tert-butyl N-[(3S)-piperidin-3-yl]carbamate

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

Procedure: Method 1 was followed using (S)-tert-butyl piperidin-3-ylcarbamate and 2-chloro-5-nitro-4-(piperidin-1-yl)pyrimidine. LCMS (m/z): 294.2 (MH+), Rt=0.56 min.

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (5)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.23 g, 98%). 1H NMR (CDCl3, 300 MHz): 5.08 (1H, bs), 4.27-4.07 (2H, m), 3.73 (1H, bs), 2.65-2.50 (3H, m), 2.48 (1H, bs), 2.30-2.24 (1H, m), 1.74-1.61 (1H, m), 1.58-1.47 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: A mixture of 2,2-dimethylpropionic acid 2-bromoethyl ester (2.3 g, 11 mmol), (5)-piperidin-3-ylcarbamic acid tert-butyl ester (2 g, 10.0 mmol), potassium carbonate (4.15 g, 30 mmol) and sodium iodide (0.15 g, 1 mmol) in DMF (20 mL) was stirred at RT for 3 days. The reaction mixture was partitioned between water and EtOAc. The aqueous phase was extracted with EtOAc and the combined organic fractions were washed with water, followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane) affording the title compound as a colourless oil (3.23 g, 98%). 1H NMR (CDCl3, 300 MHz): 5.08 (1H, bs), 4.27-4.07 (2H, m), 3.73 (1H, bs), 2.65-2.50 (3H, m), 2.48 (1H, bs), 2.30-2.24 (1H, m), 1.74-1.61 (1H, m), 1.58-1.47 (3H, m), 1.44 (9H, s), 1.21 (9H, s). The reaction mixture was partitioned between water and EtOAc The aqueous phase was extracted with EtOAc the combined organic fractions were washed with water dried (Na2SO4) concentrated in vacuo The resulting residue was purified by column chromatography (Si—PCC, eluant 10-40% EtOAc in cyclohexane)

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

Procedure: To 40 mL screw-cap vials was added 6-chloropyrido[3,2-d]pyrimidin-4-amine (2.00 g, 11.1 mmol) followed by tert-butyl N-[(3S)-3-piperidyl]carbamate (1.1 equiv., 12.2 mmol, 2.44 g) then dimethylacetamide (10 mL) and triethylamine (3 equiv., 33.2 mmol, 4.65 mL). The reaction was capped and shaken at 100° C. for 42 h, then an additional 24 h at 115° C. The reaction was cooled to room temperature, then partitioned with ethyl acetate:water. Residual chloride starting material was removed by filtration. The filtrate phases were separated, and the organics dried over sodium sulfate, filtered and concentrated, yielding 2.53 g of product. 1H NMR (400 MHz, DMSO) δ 8.19-8.13 (s, 1H), 7.81-7.74 (d, J=9.3 Hz, 1H), 7.43-7.39 (d, J=9.1 Hz, 1H), 6.95-6.85 (d, J=6.6 Hz, 1H), 4.32-4.19 (m, 2H), 3.50-3.38 (m, 1H), 3.19-3.04 (m, 1H), 2.96-2.85 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.67 (m, 1H), 1.60-1.34 (m, 11H). LCMS M/Z (M+H)=345. To 40 mL screw-cap vials The reaction was capped an additional 24 h at 115° C The reaction was cooled to room temperature partitioned with ethyl acetate Residual chloride starting material was removed by filtration The filtrate phases were separated the organics dried over sodium sulfate filtered concentrated

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

Procedure: To 40 mL screw-cap vials was added 6-chloropyrido[3,2-d]pyrimidin-4-amine (2.00 g, 11.1 mmol) followed by tert-butyl N-[(3S)-3-piperidyl]carbamate (1.1 equiv., 12.2 mmol, 2.44 g) then dimethylacetamide (10 mL) and triethylamine (3 equiv., 33.2 mmol, 4.65 mL). The reaction was capped and shaken at 100° C. for 42 h, then an additional 24 h at 115° C. The reaction was cooled to room temperature, then partitioned with ethyl acetate:water. Residual chloride starting material was removed by filtration. The filtrate phases were separated, and the organics dried over sodium sulfate, filtered and concentrated, yielding 2.53 g of product. 1H NMR (400 MHz, DMSO) δ 8.19-8.13 (s, 1H), 7.81-7.74 (d, J=9.3 Hz, 1H), 7.43-7.39 (d, J=9.1 Hz, 1H), 6.95-6.85 (d, J=6.6 Hz, 1H), 4.32-4.19 (m, 2H), 3.50-3.38 (m, 1H), 3.19-3.04 (m, 1H), 2.96-2.85 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.67 (m, 1H), 1.60-1.34 (m, 11H). LCMS M/Z (M+H)=345. To 40 mL screw-cap vials The reaction was capped an additional 24 h at 115° C The reaction was cooled to room temperature partitioned with ethyl acetate Residual chloride starting material was removed by filtration The filtrate phases were separated the organics dried over sodium sulfate filtered concentrated

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

Procedure: The title compound was prepared by substituting dihydro-2H-pyran-4(3H)-one for 4′-chlorobiphenyl-2-carboxaldehyde and (S)-tert-butyl piperidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate on EXAMPLE 1A.

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

Procedure: To a 200-mL RBF was added (s)-3-n-boc-amino piperidine (10.9 g, 54.4 mmol), Sodium bicarbonate (11.4 g, 136 mmol), THF, and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.62 ml, 54.4 mmol). The yellow mixture was heated to 70° C. with a water-cooled reflux condenser. The orange mixture was allowed to stir for 14 h, and was then cooled to ambient temperature, and filtered through a glass frit, rinsing with EtOAc. Concentration in vacuo afforded an orange oil, which crystallized on standing to an orange solid. The material was treated with 250 mL hexanes and heated on the rotovap (no vacuum) to 60° C. Small amounts of EtOAc were added until all solid dissolved, total volume of EtOAc was approx 10 mL. The solution was allowed to cool overnight, resulting in the formation of orange crystals. The liquid was decanted and the crystals rinsed twice with 50 mL hexanes. The crystals were collected to give (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate as orange crystals. The filtrate was concentrated to an orange solid. This material was treated with 150 mL hexanes and was heated to 65° C. Almost all of the material had dissolved. The hot liquid was decanted into a flask and allowed to cool overnight, resulting in an orange solid. The liquid was discarded, and additional crystals of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate were collected. MS m/z=390 [M+H]+. Calc'd for C17H20F3N3: 389. cooled reflux condenser filtered through a glass frit rinsing with EtOAc Concentration in vacuo afforded an orange oil, which crystallized The material was treated with 250 mL hexanes heated on the rotovap (no vacuum) to 60° C Small amounts of EtOAc were added until all solid dissolved to cool overnight resulting in the formation of orange crystals The liquid was decanted the crystals rinsed twice with 50 mL hexanes The crystals were collected

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

Procedure: To a 200-mL RBF was added (s)-3-n-boc-amino piperidine (10.9 g, 54.4 mmol), Sodium bicarbonate (11.4 g, 136 mmol), THF, and 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (7.62 ml, 54.4 mmol). The yellow mixture was heated to 70° C. with a water-cooled reflux condenser. The orange mixture was allowed to stir for 14 h, and was then cooled to ambient temperature, and filtered through a glass frit, rinsing with EtOAc. Concentration in vacuo afforded an orange oil, which crystallized on standing to an orange solid. The material was treated with 250 mL hexanes and heated on the rotovap (no vacuum) to 60° C. Small amounts of EtOAc were added until all solid dissolved, total volume of EtOAc was approx 10 mL. The solution was allowed to cool overnight, resulting in the formation of orange crystals. The liquid was decanted and the crystals rinsed twice with 50 mL hexanes. The crystals were collected to give (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate as orange crystals. The filtrate was concentrated to an orange solid. This material was treated with 150 mL hexanes and was heated to 65° C. Almost all of the material had dissolved. The hot liquid was decanted into a flask and allowed to cool overnight, resulting in an orange solid. The liquid was discarded, and additional crystals of (S)-tert-butyl 1-(2-nitro-4-(trifluoromethyl)phenyl)piperidin-3-ylcarbamate were collected. MS m/z=390 [M+H]+. Calc'd for C17H20F3N3: 389. cooled reflux condenser filtered through a glass frit rinsing with EtOAc Concentration in vacuo afforded an orange oil, which crystallized The material was treated with 250 mL hexanes heated on the rotovap (no vacuum) to 60° C Small amounts of EtOAc were added until all solid dissolved to cool overnight resulting in the formation of orange crystals The liquid was decanted the crystals rinsed twice with 50 mL hexanes The crystals were collected

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

Procedure: A solution of 6-bromo-4-chloroquinoline (1.0 equiv.), (S)-tert-butyl piperidin-3-ylcarbamate (1.0 equiv.) and DIEA (1.5 equiv.) in NMP (0.1 M) was heated at 140° C. for 48 hours. Upon cooling the solution was poured onto ice and upon melting the solid was filtered, rinsed with H2O and pumped on to yield (S)-tert-butyl 1-(6-bromoquinolin-4-yl)piperidin-3-ylcarbamate. LC/MS=406.0/408.0 (M+H), LC=2.85 min. Upon cooling the solution was poured onto ice was filtered rinsed with H2O

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

Procedure: A solution of 6-bromo-4-chloroquinoline (1.0 equiv.), (S)-tert-butyl piperidin-3-ylcarbamate (1.0 equiv.) and DIEA (1.5 equiv.) in NMP (0.1 M) was heated at 140° C. for 48 hours. Upon cooling the solution was poured onto ice and upon melting the solid was filtered, rinsed with H2O and pumped on to yield (S)-tert-butyl 1-(6-bromoquinolin-4-yl)piperidin-3-ylcarbamate. LC/MS=406.0/408.0 (M+H), LC=2.85 min. Upon cooling the solution was poured onto ice was filtered rinsed with H2O

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

Procedure: A solution of 6-chloro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.0 equiv.), (S)-tert-butyl piperidin-3-ylcarbamate (1.0 equiv.) and DIEA (1.5 equiv.) in CH2Cl2 (0.3 M) was stirred at rt for 120 hours. The solution was partitioned between EtOAc and Na2CO3(sat.). Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (EtOAc eluant) to yield (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (61%). LC/MS=363.2 (M+H), LC=2.47 min. The solution was partitioned between EtOAc and Na2CO3(sat.) Upon separation the organic layer was washed with NaCl(sat.) dried over MgSO4 concentrated purified by silica gel chromatography (EtOAc eluant)

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

Procedure: A solution of 2,4-dichloro-5-nitropyridine (from AstaTech, 0.500 g, 2.59 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (0.52 g, 2.6 mmol) and triethylamine (1.1 mL, 7.9 mmol) in isopropyl alcohol (10 mL) was heated at 65° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was re-dissolved in EtOAc (40 mL) and washed with saturated aq. NaHCO3 and water (3×3 mL). The combined aqueous phases were extracted with EtOAc (3 mL). The combined organic layers were washed with brine (3 mL), then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the sub-title compound (0.99 g), which was used in the subsequent reaction without further purification. LCMS (ESI) calc. for C15H22ClN4O4[M+H]+: m/z=357.1. found 357.0. The reaction mixture was concentrated under reduced pressure the residue was re-dissolved in EtOAc (40 mL) washed with saturated aq. NaHCO3 and water (3×3 mL) The combined aqueous phases were extracted with EtOAc (3 mL) The combined organic layers were washed with brine (3 mL) dried over Na2SO4 filtered concentrated under reduced pressure