3,3-dimethylmorpholine

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:

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

Procedure: In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3,3-dimethylmorpholine and isolated as colorless gum (12.5 mg, 64%). MS (m/e): 415.4 (MH+).

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

Procedure: As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (124 mg, 0.40 mmol) was converted using 3,3-dimethyl-morpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 30:70, 41 mg, 25%) which was obtained as a light brown oil. MS: m/e=408.1 [M+H]+.

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

Procedure: As described for example 12, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (124 mg, 0.40 mmol) was converted using 3,3-dimethyl-morpholine instead of 2,2,2-trifluoroethylamine to the title compound (SiO2, heptane:ethyl acetate=80:20 to 30:70, 41 mg, 25%) which was obtained as a light brown oil. MS: m/e=408.1 [M+H]+.

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

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

Procedure: In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3,3-dimethylmorpholine (CAN 59229-63-9) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=382.4 [MH+].

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

Procedure: (100 mg, 0.39 mmol) 5-(3-Chloro-phenylethynyl)-pyrimidine-2-carboxylic acid (Example 4, step 1) was suspended in dichloromethane (1 ml) and DMF (10 μl). Oxalyl chloride (51 μl, 0.59 mmol, 1.5 equiv.) was added drop wise at room temperature and the mixture was stirred for 1 hour at reflux. The reaction mixture was then added to a mixture of diisopropylethylamine (235 μl, 1.34 mmol, 3.3 equiv.) and 3,3-dimethylmorpholine (46 mg, 0.40 mmol, 1 equiv.) in THF (2 ml). The mixture was stirred for 16 hours at room temperature and evaporated in presence of Isolute® sorbent to dryness. The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0→0:100. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-chloro-phenylethynyl)-pyrimidin-2-yl]-methanone (120 mg, 94% yield) was obtained as a white solid, MS: m/e=356.6/358.6 (M+H+). at reflux The mixture was stirred for 16 hours at room temperature evaporated in presence of Isolute® sorbent to dryness The crude product was purified by flash chromatography with a 20 g silica gel column eluting with heptane:ethyl acetate 100:0→0:100

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

Procedure: (50 mg, 0.21 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in DMF (0.5 ml) and Hunig's Base (44 μl, 0.31 mmol, 1.2 equiv.), 3,3-dimethylmorpholine (36 mg, 0.25 mmol, 1.5 equiv.) and TBTU (73 mg, 0.23 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone (61 mg, 87% yield) was obtained as a light yellow oil, MS: m/e=339.2 (M+H+). The reaction mixture was evaporated extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane The crude product was purified by flash chromatography eluting with an ethyl acetate

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

Procedure: (50 mg, 0.21 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in DMF (0.5 ml) and Hunig's Base (44 μl, 0.31 mmol, 1.2 equiv.), 3,3-dimethylmorpholine (36 mg, 0.25 mmol, 1.5 equiv.) and TBTU (73 mg, 0.23 mmol, 1.1 equiv.) were added at room temperature. The mixture was stirred for 16 hours at room temperature. The reaction mixture was evaporated and extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane. The crude product was purified by flash chromatography by directly loading the dichloromethane layers onto a silica gel column and eluting with an ethyl acetate:heptane gradient 0:100 to 80:20. The desired (3,3-dimethyl-morpholin-4-yl)[5-(3-fluoro-phenylethynyl)-pyridin-2-yl]-methanone (61 mg, 87% yield) was obtained as a light yellow oil, MS: m/e=339.2 (M+H+). The reaction mixture was evaporated extracted saturated NaHCO3 solution and two times with a small volume of dichloromethane The crude product was purified by flash chromatography eluting with an ethyl acetate