ethyl (1R,2S)-2-aminocyclohexane-1-carboxylate;hydrochloride

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

Procedure: To an oven-dried Schlenk flask that was evacuated and backfilled with argon was added 726 mg (3.68 mmol) of ethyl cis-2-amino-1-cyclohexanecarboxylate HCl salt, 56 mg (0.06 mmol, 2 mol % Pd) of Pd2(dba)3, 77 mg (0.12 mmol, 4 mol %) of rac-BINAP, 881 mg (9.17 mmol) of sodium tert-butoxide, 500 mg (3.06 mmol) of 8-chloroquinoline, and 7.5 mL of toluene. The flask was sealed with a glass stopper and an argon balloon replacing the source. The reaction mixture was then heated to 90° C. and stirred at that temperature for 17 hours. The mixture was allowed to cool to room temperature, taken up in diethyl ether (35 mL), washed three times with saturated brine (30 mL), dried over magnesium sulfate, and concentrated to provide the crude reaction mixture. The crude mixture was re-dissolved in ethyl acetate, partitioned between ethyl acetate and 1N HCl, dried over magnesium sulfate and concentrated to provide 125 mg (15%) of 2-(quinolin-8-ylamino)cyclohexanecarboxylic acid with both cis and trans isomers in 1:1 ratio. Confirmed by 1H NMR. To an oven-dried Schlenk flask that was evacuated The flask was sealed with a glass stopper to cool to room temperature washed three times with saturated brine (30 mL) dried over magnesium sulfate concentrated to provide the crude reaction mixture partitioned between ethyl acetate and 1N HCl dried over magnesium sulfate concentrated

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of cis-2-amino-cyclohexanecarboxylic acid ethyl ester hydrochloride (2.80 g, 12.81 mmol) in tetrahydrofuran (100 mL) at 25° C. was added magnesium sulfate (4.0 g), triethylamine (1.36 g, 13.48 mmol), and 4-fluorobenzaldehyde (3.26 g, 26.29 mmol) sequentially. The reaction was stirred at 25° C. for 16 h. The mixture was passed through a short pad of Celite and the filtrate was concentrated and dried in vacuo. The residue was re-dissolved in methanol (100 mL) at 25° C. To this solution was slowly added sodium borohydride (1.0 g, 26.29 mmol). The mixture was stirred at 25° C. for 1 h. It was then poured into a 1/2 saturated aqueous sodium bicarbonate solution and the mixture was extracted into ethyl acetate (3×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford a clear oil. Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-50% ethyl acetate in hexanes) afforded the desired product, 2-(4-fluoro-benzylamino)-cyclohexanecarboxylic acid ethyl ester (4.47 g, 16.0 mmol, >100%, product still contains ethyl acetate), as a clear oil which was directly used in the next step. LC-MS (ESI) calcd for C16H22FNO2 279.16, found 280.0 [M+H+]. the filtrate was concentrated dried in vacuo The residue was re-dissolved in methanol (100 mL) at 25° C The mixture was stirred at 25° C. for 1 h the mixture was extracted into ethyl acetate (3×100 mL) The organic layer was dried over sodium sulfate filtered concentrated in vacuo to afford a clear oil Purification by flash column chromatography (Teledyne Isco RediSep Column; 0-50% ethyl acetate in hexanes)

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: cis-2-Amino-cyclohexanecarboxylic acid ethyl ester hydrochloride (0.5 g, 2.407 mmol) was dissolved in methanol (25 mL). Cyclohexanone (0.236 g, 2.407 mmol) was added followed by acetic acid (0.1 mL). The solution was stirred at 25° C. for 10 min. Sodium cyanoborohydride (0.378 g, 6.018 mmol) was added and the mixture was stirred at 25° C. for 16 h. The mixture was poured into 1/2 saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-cyclohexylamino-cyclohexanecarboxylic acid ethyl ester (0.38 g, 1.5 mmol, 62.4%), as a clear oil. LC-MS (ESI) calcd for C15H27NO2 253.20, found 253.9 [M+H+]. the mixture was stirred at 25° C. for 16 h The aqueous layer was extracted with ethyl acetate (3×100 mL) The combined organic layers were dried over sodium sulfate filtered concentrated in vacuo

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

Procedure: To a solution of ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride (1.00 g, 4.6 mmol) in methanol (10 mL) was added triethylamine (0.72 mL, 5.1 mmol), 3,3-dimethylbutyraldehyde (0.67 mL, 5.1 mmol), and sodium cyanoborohydride (213.0 mg, 3.2 mmol) at 25° C. After stirring for 18 h, the mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-50% ethyl acetate in hexanes) to afford the desired product, cis-2-(3,3-dimethylbutylamino)-cyclohexanecarboxylic acid ethyl ester (31.2 mg, 0.061 mmol, 25%), as a white solid. 1H NMR (400 MHz, CDCl3) δ 0.99 (9H, s), 1.22-1.29 (1H, m), 1.35 (3H, t, J=7.0 Hz), 1.40-1.51 (1H, m), 1.58-1.77 (5H, m), 1.90-1.94 (1H, m), 2.12-2.15 (1H, m), 2.37-2.40 (1H, m), 2.96 (1H, bs), 3.09 (1H, bs), 3.22-3.33 (2H, m), 4.21-4.35 (2H, m). LC-MS (ESI) calcd for C15H29NO2 255.22, found 256.3 [M+H+]. the mixture was concentrated in vacuo the residue was dissolved in ethyl acetate The organic layer was washed with water dried over anhydrous magnesium sulfate concentrated in vacuo The crude material was purified by flash column chromatography (Teledyne Isco RediSep Flash Column; 0-50% ethyl acetate in hexanes)

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

Procedure: 3,5-dichloropyridazine (1.6 g, 10.74 mmol), ethyl (cis)-2-aminocyclohexanecarboxylate hydrochloride (CA, 2.454 g, 11.81 mmol), and triethylamine (5.63 mL, 32.2 mmol) were added to DMSO (10.0 ml) and heated for 5 hrs at 120° C. and then allowed to stir at room temperature for 24 hr. Solvents were removed in vacuo. The residue was dissolved in EtOAc and then poured into sat. sodium bicarb. The aqeuous layer was removed and back extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated to an oil. Purification on biotage again (DCM:MeOH, 0-9% B) and concentration afforded the product, I-22a, as a solid (2.207 g, 71.7%). Solvents were removed in vacuo The residue was dissolved in EtOAc poured into sat. sodium bicarb The aqeuous layer was removed back extracted with EtOAc The combined organics were washed with brine dried over sodium sulfate concentrated to an oil Purification on biotage again (DCM:MeOH, 0-9% B) and concentration afforded the product, I-22a

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

Procedure: 3,5-dichloropyridazine (1.6 g, 10.74 mmol), ethyl (cis)-2-aminocyclohexanecarboxylate hydrochloride (CA, 2.454 g, 11.81 mmol), and triethylamine (5.63 mL, 32.2 mmol) were added to DMSO (10.0 ml) and heated for 5 hrs at 120° C. and then allowed to stir at room temperature for 24 hr. Solvents were removed in vacuo. The residue was dissolved in EtOAc and then poured into sat. sodium bicarb. The aqeuous layer was removed and back extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated to an oil. Purification on biotage again (DCM:MeOH, 0-9% B) and concentration afforded the product, I-22a, as a solid (2.207 g, 71.7%). Solvents were removed in vacuo The residue was dissolved in EtOAc poured into sat. sodium bicarb The aqeuous layer was removed back extracted with EtOAc The combined organics were washed with brine dried over sodium sulfate concentrated to an oil Purification on biotage again (DCM:MeOH, 0-9% B) and concentration afforded the product, I-22a

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

Procedure: This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from ethyl cis-2-aminocyclohexanecarboxylate hydrochloride (Acros Organics, Cat. #26564), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=522.3. This compound was prepared

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

Procedure: To an oven-dried Schlenk flask that was evacuated and backfilled with argon was added 726 mg (3.68 mmol) of ethyl cis-2-amino-1-cyclohexanecarboxylate HCl salt, 56 mg (0.06 mmol, 2 mol % Pd) of Pd2(dba)3, 77 mg (0.12 mmol, 4 mol %) of rac-BINAP, 881 mg (9.17 mmol) of sodium tert-butoxide, 500 mg (3.06 mmol) of 8-chloroquinoline, and 7.5 mL of toluene. The flask was sealed with a glass stopper and an argon balloon replacing the source. The reaction mixture was then heated to 90° C. and stirred at that temperature for 17 hours. The mixture was allowed to cool to room temperature, taken up in diethyl ether (35 mL), washed three times with saturated brine (30 mL), dried over magnesium sulfate, and concentrated to provide the crude reaction mixture. The crude mixture was re-dissolved in ethyl acetate, partitioned between ethyl acetate and 1N HCl, dried over magnesium sulfate and concentrated to provide 125 mg (15%) of 2-(quinolin-8-ylamino)cyclohexanecarboxylic acid with both cis and trans isomers in 1:1 ratio. Confirmed by 1H NMR. To an oven-dried Schlenk flask that was evacuated The flask was sealed with a glass stopper to cool to room temperature washed three times with saturated brine (30 mL) dried over magnesium sulfate concentrated to provide the crude reaction mixture partitioned between ethyl acetate and 1N HCl dried over magnesium sulfate concentrated

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

Procedure: Ethyl-cis-2-amino-1-cyclohexanecarboxylate hydrochloride (750 mg) was suspended in 1 N NaOH (pH =12). The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4 and evaporated to give the crude ethyl-cis-2-amino- 1-cyclohexanecarboxylate (570 mg). The aqueous layer was extracted with CH2Cl2 washed with brine dried over Na2SO4 evaporated

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

Procedure: Ethyl-cis-2-amino-1-cyclohexanecarboxylate hydrochloride (750 mg) was suspended in 1 N NaOH (pH =12). The aqueous layer was extracted with CH2Cl2, washed with brine, dried over Na2SO4 and evaporated to give the crude ethyl-cis-2-amino- 1-cyclohexanecarboxylate (570 mg). The aqueous layer was extracted with CH2Cl2 washed with brine dried over Na2SO4 evaporated

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

Procedure: A mixture of (R)-1-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)cyclopentanecarboxylic acid (15 mg, 0.040 mmol), (1R,2S)-ethyl 2-aminocyclohexanecarboxylate hydrochloride (9.08 mg, 0.044 mmol), HATU (16.62 mg, 0.044 mmol), and TEA (0.017 mL, 0.119 mmol) in DMF (0.4 mL) was stirred at room temperature overnight. The mixture was acidified with 1M HCl and purified by HPLC to give the title compound. LCMS m/z=531.7 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.13 (t, J=7.1 Hz, 3H), 1.27 (d, J=6.8 Hz, 0.4H), 1.32-1.41 (m, 3H), 1.41-1.54 (m, 2H), 1.46 (d, J=7.1 Hz, 2.6H), 1.55-1.66 (m, 2H), 1.67-1.84 (m, 6H), 1.98-2.11 (m, 3H), 2.22-2.32 (m, 1H), 2.45-2.55 (m, 3H), 2.62-2.68 (m, 1H), 3.06-3.18 (m, 4H), 3.35-3.47 (m, 1H), 3.49-3.60 (m, 1H), 3.73-3.85 (m, 1H), 3.92-4.01 (m, 2H), 4.02-4.11 (m, 1H), 6.19 (d, J=8.3 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.3 Hz, 2H), 7.60-7.67 (m, 4H). purified by HPLC

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

Procedure: To an oven-dried Schlenk flask that was evacuated and backfilled with argon was added 726 mg (3.68 mmol) of ethyl cis-2-amino-1-cyclohexanecarboxylate HCl salt, 56 mg (0.06 mmol, 2 mol % Pd) of Pd2(dba)3, 77 mg (0.12 mmol, 4 mol %) of rac-BINAP, 881 mg (9.17 mmol) of sodium tert-butoxide, 500 mg (3.06 mmol) of 8-chloroquinoline, and 7.5 mL of toluene. The flask was sealed with a glass stopper and an argon balloon replacing the source. The reaction mixture was then heated to 90° C. and stirred at that temperature for 17 hours. The mixture was allowed to cool to room temperature, taken up in diethyl ether (35 mL), washed three times with saturated brine (30 mL), dried over magnesium sulfate, and concentrated to provide the crude reaction mixture. The crude mixture was re-dissolved in ethyl acetate, partitioned between ethyl acetate and 1N HCl, dried over magnesium sulfate and concentrated to provide 125 mg (15%) of 2-(quinolin-8-ylamino)cyclohexanecarboxylic acid with both cis and trans isomers in 1:1 ratio. Confirmed by 1H NMR. To an oven-dried Schlenk flask that was evacuated The flask was sealed with a glass stopper to cool to room temperature washed three times with saturated brine (30 mL) dried over magnesium sulfate concentrated to provide the crude reaction mixture partitioned between ethyl acetate and 1N HCl dried over magnesium sulfate concentrated