfate filtered concentrated under reduced pressure

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 3-(6-chloro-3-methylpicolinamido)-2,4-dimethylbenzoate (0.50 g, 0.0015 mol), tert-butyl-dimethyl-(4-piperidyloxy)silane (0.90 g, 0.0045 mol) and Cs2CO3 (2.00 g, 0.006 mol) in toluene (6 ml) is added Pd2(dba)3 (0.14 g, 0.00015 mol) followed by BINAP (0.086 g, 0.00015 mol). The reaction mixture is purged with nitrogen for 5 minutes and then heated at 120° C. After 4 hours, the reaction is cooled to ambient temperature, filtered through Celite™, and washed with EtOAc. The combined filtrate is dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound as a white semi-solid (0.220 g, 29%). Mass spectrum (m/z): 398.2 (M+1). The reaction mixture is purged with nitrogen for 5 minutes the reaction is cooled to ambient temperature filtered through Celite™ washed with EtOAc The combined filtrate is dried over sodium sulfate filtered concentrated under reduced pressure

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

Procedure: To a solution of 4-hydroxypiperidine (2.00 g, 9.89 mmoles) in CH2Cl2 (30 mL) is added 1H-imidazole (2.69 g, 39.55 mmoles) followed by t-butyldimethylchlorosilane (3.58 g, 23.73 mmoles) and the reaction mixture is stirred at room temperature. After 12 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 100% CH2Cl2 to 10% 7N ammonia in MeOH/90% CH2Cl2 to afford the title compound (3.69 g, 86.3%). Mass spectrum (m/z): 216.2 (M+1). the reaction mixture is washed with water, saturated solution of NaHCO3, and brine dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel) over a gradient

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

Procedure: Scheme 1, step C reagent. To a solution of 4-hydroxypiperidine (2.00 g, 9.89 mmoles) in CH2Cl2 (30 mL) is added 1H-imidazole (2.69 g, 39.55 mmoles) followed by t-butyldimethylchlorosilane (3.58 g, 23.73 mmoles) and the reaction mixture is stirred at room temperature. After 12 hours, the reaction mixture is washed with water, saturated solution of NaHCO3, and brine. The organic layers are combined and dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 100% CH2Cl2 to 10% 7N ammonia in MeOH/90% CH2Cl2 to afford the title compound (3.69 g, 86.3%). Mass spectrum (m/z): 216.2 (M+1). the reaction mixture is washed with water, saturated solution of NaHCO3, and brine dried over sodium sulfate filtered concentrated under reduced pressure The resulting residue is purified by flash chromatography (silica gel) over a gradient

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (I13A): A round bottom flask was charged with tert-butyl (3-bromo-2-chloro-5-cyanophenyl)carbamate (Intermediate 1)(5.39 g, 16.25 mmol), 4-((tert-butyldimethylsilyl)oxy) piperdine (3.5 g, 16.25 mmol), cesium carbonate (10.5 g, 32.5 mmol), Pd2(dba)3 (1.488 g, 1.625 mmol) and BINAP (1.012 g, 1.625 mmol) in toluene (54.2 ml). The flask was evacuated and purged with nitrogen (4×) and heated at 100° C. 2 d. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite. The filtrate was concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (330 g, 60-95% CH2Cl2/Hex) to provide tert-butyl (3-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-chloro-5-cyanophenyl)carbamate (3.27 g) as a yellow solid. The flask was evacuated purged with nitrogen (4×) 2 d After cooling to room temperature the reaction mixture was diluted with ethyl acetate and vacuum filtered through a pad of Celite The filtrate was concentrated in vacuo The crude residue was purified by column chromatography on the ISCO system (330 g, 60-95% CH2Cl2/Hex)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromobenzonitrile (2.76 g, 15.16 mmol), 4-(tert-butyldimethylsiloxy)piperidine (2.9 g, 13.79 mmol), palladium acetate (62 mg, 0.28 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (258 mg, 0.41 mmol), and sodium tert-butoxide (1.99 g, 20.68 mmol) in toluene (60 ml) was stirred at 80° C. for 1 hour. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (60 ml) was added, and the mixture was filtered. The filtration was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1) to afford 4-[4-(tert-butyldimethylsiloxy)piperidin-1-yl]benzonitrile (2.8 g, yield 66%) as a pale yellow crystalline powder. was added the mixture was filtered The filtration was washed with water and brine dried over magnesium sulfate After filtration the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1)

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4-bromobenzonitrile (2.76 g, 15.16 mmol), 4-(tert-butyldimethylsiloxy)piperidine (2.9 g, 13.79 mmol), palladium acetate (62 mg, 0.28 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (258 mg, 0.41 mmol), and sodium tert-butoxide (1.99 g, 20.68 mmol) in toluene (60 ml) was stirred at 80° C. for 1 hour. The reaction mixture was allowed to return to room temperature, to which ethyl acetate (60 ml) was added, and the mixture was filtered. The filtration was washed with water and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1) to afford 4-[4-(tert-butyldimethylsiloxy)piperidin-1-yl]benzonitrile (2.8 g, yield 66%) as a pale yellow crystalline powder. was added the mixture was filtered The filtration was washed with water and brine dried over magnesium sulfate After filtration the filtrate was concentrated under reduced pressure The residue was purified by silica gel column chromatography (n-hexane/methylene chloride=1/1)

Conditions: temp:130.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,6-dichloro-N-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]pyrimidin-4-amine (Preparation 10a, 0.66 g, 2.31 mmol), 4-(tert-butyl-dimethylsilanyloxy)piperidine (prepared as described in WO2004/006926, 0.60 g, 2.77 mmol) and cesium carbonate (1.13 g, 3.46 mmol) in N,N′-dimethylformamide (15 mL) was stirred and heated to 130° C. in a sealed tube for 2 hours. After cooling to ambient temperature, water was added and the resulting mixture was extracted with ethyl acetate (×3). The combined organic extract was washed with water and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate) to give the title compound (0.53 g, 50%) as a white solid. After cooling to ambient temperature the resulting mixture was extracted with ethyl acetate (×3) The combined organic extract was washed with water and brine dried (MgSO4) filtered the solvent was evaporated under reduced pressure The residue was purified by flash chromatography (hexanes to 6:4 hexanes/ethyl acetate)