1,1-dimethylurea

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:

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

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

Procedure: Using the procedure of Example 4, N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.100 g, 0.194 mmol), N,N-dimethylurea (0.102 g, 1.163 mmol), Cs2CO3 (0.158 g, 0.485 mmol), Xantphos (0.034 g, 0.058 mmol), Pd2(dba)3 (0.023 g, 0.025 mmol), and dioxane (5 mL) were combined to afford N-(4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (40 mg, 36.4% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.19 (s, 1 H), 8.92 (s, 1 H), 8.31 (dd, J=12.6, 7.2 Hz, 1 H), 8.10 (d, J=5.7 Hz, 1 H), 7.92 (d, J=7.8 Hz, 1 H), 7.52-7.46 (m, 3 H), 7.41-7.33 (m, 3 H), 6.62 (dd, J=5.7, 2.4 Hz, 1 H), 6.55 (d, J=7.9 Hz, 1 H), 4.28 (q, J=7.0 Hz, 2 H), 2.87 (s, 6 H), 1.33 (t, J=7.0 Hz, 3 H); MS (ESI) m/z: 568.2 (M+H+).

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

Procedure: Reaction of THPC (9.53 g, 0.05 mol) with 1,1-dimethylurea (17.62 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 23.47 g (99.7%) of tetrakis(3,3-dimethylureidomethyl)phosphonium chloride (I, R=H, R'=R"=CH3, X=Cl) as a colorless, hygroscopic resin.

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

Procedure: Reaction of THPC (9.53 g, 0.05 mol) with 1,1-dimethylurea (17.62 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 23.47 g (99.7%) of tetrakis(3,3-dimethylureidomethyl)phosphonium chloride (I, R=H, R'=R"=CH3, X=Cl) as a colorless, hygroscopic resin.

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

Procedure: To a solution of N,N-dimethyl urea (10.0 g, 113.588 mmol) and 4-dimethylamino pyridine (13.873 g, 113.588 mmol) in dry pyridine (30 ml), acetic anhydride (32.20 ml, 340.67 mmol) was added dropwise at 0° C. The reaction mixture was stirred at room temperature for overnight. The reaction mixture was quenched into 2 N HCl (250 ml) and extracted with chloroform (2×250 ml). The organic layer was washed with 1 N HCl (100 ml), sodium bicarbonate solution (75 ml), brine (75 ml) and dried (Na2SO4). The solvent was evaporated under reduced pressure to obtain 10.25 g of the product as a yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.24 (s, 3H), 3.33 (s, 3H), 3.40 (s, 3H), 5.62 (s, 1H). The reaction mixture was quenched into 2 N HCl (250 ml) extracted with chloroform (2×250 ml) The organic layer was washed with 1 N HCl (100 ml), sodium bicarbonate solution (75 ml), brine (75 ml) dried (Na2SO4) The solvent was evaporated under reduced pressure

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

Procedure: 100 mg (0.23 mmol) of 2-[(2-bromopyridin-4-ylmethyl)-amino]-N-(3-isoquinolinyl)-benzamide is heated in 2 ml of dioxane with 89 mg (0.28 mmol) of cesium carbonate, 61 mg (0.69 mmol) of N,N-dimethylurea, 4.7 mg (0.0046 mmol) of dipalladium-tribenzylidene acetone and 7.9 mg (0.014 mmol) of Xanthphos under a cover gas and in a moisture-free environment for 9 hours to a bath temperature of 100° C. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel with ethyl acetate as an eluant. 24 mg (24% of theory) of 2-{[2-(3,3-dimethyl-ureido)-pyridin-4-ylmethyl]-amino}-N-(3-isoquinolinyl)-benzamide is obtained. concentrated by evaporation The residue is chromatographed on silica gel with ethyl acetate as an eluant

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

Procedure: A solution of Example A3 (8.0 g, 30 mmol) in dioxane (150 mL) was sparged with Ar under sonication for 20 min, treated with N,N-dimethylurea (10.6 g, 120 mmol), XANTPHOS (3.48 g, 6.02 mmol), and Cs2CO3 (1.226 g, 3.76 mmol), sparged with Ar under sonication for 30 min, treated with Pd2(dba)3 (2.76 g, 3.01 mmol), sparged again with Ar under sonication for 30 min and heated at 100° C. overnight. The mixture was cooled to RT and diluted with EtOAc. The solids were removed via filtration through diatomaceous earth and washed with EtOAc. The filtrates were concentrated to dryness. The residue was partitioned into EtOAc and water. The aqueous layer was back-extracted with EtOAc (3×) and the combined organics were dried (Na2SO4) and concentrated. MeCN was added and the mixture was sonicated. The solids were collected by filtration to provide 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 1. The filtrate was concentrated to dryness. Fresh MeCN was added and the mixture was again sonicated. The solids were collected by filtration to provide 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 2. The filtrate was concentrated in vacuo and purified via silica gel chromatography (MeOH/EtOAc) to afford 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea, crop 3. Crops 1-3 of 1,1-dimethyl-3-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea were combined (5.2 g, 54%). MS (ESI) m/z: 288.1 (M+H+). sparged with Ar under sonication for 30 min sparged again with Ar under sonication for 30 min The mixture was cooled to RT diluted with EtOAc The solids were removed via filtration through diatomaceous earth washed with EtOAc The filtrates were concentrated to dryness The residue was partitioned into EtOAc and water The aqueous layer was back-extracted with EtOAc (3×) the combined organics were dried (Na2SO4) concentrated MeCN was added the mixture was sonicated The solids were collected by filtration