N-ethyl-2-methylpropan-2-amine

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

Procedure: Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 79 mg, 0.280 mmol) and N-ethyl-2-methylpropan-2-amine (142 mg, 1.399 mmol, TCI International, Portland, Oreg.), heating at 120° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10100% ACN/water with 0.1% TFA) provided 2-(3-(tert-butyl(ethyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=6.94 Hz, 3H) 1.60 (s, 9H) 2.85 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 3.80 (q, J=6.91 Hz, 2H) 6.94 (br. s., 1H) 7.03 (d, J=2.15 Hz, 1H) 7.41 (t, J=7.73 Hz, 1H) 7.69 (d, J=8.22 Hz, 1H) 7.87 (d, J=7.43 Hz, 1H) 8.71 (s, 1H) 11.69 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.1 (M+1). Prepared similarly to that Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10100% ACN/water with 0.1% TFA)

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 N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) in the presence of TBTU and DIEA to give the title compound as colorless oil; MS (EI): m/e=368.5 [MH+].

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

Procedure: Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid and tert-butylethylamine.

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

Procedure: Starting material: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and tert-butylethylamine.

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

Procedure: Starting material: 2,6,10-trimethyl-14-oxo-2,6,10-pentadecatrienoic acid and tert-butylethylamine.

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

Procedure: (100 mg, 0.41 mmol) 5-(3-Fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid (Example 3, step 1) was suspended in dichloromethane (1 ml) and DMF (10 μl). Oxalyl chloride (40 μl, 0.45 mmol, 1.1 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 tert-butylethylamine (43 mg, 0.41 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 5-(3-fluoro-phenylethynyl)-pyrimidine-2-carboxylic acid tert-butyl-ethyl-amide (97 mg, 78% yield) was obtained as a white solid, MS: m/e=326.5 (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: (100 mg, 0.41 mmol) 5-(3-Fluoro-phenylethynyl)-pyridine-2-carboxylic acid (Example 1, step 2) was dissolved in dioxane (1 ml) and Hunig's Base (217 μl, 1.24 mmol, 3 equiv.), tert.-butylethylamine (63 mg, 0.62 mmol, 1.5 equiv.) and TBTU (146 mg, 0.45 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 0:100. The desired 5-(3-fluoro-phenylethynyl)-pyridine-2-carboxylic acid tert-butyl-ethyl-amide (102 mg, 76% yield) was obtained as a light yellow oil, MS: m/e=325.3 (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: According to the same manner as that described in Example 1, 2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-3-valerylquinoline was reacted with N-tert-butyl-N-ethylamine to give 4-(3,4-dimethoxyphenyl)-2-(N-tert-butyl-N-ethylaminomethyl)-6,7-dimethoxy-3-valerylquinoline. This compound was recrystallized from ethyl acetate-hexane to give colorless prisms. mp. 137°-139° C.

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

Procedure: According to the same manner as that described in Example 1, 3-acetyl-2-bromomethyl-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline was reacted with N-tert-butyl-N-ethylamine to give 3-acetyl-2-(N-tert-butyl-N-ethylaminomethyl)-4-(3,4-dimethoxyphenyl)-6,7-dimethoxyquinoline. This compound was recrystallized from methanol to give colorless prisms. mp. 156°-157° C.

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

Procedure: The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) as starting materials and isolated (50 mg, 47%) as a light yellow solid; MS (ESI, m/z): 345.7 (M+H+). isolated (50 mg, 47%) as a light yellow solid

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

Procedure: The title compound was synthesized in analogy to Example 23b, using 5-Cyclopropyl-4-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42c) and N-ethyl-2-methylpropan-2-amine (CAN 4432-77-3) as starting materials and isolated (9 mg, 4.5%) as colorless oil; MS (ESI, m/z): 317.6 (M+H+). isolated (9 mg, 4.5%) as colorless oil

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

Procedure: Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 79 mg, 0.280 mmol) and N-ethyl-2-methylpropan-2-amine (142 mg, 1.399 mmol, TCI International, Portland, Oreg.), heating at 120° C. for 16 h. Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10100% ACN/water with 0.1% TFA) provided 2-(3-(tert-butyl(ethyl)amino)quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (16% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (t, J=6.94 Hz, 3H) 1.60 (s, 9H) 2.85 (t, J=6.94 Hz, 2H) 3.43 (td, J=6.80, 2.25 Hz, 2H) 3.80 (q, J=6.91 Hz, 2H) 6.94 (br. s., 1H) 7.03 (d, J=2.15 Hz, 1H) 7.41 (t, J=7.73 Hz, 1H) 7.69 (d, J=8.22 Hz, 1H) 7.87 (d, J=7.43 Hz, 1H) 8.71 (s, 1H) 11.69 (br. s., 1H). MS (ESI, pos. ion) m/z: 364.1 (M+1). Prepared similarly to that Purification by rpHPLC (Phenomenex Gemini C18, 10 μm, 150×30 mm; 10100% ACN/water with 0.1% TFA)