2-fluoro-4-methylsulfonylaniline

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

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

Procedure: In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.36 g, 0.62 mmol), was reacted with diisopropylethylamine (0.64 g, 5 mmol), diphenylphosphinic chloride (0.59 g, 2.5 mmol), then reacted with 2-fluoro-4-(methylsulfonyl)aniline (Matrix) (0.12 g, 0.62 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-fluoro-4-methanesulfonyl-phenyl)-amide as a off white solid (Yield 20 mg, 5%).

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

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

Procedure: A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester (1.2234 g, 3.7 mmol), 2-fluoro-4-methanesulfonyl-phenylamine (702 mg, 3.7 mmol), palladium acetate (84.3 mg, 0.37 mmol), 2-(di-t-butylphosphino)biphenyl (11 mg, 0.037 mmol), and sodium tert-butoxide (891.8 mg, 9.28 mmol) in 15 mL 1,4-dioxane was heated in microwave for 2 hours at 120° C. The mixture was purified by HPLC to give Compound E1 as a tanned solid (TFA salt, 601.1 mg, 27%). 1H NMR (MeOH-d4, 400 MHz) δ 1.16-1.17 (d, J=6.32 Hz, 6H), 1.49-1.58 (m, 2H), 2.00-2.04 (m, 2H), 2.14 (s, 3H), 3.07 (s, 3H), 3.21-3.23 (m, 2H), 3.90-3.94 (m, 2H), 4.01-4.08 (m, 1H), 4.75-4.81 (m, 1H), 7.66-7.68 (d, J=8.08 Hz, 2H), 8.01-8.05 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C21H27FN4O4S2 482.15, found 483.4 (MH+). The mixture was purified by HPLC

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-bromo-2-fluoroaniline (10.0 g, 52.62 mmol, 1.0 eq), sodium methansulfinate (9.5 g, 1.5 eq), copper(I) iodide (1.0 g, 0.1 eq), L-Proline (1.2 g, 0.2 eq) and sodium hydroxide (0.4 g, 0.2 eq) were placed in a sealed tube, and dimethylsulfoxide (100 mL) was added thereto. The reaction mixture was stirred at 90° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added thereto, followed by extraction three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound was purified using column chromatography (MC:MeOH=50:1) to obtain the title compound (9.9 g). After completion of the reaction the reaction mixture was cooled to room temperature followed by extraction three times with ethyl acetate The extract was dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting compound was purified

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-bromo-2-fluoroaniline (10.0 g, 52.62 mmol, 1.0 eq), sodium methansulfinate (9.5 g, 1.5 eq), copper(I) iodide (1.0 g, 0.1 eq), L-Proline (1.2 g, 0.2 eq) and sodium hydroxide (0.4 g, 0.2 eq) were placed in a sealed tube, and dimethylsulfoxide (100 mL) was added thereto. The reaction mixture was stirred at 90° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water was added thereto, followed by extraction three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting compound was purified using column chromatography (MC:MeOH=50:1) to obtain the title compound (9.9 g). After completion of the reaction the reaction mixture was cooled to room temperature followed by extraction three times with ethyl acetate The extract was dried over anhydrous sodium sulfate concentrated under reduced pressure The resulting compound was purified

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

Procedure: In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.36 g, 0.62 mmol), was reacted with diisopropylethylamine (0.64 g, 5 mmol), diphenylphosphinic chloride (0.59 g, 2.5 mmol), then reacted with 2-fluoro-4-(methylsulfonyl)aniline (Matrix) (0.12 g, 0.62 mmol) at 80° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (2-fluoro-4-methanesulfonyl-phenyl)-amide as a off white solid (Yield 20 mg, 5%).

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

Procedure: A mixture of 2-fluoro-4-methylsulfonyl-aniline (22.76 mmol) and KOAc (22.7 mmol) in AcOH was stirred at room temperature. The mixture was cooled to 0° C. and Br2 (22.7 mmol) was added dropwise. The mixture was stirred for 30 min at 0° C. The mixture was concentrated and the residue was taken up in EtOAc. The organic mixture was washed (sat. NaHCO3, sat. Na2S2O3), dried (Na2SO4) and concentrated to yield the desired product. The mixture was cooled to 0° C. The mixture was stirred for 30 min at 0° C The mixture was concentrated The organic mixture was washed (sat. NaHCO3, sat. Na2S2O3) dried (Na2SO4) concentrated

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

Procedure: A mixture of 2-fluoro-4-methylsulfonyl-aniline (22.76 mmol) and KOAc (22.7 mmol) in AcOH was stirred at room temperature. The mixture was cooled to 0° C. and Br2 (22.7 mmol) was added dropwise. The mixture was stirred for 30 min at 0° C. The mixture was concentrated and the residue was taken up in EtOAc. The organic mixture was washed (sat. NaHCO3, sat. Na2S2O3), dried (Na2SO4) and concentrated to yield the desired product. The mixture was cooled to 0° C. The mixture was stirred for 30 min at 0° C The mixture was concentrated The organic mixture was washed (sat. NaHCO3, sat. Na2S2O3) dried (Na2SO4) concentrated

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

Procedure: A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-ylsulfanyl)-piperidine-1-carboxylic acid isopropyl ester (1.2234 g, 3.7 mmol), 2-fluoro-4-methanesulfonyl-phenylamine (702 mg, 3.7 mmol), palladium acetate (84.3 mg, 0.37 mmol), 2-(di-t-butylphosphino)biphenyl (11 mg, 0.037 mmol), and sodium tert-butoxide (891.8 mg, 9.28 mmol) in 15 mL 1,4-dioxane was heated in microwave for 2 hours at 120° C. The mixture was purified by HPLC to give Compound E1 as a tanned solid (TFA salt, 601.1 mg, 27%). 1H NMR (MeOH-d4, 400 MHz) δ 1.16-1.17 (d, J=6.32 Hz, 6H), 1.49-1.58 (m, 2H), 2.00-2.04 (m, 2H), 2.14 (s, 3H), 3.07 (s, 3H), 3.21-3.23 (m, 2H), 3.90-3.94 (m, 2H), 4.01-4.08 (m, 1H), 4.75-4.81 (m, 1H), 7.66-7.68 (d, J=8.08 Hz, 2H), 8.01-8.05 (m, 1H), 8.27 (s, 1H). Exact mass calculated for C21H27FN4O4S2 482.15, found 483.4 (MH+). The mixture was purified by HPLC

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

Procedure: 4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure C by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-fluoro-4-(methylsulfonyl)aniline (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.90-2.00 (m, 4H), 2.95-3.05 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.03-4.09 (m, 2H), 4.90-4.93 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.91 (m, 1H), 8.21-8.24 (m, 1H), 8.40-8.42 (m, 2H), 10.36 (s, 1H). Mass spectrum MH+=491.

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

Procedure: tert-Butyl 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (54.8 mg, 0.163 mmol) was dissolved in 1,4-dioxane (0.5 mL), 2-fluoro-4-methylsulfonylaniline (32.0 mg, 0.169 mmol), tert-butoxysodium (15.9 mg, 0.109 mmol) and bis(tri-tert-butyl-phosphine)palladium (0) (5.8 mg, 0.011 mmol) were added, and the mixture was irradiated with microwave in a sealed tube at 130° C. for 3 hours. The reaction liquid was filtered, the filtrate was concentrated under a reduced pressure, and the obtained residue was purified by using silica gel chromatography (ethyl acetate:hexane=3:1) to give the titled compound (3.6 mg, 6.5%) as a white amorphous. the mixture was irradiated with microwave in a sealed tube at 130° C. for 3 hours The reaction liquid was filtered the filtrate was concentrated under a reduced pressure the obtained residue was purified