tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate

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

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

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

Procedure: 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (74 mg, 0.249 mmol) was dissolved in dry DMF (1 mL) nitrogen atmosphere. tert-Butyl 3-(2-aminoethyl)azetidine-1-carboxylate (50 mg, 0.249 mmol) was added followed by TEA (25 mg, 0.247 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (33 mg, 28.8%). 1H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.62 (q, 2H), 1.73 (s, 9H), 2.19-2.27 (m, 1H), 2.83 (q, 2H), 3.23-3.26 (m, 2H), 3.84 (t, 2H), 5.25 (t, 1H), 7.42-7.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 26.24, 27.82, 28.61, 34.35, 41.72, 54.06, 61.82, 79.63, 107.55, 125.15, 128.93, 130.09, 131.79, 135.04, 156.38, 159.81; Mass Spectrum: M−H+ 462. washed with saturated aqueous NaHCO3-solution dried over Na2SO4 filtered evaporated The crude product was purified by preparative HPLC

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

Procedure: tert-Butyl 3-(2-amino-2-oxoethyl)azetidine-1-carboxylate (70 mg, 0.327 mmol) was dissolved in THF (2 mL) and cooled on an ice-bath. Borane dimethyl sulfide complex (0.41 mL, 2M in THF) was added dropwise, whereafter the mixture was refluxed for 6 h. The reaction mixture was allowed to attain rt and a mixture of DIPEA:MeOH (0.6 mL, 1:2) and iodine (166 mg, 0.654 mmol) was added. The mixture was stirred at rt overnight and then evaporated to dryness. Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated. Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4). NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2). The extracts were combined, dried (Na2SO4) and evaporated, and the residue was purified by using an ion exchange column (ISOLUTE PRS, 2 g/15 mL), eluting with MeOH and DCM (10:90), then MeOH and then MeOH (saturated with NH3) to give the title compound (35 mg, 53.5%). 1H NMR (400 MHz, CDCl3): 1.41 (s, 9H), 1.71 (dt, 2H), 2.49-2.60 (m, 1H), 2.64 (t, 2H), 3.54 (dd, 2H), 3.99 (t, 2H); 13C NMR (100 MHz, CDCl3): 26.6, 28.3, 38.3, 39.8, 54.3 (br), 79.1, 156.3. cooled on an ice-bath was refluxed for 6 h to attain rt evaporated to dryness Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4) NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2) dried (Na2SO4) evaporated the residue was purified eluting with MeOH and DCM (10:90)

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

Procedure: 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (74 mg, 0.249 mmol) was dissolved in dry DMF (1 mL) nitrogen atmosphere. tert-Butyl 3-(2-aminoethyl)azetidine-1-carboxylate (50 mg, 0.249 mmol) was added followed by TEA (25 mg, 0.247 mmol) and the reaction mixture was heated in a microwave reactor for at 120° C. for 20 mins. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3-solution, dried over Na2SO4, filtered and evaporated. The crude product was purified by preparative HPLC affording the title compound (33 mg, 28.8%). 1H NMR (500 MHz, CDCl3): δ 1.43 (s, 9H), 1.62 (q, 2H), 1.73 (s, 9H), 2.19-2.27 (m, 1H), 2.83 (q, 2H), 3.23-3.26 (m, 2H), 3.84 (t, 2H), 5.25 (t, 1H), 7.42-7.51 (m, 5H); 13C NMR (125 MHz, CDCl3): δ 26.24, 27.82, 28.61, 34.35, 41.72, 54.06, 61.82, 79.63, 107.55, 125.15, 128.93, 130.09, 131.79, 135.04, 156.38, 159.81; Mass Spectrum: M−H+ 462. washed with saturated aqueous NaHCO3-solution dried over Na2SO4 filtered evaporated The crude product was purified by preparative HPLC

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

Procedure: tert-Butyl 3-(2-amino-2-oxoethyl)azetidine-1-carboxylate (70 mg, 0.327 mmol) was dissolved in THF (2 mL) and cooled on an ice-bath. Borane dimethyl sulfide complex (0.41 mL, 2M in THF) was added dropwise, whereafter the mixture was refluxed for 6 h. The reaction mixture was allowed to attain rt and a mixture of DIPEA:MeOH (0.6 mL, 1:2) and iodine (166 mg, 0.654 mmol) was added. The mixture was stirred at rt overnight and then evaporated to dryness. Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated. Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4). NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2). The extracts were combined, dried (Na2SO4) and evaporated, and the residue was purified by using an ion exchange column (ISOLUTE PRS, 2 g/15 mL), eluting with MeOH and DCM (10:90), then MeOH and then MeOH (saturated with NH3) to give the title compound (35 mg, 53.5%). 1H NMR (400 MHz, CDCl3): 1.41 (s, 9H), 1.71 (dt, 2H), 2.49-2.60 (m, 1H), 2.64 (t, 2H), 3.54 (dd, 2H), 3.99 (t, 2H); 13C NMR (100 MHz, CDCl3): 26.6, 28.3, 38.3, 39.8, 54.3 (br), 79.1, 156.3. cooled on an ice-bath was refluxed for 6 h to attain rt evaporated to dryness Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4) NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2) dried (Na2SO4) evaporated the residue was purified eluting with MeOH and DCM (10:90)

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

Procedure: tert-Butyl 3-(2-amino-2-oxoethyl)azetidine-1-carboxylate (70 mg, 0.327 mmol) was dissolved in THF (2 mL) and cooled on an ice-bath. Borane dimethyl sulfide complex (0.41 mL, 2M in THF) was added dropwise, whereafter the mixture was refluxed for 6 h. The reaction mixture was allowed to attain rt and a mixture of DIPEA:MeOH (0.6 mL, 1:2) and iodine (166 mg, 0.654 mmol) was added. The mixture was stirred at rt overnight and then evaporated to dryness. Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated. Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4). NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2). The extracts were combined, dried (Na2SO4) and evaporated, and the residue was purified by using an ion exchange column (ISOLUTE PRS, 2 g/15 mL), eluting with MeOH and DCM (10:90), then MeOH and then MeOH (saturated with NH3) to give the title compound (35 mg, 53.5%). 1H NMR (400 MHz, CDCl3): 1.41 (s, 9H), 1.71 (dt, 2H), 2.49-2.60 (m, 1H), 2.64 (t, 2H), 3.54 (dd, 2H), 3.99 (t, 2H); 13C NMR (100 MHz, CDCl3): 26.6, 28.3, 38.3, 39.8, 54.3 (br), 79.1, 156.3. cooled on an ice-bath was refluxed for 6 h to attain rt evaporated to dryness Water (5 mL) and EtOAc (5 mL) were added to the residue an the two phases were separated Saturated, aqueous NaHCO3 (1 mL) was added into the water phase, and it was extracted with EtOAc (5 mL×4) NaOH (1M, ca 1 mL) was added into the water phase and it was extracted with EtOAc (5 mL×2) dried (Na2SO4) evaporated the residue was purified eluting with MeOH and DCM (10:90)

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

Procedure: 1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-yn-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate, (4-phenoxyphenyl)boronic acid and propiolic acid according to general scheme 3 using methods S1, S2, S3 and S4A. HPLC purity: 99%. MS: m/z=414[M+H]+. 1H NMR (CD3OD) δ 8.27 (s, 1H), 7.14-7.45 (m, 9H), 4.33 (t, 1H), 4.09 (dd, 1H), 3.91 (m, 2H), 3.68 (dd, 1H), 3.49 (t, 2H), 2.69 (m, 1H), 1.87 (m, 2H).

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

Procedure: 1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 3-(2-aminoethyl)azetidine-1-carboxylate, (4-phenoxyphenyl)boronic acid and acrylic acid according to general scheme 3 using methods S1, S2, S3 and S4A. HPLC purity: 99%. MS: m/z=416 [M+H]+. 1H NMR (CD3OD) δ 8.27 (s, 1H), 7.12-7.45 (m, 9H), 6.25 (m, 2H), 5.73 (d, 1H), 4.37 (t, 1H), 4.12 (dd, 1H), 2.94 (dd, 1H), 3.71 (dd, 1H), 3.49 (t, 2H), 2.69 (m, 1H), 1.88 (m, 2H).

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