sodium;methanesulfonate

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

Procedure: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (50 mg, 0.11 mmol) prepared in Example 5 was dissolved in N,N-dimethylformamide (2 mL). Sodium methanesulfonate (54 mg, 0.55 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 mg, Yield 45%). The reaction was quenched by water The reaction mixture was extracted with ethyl acetate dried over anhydrous magnesium sulfate filtered The solvent was removed under reduced pressure the residue was purified by column chromatography

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

Procedure: To N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]-L-leucinamide (1 eq) in DMSO (0.3 M) were added methane sulfonic acid sodium salt (2 eq) and copper iodide (3 eq) and the mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed with brine and water, dried over Na2SO4, filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex. The reaction mixture was cooled The organic layer was washed with brine and water dried over Na2SO4 filtered concentrated The crude compound was purified by automated SiO2 flash chromatography system

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

Procedure: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (50 mg, 0.11 mmol) prepared in Example 5 was dissolved in N,N-dimethylformamide (2 mL). Sodium methanesulfonate (54 mg, 0.55 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 mg, Yield 45%). The reaction was quenched by water The reaction mixture was extracted with ethyl acetate dried over anhydrous magnesium sulfate filtered The solvent was removed under reduced pressure the residue was purified by column chromatography

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

Procedure: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (50 mg, 0.11 mmol) prepared in Example 5 was dissolved in N,N-dimethylformamide (2 mL). Sodium methanesulfonate (54 mg, 0.55 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 mg, Yield 45%). The reaction was quenched by water The reaction mixture was extracted with ethyl acetate dried over anhydrous magnesium sulfate filtered The solvent was removed under reduced pressure the residue was purified by column chromatography

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

Procedure: To a solution of L-proline (27.8 mg, 242 μmol) in DMSO (3 ml) was added sodium hydride (9.66 mg, 242 μmol, 60% dispersion in mineral oil). The mixture was stirred at room temperature for 30 minutes then copper(I)iodide (46.0 mg, 242 μmol) and N-[4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-3-iodo-5-methanesulfonyl-N-methyl-benzamide (150 mg, 302 μmol) and sodium methanesulfonate (247 mg, 2.42 mmol) were added. The reaction mixture was stirred for 4 hours at 120° C. The reaction mixture was poured on 30 mL 10% aqueous NH4Cl solution and 30 mL EtOAc and the layers were separated. The aqueous layer was extracted a second time with 30 mL EtOAc. The organic layers were washed with 30 mL brine, dried over MgSO4, filtered and concentrated under vacuum. The residue was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light yellow solid (121 mg, 89.3%). MS (ESI): m/z=449.071 [M+H]+. The reaction mixture was stirred for 4 hours at 120° C the layers were separated The aqueous layer was extracted a second time with 30 mL EtOAc The organic layers were washed with 30 mL brine dried over MgSO4 filtered concentrated under vacuum The residue was purified by silica gel chromatography on a 20 g column eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100)

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

Procedure: To a solution of 1-(2-bromo-thiazol-5-yl)-propan-1-one (75 mg, 0.34 mmol) in dimethyl sulfoxide (3 mL) was added the sodium methanesulfonate (41 mg, 0.34 mmol) followed by copper (I) iodide (65 mg, 0.34 mmol). The mixture was heated in a microwave at 120° C. for 1 hour. The reaction was diluted with EtOAc (20 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to afford 1-(2-methanesulfonyl-thiazol-5-yl)-propan-1-one which was used without further purification. washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (10 mL) The aqueous phase was extracted with EtOAc (2×10 mL) The combined organic extracts were dried over magnesium sulfate filtered concentrated

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

Procedure: To a solution of 2923 g. (20 mol) 1.4:3.6-dianhydro-D-glucitol in 16 liters of anhydrous pyridine, one adds dropwise, with stirring and cooling to -15°, 2 liters (25 mol) methanesulphonic acid chloride, stirs for 15 hrs. at -15° and distils off the pyridine under reduced pressure. The oily residue is mixed with 10 liters of water, briefly heated to boiling and, after cooling, filtered off from 1.4;3.6-dianhydro-D-glucitol 2,5-dimethanesulphonate which has crystallised out and the filter cake is washed 2 times with 2.5 liters amounts of water. The combined filtrates are, after the addition of 1 kg. (25 mol) sodium hydroxide, evaporated under reduced pressure. The residue, consisting of a mixture of 1.4;3.6-dianhydro-D-glucitol 2- and 5-methanesulphonate and sodium methanesulphonate, is, without further purification, subjected to aqueous ammonolysis. For this purpose, one mixes with 4 liters of water and 12 liters of 25% aqueous ammonia and heats the solution thus obtained for 2 days, with stirring, in a closed steel autoclave to 120° (pressure: about 7-8 bar). After cooling and decompressing, one adds 400 g. active charcoal thereto, filters, concentrates the filtrate to about 4 liters and extracts therefrom twice with 1 liter amounts of chloroform the 1.4;2.5;3.6-trianhydro-D-mannitol formed as by-product (in all about 90 g.=0.7 mol) from the 1.4;3.6-dianhydro-D-glucitol 2-methanesulphonate. The aqueous phase is brought to pH=9 by the addition of sodium hydroxide and evaporated to dryness. The semi-solid residue is, for the separating off of inorganic material, boiled with 10 liters of ethanol and, after cooling, filtered. The evaporated filtrate is dissolved, with warming, in 10 liters of n-butanol, dried over anhydrous sodium sulphate, filtered, evaporated and fractionally distilled in vacuo. After a pre-running (0.4 mm.Hg 122°-135°) of 55 g. (0.38 mol) 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol slightly contaminated with trianhydro-D-mannitol, there distil, between 140° and 144° at 0.15 to 0.2 mm.Hg, a total of 681 g. (4.69 mol) pure 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol as a slowly solidifying pale yellowish oil. M.p. (after recrystallisation from chloroform/ethyl acetate/ether) 103°-4°; [α]D25 31.6 (c 2.0; water). cooling to -15° at -15° and distils off the pyridine under reduced pressure The oily residue is mixed with 10 liters of water briefly heated after cooling filtered off from 1.4;3.6-dianhydro-D-glucitol 2,5-dimethanesulphonate which has crystallised out the filter cake is washed 2 times with 2.5 liters amounts of water after the addition of 1 kg is, without further purification thus obtained for 2 days After cooling one adds 400 g

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

Procedure: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (50 mg, 0.11 mmol) prepared in Example 5 was dissolved in N,N-dimethylformamide (2 mL). Sodium methanesulfonate (54 mg, 0.55 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 mg, Yield 45%). The reaction was quenched by water The reaction mixture was extracted with ethyl acetate dried over anhydrous magnesium sulfate filtered The solvent was removed under reduced pressure the residue was purified by column chromatography

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

Procedure: 2-[(R)-2-(5-chloro-7-cyclopentylamino-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-ethanol (50 mg, 0.11 mmol) prepared in Example 5 was dissolved in N,N-dimethylformamide (2 mL). Sodium methanesulfonate (54 mg, 0.55 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water. The reaction mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (19 mg, Yield 45%). The reaction was quenched by water The reaction mixture was extracted with ethyl acetate dried over anhydrous magnesium sulfate filtered The solvent was removed under reduced pressure the residue was purified by column chromatography

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

Procedure: To N2-[(1S)-1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N-[(1S)-1-cyano-2-(4-iodophenyl)ethyl]-L-leucinamide (1 eq) in DMSO (0.3 M) were added methane sulfonic acid sodium salt (2 eq) and copper iodide (3 eq) and the mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled and diluted with EtOAc. The organic layer was washed with brine and water, dried over Na2SO4, filtered and concentrated. The crude compound was purified by automated SiO2 flash chromatography system using solvent gradient of 40% EtOAc/Hex to 100% EtOAc/Hex. The reaction mixture was cooled The organic layer was washed with brine and water dried over Na2SO4 filtered concentrated The crude compound was purified by automated SiO2 flash chromatography system

Conditions: temp:95.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3′-[(3-bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.50 mmol), sodium methanesulfonate (0.071 g, 0.60 mmol), copper iodide (0.010 g, 0.05 mmol), and the sodium salt of L-proline (0.014 g, 0.10 mmol) were combined in dimethyl sulfoxide (1 mL) and heated at 95° C. for 48 h, then stirred at ambient temperature for 30 h. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated from methanol and further purified by column chromatography, and eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane to yield 3′-{[3-(methylsulfonyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.103 g, 44%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J=4.2 Hz, 1H), 8.35 (dd, J=8.0, 0.5 Hz, 1H), 7.64 (dd, J=7.9, 4.7 Hz, 1H), 7.24 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=7.3 Hz, 1H), 7.05-6.99 (m, 2H), 6.50 (s, 1H), 6.39 (s, 1H), 5.50 (ABq, 2H), 4.76 (ABq, 2H), 4.19-4.12 (m, 4H), 3.52 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.6, 155.0, 153.7, 153.6, 144.6, 143.4, 138.4, 138.2, 135.9, 132.4, 129.1, 124.1, 123.9, 123.3, 122.1, 112.2, 109.8, 99.1, 79.6, 64.7, 64.1, 57.7, 44.2, 42.7; MS (ES+) m/z 465.0 (M+1). washed with water (100 mL) dried over sodium sulfate filtered concentrated in vacuo The residue was triturated from methanol further purified by column chromatography eluted with a 0% to 50% gradient of ethyl acetate in dichloromethane

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

Procedure: 1,2-Difluoro-3-iodobenzene (1.70 g; 7.08 mmol), 2.17 g (21.2 mmol) of sodium methanesulfonate and 4.03 g (21.2 mmol) of copper iodide were heated with stirring at 111° C. for 20 hours in 50 ml of N,N-dimethylacetamide. The reaction solution was filtered, chloroform was added to the filtrate and the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic layer was dried and concentrated and the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1) to give 987 mg (yield: 72%) of 1,2-difluoro-3-methanesulfonylbenzene as a colorless transparent solution. The reaction solution was filtered chloroform was added to the filtrate the mixture was washed with a saturated aqueous solution of sodium hydrogen carbonate The organic layer was dried concentrated the resulting residue was purified by a silica gel column chromatography (hexane:ethyl acetate=2:1)