(R)-2-methylpropane-2-sulfinamide

Conditions: temp:75.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-4-(3-methyl-3H-imidazole-4-carbonyl)-benzonitrile (2.56 g, 11.2 mmol), titanium(IV) ethoxide (7.02 mL, 33.5 mmol) and commercially available (R)-(+)-2-methyl-2-propanesulfinamide (1.35 g, 11.17 mmol) were dissolved in anhydrous THF (100 mL) and heated at 75° C. for 7 days. The solution was cooled, diluted with brine (100 mL), filtered through a celite pad and washed generously with EtOAc and H2O. The filtrate was separated, dried (MgSO4), and purified using SiO2 chromatography (0-3% MeOH/CH2Cl2) to give the title compound. The solution was cooled filtered through a celite pad washed generously with EtOAc and H2O The filtrate was separated dried (MgSO4) purified

Conditions: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 20-mL microwave vial containing a solution of dicyclopropyl ketone (0.778 ml, 6.81 mmol), (R)-2-methylpropane-2-sulfinamide (0.825 g, 6.81 mmol), and titanium ethoxide (1.427 ml, 6.81 mmol) in tetrahydrofuran (13.5 mL) under argon was heated in a microwave for 5 minutes at 150° C. and then again at 160° C. for an additional 5 minutes. The reaction mixture was poured into brine (14 mL), the resulting slurry filtered through Celite, and the two resulting layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated. The crude material was purified by silica gel flash chromatography (10-50% ethyl acetate/hexanes) to afford (R)—N-(dicyclopropylmethylidene)-2-methylpropane-2-sulfinamide (0.325 g, 1.52 mmol, 22% yield). MS ESI: [M+H]+ m/z 214.1. the resulting slurry filtered through Celite the two resulting layers were separated The aqueous layer was extracted with ethyl acetate the combined organic layers were dried over sodium sulfate filtered concentrated The crude material was purified by silica gel flash chromatography (10-50% ethyl acetate/hexanes)

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

Procedure: The title compound was prepared from 1-(4-bromo-3-methyl-phenyl)-ethanone and (R)-2-methyl-2-propanesulfinamide following a procedure analogous to that described in Step 1 of Intermediate 1. Mass spectrum (ESI+): m/z=316/318 (Br) [M+H]+.

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Titanium(IV) ethoxide (10.7 mL) was added to a solution of 1-(4-bromo-2-methyl-phenyl)-ethanone (4.41 g) and (R)-2-methyl-2-propanesulfinamide (2.76 g) in tetrahydrofuran (45 mL). The resulting solution was heated to 65° C. and stirred at this temperature for 20 h. Then, the solution was cooled to ambient temperature and another portion of titanium(IV) ethoxide (5.4 mL) and (R)-2-methyl-2-propane-sulfinamide (1.25 g) were added. After stirring the solution at 65° C. for another 12 h, the solution was cooled to ambient temperature and poured into brine. The resulting mixture was filtered over Celite and the organic phase of the filtrate was separated. The aqueous phase of the filtrate was extracted with ethyl acetate and the extracts were combined with the separated organic phase. The combined organic phases were washed with brine and dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 9:1→1:1) to afford the title compound. Yield: 6.24 g (95% of theory); Mass spectrum (ESI+): m/z=316/318 (Br) [M+H]+. Then, the solution was cooled to ambient temperature After stirring the solution at 65° C. for another 12 h the solution was cooled to ambient temperature The resulting mixture was filtered over Celite the organic phase of the filtrate was separated The aqueous phase of the filtrate was extracted with ethyl acetate The combined organic phases were washed with brine dried (MgSO4) the solvent was evaporated The residue was chromatographed on silica gel (cyclohexane/ethyl acetate 9:1→1:1)

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

Procedure: In a manner analogous to that described for the preparation of sulfinyl imine A2.1 the reaction of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (CAS 1262858-97-8; WO2011009943) with (R)-tert-butylsulfinamide yielded the (R)-2-methyl-propane-2-sulfinic acid [1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(E)-ylidene]-amide (77% of theory) as a yellow oil. MS (ISP): m/z=356.1 [M+H]+and 358.0 [M+2+H]+.

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

Procedure: In a manner analogous to that described for the preparation of sulfinyl imine A2.1 the reaction of 2-fluoro-1-(2-fluoro-phenyl)-ethanone with (R)-tert-butylsulfinamide yielded the (R)-2-methyl-propane-2-sulfinic acid [2-fluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-amide (52% of theory) as an orange oil. MS (ISP): m/z=260.2 [M+H]+.

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(2-fluorophenyl)ethanone (20 g, 145 mmol) in tetrahydrofuran (250 ml) was treated under an inert atmosphere at room temperature with (R)-(+)-tert-butylsulfinamide (21.1 g, 174 mmol) followed by the addition of titanium(IV)ethoxide (66.1 g, 290 mmol). The solution was stirred at 50° C. for 15 hours. For the workup, the dark brown solution was cooled to room temperature, then poured into a saturated solution of ammonium chloride. After addition of ethyl acetate, the mixture was stirred vigorously for 15 minutes. After separation of the layers, the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, dried over sodium sulphate and evaporated at reduced pressure. Purification of the crude product by chromatography on silica gel using a 4:1-mixture of cyclohexane and ethyl acetate yielded the (R)-E-N(1-(2-fluorophenyl)ethylidene)-2-methylpropane-sulfinamide (25.9 g, 74% of theory) as a brown oil. MS (ISP): m/z=242.3 [M+H]+. For the workup, the dark brown solution was cooled to room temperature the mixture was stirred vigorously for 15 minutes After separation of the layers the aqueous phase was extracted twice with ethyl acetate The combined organic layers were washed twice with water dried over sodium sulphate evaporated at reduced pressure Purification of the crude product by chromatography on silica gel using a 4

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

Procedure: To a solution of 5-benzyl-2-(2,5-difluorophenyl)thiazole-4-carbaldehyde (5.2 g, 16.49 mmol) in THF (55.0 mL) was added (R)-(+)-t-butylsulfinamide (2.2 g, 18.14 mmol), and Ti(OEt)4 (7.52 mL, 36.3 mmol). The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was diluted with brine (50 mL) and EtOAc (70 mL) followed by addition of Celite®. Then, the mixture was vigorously stirred for 1 h, and filtered. The filtrate was extracted by EtOAc. The organic layers was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield (R)—N-((5-benzyl-2-(2,5-difluorophenyl)thiazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (6.5 g, 94%) as pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.91 (1H, s), 8.04 (1H, m), 7.38-7.22 (5H, m), 7.16-7.05 (2H, m), 4.62 (2H, s), 1.25 (9H, s). LC/MS (uplc): MH+ 419.1, 1.31 min. followed by addition of Celite® Then, the mixture was vigorously stirred for 1 h filtered The filtrate was extracted by EtOAc The organic layers was washed with water and brine dried over anhydrous Na2SO4 filtered concentrated The crude product was purified by automatic column chromatography

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

Procedure: In a 500 mL round-bottomed flask was dissolved (S)-2-(2,3-difluorophenyl)hex-5-enal (3.61 g, 17.2 mmol) (freshly azeotroped with dry benzene) and (R)-2-methylpropane-2-sulfinamide (2.08 g, 17.2 mmol) in tetrahydrofuran (100 mL) to give a yellow solution. Titanium(IV) ethoxide (36.0 mL, 34.3 mmol) was added dropwise, and the mixture was stirred at rt under nitrogen for 6 h. It was transferred to a stirred solution of brine (90 mL) and a white solid was formed. This was filtered through a plug of celite and washed with ethyl acetate. The eluent was concentrated to give a tan oil. The residue was purified by flash column chromatography up to 40% ethyl acetate/hexane afforded the desired product (3.94 g, 73% for 2 steps) as a light yellow oil: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.09 (d, J=4.52 Hz, 1H) 7.02-7.14 (m, 2H) 6.97 (d, J=8.28 Hz, 1H) 5.68-5.87 (m, 1H) 5.02 (d, J=13.05 Hz, 2H) 4.07-4.18 (m, 1H) 2.19 (dt, J=13.30, 6.65 Hz, 1H) 2.05-2.13 (m, 2H) 1.90-2.03 (m, 1H) 1.17 (s, 9H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −137.55 (br. s., 1F) −142.03 (br. s., 1F); 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 167.97 (s, 1C) 151.70-149.09 (m, 1C) 149.93-147.27 (m, 1C) 136.71 (d, J=9.25 Hz, 1C) 128.43 (d, J=9.25 Hz, I C) 122.99-124.42 (m, 1C) 115.88-115.68 (m, 1C) 115.37 (m, 1C) 109.63 (s, 1C) 56.77 (s, 1C) 43.94 (d, J=12.33 Hz, 1C) 30.83 (s, 1C) 30.40 (s, 1C) 21.96 (d, J=5.39 Hz, 3C). to give a yellow solution a white solid was formed This was filtered through a plug of celite washed with ethyl acetate The eluent was concentrated to give a tan oil The residue was purified by flash column chromatography up to 40% ethyl acetate/hexane

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

Procedure: To a solution of (2R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-oxo-1-piperidinecarboxamide (WO0232867) (4 g, 7.93 mmol) and Titanium(IV) ethoxide (8 mL) in THF (10 mL) was added at 25° C., under Nitrogen, (R)-(+)-2-Methyl-2-propanesulfinamide (1.15 g, 9.52 mmol, Aldrich) and the reaction mixture was heated to 100° C. It was stirred at this temperature for 3 hrs, then it was diluted with DCM and brine (2 mL) was added. A white precipitate was formed and it was filtered-off. The resulting solution was dried (Na2SO4) and evaporated to dryness. The crude was purified by silica cartridge (25 g) (from 1:0 to 0:1 Cyclohexane/EtOAc) to give the title compound (2.2 g, 3.62 mmol, 45% yield) as a yellow gum. A further purification of the crude fractions containing the desired compound by flash chromatography on Companion CombiFlash (from 1:0 to 0:1 Cyclohexane/EtOAc) gave further title compound (848 mg, 1.40 mmol, 17.6% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.68-8.07 (m, 3H) 6.70-7.43 (m, 3H) 4.80-5.35 (m, 2H) 3.10-3.79 (m, 2H) 2.42-2.95 (m, 7H) 2.19-2.30 (m, 3 H) 1.46-1.62 (m, 3H) 1.01-1.22 (m, 9H); mixture of E+Z isomers was added A white precipitate was formed The resulting solution was dried (Na2SO4) evaporated to dryness The crude was purified by silica cartridge (25 g) (from 1:0 to 0:1 Cyclohexane/EtOAc)

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

Procedure: 2-Chloro-3-fluorobenzaldehyde (2.5 g) and (R)-(+)-2-methyl-2-propanesulfinamide were dissolved in dichloromethane (50 ml), and then titanium(IV) isopropoxide (23.6 ml) was added. The mixture was heated for three hours under reflux, then poured onto ice (150 g) and stirred vigorously for ten minutes. The mixture was filtered through kieselguhr and the filtrate was extracted with dichloromethane (3×50 ml). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The product (4 g) was used further without further purification. The mixture was heated for three hours under reflux poured onto ice (150 g) The mixture was filtered through kieselguhr the filtrate was extracted with dichloromethane (3×50 ml) The organic phase was dried (Na2SO4) filtered concentrated under reduced pressure The product (4 g) was used further without further purification

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of diisobutylaluminium hydride in tetrahydrofuran (1M, 50 mL) was added dropwise to a stirred solution of (2S)-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-N-methoxy-N,2-dimethyl-propanamide (Example 136a, 6.2 g) in tetrahydrofuran (40 mL) at 0° C. The mixture was stirred for 30 minutes and poured onto a mixture of ethyl acetate (250 mL) and 2M hydrochloric acid (100 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the crude aldehyde. Tetrahydrofuran (30 mL) was added followed by (R)-(+)-2-methyl-2-propanesulfinamide (2.6 g) and titanium ethoxide (10 mL). The mixture was stirred at room temperature for 90 min., then diluted with ethyl acetate (300 mL) and quenched with brine (100 mL). The mixture was stirred for 1 h. The organic phase was separated, dried (Na2SO4), filtered through a pad of Celite and concentrated in vacuo to give the crude sulfinimine, which was dissolved in dry dichloromethane (90 mL) and the solution was cooled to −50° C. A solution of phenylmagnesium bromide in diethyl ether (3M, 13 mL) was added dropwise and the reaction mixture was warmed up to 0° C. over 3 h, quenched with sat. aqueous NH4Cl (150 mL) and extracted into dichloromethane. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (SiO2 chromatography eluting with iso-hexane:ethyl acetate (0-100%)) to give the subtitle compound (5.2 g). The organic phase was washed with brine dried (Na2SO4) filtered concentrated in vacuo to give the crude aldehyde The mixture was stirred at room temperature for 90 min. quenched with brine (100 mL) The mixture was stirred for 1 h The organic phase was separated dried (Na2SO4) filtered through a pad of Celite concentrated in vacuo to give the crude sulfinimine, which the reaction mixture was warmed up to 0° C. over 3 h quenched with sat. aqueous NH4Cl (150 mL) extracted into dichloromethane The organic phase was dried (Na2SO4) filtered concentrated in vacuo The residue was purified (SiO2 chromatography eluting with iso-hexane:ethyl acetate (0-100%))