(1R,2R)-cyclohexane-1,2-diamine

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-iodo-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indazole (0.316 g, 0.923 mmol) in N-methylpyrrolidone (NMP) (2.7 mL) was added to 2-phenyl-5H-furo[3,2-c]pyridine-4-one (0.232 g, 1.10 mmol), Cs2CO3 (0.601 g, 1.84 mmol), trans-1,2-diaminocyclohexane (21.2 mL, 0.184 mmol) and CuI (0.210 g, 1.10 mmol) and deoxygenated with argon for 30 minutes. After stirring at 110° C. for 48 hours, the reaction mixture was cooled and diluted with MeOH (3 mL) and a solution of 7:1 MeOH/NH4OH (3 mL) and filtered through Celite. The filtrate was concentrated and then suspended with CH2Cl2 (20 mL) and water (20 mL) and extracted with CH2Cl2 (4×50 mL). The combined organics were dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100) yielded the title compound (29.6 mg, 7%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 8.05 (s, 1H), 7.80 (d, J=7.5 Hz, 2H), 7.73 (d, J=2.0 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H), 7.47-7.42 (m, 3H), 7.37-7.33 (m, 3H), 6.68 (d, J=7.5 Hz, 1H), 4.60 (t, J=7.0 Hz, 2H), 3.06 (br m, 2H), 2.62 (br m, 4H), 1.81 (br m, 4H); ESI MS m/z 425 [M+H]+; HPLC (Method A) 96.4% (AUC), tR=15.0 mm. deoxygenated with argon for 30 minutes the reaction mixture was cooled diluted with MeOH (3 mL) a solution of 7:1 MeOH/NH4OH (3 mL) and filtered through Celite The filtrate was concentrated extracted with CH2Cl2 (4×50 mL) The combined organics were dried (Na2SO4) concentrated Purification by flash chromatography (silica gel, CH2Cl2/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 to 0:100)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirred mixture of 2-amino-9H-pyrido[2,3-b]indole-3-carboxamide (5, 100 mg, 0.44 mmol), Copper(I) iodide (8 mg, 0.045 mmol) and potassium phosphate (190 mg, 0.88 mmol) under dry nitrogen was added (±)-trans-1,2-diaminocyclohexane (5 μL, 0.04 m mol) and 3-bromopyridine (43 μL, 0.442 mmol), followed by 1,4-dioxane (2 mL). The mixture was heated at 110° C. for 2 days. The reaction mixture was cooled to room temperature, extracted with methylene chloride (3×30 ml) and washed with water. The extracts were combined, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient) to yield 2-amino-9-pyridin-3-yl-9H-pyrido[2,3-b]indole-3-carboxamide (67, 20 mg, 10%). NH4OAc standard conditions. DAD Retention time=5.99 min. M+H=310. 1H NMR (300 MHz, MeOD): δ 8.86 (d, J=2.4 Hz, 1H), 8.74 (s, 1H), 8.66-8.63 (m, 1H), 8.14 (d, J=8.2 Hz, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.70 (dd, J=4.7, 8.2 Hz, 1H), 7.36-7.28 (m, 4H). The reaction mixture was cooled to room temperature extracted with methylene chloride (3×30 ml) washed with water dried over sodium sulfate filtered concentrated The crude product was purified by silica gel chromatography (12 g silica, methylene chloride to 90/10 methylene chloride/methanol gradient)

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

Procedure: (S)-3-(4-bromo-2-fluoro-5-methylphenoxy)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (200 mg, 0.42 mmol), trans-cyclohexane-1,2-diamine (20 μL, 0.17 mmol), sodium methanesulfinate (64 mg, 0.63 mmol) was dissolved in DMSO (3 mL) and nitrogen bubbled through for 15 minutes. Cu(I) triflate benzene-complex (21 mg, 0.04 mmol) was added and the reaction was plunged into 110° C. oil bath and stirred under nitrogen overnight. Additional trans-cyclohexane-1,2-diamine (20 μL, 0.17 mmol), sodium methanesulfinate (64 mg, 0.63 mmol) and Cu(I) triflate benzene-complex (21 mg, 0.04 mmol) were added and stirred for another 4 hours at 110° C. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenoxy)pyrrolidin-2-one (119.8 mg, 0.25 mmol, 60% yield) as a white solid. Mass spectrum (apci) m/z=477.3 (M+H). nitrogen bubbled through for 15 minutes was plunged into 110° C. stirred for another 4 hours at 110° C partitioned between water and EtOAc extracted with EtOAc washed with brine dried over Na2SO4 filtered concentrated The residue was purified over silica gel (100% EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (S)-tert-butyl-4-(3-(6-bromopyridin-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (315 mg, 0.714 mmol) in degassed DMSO (5 mL) was added sodium ethanesulfinate (117 mg, 1.15 mmol), trans-cyclohexane-1,2-diamine (33 mg, 0.286 mmol) and Cu(I) triflate benzene complex (54 mg, 0.107 mmol). The reaction was heated to 110° C. for 12 hours at which point the reaction was cooled to ambient temperature and partitioned between water (5 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc to yield (S)-tert-butyl-4-(3-(6-(methylsulfonyl)pyridine-3-yloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (315 mg, 94%) as a white solid. was cooled to ambient temperature partitioned between water (5 mL) and EtOAc (10 mL) The organic layer was separated the aqueous layer extracted with EtOAc (2×5 mL) The combined organic layers were dried over MgSO4 filtered concentrated in vacuo The resulting material was purified by silica gel chromatography eluting with 1:1 hexanes/EtOAc

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (300 mg, 0.532 mmol) was dissolved in DMSO (5 mL) and degassed for 10 minutes. Sodium methanesulfinate (81.5 mg, 0.799 mmol) and trans-cyclohexane-1,2-diamine (25.6 μL, 0.213 mmol) were added, followed by Cu(I) triflate benzene complex (26.8 mg, 0.0532 mmol) and the reaction was heated to 110° C. overnight. The reaction was cooled, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford tert-butyl 4-((3S,4S)-4-(benzyloxy)-3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (160 mg, 0.284 mmol, 53.4% yield). degassed for 10 minutes The reaction was cooled partitioned between water and EtOAc extracted with EtOAc washed with brine dried over Na2SO4 filtered concentrated The residue was purified over silica gel (100% EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl 3-(4-bromo-2,5-difluorophenoxy)-2-oxo-1,4′-bipiperidine-1′-carboxylate (710 mg, 1.45 mmol) in DMSO (4 mL) was added Cu(I) triflate benzene complex (73 mg, 0.145 mmol), sodium methanesulfinate (222 mg, 2.18 mmol) and trans-cyclohexane-1,2-diamine (66.3 mg, 0.580 mmol). The reaction was heated at 110° C. overnight. The reaction was cooled to ambient temperature and diluted with water (5 mL) and EtOAc (5 mL). The organic layer was separated and the aqueous washed with EtOAc (2×10 mL). The combined organic layers were dried with MgSO4 and concentrated. The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give a clear oil. This material was then dissolved in CH2Cl2 (10 mL) and excess 2 N HCl in ether (5 mL) added. The reaction was allowed to stir overnight and then concentrated under vacuum to give 3-(2,5-difluoro-4-(methylsulfonyl)phenoxy)-1,4′-bipiperidin-2-one HCl salt (238 mg, 89%) was an off white solid. The reaction was cooled to ambient temperature The organic layer was separated the aqueous washed with EtOAc (2×10 mL) The combined organic layers were dried with MgSO4 concentrated The crude residue was purified over silica gel (2:1 hexanes/EtOAc) to give a clear oil concentrated under vacuum

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

Procedure: (S)-tert-Butyl 4-(3-(4-bromo-2-fluorophenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.8 g, 3.9 mmol) was dissolved in DMSO (30 mL) and purged with nitrogen. Sodium methanesulfinate (0.60 g, 5.9 mmol) and trans-cyclohexane-1,2-diamine (0.19 mL, 1.6 mmol) were added followed by Cu(I) triflate benzene complex (0.20 g, 0.39 mmol). The reaction was plunged into a 110° C. oil bath under nitrogen and stirred overnight. The reaction was cooled to ambient temperature, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (100% EtOAc) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(methylsulfonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.6 g, 3.5 mmol, 89% yield) as a white solid. purged with nitrogen was plunged into a 110° C. partitioned between water and EtOAc extracted with EtOAc washed with brine dried over Na2SO4 filtered concentrated The residue was purified over silica gel (100% EtOAc)

Conditions: temp:110.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 5 mL microwave tube under N2 flush were added 1-tert-butyl-3,5-diiodo-2-methoxybenzene (208 mg, 0.5 mmol), 2-pyrrolidone (0.092 mL, 1.200 mmol), potassium phosphate (223 mg, 1.050 mmol), (+/−)-trans-1,2-diaminocyclohexane (0.012 mL, 0.100 mmol) and copper(I) iodide (2.381 mg, 0.013 mmol) in dioxane (2 mL). The tube was sealed, sparged with N2 for 10 minutes, heated by microwave irradiation at 110° C. for 1 hour, cooled and partitioned between ethyl acetate and water adjusting the pH to 1 with HCl. The aqueous layer was extracted with ethyl acetate. The organics were combined, washed with H2O, and brine. The organic was dried (Na2SO4), filtered, and stirred for 0.5 hours with 3-mercaptopropyl functionalized silica, filtered and concentrated. The crude product was purified on an Isco 12 g silica cartridge eluting with 4:1 hexane/ethyl acetate to give the title compound. In a 5 mL microwave tube under N2 flush The tube was sealed sparged with N2 for 10 minutes cooled partitioned between ethyl acetate and water adjusting the pH to 1 with HCl The aqueous layer was extracted with ethyl acetate washed with H2O, and brine The organic was dried (Na2SO4) filtered filtered concentrated The crude product was purified on an Isco 12 g silica cartridge eluting with 4:1 hexane/ethyl acetate

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

Procedure: A solution of 0.46 g of trans-1,2-diaminocyclohexane in 10 ml of THF was added to a solution of 1.6 g of 2-chloro-6-trifluoromethylphenyl isocyanate in 30 ml of THF, and the mixture was stirred at room temperature for about 3 hours. The mixture was allowed to stand overnight and the solvent was then distilled off, giving 0.57 g of the desired compound as a semi-solid yellow product. to stand overnight the solvent was then distilled off

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

Procedure: A solution of 1.6 g of 2-phenoxyphenyl isothiocyanate in 10 ml of THF was added to a solution of 0.8 g of trans-1,2-diaminocyclohexane in 30 ml of THF, and the mixture was stirred at room temperature for about 4 hours. The solvent was evaporated and the residue was subsequently subjected to column chromatography on silica gel using a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of methylene chloride, 5 parts of methanol and 1 part of concentrated aqueous ammonia solution, giving the desired compound as an amorphous oily product. The solvent was evaporated a mixture of 10 parts of ethyl acetate, 5 parts of n-heptane, 5 parts of methylene chloride, 5 parts of methanol and 1 part of concentrated aqueous ammonia solution

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

Procedure: A mixture of 5-bromopyrazin-2-amine (5 g, 29 mmol), pyrrolidin-2-one (11 mL, 144 mmol), copper (T) iodide (1.1 g, 5.75 mmol), potassium carbonate (7.94 g, 57.5 mmol), and (1R,2R)-cyclohexane-1,2-diamine (1.38 mL, 11.49 mmol) was refluxed under nitrogen in dioxane (100 mL) for 18 h. After cooling, 200 mL ethyl acetate and 20 mL methanol were added to the reaction. This was filtered through celite, concentrated, and absorbed onto sodium sulfate for purification by column chromatography (0-5% methanol/methylene chloride). The purified product was recrystallized from ether/ethyl acetate to afford 1-(5-aminopyrazin-2-yl)pyrrolidin-2-one (1.57 g, 8.81 mmol, 30.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1 H, d, J=1.51 Hz), 7.69 (1 H, d, J=1.51 Hz), 6.20 (2 H, s), 3.84 (2 H, t, J=7.05 Hz), 2.49 (2 H, t, J=7.93 Hz), 2.04 (2 H, dq, J=7.68, 7.51 Hz). MS (LC/MS) R.T.=0.48; [M+H]+=179.27. After cooling This was filtered through celite, concentrated absorbed onto sodium sulfate for purification by column chromatography (0-5% methanol/methylene chloride) The purified product was recrystallized from ether/ethyl acetate

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

Procedure: A mixture of 5-bromopyrazin-2-amine (5 g, 29 mmol), pyrrolidin-2-one (11 mL, 144 mmol), copper (T) iodide (1.1 g, 5.75 mmol), potassium carbonate (7.94 g, 57.5 mmol), and (1R,2R)-cyclohexane-1,2-diamine (1.38 mL, 11.49 mmol) was refluxed under nitrogen in dioxane (100 mL) for 18 h. After cooling, 200 mL ethyl acetate and 20 mL methanol were added to the reaction. This was filtered through celite, concentrated, and absorbed onto sodium sulfate for purification by column chromatography (0-5% methanol/methylene chloride). The purified product was recrystallized from ether/ethyl acetate to afford 1-(5-aminopyrazin-2-yl)pyrrolidin-2-one (1.57 g, 8.81 mmol, 30.7% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (1 H, d, J=1.51 Hz), 7.69 (1 H, d, J=1.51 Hz), 6.20 (2 H, s), 3.84 (2 H, t, J=7.05 Hz), 2.49 (2 H, t, J=7.93 Hz), 2.04 (2 H, dq, J=7.68, 7.51 Hz). MS (LC/MS) R.T.=0.48; [M+H]+=179.27. After cooling This was filtered through celite, concentrated absorbed onto sodium sulfate for purification by column chromatography (0-5% methanol/methylene chloride) The purified product was recrystallized from ether/ethyl acetate