Name: 1312535-32-2|Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate|95%
Brand: Ambeed
SKU: A958008
Rating: 92 (26 reviews)

1
[ 35490-07-4 ]
[ 917-54-4 ]
[ 1312535-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyllithium With copper(l) iodide In diethyl ether at -40℃; for 3h; Stage #2: methyl 2-methyl-4-oxocyclohex-2-enecarboxylate In diethyl ether at -40 - -20℃; for 5.03333h;	14.3 Step 3: Copper iodide (121.8 g, 639.54 mmol) was suspended in Et20 (800 mL). Methyllithium(1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at -40 °C over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in Et20 (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred 5 hours at -20 °C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with EtOAc (3 x 2 L). The combined organic extracts were dried over Na2S04, filtered, and concentrated in vacuo. The residue was purified via silica gel column chromatography (1 :20 EtOAc/petroleum ether). Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate was obtained as a yellow oil. MS ESI calc'd. for C10H17O3 [M + H]+ 185, found 185. *H NMR (600 MHz, CDCI3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.91 - 1.85 (m, 1H), 0.85 (s, 3H), 0.77 (s, 3H).
	Stage #1: methyllithium With copper(l) iodide In diethyl ether at -40℃; for 3h; Stage #2: methyl 2-methyl-4-oxocyclohex-2-enecarboxylate In diethyl ether at -40 - -20℃; for 5h;	26.3 Step 3: Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added drop wise at -40 oC over 3 hours to a solution of copper iodide (121.8 g, 639.54 mmol) in diethyl ether (800 mL). A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 320 mmol) in diethyl ether (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred 5 hours at -20 °C. The reaction mixture was diluted via the addition of saturated aqueous ammonium chloride (2.5 L), and then extracted with EtO Ac (3 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified column chromatography on silica (1 :20 EtO Ac/petroleum ether) to afford methyl 2,2-dimethyl-4-oxo-cyclohexanecarboxylate as a yellow oil. MS ESI [M + H]+ 185, found 185. lH NMR (600 MHZ, CDCI3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.91 - 1.85 (m, 1H), 0.85 (s, 3H), 0.77 (s, 3H).
	Stage #1: methyllithium With copper(l) iodide In diethyl ether at -40℃; for 3h; Stage #2: methyl 2-methyl-4-oxocyclohex-2-enecarboxylate In diethyl ether at -40 - -20℃; for 5h;	2.1 Preparative Example 2.1-Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate Step 3: Copper iodide (121.8 g, 639.54 mmol) was suspended in Et20 (800 mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at -40 °C over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in Et20 (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred for 5 hours at -20 °C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with EtOAc (3 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/petroleum ether) to afford methyl 2,2-dimethyl-4- oxocyclohexanecarboxylate as a yellow oil. MS ESI calc’d. for C,0H,703 [M + H]+ 185, found 185. ‘H NMR (600 MHz, CDC13) ö 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 -2.17 (m, 1H), 2.11 -2.04 (m, 1H), 2.00- 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 0.85 (s, 3H), 0.77 (s, 3H).

	Stage #1: methyllithium With copper(l) iodide In diethyl ether at -40℃; for 3h; Stage #2: methyl 2-methyl-4-oxocyclohex-2-enecarboxylate In diethyl ether at -40 - -20℃; for 5.03333h;	2.2.1.3 Preparative Example 2.1 - Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate Step 3 : Copper iodide (121.8 g, 639.54 mmol) was suspended in diethyl ether (800 mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at -40 °C over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in diethyl ether (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred for 5 hours at -20 °C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with ethyl acetate (3 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to afford methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate as a yellow oil. MS ESI calc'd. for C10H17O3 [M + H]+ 185, found 185. NMR (600 MHz, CDCI3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.1 1 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 0.85 (s, 3H), 0.77 (s, 3H).
	With copper(l) iodide In diethyl ether at -40 - -20℃; for 5h;	2.3 Preparative Example 2.1 - Methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate [00184] Step 3: Copper iodide (121.8 g, 639.54 mmol) was suspended in diethyl ether (800 mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at -40 °C over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 319.88 mmol) in diethyl ether (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred for 5 hours at -20 °C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with ethyl acetate (3 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether) to afford methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate as a yellow oil. MS ESI calc'd. for C10H17O3 [M + H]+ 185, found 185. NMR (600 MHz, CDCI3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.1 1 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 0.85 (s, 3H), 0.77 (s, 3H).
	Stage #1: methyllithium With copper(l) iodide In diethyl ether at -40℃; for 3h; Stage #2: methyl 2-methyl-4-oxocyclohex-2-enecarboxylate In diethyl ether at -40 - -20℃; for 5h;	2.1.3 Step 3: Copper iodide (121.8 g, 639 mmol) was suspended in diethyl ether (800 mL). Methyl lithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at -40 °C over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 320 mmol) in diethyl ether (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred for 5 hours at -20 °C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with ethyl acetate (3 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to afford methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate as a yellow oil. MS ESI calc'd. for C10H17O3 [M + H]+ 185, found 185. NMR (600 MHz, CDCI3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.11 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 0.85 (s, 3H), 0.77 (s, 3H).
	Stage #1: methyllithium With copper(l) iodide In diethyl ether at -40℃; for 3h; Stage #2: methyl 2-methyl-4-oxocyclohex-2-enecarboxylate In diethyl ether at -40 - -20℃; for 5h;	2.1.3 Step 3: Copper iodide (121.8 g, 639.5 mmol) was suspended in diethyl ether (800 mL). Methyllithium (1.6 M in diethyl ether, 800 mL, 1.28 mol) was added dropwise at -40 °C over 3 hours. A solution of methyl 2-methyl-4-oxocyclohex-2-enecarboxylate (53.8 g, 320 mmol) in diethyl ether (400 mL) was added at -40 °C over 2 minutes. The resulting solution was stirred for 5 hours at -20 °C. The mixture was diluted with saturated aqueous ammonium chloride (2.5 L) and extracted with ethyl acetate (3 x 2 L). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to afford methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate as an oil. MS ESI calc'd. for C10H17O3 [M + H]+ 185, found 185. 'H NMR (600 MHz, CDCI3) δ 3.49 (s, 3H), 2.43 - 2.40 (m, 1H), 2.35 - 2.29 (m, 1H), 2.21 - 2.17 (m, 1H), 2.1 1 - 2.04 (m, 1H), 2.00 - 1.96 (m, 1H), 1.91 - 1.85 (m, 2H), 0.85 (s, 3H), 0.77 (s, 3H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2012/154518, 2012, A1 Location in patent: Page/Page column 48
[2]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1 Location in patent: Page/Page column 92
[3]Current Patent Assignee: MERCK & CO INC - WO2014/176216, 2014, A1 Location in patent: Paragraph 00194
[4]Current Patent Assignee: ALTMAN MICHEAL D; MERCK & CO INC; FRIO ANTHONY; ANDERSEN BRAIN M - WO2014/176210, 2014, A1 Location in patent: Paragraph 00206
[5]Current Patent Assignee: NORTHUP ALAN B; MERCK & CO INC - WO2015/94997, 2015, A1 Location in patent: Paragraph 00184
[6]Current Patent Assignee: MERCK & CO INC - WO2015/95444, 2015, A1 Location in patent: Paragraph 00195
[7]Current Patent Assignee: MERCK & CO INC - WO2015/95445, 2015, A1 Location in patent: Paragraph 00192

2
[ 1312535-33-3 ]
[ 1312535-32-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium methylate / methanol / 0.5 h / 80 °C 2.1: copper(l) iodide / diethyl ether / 3 h / -40 °C 2.2: 5.03 h / -40 - -20 °C
	Multi-step reaction with 2 steps 1.1: sodium methylate; methanol / 1 h / 80 °C 2.1: copper(l) iodide / diethyl ether / 3 h / -40 °C 2.2: 5 h / -40 - -20 °C
	Multi-step reaction with 2 steps 1.1: sodium methylate / methanol / 1 h / 80 °C 2.1: copper(l) iodide / diethyl ether / 3 h / -40 °C 2.2: 5.03 h / -40 - -20 °C

	Multi-step reaction with 2 steps 1: sodium methylate / methanol / 0.5 h / 80 °C 2: copper(l) iodide / diethyl ether / 5 h / -40 - -20 °C
	Multi-step reaction with 2 steps 1.1: sodium methylate / methanol / 1 h / 80 °C 2.1: copper(l) iodide / diethyl ether / 3 h / -40 °C 2.2: 5 h / -40 - -20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2012/154518, 2012, A1
[2]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1 Current Patent Assignee: MERCK & CO INC - WO2014/176216, 2014, A1
[3]Current Patent Assignee: ALTMAN MICHEAL D; MERCK & CO INC; FRIO ANTHONY; ANDERSEN BRAIN M - WO2014/176210, 2014, A1
[4]Current Patent Assignee: NORTHUP ALAN B; MERCK & CO INC - WO2015/94997, 2015, A1
[5]Current Patent Assignee: MERCK & CO INC - WO2015/95444, 2015, A1

3
[ 1312535-00-4 ]
[ 1312535-32-2 ]
[ 76-05-1 ]
[ 1412492-90-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at -78 - -50℃; for 0.75h; Stage #2: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate In tetrahydrofuran at -65℃; for 0.333333h; Stage #3: trifluoroacetic acid In water; acetonitrile	11 EXAMPLE 1 1N-(3-{2-[(2,2-dimethyl-4-oxocyclohexyl)carbonyl]-l,3-thiazol-5-yl}-5-methylphenyl)-4- (trifluoromethyl)pyrimidin-2-aminium trifluoroacetateA solution of N,N-diisopropylamine (13.98 mL, 98 mmol) in THF (55 mL) was cooled to -78 °C. While at -78 °C, «-butyllithium (61.3 mL, 1.6 M in hexanes, 98 mmol) was added to the solution portionwise via syringe, maintaining an internal temperature lower than -65 °C. The reaction mixture was warmed to -60 °C and aged for 45 minutes, then cooled back to -78 °C. A solution of N-[3-methyl-5-(l,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (2.113 g, 6.28 mmol) in 55 mL of THF was transferred via cannula (using positive pressure) to the previously described freshly made solution of LDA over the course of 30 minutes, maintaining the internal temperature below -70 °C. The reaction was aged at -78 °C for 35 minutes, warmed to -50 °C, and aged for another 15 minutes. The mixture was cooled to -70 °C and a solution of methyl 2,2- dimethyl-4-oxocyclohexanecarboxylate (9.04 g, 49.1 mmol) in THF (50 mL) was transferred via cannula (using positive pressure) to the flask containing the lithium salt over the course of 45 minutes, maintaining the internal temperature below -65 °C then aged at -65 °C for 20 minutes. The cold bath was removed and the reaction was allowed to warm to room temperature. The mixture was cooled to 0 °C, and the reaction was diluted with ethanol (1 mL) and water (1 mL). The mixture was diluted with EtOAc (1 L) and washed three times with saturated ammonium chloride (total volume of wash 1.5 L). The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel column chromatography (0-30%EtOAc: Hexanes), followed by reverse phase high pressure liquid chromatography(acetonitrile/water with 0.1% TFA modifier) to afford racemic N-(3-{2-[(2,2-dimethyl-4- oxocyclohexyl)carbonyl]- 1 ,3-thiazol-5-yl} -5-methylphenyl)-4-(trifluoromethyl)pyrimidin-2- aminium trifluoroacetate. MS ESI calc'd. for C24H24F3N4O2S [M + H]+ 489, found 489. lH NMR (500 MHz, CDCI3) δ 8.65 (d, J= 5.0, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.32 (s, 1H), 7.20 (s, IH), 7.1 1 (d, J= 5.0, IH), 4.22 (t, J= 6.5, IH), 2.65 - 2.55 (m, 2H), 2.44 (s, 3H), 2.43 - 2.30 (m, 2H), 2.19 (dd, J- 13.8, 6.6, 2H), 1.09 (s, 3H), 1.07 (s, 3H). rhSyk activity = ++.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2012/154519, 2012, A1 Location in patent: Page/Page column 94-95

4
[ 1312535-32-2 ]
methyl (1,4-cis)-4-[5-(3-fluoro-5-[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridine-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: n-butyllithium / toluene / 1 h / -78 °C 1.2: 20 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate / 1,4-dioxane; water / 15 h / 100 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192098, 2013, A1

5
[ 1312535-32-2 ]
4-[5-(3-fluoro-5-[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)pyridin-2-yl]-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / toluene / 1 h / -78 °C 1.2: 20 °C 2.1: dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate / 1,4-dioxane; water / 15 h / 100 °C / Inert atmosphere 3.1: sodium hydroxide / methanol / 0.17 h / 110 °C / Microwave irradiation

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192098, 2013, A1

6
[ 624-28-2 ]
[ 1312535-32-2 ]
methyl 4-(5-bromopyridin-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,5-dibromopyridine With n-butyllithium In toluene at -78℃; for 1h; Stage #2: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate In toluene at 20℃;	9.4.1 Step 1 : w-BuLi was added dropwise to a solution of 2,5-dibromopyridine in toluene (30 mL) at -78 °C. The reaction mixture was stirred for 1 hour at -78 °C, then a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate in toluene (5 mL) was added. The reaction mixture was warm to room temperature, quenched with saturated aqueous ammonium chloride, extracted with CH2CI2 (3x), dried over a2S04 and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to afford methyl 4-(5- bromopyridin-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylate as a colorless oil. MS ESI calc'd for Ci5H21BrN03 [M + H]+ 342 and 344, found 342 and 344.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192098, 2013, A1 Location in patent: Paragraph 00271

7
[ 1312535-32-2 ]
methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; ethanol at -20℃; for 2h;	4.4.1 Preparative Example 4.4 Racemic methyl 2,2-dimethyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yljcyclohexanecarboxylate Step 1 Preparative Example 4.4 Racemic methyl 2,2-dimethyl-4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l- yljcyclohexanecarboxylate Step 1 : Sodium borohydride (1.85 g, 48.9 mmol) was added to a solution of methyl 2,2- dimethyl-4-oxocyclohexanecarboxylate (3.0 g, 16.3 mmol) in ethanol (65 mL) at -20°C. The solution was stirred at -20°C for 2 hours. Aqueous hydrochloric acid (1M) was added drop wise and the mixture was extracted with dichloromethane (3x). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 4- hydroxy-2,2-dimethylcyclohexanecarboxylate. NMR (500 MHz, DMSO-d6) δ 3.70 - 3.58 (m, 1H), 3.54 (s, 3H), 2.16 - 2.11 (m, 1H), 1.73 - 1.68 (m, 1H), 1.65 - 1.48 (m, 4H), 1.07 - 0.99 (m, 1H), 0.91 (s, 6H).
	With sodium tetrahydroborate; ethanol at -20℃; for 2h;	9.1.1 Step 1 : Sodium borohydride (1.85 g, 48.9 mmol) was added to a flask containing methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (3.0 g, 16.3 mmol) dissolved in ethanol (65 mL) at - 20°C. The mixture was stirred at -20°C for 2 h. Hydrochloric acid (1M) was added drop wise and the mixture was extracted with dichloromethane (3X). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 4-hydroxy-2,2-dimethylcyclohexanecarboxylate as a 3 : 1 mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 4.45 (d, / = 4.6, 1H), 4.37 (d, / = 4.0, 1H1), 3.69 - 3.59 (m, 1H), 3.57 - 3.52 (m, 3H), 2.15 - 2.05 (m, 1H), 1.75 - 1.46 (m, 5H), 1.09 - 0.97 (m, 1H), 0.96 - 0.88 (m, 6H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192125, 2013, A1 Location in patent: Page/Page column 111
[2]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1 Location in patent: Page/Page column 149

8
[ 1312535-32-2 ]
methyl 2,2-dimethyl-4-[(methylsulfonyl)oxy]cyclohexane carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium tetrahydroborate; ethanol / 2 h / -20 °C 2: triethylamine / dichloromethane / 3 h / -20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192125, 2013, A1 Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1

9
[ 1312535-32-2 ]
rac-methyl 2,2-dimethyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium tetrahydroborate; ethanol / 2 h / -20 °C 2: triethylamine / dichloromethane / 3 h / -20 °C 3: caesium carbonate / N,N-dimethyl-formamide / 22 h / 90 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192125, 2013, A1

10
[ 1312535-32-2 ]
methyl 4-(4-bromo-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium tetrahydroborate; ethanol / 2 h / -20 °C 2: triethylamine / dichloromethane / 3 h / -20 °C 3: caesium carbonate / N,N-dimethyl-formamide / 16 h / 80 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2013/192125, 2013, A1

11
[ 37595-74-7 ]
[ 1312535-32-2 ]
[ 73183-34-3 ]
[ 1562375-14-7 ]
[ 1562375-15-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 12h; Stage #3: bis(pinacol)diborane With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 100℃; for 2h; Inert atmosphere; Overall yield = 43 %; Overall yield = 400 mg;	10A; 10B.2 Step 2: Preparation of mixture of methyl 2,2-dimethyl-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2). Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-i).To a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.5 g, 8.14 mmol) inTHF (15 mL), was added dropwise LDA (10 mL, 10 mmol) at -78 °C for 15 mi Tf2NPh(3.78 g, 10.6 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78 °C for 2 h and stirred at 20 oC for additional 10 h. The resulting mixture was quenched with 30 mL of saturated aqueous NH4C1 and extracted with ethyl acetate (15 mLx2). The combined organic fractions were washed with brine (saturated, 1 OmL), dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1/20) to give the title compounds (ratio = 1:6, 1 g, yield: 34.9%) as yellow oils.;_Step 2: Preparation of mixture of methyl 2,2-dimethyl-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2).To a mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate (K-i, ratio = 1:6, 900 mg, 2.85 mmol) in 1,4-dioxane (50 mL) was added Bis(pinacolato)diboron (723 mg, 2.85 mmol) and potassium acetate (838 mg, 8.54 mmol). The mixture was purged with nitrogen for 20 minutes, and PdC12(dppf)-CH2C12 (697 mg, 0.854 mmol) and dppf (4732 mg, 8.54 mmol) were added. The mixture was stirred at 100 °Cfor 2 h. The resulting mixture was filtered over a Celite pad and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate/petroleum = 1/20) to give the title compound (ratio = 1:6, 400 mg, yield: 43%) as a yellow oil. LCMS(ESI) calc’d for C16H27B04 [M+H]: 295, found: 295.
71.429 % de	Stage #1: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 12h; Stage #3: bis(pinacol)diborane With 1,1'-bis-(diphenylphosphino)ferrocene; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 100℃; for 2h; Inert atmosphere; Overall yield = 43%; Overall yield = 400 mg;	10A.2, 10B.2 Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-1) Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-1) [0359] To a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.5 g, 8.14 mmol) in THF (15 mL), was added dropwise LDA (10 mL, 10 mmol) at -78° C. for 15 min. Tf2NPh (3.78 g, 10.6 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78° C. for 2 h and stirred at 20° C. for additional 10 h. The resulting mixture was quenched with 30 mL of saturated aqueous NH4Cl and extracted with ethyl acetate (15 mL×2). The combined organic fractions were washed with brine (saturated, 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1/20) to give the title compounds (ratio=1:6, 1 g, yield: 34.9%) as yellow oils. Step 2: Preparation of mixture of methyl 2,2-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2) [0360] To a mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-1, ratio=1:6, 900 mg, 2.85 mmol) in 1,4-dioxane (50 mL) was added Bis(pinacolato)diboron (723 mg, 2.85 mmol) and potassium acetate (838 mg, 8.54 mmol). The mixture was purged with nitrogen for 20 minutes, and PdCl2(dppf)-CH2Cl2 (697 mg, 0.854 mmol) and dppf (4732 mg, 8.54 mmol) were added. The mixture was stirred at 100° C. for 2 h. The resulting mixture was filtered over a Celite pad and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate/petroleum=1/20) to give the title compound (ratio=1:6, 400 mg, yield: 43%) as a yellow oil. LCMS (ESI) calc'd for C16H27BO4 [M+H]+: 295. found: 295.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/28597, 2014, A2 Location in patent: Page/Page column 85; 86; 87
[2]Current Patent Assignee: MERCK & CO INC - US2015/191434, 2015, A1 Location in patent: Paragraph 0360

12
[ 37595-74-7 ]
(2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3-iodo-1H-indazol-1-yl)methanone [ No CAS ]
[ 1312535-32-2 ]
[ 73183-34-3 ]
[ 1562375-16-9 ]
[ 1562375-17-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 12h; Stage #3: (2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3-iodo-1H-indazol-1-yl)methanone; bis(pinacol)diborane Overall yield = 26.4 %; Overall yield = 191 mg; Further stages;	10A; 10B.3 Step 3: Preparation of mixture of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4- fluoro- 1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylate and methyl 4-(1-(2- chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylate (K-3). Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-i).To a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.5 g, 8.14 mmol) inTHF (15 mL), was added dropwise LDA (10 mL, 10 mmol) at -78 °C for 15 mi Tf2NPh(3.78 g, 10.6 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78 °C for 2 h and stirred at 20 oC for additional 10 h. The resulting mixture was quenched with 30 mL of saturated aqueous NH4C1 and extracted with ethyl acetate (15 mLx2). The combined organic fractions were washed with brine (saturated, 1 OmL), dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1/20) to give the title compounds (ratio = 1:6, 1 g, yield: 34.9%) as yellow oils.;_Step 2: Preparation of mixture of methyl 2,2-dimethyl-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2).To a mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate (K-i, ratio = 1:6, 900 mg, 2.85 mmol) in 1,4-dioxane (50 mL) was added Bis(pinacolato)diboron (723 mg, 2.85 mmol) and potassium acetate (838 mg, 8.54 mmol). The mixture was purged with nitrogen for 20 minutes, and PdC12(dppf)-CH2C12 (697 mg, 0.854 mmol) and dppf (4732 mg, 8.54 mmol) were added. The mixture was stirred at 100 °Cfor 2 h. The resulting mixture was filtered over a Celite pad and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate/petroleum = 1/20) to give the title compound (ratio = 1:6, 400 mg, yield: 43%) as a yellow oil. LCMS(ESI) calc’d for C16H27B04 [M+H]: 295, found: 295.;_Step 3: Preparation of mixture of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4- fluoro- 1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylate and methyl 4-(1-(2- chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylate (K-3).To a solution of (2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3 -iodo- 1 H-indazol- 1- yl)methanone (510 mg, 1.088 mmol) in THF/H20 (40 mL/lOmL) was added a mixture of methyl 2,2-dimethyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 - enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2, ratio = 1:6, 400 mg, 1.36 mmol) and Na2CO3 (432 mg,4.08 mmol). The mixture was purged with nitrogen for 20 minutes, Pd(dppf)C12 (298 mg,0.408 mmol) was added and the mixture was stirred at 80 °C for 10 h. The resulting mixturewas filtered over a Celite pad, and the filtrate was diluted with water (40 mL) and extractedwith ethyl acetate (60 mL x 3). The combined organic layers were washed with brine, driedover anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel (ethyl acetate/petroleum ether = 1/10) to give the title compound (ratio: 1:6, 191 mg, yield: 26.4 %) as a yellow oil. LCMS (ESI) calc’d for C25H21C1F4N203 [M+H]: 509, found: 509.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/28597, 2014, A2 Location in patent: Page/Page column 85; 86; 87

13
[ 37595-74-7 ]
(2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3-iodo-1H-indazol-1-yl)methanone [ No CAS ]
[ 1312535-32-2 ]
[ 73183-34-3 ]
[ 1562374-82-6 ]
[ 1562374-83-7 ]

Yield	Reaction Conditions	Operation in experiment
1: 5 mg 2: 20 mg	Stage #1: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 12h; Stage #3: (2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3-iodo-1H-indazol-1-yl)methanone; bis(pinacol)diborane Further stages;	10A; 10B.4 Step 4: Preparation of (R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylic acid (1OA) and (R and S)-4-(i-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylic acid (lOB). Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-i).To a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.5 g, 8.14 mmol) inTHF (15 mL), was added dropwise LDA (10 mL, 10 mmol) at -78 °C for 15 mi Tf2NPh(3.78 g, 10.6 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78 °C for 2 h and stirred at 20 oC for additional 10 h. The resulting mixture was quenched with 30 mL of saturated aqueous NH4C1 and extracted with ethyl acetate (15 mLx2). The combined organic fractions were washed with brine (saturated, 1 OmL), dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1/20) to give the title compounds (ratio = 1:6, 1 g, yield: 34.9%) as yellow oils.;_Step 2: Preparation of mixture of methyl 2,2-dimethyl-4-(4,4,5,5-tetramethyl-i,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2).To a mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3 -enecarboxylate (K-i, ratio = 1:6, 900 mg, 2.85 mmol) in 1,4-dioxane (50 mL) was added Bis(pinacolato)diboron (723 mg, 2.85 mmol) and potassium acetate (838 mg, 8.54 mmol). The mixture was purged with nitrogen for 20 minutes, and PdC12(dppf)-CH2C12 (697 mg, 0.854 mmol) and dppf (4732 mg, 8.54 mmol) were added. The mixture was stirred at 100 °Cfor 2 h. The resulting mixture was filtered over a Celite pad and the filtrate was diluted with water (50 mL) and extracted with ethyl acetate (50 mLx3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate/petroleum = 1/20) to give the title compound (ratio = 1:6, 400 mg, yield: 43%) as a yellow oil. LCMS(ESI) calc’d for C16H27B04 [M+H]: 295, found: 295.;_Step 3: Preparation of mixture of methyl 4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4- fluoro- 1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylate and methyl 4-(1-(2- chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylate (K-3).To a solution of (2-chloro-6-(trifluoromethyl)phenyl)(4-fluoro-3 -iodo- 1 H-indazol- 1- yl)methanone (510 mg, 1.088 mmol) in THF/H20 (40 mL/lOmL) was added a mixture of methyl 2,2-dimethyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3 - enecarboxylate and methyl 6,6-dimethyl-4-(4,4,5 ,5 -tetramethyl- 1,3 ,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (K-2, ratio = 1:6, 400 mg, 1.36 mmol) and Na2CO3 (432 mg,4.08 mmol). The mixture was purged with nitrogen for 20 minutes, Pd(dppf)C12 (298 mg,0.408 mmol) was added and the mixture was stirred at 80 °C for 10 h. The resulting mixturewas filtered over a Celite pad, and the filtrate was diluted with water (40 mL) and extractedwith ethyl acetate (60 mL x 3). The combined organic layers were washed with brine, driedover anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica gel (ethyl acetate/petroleum ether = 1/10) to give the title compound (ratio: 1:6, 191 mg, yield: 26.4 %) as a yellow oil. LCMS (ESI) calc’d for C25H21C1F4N203 [M+H]: 509, found: 509.;_Step 4: Preparation of (R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-2,2-dimethylcyclohex-3-enecarboxylic acid (1OA) and (R and S)-4-(i-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6-dimethylcyclohex-3-enecarboxylic acid (lOB).A mixture of methyl 4-( 1 -(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1 H-indazol-3 -yl)35 2,2-dimethylcyclohex-3 -enecarboxylate, methyl 4-( 1 -(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1 H-indazol-3 -yl)-6,6-dimethylcyclohex-3 -enecarboxylate (K-3, ratio = 1:6, 200 mg,0.39 mmol), NaOH (47.2 mg, 1.18 mmol) and methanol (10 mL) was stirred at 40 °C for 10 h. The resulting mixture was concentrated in vacuo, diluted with water (10 mL) and washed with ethyl acetate (10 mLx2). The aqueous layer was acidified with 2 M HC1 to pH = 2. The precipitate was collected by filtration and dried in vacuo. The desired product was purified by prep-HPLC (acetonitrile + 0.75% trifluoroacetic acid in water) to give two separate isomers:(R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro- 1H-indazol-3-yl)-2,2- dimeth yl yclohex-3-enecarboxylic acid (1OA): 5 mg, LCMS (ESI) calc’d for C24H,9C1F4N203 [M+H]: 495, found: 495; ‘H NMR (400 MHz, CDC13) ö 8.43 (1H, d, J 8.53 Hz), 7.65-7.75 (2H, m), 7.51-7.64 (2H, m), 7.11 (1H, dd,J= 11.04, 8.03 Hz), 6.57 (1H, br.s.), 2.48-2.55 (2H, m), 2.23 (2H, d, J= 8.03 Hz), 1.08 (3H, s), 2.18 (1H, s),1.02 (3H, d, J=3.01 Hz).(R and S)-4-(1-(2-chloro-6-(trifluoromethyl)benzoyl)-4-fluoro-1H-indazol-3-yl)-6,6- dimeth y lcyclohex-3-enecarboxylic acid (lOB): 20 mg, LCMS (ESI) calc’d for C24H,9C1F4N203 [M+H]: 495, found: 495; ‘H NMR (400 MHz, CDC13) ö 8.43 (1H, d, J 8.53 Hz), 7.65-7.74 (2H, m), 7.52-7.63 (2H, m), 7.11 (1H, dd, J= 10.54, 8.03 Hz), 6. 37 (1H,br.s.), 2.44-2.60 (2H, m), 2.14-2.28 (3H, m), 1.08 (3H, s),1.02 (3H, d, J= 3.01 Hz).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/28597, 2014, A2 Location in patent: Page/Page column 85; 86; 87; 88

14
[ 37595-74-7 ]
[ 1312535-32-2 ]
[ 1562375-12-5 ]
[ 1562375-13-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 12h; Overall yield = 34.9 %; Overall yield = 1 g;	10A; 10B.1 Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-i). Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-i).To a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.5 g, 8.14 mmol) inTHF (15 mL), was added dropwise LDA (10 mL, 10 mmol) at -78 °C for 15 mi Tf2NPh(3.78 g, 10.6 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78 °C for 2 h and stirred at 20 oC for additional 10 h. The resulting mixture was quenched with 30 mL of saturated aqueous NH4C1 and extracted with ethyl acetate (15 mLx2). The combined organic fractions were washed with brine (saturated, 1 OmL), dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether = 1/20) to give the title compounds (ratio = 1:6, 1 g, yield: 34.9%) as yellow oils.
	Stage #1: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 0.25h; Stage #2: N,N-phenylbistrifluoromethane-sulfonimide In tetrahydrofuran at -78 - 20℃; for 12h; Overall yield = 34.9 %; Overall yield = 1 g;	10A.1, 10B.1 Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-1) Step 1: Preparation of mixture of methyl 2,2-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate and methyl 6,6-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)cyclohex-3-enecarboxylate (K-1) [0359] To a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.5 g, 8.14 mmol) in THF (15 mL), was added dropwise LDA (10 mL, 10 mmol) at -78° C. for 15 min. Tf2NPh (3.78 g, 10.6 mmol) in THF (10 mL) was added dropwise. The mixture was stirred at -78° C. for 2 h and stirred at 20° C. for additional 10 h. The resulting mixture was quenched with 30 mL of saturated aqueous NH4Cl and extracted with ethyl acetate (15 mL×2). The combined organic fractions were washed with brine (saturated, 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether=1/20) to give the title compounds (ratio=1:6, 1 g, yield: 34.9%) as yellow oils.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/28597, 2014, A2 Location in patent: Page/Page column 85; 86
[2]Current Patent Assignee: MERCK & CO INC - US2015/191434, 2015, A1 Location in patent: Paragraph 0359

15
[ 1312535-32-2 ]
[ 1774-47-6 ]
syn-methyl 5,5-dimethyl-1-oxaspiro[2.5]octane-6-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: trimethylsulfoxonium iodide With sodium hydride In dimethyl sulfoxide; mineral oil at 0 - 20℃; for 3h; Stage #2: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate In dimethyl sulfoxide; mineral oil at 0 - 20℃;	22.1 Step 1 : Trimethylsulfoxonium iodide (1.20 g, 5.43 mmol) was dissolved in DMSO (lOmL) and cooled to 0 °C. Sodium hydride (0.26 g, 6.51 mmol) was added and the reaction mixture warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled to 0 °C and methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.0 g, 5.4 mmol) was added, then warmed to room temperature and stirred overnight. The crude reaction mixture was diluted with ether and washed with water. The product was extracted with ether and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, silica gel was added, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5 to 40% EtOAc/isohexane) to afford methyl 5, 5 -dimethyl- 1- oxaspiro[2.5]octane-6-carboxylate (syn) as a yellow liquid. 1H NMR (500 MHz, CDC13) δ 3.66 (s, 3H), 2.50-2.49 (m, 2H), 2.06-2.04 (m, 2H), 1.76-1.75 (m, 2H), 1.67-1.66 (m, 1H), 1.47-1.45 (m, 1H), 1.27-1.25 (m, 1H), 1.07 (s, 3H), 1.00 (s, 3H).

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1 Location in patent: Page/Page column 89-90

16
[ 1312535-32-2 ]
[ 1066-54-2 ]
syn-methyl 4-hydroxy-2,2-dimethyl-4-((trimethylsilyl)ethynyl)cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran at -78℃; for 2h; Inert atmosphere;	8.1 Step 1 : n-Butyl lithium (4.34 mL, 10.86 mmol) was added to a solution of trimethylsilyl- acetylene (1.83 mL, 13.0 mmol) in THF (20 mL) cooled to -78 °C under nitrogen. In a separate flask, under nitrogen, methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (2.00 g, 10.86 mmol) was dissolved in THF (30 mL) and cooled to -78 °C. After stirring for 20 min at -78 °C, the lithium acetylide solution was transferred drop wise by cannula to the cold solution of the ketone. Upon completion of the addition, the reaction was stirred at -78 °C for 2 h. Saturated ammonium chloride was then added and the mixture was allowed to warm to room temperature. The mixture was extracted with ethyl acetate (2X) and the combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 25% diethyl ether/hexanes) to afford methyl 4-hydroxy-2,2-dimethyl-4-((trimethylsilyl)ethynyl)cyclohexane- carboxylate as a colorless gum. 1H NMR (500 MHz, CDC13) δ 3.66 (s, 3H), 2.22 (dd, / = 3.1, 10.6, 1H), 2.05 (m, 2H), 1.86 (d, / = 14.3, 1H), 1.69 (m, 4H), 1.06 (d, / = 9.8, 6H), 0.15 (s, / = 1.3, 9H). NMR analysis of a later stage intermediate confirmed the syn stereochemistry.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1 Location in patent: Page/Page column 80-81

17
[ 1312535-32-2 ]
[ 1582755-73-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: sodium tetrahydroborate; ethanol / 2 h / -20 °C 2: triethylamine / dichloromethane / 3 h / -20 °C 3: sodium azide / N,N-dimethyl-formamide / 19 h / 90 °C 4: copper(ll) sulfate pentahydrate; sodium L-ascorbate / water; <i>tert</i>-butyl alcohol / 17 h / 65 °C 5: sodium hydroxide; water / tetrahydrofuran; methanol / 48 h / 65 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1

18
[ 1312535-32-2 ]
methyl 4-azido-2,2-dimethylcyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium tetrahydroborate; ethanol / 2 h / -20 °C 2: triethylamine / dichloromethane / 3 h / -20 °C 3: sodium azide / N,N-dimethyl-formamide / 19 h / 90 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1

19
[ 1312535-32-2 ]
[ 1582758-46-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium tetrahydroborate; ethanol / 2 h / -20 °C 2: triethylamine / dichloromethane / 3 h / -20 °C 3: sodium azide / N,N-dimethyl-formamide / 19 h / 90 °C 4: copper(ll) sulfate pentahydrate; sodium L-ascorbate / water; <i>tert</i>-butyl alcohol / 17 h / 65 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1

20
[ 1312535-32-2 ]
syn-methyl 4-ethynyl-4-hydroxy-2,2-dimethylcyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: n-butyllithium / tetrahydrofuran / 2 h / -78 °C / Inert atmosphere 2: potassium carbonate; methanol / tetrahydrofuran / 2 h / 20 °C

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/48065, 2014, A1

21
[ 589-87-7 ]
[ 1312535-32-2 ]
1-(4-bromophenyl)-5,5-dimethyl-2-oxabicyclo[2.2.2]octan-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1,4-bromoiodobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h; Inert atmosphere; Stage #2: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate In tetrahydrofuran; hexane at -78 - 25℃; Inert atmosphere;	1-(4-bromophenyl)-5,5-dimethyl-2-oxabicyclo[2.2.2]octan-3-one To l-bromo-4-iodobenzene (600 mg, 2.12 mmol) in THF (7.1 mL) at -78°C was added (dropwise) w-BuLi (1.46 mL, 2.33 mmol, 1.60 M in hexanes) and the reaction was stirred at -78°C for 2 hours. A solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (430 mg, 2.33 mmol) in THF (1.5 mL) was then added dropwise and the reaction was stirred to room temperature overnight. The reaction was quenched by pouring into a separatory funnel containing water and was extracted with ethyl acetate (x 3). The organic layers were combinedand dried over Na2S04, filtered, and concentrated in vacuo. The crude product was then purified by silica chromatography, eluting with 0-50% EtOAc/hexane. The product was collected and concentrated to afford 1-18 as a oil. LRMS (ESI) calc'd for Ci5Hi8Br02 [M+H]+: 309, found 309.
	Stage #1: 1,4-bromoiodobenzene With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h; Stage #2: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate In tetrahydrofuran; hexane at 15 - 25℃;	I-57 l-(4-Bromophenyl)-5,5-dimethyl-2-oxabicyclo[2.2.2]octan-3-one To l-bromo-4-iodobenzene (600 mg, 2.12 mmol) in THF (7.1 mL) at -78°C was added (dropwise) w-BuLi (1.46 mL, 2.33 mmol, 1.60 M in hexanes) and the reaction was stirred at -78°C for 2 hours before a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (430 mg, 2.33 mmol) in THF (1.5 mL) was added dropwise and the reaction was stirred to room temperature overnight. The reaction was then quenched by pouring into a separatory funnel containing water and was extracted with ethyl acetate (3 ><50 mL). The organic layers were combined and dried over Na2S04, filtered, and concentrated in vacuo. The crude product was then purified by silica chromatography, eluting with 0-50% EtOAc/hexane. The product was collected and concentrated to afford the desired product. LRMS (ESI) calc'd for Ci5Hi8Br02 [M+H]+: 309, found 309.

Reference： [1]Current Patent Assignee: PHARMARON INC - WO2014/146492, 2014, A1 Location in patent: Page/Page column 54-55
[2]Current Patent Assignee: PHARMARON INC - WO2014/146493, 2014, A1 Location in patent: Page/Page column 61

22
[ 288-47-1 ]
[ 1312535-32-2 ]
rel-methyl 4-hydroxy-2,2-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane at -78 - 0℃; for 1.75h;	3.1.1 Step 1: n-Butyllithium (2.2 mL, 5.5 mmol, 2.5 M solution in hexanes) was addeddropwise over 12 minutes to a solution of thiazole (0.52 g, 6.05 mmol) in tetrahydrofuran (15 mL) at -78 °C. After 30 minutes, the reaction mixture was transferred over 5 minutes via a dry ice-cooled cannula to a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.01 g, 5.5 mmol) in tetrahydrofuran (15 mL) at -78 °C. The resulting yellow solution was kept at -78°C for 1 hour, moved to a 0 °C bath for 15 minutes, and then cooled back to -78 °C. Aqueous saturated ammonium chloride solution (10 mL) was added and the mixture was allowed to warm to room temperature. The biphasic mixture was partitioned between ethyl acetate (50 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (10-35% ethyl acetate in hexanes) to afford methyl (1R,4S or 1S,4R)-4-hydroxy- 2,2-dimethyl-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate as a white solid. MS ESI calcd. for C13H20N035 [M+H] 270, found 270.
	Stage #1: 1,3-thiazole With n-butyllithium In tetrahydrofuran at -78℃; for 0.7h; Stage #2: methyl 2,2-dimethyl-4-oxocyclohexane-1-carboxylate In tetrahydrofuran at -78 - 0℃; for 1.33333h;	4.4.7 Preparative Example 4.7 - Methyl (1R,4S or lS,4R)-4-hydroxy-2,2-dimethyl-4-(l,3-thiazol-2-yl)- cyclohexanecarboxylate M-Butyllithium (2.2 mL, 5.5 mmol, 2.5 M solution in hexanes) was added dropwise over 12 minutes to a solution of thiazole (0.52 g, 6.05 mmol) in tetrahydrofuran (15 mL) at -78 °C. After 30 minutes, the reaction mixture was transferred over 5 minutes via a dry ice-cooled cannula to a solution of methyl 2,2-dimethyl-4-oxocyclohexanecarboxylate (1.01 g, 5.5 mmol) in tetrahydrofuran (15 mL) at -78 °C. The resulting yellow solution was kept at -78 °C for 1 hour, moved to a 0 °C bath for 15 minutes, and then cooled back to -78 °C. Aqueous saturated ammonium chloride solution (10 mL) was added and the mixture was allowed to warm to room temperature. The biphasic mixture was partitioned between ethyl acetate (50 mL) and water (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (10-35% ethyl acetate in hexanes) to afford methyl (1R,4,S or 15',4R)-4-hydroxy- 2,2-dimethyl-4-(l,3-thiazol-2-yl)cyclohexanecarboxylate as a white solid. MS ESI calcd. for Ci3H2oN03S [M+H]+ 270, found 270.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2014/176216, 2014, A1 Location in patent: Paragraph 00195
[2]Current Patent Assignee: ALTMAN MICHEAL D; MERCK & CO INC; FRIO ANTHONY; ANDERSEN BRAIN M - WO2014/176210, 2014, A1 Location in patent: Paragraph 00226

23
[ 1312535-32-2 ]
rel-4-(5-(3-chloro-5-((4-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)thiazol-2-yl)-4-hydroxy-2,2-dimethylcyclohexanecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 1.75 h / -78 - 0 °C 2.1: sodium hydroxide / methanol; water / 30 - 75 °C 2.2: 2 h / pH Ca_. 6 3.1: catacxium A; palladium diacetate; Trimethylacetic acid; cesium fluoride / 1,4-dioxane / 24 h / 100 °C / Inert atmosphere