4-bromo-N,N-dimethylbenzamide

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

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

Conditions: temp:120.01; pressure:0.00; stir:

Procedure: 8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-amine (101 mg, 0.43 mmol), 4-bromo-N,N-dimethylbenzamide (100 mg, 0.44 mmol), Cesium carbonate (211 mg, 0.65 mmol), Palladium(II) acetate (9.8 mg, 0.04 mmol) and 2-(Dicyclohexylphosphino)biphenyl (15.8 mg, 0.05 mmol) were added to a microwave vial. The vial was capped and flushed with nitrogen. Dioxane (2.5 mL) was added and the vial was flushed with additional nitrogen before it was irradiated in a microwave reactor at 120 °C for 1.5 h. The reaction mixture was diluted with dichloromethane and filtered through a pad of diatomaceous earth. The pad was rinced repeatedly with dichloromethane, then the solvents were removed _in vacuo_. Handed over to the preparative chromatography group for purification (see attached report). The desired fractions were pooled and concentrated _in vacuo_. The residue was partitioned between water and dichloromethane (x1), the organic layer was passed through a phase separator and concentrated _in vacuo_. The residue was redissolved in acetonitrile and water was added. Freeze-dried over weekend to give 4-(8-(4-fluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)-N,N-dimethylbenzamide (67.5 mg, 40.9 %).

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

Procedure: Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-N,N-dimethylbenzamide (Intermediate 176), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.

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

Procedure: Following the general method as outlined in Intermediate 174, starting from 4-bromobenzoyl chloride and dimethylamine, the title compound was obtained as a pink solid in 93% yield.

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

Procedure: 3-amino-1-phenyl-1H-pyrazole-4-carbonitrile (60 mg, 0.326 mmol), 4-bromo-N,N-dimethylbenzamide (74.3 mg, 0.326 mmol), Pd2 dba3 (14.91 mg, 0.016 mmol), K2CO3 (49.5 mg, 0.358 mmol) and X-Phos (38.8 mg, 0.081 mmol) were added to a 5 mL microwave vial. Tert-amyl alcohol (1 mL) was added and the vial was evacuated and back-filled with N2 (×3). The resulting mixture was stirred at 100° C. overnight. Room temperature was attained, EtOAc was added and the solvent removed in vacuo while loading onto silica. Purification of the residue by MPLC (0-10% MeOH—CHCl3) followed by MPLC (12-100% EtOAc-hexanes) gave 4-[(4-cyano-1-phenyl-1H-pyrazol-3-yl)amino]-N,N-dimethylbenzamide as a pale yellow solid. the vial was evacuated back-filled with N2 (×3) Room temperature EtOAc was added the solvent removed in vacuo Purification of the residue by MPLC (0-10% MeOH—CHCl3)

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

Procedure: A mixture of the product from Step 5 (65 mg, 0.159 mmol), 4-bromo-N,N-dimethylbenzamide (72.4 mg, 0.318 mmol), 2.0 M aqueous potassium phosphate (0.397 mL, 0.794 mmol) and Pd(Ph3P)4 (27.5 mg, 0.024 mmol) in DMF (3 mL) was purged with N2, heated to 100° C. for 15 h, and cooled to room temperature. After addition of ethyl acetate (80 mL), the mixture was washed with water (10 mL), brine (10 mL), dried (MgSO4) and concentrated. The residue was purified by flash column chromatography (silica, 30-100% ethyl acetate in hexanes) to provide methyl 2-(8-(4-(dimethylcarbamoyl)phenyl)-5H-chromeno[2,3-b]pyridin-5-yl)-2-methylpropanoate (50 mg, 73%). MS (ES+) m/z: 431 (M+H). was purged with N2 cooled to room temperature After addition of ethyl acetate (80 mL) the mixture was washed with water (10 mL), brine (10 mL) dried (MgSO4) concentrated The residue was purified by flash column chromatography (silica, 30-100% ethyl acetate in hexanes)

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

Procedure: A mixture of 4-bromo-N,N-dimethyl-benzamide (149a) (428 mg, 1.87 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K3PO4 (796 mg, 3.75 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (21 mg, 0.094 mmol), and Pd(OAc)2 (39.8 mg, 0.094 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 5 hr, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 20-55% EtOAc in hexanes to give a yellow foam (662 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.36-7.50 (m, 2 H) 7.20 (dd, J=10.36, 1.26 Hz, 2 H) 6.92-7.04 (m, 2 H) 3.86 (s, 3 H) 3.07 (br. s., 6 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C21H23NO5 m/z 370.20 (M+H+). cooled to room temperature filtered through celite washed with EtOAc concentrated purified by Biotage column chromatography with 20-55% EtOAc in hexanes

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

Procedure: To a solution of 4-bromobenzoyl chloride (2.00 g, 9.11 mmol) and dimethyl amine hydrochloride (892 mg, 10.90 mmol) in 20 mL of CH2Cl2 was added triethylamine (3.81 mL, 27.30 mmol). The mixture was stirred at room temperature for 2 h, quenched with water, extracted with 3×CHCl3, dried with Na2SO4, concentrated and purified by Biotage column chromatography with 1-4% MeOH in 1:1 EtOAc/CH2Cl2 to give a white solid (1.73 g, 83% yield). 1H NMR (400 MHz, CDCl3) δ 7.48-7.65 (m, 2 H) 7.20-7.37 (m, 2 H) 3.05 (d, J=50.78 Hz, 6 H); LCMS for C9H10BrNO m/z 228.00 and 230.00 (M+H)+ quenched with water extracted with 3×CHCl3 dried with Na2SO4 concentrated purified by Biotage column chromatography with 1-4% MeOH in 1:1 EtOAc/CH2Cl2

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

Procedure: To a mixture of dimethylamine hydrochloride (2.79 g) and triethylamine (6.92 g) in dichloromethane (50 ml) was added 4-bromobenzoyl chloride (5 g) was added slowly under ice-cooling, and the mixture was stirred for 20 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and concentrated invacuo to give 4-(dimethylcarbamoyl)-1-bromobenzene (5.20 g) as brown oil. was added slowly under ice- cooling The mixture was washed with water, saturated sodium bicarbonate solution and brine dried over magnesium sulfate concentrated invacuo

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

Procedure: A 20-mL eggplant flask equipped with a three-way cock and a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with argon atmosphere. Into the flask, iron complex A (1.0 mg, 0.002 mmol) was admitted as catalyst and dissolved in toluene (0.5 mL). To the solution, 1,2-bis(dimethylsilyl)benzene (475 μL) was added through a syringe, and N,N-dimethyl-4-bromobenzamide (228 mg, 1.0 mmol) was added. The solution was stirred at 100° C. for 30 minutes. Toluene was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (20/1) as developing solvent, obtaining N,N-dimethyl-4-bromobenzylamine (184 mg, 0.86 mmol, 86%). The results are shown as Entry 2 in Table 5. The resulting amine was identified for geometry by 1H and 13C-NMR spectroscopy and IR spectroscopy. A 20-mL eggplant flask equipped with a three-way cock and a magnetic stirrer was heat dried was purged with argon atmosphere Toluene was distilled off in vacuum The crude product was purified by silica gel-

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

Procedure: A mixture of 4-bromo-N,N-dimethyl-benzamide (149a) (428 mg, 1.87 mmol), 4-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran-6-carboxylic acid methyl ester (3e) (500 mg, 2.25 mmol), K3PO4 (796 mg, 3.75 mmol), 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphyl (21 mg, 0.094 mmol), and Pd(OAc)2 (39.8 mg, 0.094 mmol) in toluene (10 mL) was heated to 100° C. in a microwave for 5 hr, cooled to room temperature, filtered through celite, washed with EtOAc, concentrated, and purified by Biotage column chromatography with 20-55% EtOAc in hexanes to give a yellow foam (662 mg, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.36-7.50 (m, 2 H) 7.20 (dd, J=10.36, 1.26 Hz, 2 H) 6.92-7.04 (m, 2 H) 3.86 (s, 3 H) 3.07 (br. s., 6 H) 2.90 (s, 2 H) 1.48 (s, 6 H); LCMS for C21H23NO5 m/z 370.20 (M+H+). cooled to room temperature filtered through celite washed with EtOAc concentrated purified by Biotage column chromatography with 20-55% EtOAc in hexanes