2-methoxy-N-methylaniline

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: 1-(Benzo[d][1,3]dioxol-5-yl)-N-(6-((2-methoxyphenyl)(methyl)amino)pyridin-2-yl)cyclopropanecarboxamide was synthesized using the procedure of 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-(2-methoxyphenylamino)pyridin-2-yl)cyclopropanecarboxamide by reacting 2-methoxy-N-methylaniline with 1-(benzo[d][1,3]dioxol-5-yl)-N-(6-bromopyridin-2-yl)cyclopropanecarboxamide.

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

Procedure: To a solution of 0.65 g of N-methyl o-anisidine in 15 mL of acetonitrile, was added 0.280 g of K2CO3, followed by 0.650 g of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction mixture was heated at 80° C. for 1 h then at 50° C. overnight. Water was added and the mixture was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The product was filtered through 100 mL of silica gel, eluting a with 15% ethyl acetate/hexanes then 25% ethyl acetate/hexanes to give 0.200 g of the desired product: mp 91-95° C. MS (ES) m/z (relative intensity): 356 (M++H). at 50° C. overnight the mixture was extracted with ether The organic phase was dried the solvent was removed under vacuo The product was filtered through 100 mL of silica gel eluting a with 15% ethyl acetate/hexanes

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

Procedure: To a solution of 0.65 g of N-methyl o-anisidine in 15 mL of acetonitrile, was added 0.280 g of K2CO3, followed by 0.650 g of 1-(diphenylmethyl)-3-methane sulfonyl azetidine. The reaction mixture was heated at 80° C. for 1 h then at 50° C. overnight. Water was added and the mixture was extracted with ether. The organic phase was dried and the solvent was removed under vacuo. The product was filtered through 100 mL of silica gel, eluting a with 15% ethyl acetate/hexanes then 25% ethyl acetate/hexanes to give 0.200 g of the desired product: mp 91-95° C. MS (ES) m/z (relative intensity): 356 (M++H). at 50° C. overnight the mixture was extracted with ether The organic phase was dried the solvent was removed under vacuo The product was filtered through 100 mL of silica gel eluting a with 15% ethyl acetate/hexanes

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a cold solution of 9.0 g of N-formyl o-anisidine in 50 mL of THF was added 66 mL of a 1M solution of LAH in THF dropwise at 0° C. After complete addition the reaction mixture was stirred at 0° C. for one h. The reaction was then quenched with ethyl acetate, then with a saturated solution of NH4Cl. The mixture was extracted with ether, the combined extracts were dried over magnesium sulfate, and the solvent was removed to give 6.0 g of product. 1H NMR (300 MHz, CDCl3) δ 2.85 (s, 3H), 3.83 (s, 3H), 4.16 (s, 1H), 6.61 (dd, 1H), 6.69 (m, 1H), 6.75 (dd, 1H), 6.87 (m, 1H). After complete addition the reaction mixture The reaction was then quenched with ethyl acetate The mixture was extracted with ether the combined extracts were dried over magnesium sulfate the solvent was removed

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

Procedure: The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 2-methoxy-N-methylaniline (commercially available; CAS RN 10541-78-3) and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60). The compound was further purified through a second preparative HPLC chromatography (Phenomenex Gemini column) using a gradient of acetonitrile:water (containing 0.05% formic acid) (50:50 to 95:5). White solid (57%). MS (ESI): m/z=403.062 [M+H]+. The compound was further purified through a second preparative HPLC chromatography (Phenomenex Gemini column)

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

Procedure: 2-Methoxy-N-methylaniline (7.4 g, 53.8 mmol) and triethylamine (10.9 g, 107.7 mmol) were added to 5-bromo-4-chloro-2-fluoro-benzoyl chloride (Step 21D, 11.7 g, 43.1 mmol) in DCM (200 mL) at 0° C. The mixture was then allowed to warm to rt and concentrated. The mixture was partitioned in water and ethyl acetate. The organic layer was separated, washed with NaHSO4 solution, water and brine, and was dried. After filtration and concentration, the residue was purified via silica gel flash column chromatography eluting with ethyl acetate in hexane (50%) to give 5-bromo-4-chloro-2-fluoro-N-(2-methoxy-phenyl)-N-methyl-benzamide (12.5 g). MS: [M+H]+374.0/372.0; tR=2.70 min (method 1) concentrated The mixture was partitioned in water The organic layer was separated washed with NaHSO4 solution, water and brine was dried After filtration and concentration the residue was purified via silica gel flash column chromatography eluting with ethyl acetate in hexane (50%)