Name: 4341-24-6|5-Methylcyclohexane-1,3-dione|98%
Brand: Ambeed
SKU: A159241
Price: 9.0 USD
Availability: InStock
Rating: 94 (27 reviews)

1
[ 4341-24-6 ]
[ 3780-58-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; hydrazine hydrate; ethylene glycol at 125℃; Reagens 4:Methanol;

Reference： [1]Stetter; Meisel [Chemische Berichte, 1957, vol. 90, p. 2928,2930]

2
[ 4341-24-6 ]
[ 626-51-7 ]

Reference： [1]Journal of the American Chemical Society,1951,vol. 73,p. 3632

3
[ 4341-24-6 ]
[ 74-88-4 ]
[ 61621-47-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With sodium hydroxide for 20h; Heating;
48%	With sodium hydroxide In water for 12h; Heating;
41.4%	With sodium hydroxide In water at 17 - 60℃; for 18h;	59 Preparation of compound 60-A Mel (67.53 g, 0.476 mol, 2.0 eq.) was added to 5 -methyl- 1,3 cyclohexanedione (30 g, 0.238 mol, 1.0 eq.) in 77 mL of NaOH (aq, 4 N, 0.71 mol, 1.3 eq.) at 17 ~ 23 °C, then the mixture was stirred at 50 ~ 60 °C for 18 hours. TLC (PE/EA = 1/2) showed the desired compound was detected. The mixture was stirred at 0 °C for 2 hours, filtered and the filter cake was collected and then dried in vacuum to give 13.8 g of compound 60-A (yield -41.4%) as a white solid which was used.

23%	With sodium hydroxide In water at 100℃; for 17h;
	With potassium hydroxide; acetone at 60 - 70℃;
	With potassium hydroxide In acetone

Reference： [1]Majetich, George; Defauw, Jean; Ringold, Clay [Journal of Organic Chemistry, 1988, vol. 53, # 1, p. 50 - 68]
[2]Leed, Andrew R.; Boettger, Susan D.; Ganem, Bruce [Journal of Organic Chemistry, 1980, vol. 45, # 6, p. 1098 - 1106]
[3]Current Patent Assignee: BIOGEN IDEC INC. - WO2019/104030, 2019, A1 Location in patent: Page/Page column 113
[4]Schroeder, Sybrin P.; Taylor, Nicholas J.; Jackson, Paula; Franckevicius, Vilius [Organic Letters, 2013, vol. 15, # 14, p. 3778 - 3781]
[5]Sonn [Chemische Berichte, 1931, vol. 64, p. 1851]
[6]Cleaver,L. et al. [Australian Journal of Chemistry, 1976, vol. 29, p. 1989 - 2001]

4
[ 4341-24-6 ]
[ 37408-18-7 ]
[ 40397-71-5 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine

Reference： [1]Current Patent Assignee: PFIZER INC - DE2201668, 1972, A1 [Chem.Abstr., 1973, vol. 78, # 71706][Chem.Abstr., 1973, vol. 78, # 71706]

5
[ 4341-24-6 ]
[ 64-17-5 ]
[ 35023-83-7 ]

Yield	Reaction Conditions	Operation in experiment
91%	With toluene-4-sulfonic acid In benzene for 8h; Heating;
89%	With toluene-4-sulfonic acid In benzene for 28h; Heating;
87%	With Fe(OTs)3 for 3h; Heating;

83%	With toluene-4-sulfonic acid for 9h; Heating;
82%	With toluene-4-sulfonic acid In toluene at 85℃; for 6h;
	In benzene Heating;
	With toluene-4-sulfonic acid In toluene at 125℃; for 14h; Dean-Stark;

Reference： [1]Foote, Kevin M; Hayes, Christopher J; John, Matthew P; Pattenden, Gerald [Organic and biomolecular chemistry, 2003, vol. 1, # 22, p. 3917 - 3948]
[2]Gould, Steven J.; Cheng, Xing-Chun; Melville, Chris [Journal of the American Chemical Society, 1994, vol. 116, # 5, p. 1800 - 1804]
[3]Mansilla, Horacio; Afonso, Maria M. [Synthetic Communications, 2008, vol. 38, # 15, p. 2607 - 2618]
[4]Majetich, George; Lowery, Derric; Khetani, Vikram; Song, Jee-Seop; Hull, Kenneth; Ringold, Clay [Journal of Organic Chemistry, 1991, vol. 56, # 12, p. 3988 - 4001]
[5]Brenninger, Christoph; Pöthig, Alexander; Bach, Thorsten [Angewandte Chemie - International Edition, 2017, vol. 56, # 15, p. 4337 - 4341][Angew. Chem., 2017, vol. 129, p. 4401 - 4405]
[6]Guingant, Andre; Barreto, Marie Manuel [Tetrahedron Letters, 1987, vol. 28, # 27, p. 3107 - 3110]
[7]Maji, Biplab; Yamamoto, Hisashi [Journal of the American Chemical Society, 2015, vol. 137, # 50, p. 15957 - 15963]

6
[ 4341-24-6 ]
[ 1618-26-4 ]
[ 88790-44-7 ]

Reference： [1]Tetrahedron Letters,1987,vol. 28,p. 3107 - 3110

7
[ 4341-24-6 ]
[ 3240-34-4 ]
[ 86396-03-4 ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane at 20℃; for 2h;	1 General procedure for the preparation of iodonium ylides 4 General procedure: A solution of 1,3-cyclohexanedione 1 (10.00-30.00 mmol) and iodobenzene diacetate (10.00-30.00 mmol) in dichloromethane (200 mL) was stirred at room temperature for 120-180 min. The yellow solution was then washed with an aqueous 5% KOH solution (2100 mL), water (250 mL) and dried (MgSO4). The solvent was evaporated under reduced pressure (water bath below 30 °C), the solid residue triturated with hexanes (100 mL) and filtered to afford iodonium ylide 4.
72%	With sodium carbonate In ethanol for 0.5h; Ambient temperature;
	In dichloromethane at 20℃; for 2h;

	With potassium hydroxide In methanol; water at 20℃; for 2h;
	With potassium hydroxide In methanol; water at 20℃; for 2h;
	With potassium hydroxide In methanol; water at 20℃; Inert atmosphere;
	With potassium hydroxide In methanol at 20℃; Green chemistry;

Reference： [1]Kalpogiannaki, Dimitra; Martini, Catherine-Irene; Nikopoulou, Aggeliki; Nyxas, John A.; Pantazi, Vassiliki; Hadjiarapoglou, Lazaros P. [Tetrahedron, 2013, vol. 69, # 5, p. 1566 - 1575]
[2]Schank, Kurt; Lick, Carlo [Synthesis, 1983, # 5, p. 392 - 395]
[3]Antos, Anna; Elemes, Yiannis; Michaelides, Adonis; Nyxas, John A.; Skoulika, Stavroula; Hadjiarapoglou, Lazaros P. [Journal of Organic Chemistry, 2012, vol. 77, # 23, p. 10949 - 10954]
[4]Pradhan, Samjhana; Mishra, Kanchan; Lee, Yong Rok [Chemistry - A European Journal, 2019, vol. 25, # 46, p. 10886 - 10894]
[5]Jiang, Yuqin; Li, Pengfei; Li, Xingwei; Liu, Bingxian; Zhao, Jie [Organic Letters, 2020, vol. 22, # 19, p. 7475 - 7479] Chen, Lu; Hao, Liqiang; Ji, Yafei; Wang, Yangyang; Wang, Zhichao; Wu, Gaorong; Xu, Xiaobo [Organic and Biomolecular Chemistry, 2022, vol. 20, # 4, p. 887 - 894]
[6]Kanchupalli, Vinaykumar; Kumar, Sanjeev; Nanduri, Srinivas; Nunewar, Saiprasad; Pandhare, Harishchandra [Organic Letters, 2021, vol. 23, # 11, p. 4233 - 4238]
[7]Han, Zhi-Peng; Xu, Meng-Meng; Zhang, Rui-Ying; Xu, Xiao-Ping; Ji, Shun-Jun [Green Chemistry, 2021, vol. 23, # 17, p. 6337 - 6340]

8
[ 4341-24-6 ]
[ 78146-52-8 ]
[ 111853-17-9 ]

Yield	Reaction Conditions	Operation in experiment
66%	In acetic anhydride; acetic acid for 1h; Heating;

Reference： [1]Bisenieks, E. A.; Bundule, M. F.; Uldrikis, Ya. R.; Dubur, G. Ya.; Mishnev, A. F.; Bleidelis, Ya. Ya. [Chemistry of Heterocyclic Compounds, 1987, vol. 23, # 1, p. 88 - 92][Khimiya Geterotsiklicheskikh Soedinenii, 1987, vol. 23, # 1, p. 107 - 112]

9
[ 4341-24-6 ]
[ 15646-46-5 ]
[ 125812-06-8 ]

Yield	Reaction Conditions	Operation in experiment
39%	With triethylamine In ethanol for 24h; Ambient temperature;

Reference： [1]Kocevar, M.; Polanc, S.; Tisler, M.; Vercek, B. [Synthetic Communications, 1989, vol. 19, # 9-10, p. 1713 - 1720]

10
[ 4341-24-6 ]
[ 106-47-8 ]
3-<(4'-chlorophenyl)amino>-5-methyl-2-cyclohexen-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	In ethanol; benzene for 4h; Heating;
76%	With iron ethylene-1,2-diamine complex loaded on carbon nanotubes In 1,2-dichloro-ethane at 80℃; for 24h;

Reference： [1]Scott, K. R.; Edafiogho, Ivan O.; Richardson, Erica L.; Farrar, Vida A.; Moore, Jacqueline A.; et al. [Journal of Medicinal Chemistry, 1993, vol. 36, # 14, p. 1947 - 1955]
[2]Baell, Jonathan B.; Ding, Qifeng; Huang, Fei; Huang, He; Xu, Mingjie; Yu, Yang; Zhang, Lihui; Zheng, Jian-Guo [Chemistry - A European Journal, 2020]

11
[ 4341-24-6 ]
[ 31608-22-7 ]
[ 91214-52-7 ]

Reference： [1]Bulletin de la Societe Chimique de France,1961,p. 669

12
[ 4341-24-6 ]
[ 1729-99-3 ]
[ 54245-23-7 ]

Reference： [1]Australian Journal of Chemistry,1974,vol. 27,p. 2209 - 2228

13
[ 4341-24-6 ]
[ 40480-10-2 ]
Heptadecanoic acid 5-methyl-3-oxo-cyclohex-1-enyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With pyridine In chloroform for 1h;

Reference： [1]Lakhvich, F. A.; Petrusevich, I. I.; Sergeeva, A. N. [Russian Journal of Organic Chemistry, 1995, vol. 31, # 11, p. 1473 - 1479][Zhurnal Organicheskoi Khimii, 1995, vol. 31, # 11, p. 1643 - 1649]

14
[ 4341-24-6 ]
[ 54398-84-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	With ammonium acetate In toluene Dean-Stark; Reflux;	3-amino-5-methyl-cyclohex-2-en-1-one(4b) Compound 3b(12.62 g, 100.00 mmol), ammonium acetate (7.81 g, 101.32 mmol) and dry toluene(200 mL) were placed in a three-neck flask fitted with a Dean-Stark trap. Thereaction mixture was stirred at reflux temperature until the completion(monitored by TLC). The stirring was continued until the mixture was cooled toroom temperature. The precipitate was filtered, washed with diethyl ether anddried.Yield: 11.65 g (93%)Molecular Formula = C7H11NOcalc: 125.17 LCMS m/z [M+H]+ : 126.1,[M-H]- : no ionization, tR: 1.05 min.
85%	With ammonium acetate In ethanol at 70℃; for 6h;
83%	With ammonium acetate In toluene for 5h; Reflux;	A Step A: 3-Amino-5-methyl-cyclohex-2-enone The solution of 50.00 g (396 mmol) 5-methyl-cyclohexane-1 ,3-dione and 31.13 g (404 mmol) ammonium acetate in 1000 mL toluene was stirred at reflux temperature for 5 hours in a flask equipped with Marcusson separator. After cooling down to room temperature the toluene was removed under vacuum, the remaining solid was washed with saturated NaHC03/aq, water and diisopropyl ether.Yield: 83 %.

80%	Stage #1: 5-methyl-cyclohexane-1,3-dione With ammonium acetate for 0.25h; Dean-Stark; Inert atmosphere; Cooling with ice; Stage #2: at 20℃; for 0.5h; Dean-Stark; Inert atmosphere;	2.1.1. General procedure A: Synthesis of enaminone intermediate 3-amino-5-methylcyclohex-2-enone (2): To a 500 mL two-neck roundbottom flask fitted with a condenser, Dean-Stark trap, and magneticstirrer was added 300 mL of anhydrous benzene under nitrogen. Thereaction flask was placed on an ice bath before adding 5-methylcyclohexane-1, 3-dione (1, 13.40 g, 106.0 mmol) and ammonium acetate(16.34 g, 212.0 mmol). After stirring for 15 min, 5.5 mL of acetic acidwas added dropwise, and the reaction mixture was brought to roomtemperature and allowed to stir for 30 min. The mixture was refluxed for1 h and once cooled allowed to stir overnight at room temperature. Thecrude product precipitated and was collected via vacuum filtration andallowed to air dry. Once dried, the crude product was recrystallized fromhot ethyl acetate as a yellow solid 80% (10.64 g), mp. 175-177 C (lit.173-174.5 C). 1H NMR (400 MHz, DMSO): δ, ppm 6.70 (2H, s), 4.90(1H, s), 2.29-2.20 (1H, m), 2.08-1.96 (3H, m), 1.82-1.73 (1H, m),0.97-0.94 (3H, m). 13C NMR (101 MHz, DMSO): δ, ppm 194.8, 166.9,97.5, 44.8, 36.5, 29.3, 21.4. Anal. Calcd for C7H11NO: C, 67.2; H, 8.9; N,11.2; Found: C, 67.2; H, 8.8; N, 11.2.
80%	Stage #1: 5-methyl-cyclohexane-1,3-dione With ammonium acetate for 0.25h; Dean-Stark; Inert atmosphere; Cooling with ice; Stage #2: at 20℃; for 0.5h; Dean-Stark; Inert atmosphere;	2.1.1. General procedure A: Synthesis of enaminone intermediate 3-amino-5-methylcyclohex-2-enone (2): To a 500 mL two-neck roundbottom flask fitted with a condenser, Dean-Stark trap, and magneticstirrer was added 300 mL of anhydrous benzene under nitrogen. Thereaction flask was placed on an ice bath before adding 5-methylcyclohexane-1, 3-dione (1, 13.40 g, 106.0 mmol) and ammonium acetate(16.34 g, 212.0 mmol). After stirring for 15 min, 5.5 mL of acetic acidwas added dropwise, and the reaction mixture was brought to roomtemperature and allowed to stir for 30 min. The mixture was refluxed for1 h and once cooled allowed to stir overnight at room temperature. Thecrude product precipitated and was collected via vacuum filtration andallowed to air dry. Once dried, the crude product was recrystallized fromhot ethyl acetate as a yellow solid 80% (10.64 g), mp. 175-177 C (lit.173-174.5 C). 1H NMR (400 MHz, DMSO): δ, ppm 6.70 (2H, s), 4.90(1H, s), 2.29-2.20 (1H, m), 2.08-1.96 (3H, m), 1.82-1.73 (1H, m),0.97-0.94 (3H, m). 13C NMR (101 MHz, DMSO): δ, ppm 194.8, 166.9,97.5, 44.8, 36.5, 29.3, 21.4. Anal. Calcd for C7H11NO: C, 67.2; H, 8.9; N,11.2; Found: C, 67.2; H, 8.8; N, 11.2.
	With ammonia In benzene for 1h; Heating;
	With ammonia In benzene	13 1-Amino-5-methylcyclohex-1-en-3-one Preparation 13 1-Amino-5-methylcyclohex-1-en-3-one 5-Methyl-1,3-cyclohexanedione (40 g, 0.32 mol) was dissolved in 500 ml of benzene at 70° C. The solution was heated at reflux for 2 hours, during which NH3 was bubbled through the reaction mixture and formed H2 O was collected in a Dean-Stark trap. The mixture was then cooled to 0° C. and title product recovered by filtration, 39.8 g, m.p. 165-169° C. 1 H-NMR(DMSO-d6)delta(ppm): 0.98 (s, 3H), 1.6-1.88 (2H), 2.14-2.38 (2H), 3.14-3.6 (1H), 4.93 (s, 1H), 6.2-7.2 (m, 2H).
	With ammonia In benzene	13 1-Amino-5-methylcyclohex-1-en-3-one PREPARATION 13 1-Amino-5-methylcyclohex-1-en-3-one 5-Methyl-1,3-cyclohexanedione (40 g, 0.32 mol) was dissolved in 500 ml of benzene at 70° C. The solution was heated at reflux for 2 hours, during which NH3 was bubbled through the reaction mixture and formed H2 O was collected in a Dean-Stark trap. The mixture was then cooled to 0° C. and title product recovered by filtration, 39.8 g, m.p. 165°-169° C. 1 H-NMR(DMSO-d6)delta(ppm): 0.98 (s, 3H), 1.6-1.88 (2H), 2.14-2.38 (2H), 3.14-3.6 (1H), 4.93 (s, 1H), 6.2-7.2 (m, 2H).
	With ammonium acetate In toluene
	With ammonium acetate In benzene Dean-Stark;

Reference： [1]Gyulavári, Pál; Szokol, Bálint; Szabadkai, István; Brauswetter, Diána; Bánhegyi, Péter; Varga, Attila; Markó, Péter; Boros, Sándor; Illyés, Eszter; Szántai-Kis, Csaba; Krekó, Marcell; Czudor, Zsófia; Őrfi, László [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 19, p. 3265 - 3270]
[2]Chandran; Pise, Ashwini; Shah, Suraj Kumar; Rahul; Suman; Tiwari, Keshri Nath [Organic Letters, 2020, vol. 22, # 16, p. 6557 - 6561]
[3]Current Patent Assignee: VICHEM CHEMIE KUTATO KFT - WO2017/153789, 2017, A1 Location in patent: Page/Page column 12; 21; 22
[4]Amaye, Isis J.; Jackson-Ayotunde, Patrice L.; Martin-Caraballo, Miguel [Bioorganic and Medicinal Chemistry, 2022, vol. 65]
[5]Amaye, Isis J.; Jackson-Ayotunde, Patrice L.; Martin-Caraballo, Miguel [Bioorganic and Medicinal Chemistry, 2022, vol. 65]
[6]Foster, James E.; Nicholson, Jesse M.; Butcher, Raymond; Stables, James P.; Edafiogho, Ivan O.; Goodwin, Angela M.; Henson, Michael C.; Smith, Carlynn A.; Scott [Bioorganic and Medicinal Chemistry, 1999, vol. 7, # 11, p. 2415 - 2425]
[7]Current Patent Assignee: PFIZER INC - US6166031, 2000, A
[8]Current Patent Assignee: PFIZER INC - US5059609, 1991, A
[9]Wu, Ming-Yu; Shaban, Elkhabiry; Switalska, Marta; Wang, Ning; Shimoda, Miho; Mizutani, Yusuke; Yoshida, Megumi; Mei, Zhen-Wu; Kawafuchi, Hiroyuki; Nokami, Junzo; Wietrzyk, Joanna; Yu, Xiao-Qi; Inokuchi, Tsutomu [Heterocycles, 2014, vol. 89, # 6, p. 1427 - 1440]
[10]Amaye, Isis J.; Heinbockel, Thomas; Woods, Julia; Wang, Zejun; Martin-Caraballo, Miguel; Jackson-Ayotunde, Patrice [International Journal of Environmental Research and Public Health, 2018, vol. 15, # 8]

15
[ 67-56-1 ]
[ 4341-24-6 ]
[ 61621-44-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With Fe(OTs)3 at 20℃; for 2h;
95%	With iodine at 20℃; for 0.05h;
93%	With iodine

93%	With titanium tetrachloride In dichloromethane at 20℃; for 8h;	10 3-Methoxy-5-methyl-cyclohex-2-enone 5-methyl-1,3-cyclohexanedione (50 g, 0.36 mol),Methanol (400ml) was added to a 1000ml three-necked flask.After stirring and dissolving, 1M titanium tetrachloride (2.0 g, 0.01 mol) was added dropwiseDichloromethane solution (10.75 ml),After the drop, the reaction was performed at room temperature for 8 hours.The reaction was quenched by the slow addition of water (300 ml), and a 5% NaHCO3 solution (about 80 ml) was added dropwise, extracted with ethyl acetate (200 ml x 3), and the layers were separated. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a light yellow oily liquid.(49.8 g, 93%), used directly in the next step
90%	With titanium tetrachloride In dichloromethane at 20℃; for 0.5h;
85%	With sulfuric acid at 65℃; for 12h;
85%	With sulfuric acid In methanol at 65℃; for 12h;
	With sulfuric acid for 12h; Heating;
	With toluene-4-sulfonic acid

Reference： [1]Mansilla, Horacio; Afonso, Maria M. [Synthetic Communications, 2008, vol. 38, # 15, p. 2607 - 2618]
[2]Bhosale, Rajesh S.; Bhosale, Sidhanath V.; Bhosale, Sheshanath V.; Wang, Tianyu; Zubaidha [Tetrahedron Letters, 2004, vol. 45, # 39, p. 7187 - 7188]
[3]He, Jia; Jia, Zizi; Tan, Hongcheng; Luo, Xiaohua; Qiu, Dachuan; Shi, Jiarong; Xu, Hai; Li, Yang [Angewandte Chemie - International Edition, 2019, vol. 58, # 51, p. 18513 - 18518][Angew. Chem., 2019, vol. 131, p. 18684 - 18689,6]
[4]Current Patent Assignee: JIANGSU AIFAN BIOPHARMACEUTICAL; JIANGNAN UNIVERSITY - CN107383019, 2017, A Location in patent: Paragraph 0126-0129
[5]Clerici, Angelo; Pastori, Nadia; Porta, Ombretta [Tetrahedron, 2001, vol. 57, # 1, p. 217 - 225]
[6]Nicolaou; Vassilikogiannakis, Georgios; Montagnon, Tamsyn [Angewandte Chemie - International Edition, 2002, vol. 41, # 17, p. 3276 - 3281]
[7]Nicolaou; Montagnon, Tamsyn; Vassilikogiannakis, Georgios [Chemical Communications, 2002, # 21, p. 2478 - 2479]
[8]Nicolaou; Montagnon, Tamsyn; Vassilikogiannakis, Georgios; Mathison, Casey J. N. [Journal of the American Chemical Society, 2005, vol. 127, # 24, p. 8872 - 8888]
[9]Location in patent: scheme or table Mandal; Paira; Roy [Journal of Chemical Sciences, 2010, vol. 122, # 3, p. 423 - 426]

16
[ 4341-24-6 ]
[ 478012-54-3 ]
[ 478012-59-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine In tetrahydrofuran at 25℃;
	With triethylamine In tetrahydrofuran at 25℃;

Reference： [1]Nicolaou; Vassilikogiannakis, Georgios; Montagnon, Tamsyn [Angewandte Chemie - International Edition, 2002, vol. 41, # 17, p. 3276 - 3281]
[2]Nicolaou; Montagnon, Tamsyn; Vassilikogiannakis, Georgios; Mathison, Casey J. N. [Journal of the American Chemical Society, 2005, vol. 127, # 24, p. 8872 - 8888]

17
[ 4341-24-6 ]
[ 570377-89-8 ]
[ 570377-90-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine In ethanol at 50℃; for 24h;
88%	With triethylamine In ethanol at 20 - 50℃; for 24h;	2.2 (Step 2) Triethylamine (NEt3 : 2.17 mmols, 1.40 equiv) was added to the compound (IIb) (2.32 mmols, 1.50 equiv) described above in 10 mL of ethanol at room temperature. The solution obtained was warmed at 50°C and stirred for 24 hours at the temperature. After concentrating under reduced pressure, the concentrate was purified by silica gel column chromatography (1:1 hexane/EtOAc) to give the compound (Ib) described above as white foam (1.36 mmol, yield: 88%). The physicochemical properties of the compound (Ib) described above are shown below.1H NMR (400 MHz, CDCl3) δ {1.21 (d, J = 6.4 Hz), 1.23 (d, J = 6.4 Hz), 3H}, 1.28-1.35 (m, 1H), 2.07-2.18 (m, 1H), 2.21-2.31 (m, 1H), 2.50-2.32 (m, 2H), 2.68-2.77 (m, 1H), 3.15-3.24 (m, 1H), 3.61-3.69 (m, 1H), {3.71 (s), 3.73 (s), 3H}, 3.82-3.89 (m, 1H), 3.97-4.05 (m, 1H), 4.14-4.22 (m, 1H), 5.46 (s, 1H), 6.97 (dd, 1H, J = 7.4, 4.8 Hz), 7.38 (dd, 1H, J = 7.4, 4.8 Hz), 7.47 (t, 1H, J = 7.4 Hz)13C NMR (400 MHz, CDCl3) δ 14.1, 15.5, 20.5, 20.7, 25.5, 25.7, 30.2, 30.7, 30.9, 31.0, 46.4, 46.6, 55.8, 55.9, 60.3, 61.2, 67.0, 67.1, 67.1, 67.4, 99.1, 99.4, 111.1, 111.2, 112.2, 115.1, 116.0, 116.1, 118.2, 118.3, 118.4, 127.2, 130.9, 130.9, 138.7, 155.6, 155.7, 157.6, 157.8, 179.7, 179.9, 190.3, 190.5 (this compound is present in a mixing ratio of 1 : 1 as an atropisomer; symbol * indicates the peaks, which became double intensity by the atropisomer.)IR (thin layer) n 2964, 2884, 1694, 1599, 1479, 1446, 1272, 1075, 995.
84%	With 4 A molecular sieve In isopropyl alcohol at 50℃; for 24h;

81%

With 4 A molecular sieve In isopropyl alcohol at 50℃; for 36h;

2.1 (Step 1) The compound (IIb) (4.8 mmols, 1.2 equiv) described above was added to the compound (IIIb) (4.0 mmols, 1.0 equiv) described above in 30 mL of isopropyl alcohol at room temperature. Thereafter, powdered 4Å molecular sieves (4 g, 1 g/mmol) were added to the mixture. The resulting yellow slurry was heated to 50°C and this temperature was maintained for 36 hours. The mixture was cooled to room temperature, then filtered, concentrated and purified by silica gel column chromatography (1:1 hexane/EtOAc). The compound (Ib) described above was obtained as white foam (3.24 mmols, yield: 81%).

Reference： [1]Bode, Jeffrey W.; Hachisu, Yoshifumi; Matsuura, Tomoo; Suzuki, Keisuke [Tetrahedron Letters, 2003, vol. 44, # 17, p. 3555 - 3558]
[2]Current Patent Assignee: JAPAN SCIENCE AND TECHNOLOGY AGENCY - EP1484325, 2004, A1 Location in patent: Page 10
[3]Matsuura, Tomoo; Bode, Jeffrey W.; Hachisu, Yoshifumi; Suzuki, Keisuke [Synlett, 2003, # 11, p. 1746 - 1748]
[4]Current Patent Assignee: JAPAN SCIENCE AND TECHNOLOGY AGENCY - EP1484325, 2004, A1 Location in patent: Page 10

18
[ 4341-24-6 ]
[ 54884-55-8 ]
[ 879219-91-7 ]

Reference： [1]Journal of Chemical Research,2005,p. 454 - 456

19
[ 4341-24-6 ]
[ 17282-00-7 ]
[ 1005499-36-4 ]

Yield	Reaction Conditions	Operation in experiment
79%		In a 100-ml flask connected to a Dean-Stark trap, 2- amino-3-bromo-5-methylpyridine (39.6 mmol, 5.93 g) , 5-methyl- 1, 3-cyclohexanedione (39.6 mmol, 1,25 eq, 5.00 g) , p- toluenesulfonic acid monohydrate (3.17 mmol, 0.1 eq, 603 mg) and toluene (59.3 ml) were mixed, and the mixture was heated to reflux for 7.5 hours. After completion of the reaction, the reaction solution was cooled, a 3% aqueous sodium bicarbonate solution (50 ml) was added thereto, and the mixture was extracted three times with ethyl acetate (50 ml) . The organic layers were combined and concentrated to approximately a half the original amount. Ethyl acetate (250 ml) was added to the concentrate, and the mixture was further concentrated. This operation was performed three times in total, to adjust the concentrated residual amount to about 19 g. The concentrated slurry was stirred with heating for 1 hour, and then stood to cool and ice-cooled. Precipitated crystals were collected by filtration, washed with cold ethyl acetate (20 ml) , and dried under reduced pressure at 50C, to yield the title compound (7.29 g, yield 79%) .1H-NMR (DMSOd6, TMS, 300 MHz): delta (ppm) : 1.01 (3H, d, J = 6.3 Hz), 1.9-2.0 (IH, m) , 2.0-2.4 (3H, m) , 2.26 (3H, s) , 2.5- 2.6 (IH, m), 5.96 (IH, s) , 7.97 (IH, d, J = 1.9 Hz), 8.21 (IH, d, J = 2.0 Hz) , 8.42 (IH, br) .

Reference： [1]Patent: WO2008/16184,2008,A1 .Location in patent: Page/Page column 199-200

20
[ 4341-24-6 ]
[ 934-00-9 ]
C₁₄H₁₄O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With air In phosphate buffer at 20℃; for 20h; Enzymatic reaction;
37%	With laccase from Myceliophthora thermophila; oxygen In aq. phosphate buffer at 20℃; for 24h; Green chemistry;

Reference： [1]Hajdok, Szilvia; Leutbecher, Heiko; Greiner, Gerhard; Conrad, Jürgen; Beifuss, Uwe [Tetrahedron Letters, 2007, vol. 48, # 29, p. 5073 - 5076]
[2]Wellington, Kevin W.; Qwebani-Ogunleye, Tozama; Kolesnikova, Natasha I.; Brady, Dean; De Koning, Charles B. [Archiv der Pharmazie, 2013, vol. 346, # 4, p. 266 - 277]

21
[ 27151-65-1 ]
[ 4341-24-6 ]

Reference： [1]European Journal of Organic Chemistry,2002,p. 189 - 202

22
[ 4341-24-6 ]
[ 111540-00-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: 89 percent / p-TsOH / benzene / 28 h / Heating 2: 1.) Li, NH₃ / 1.) -78 deg C, 2.) THF, 45 deg C, irrad., 3 h 3: 86 percent / N-methylmorpholine, 2,6-di-tert-butyl-4-methylphenol / CH₂Cl₂ / 24 h / 22 °C 4: 46 percent / boron triacetate / CH₂Cl₂ / 20 h
	Multi-step reaction with 4 steps 1: benzene / Heating 2: H₂N(CH₂)2NH₂ / tetrahydrofuran / 24 h / 20 °C 3: N-methylmorpholine / benzene / 24 h / 20 °C 4: 75 percent / boron triacetate / CH₂Cl₂ / 20 °C
	Multi-step reaction with 3 steps 2: tetrahydrofuran / 1 h / -78 °C 3: 75 percent / boron triacetate / CH₂Cl₂ / 20 °C

Multi-step reaction with 3 steps 2: 65 percent / tetrahydrofuran / 20 h / 20 °C 3: 75 percent / boron triacetate / CH₂Cl₂ / 20 °C

Reference： [1]Gould, Steven J.; Cheng, Xing-Chun; Melville, Chris [Journal of the American Chemical Society, 1994, vol. 116, # 5, p. 1800 - 1804]
[2]Guingant, Andre; Barreto, Marie Manuel [Tetrahedron Letters, 1987, vol. 28, # 27, p. 3107 - 3110]
[3]Guingant, Andre; Barreto, Marie Manuel [Tetrahedron Letters, 1987, vol. 28, # 27, p. 3107 - 3110]
[4]Guingant, Andre; Barreto, Marie Manuel [Tetrahedron Letters, 1987, vol. 28, # 27, p. 3107 - 3110]

23
[ 4341-24-6 ]
[ 2003-10-3 ]
[ 708984-73-0 ]

Yield	Reaction Conditions	Operation in experiment
34.6%	With potassium carbonate In chloroform at 20℃;	7 Reference Example 7 Synthesis of 3-hydroxy-5-methyl-2-[2-oxo-2-(3-trifluoromethylphenyl)-ethyl]-cyclohex-2-enone To a chloroform solution (240 mL) of 2-bromo-3'-trifluoromethylacetophenone (63.5 g, 0.238 mol) obtained in Reference Example 6 and 5-methyl-1,3-cyclohexanedione (30 g, 0.238 mol) was added potassium carbonate (32.9 g, 0.238 mol) and stirred at room temperature over night. The reaction liquid was filtered and white solid obtained, which was suspended in distilled water (300 mL), followed by dropwise adding a concentrated HCl solution (300 mL) under ice cooling, extracting with ethyl acetate (700 mL) and ethanol (50 mL), drying with sodium sulfate anhydride, concentration of thus obtained organic layer under reduced pressure, adding ethyl acetate (200 mL) to residue obtained, stirring in suspension at room temperature for 4 hours and filtering off crystal to obtain an objective compound (25.7 mg, 34.6%).1H-NMR (200 MHzFT,TMS,CDCl3) 1.06(3H,d,J=5.9Hz), 1.98-2.63(5H,complex), 3.77(1H,d, J=13.6Hz), 4.29(1H,d,J=13.6Hz), 7.63(1H,brt,J=7.6Hz), 7.87(1H,brd,J=7.8Hz), 8.43-8.52(2H,complex), 9.64(1H,s) MS(ESI) m/z 31.3 [M+H]+
34.6%	Stage #1: 5-methylcyclohexan-1,3-dione; 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone With potassium carbonate In chloroform at 20℃; Stage #2: With hydrogenchloride; water In water at 0℃;
	With hydrogenchloride; potassium carbonate In chloroform; water	R.2 Synthesis of 3-hydroxy-5-methyl-2-[2-oxo-2-(3-trifluoromethylphenyl)ethyl]cyclohex-2-enone Reference Example 2 Synthesis of 3-hydroxy-5-methyl-2-[2-oxo-2-(3-trifluoromethylphenyl)ethyl]cyclohex-2-enone Potassium carbonate (32.9 g, 0.238 mol) was added to a solution of the 2-bromo-3'-trifluoromethylacetophenone obtained in Reference Example 1 (63.5 g, 0.238 mol) and 5-methyl-1,3-cyclohexanedione (30 g, 0.238 mol) in chloroform (240 ml), and the resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered and the white solid obtained was suspended in distilled water (300 ml), followed by adding dropwise thereto concentrated hydrochloric acid (30 ml) under ice-cooling. The resulting mixture was extracted with ethyl acetate (700 ml) and ethanol (50 ml) and the extract solution was dried over anhydrous sodium sulfate. The dried extract solution was filtered and the organic layer thus obtained was concentrated under reduced pressure. To the resulting residue was added ethyl acetate (200 ml), followed by suspending and stirring at room temperature for 4 hours. The crystals were collected by filtration to obtain the desired compound (25.7 g, 34.6%). 1H-NMR(200MHzFT,TMS,CDCl3) 1.06(3H,d,J=5.9Hz),1.98-2.63(5H,complex),3.77(1H,d,J-13.6Hz),4.29(1H,d, J=13.6Hz),7.63(1H,brt,J=7.6Hz),7.87(1H,brd,J=7.8Hz), 8.43-8.52(2H,complex),9.64(1H,s) MS(ESI,POS) m/z 313 [M+H]+

Reference： [1]Current Patent Assignee: NIPPON KAYAKU CO LTD - EP1571148, 2005, A1 Location in patent: Page/Page column 28
[2]Current Patent Assignee: NIPPON KAYAKU CO LTD - WO2005/121105, 2005, A1 Location in patent: Page/Page column 16
[3]Current Patent Assignee: NIPPON KAYAKU CO LTD - EP1757592, 2007, A1

24
[ 4341-24-6 ]
[ 158836-48-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With 4-acetamidobenzenesulfonyl azide; triethylamine In acetonitrile at 0 - 20℃;
	With 4-acetamidobenzenesulfonyl azide; triethylamine In dichloromethane at 20℃; for 1.25h;	55.1 12.25 ml (87.2 mmol; 2.2 eq.) of triethylamine and 8.57 g (35.67 mmol; 0.9 eq.) of 4-acetamidobenzenesulphonylazide are added to a solution of 5 g (39.6 mmol) of 5-methylcyclohexane-1,3-dione in 100 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature, then cooled down to 0° C. and filtered on a silica bed. After concentration under reduced pressure, the solution is washed with 3 times 50 ml of water. The organic phases are combined, dried over sodium sulphate and concentrated. The resulting solid is taken up in ethyl ether followed by filtering and drying under reduced pressure. It is used in the following stage without other purification. MS-LC: MH+=153.49; r.t.=7.21 min.
	With 4-acetamidobenzenesulfonyl azide; triethylamine In dichloromethane at 0 - 20℃; for 1.25h;	55.1 12.25 ml (87.2 mmol; 2.2 eq.) of triethylamine and 8.57 g (35.67 mmol; 0.9 eq.) of 4-acetamidobenzenesulphonylazide are added to a solution of 5 g (39.6 mmol) of 5-methylcyclohexane-1,3-dione in 100 ml of dichloromethane. The reaction mixture is stirred for 75 minutes at ambient temperature, then cooled down to 0° C. and filtered on a silica bed. After concentration under reduced pressure, the solution is washed with 3 times 50 ml of water. The organic phases are combined, dried over sodium sulphate and concentrated. The resulting solid is taken up in ethyl ether followed by filtering and drying under reduced pressure. It is used in the following stage without other purification. MS-LC: MH+=153.49; r.t.=7.21 min.

	With sulfonyl azide Inert atmosphere;
	With 4-toluenesulfonyl azide; 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 5h;
	With 4-acetamidobenzenesulfonyl azide; triethylamine In acetonitrile at 0 - 20℃;

Reference： [1]Chen, Xingpeng; Huang, Zhengshuo; Xu, Jiaxi [Advanced Synthesis and Catalysis, 2021, vol. 363, # 12, p. 3098 - 3108]
[2]Current Patent Assignee: IPSEN SA - US2006/40996, 2006, A1 Location in patent: Page/Page column 29
[3]Current Patent Assignee: IPSEN SA - US2006/281736, 2006, A1 Location in patent: Page/Page column 28-29
[4]Xia, Likai; Lee, Yong Rok [European Journal of Organic Chemistry, 2014, vol. 2014, # 16, p. 3430 - 3442]
[5]Hu, Wangcheng; He, Xinwei; Zhou, Tongtong; Zuo, Youpeng; Zhang, Shiwen; Yang, Tingting; Shang, Yongjia [Organic and Biomolecular Chemistry, 2021, vol. 19, # 3, p. 552 - 556]
[6]Lin, Chih-Yu; Huang, Wan-Wen; Huang, Ying-Ti; Dhole, Sandip; Sun, Chung-Ming [European Journal of Organic Chemistry, 2021, vol. 2021, # 35, p. 4984 - 4992]

25
[ 4341-24-6 ]
[ 106896-48-4 ]
3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9.98 g (67%)		c) 3-(3-Carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one A mixture of <strong>[106896-48-4]methyl 2-bromo-3-aminobenzoate</strong> (10.2 g, 44.3 mM) and 5-methyl-1,3-cyclohexanedione (6.15 g, 48.7 mm) was heated at 125 C. under a stream of nitrogen for 1.5 hours. The resultant solid was triturated with ethyl acetate to afford 9.98 g (67%) of 3-(3-carbomethoxy-2-bromoanilino)-5-methyl-cyclohex-2-en-1-one. 1H NMR (CDCl3) delta 7.55 (m, 2H), 7.35 (dd, J=8 and 8 Hz, 1H), 6.4 (bs, 1H), 5.55 (s, 1H), 3.95 (s, 3H), 2.6-2.0 (m, 5H), 1.15 (d, J=7 Hz, 3H). MS (ES) m/e 338, 340.

Reference： [1]Patent: US6177440,2001,B1

26
[ 4341-24-6 ]
[ 1546-79-8 ]
[ 950908-40-4 ]

Reference： [1]Journal of Fluorine Chemistry,2006,vol. 127,p. 1564 - 1569

27
[ 4341-24-6 ]
[ 75-36-5 ]
[ 96626-00-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With triethylamine In dichloromethane at 20℃; for 3h;	3 To a solution of 5-methyl-cyclohexane-1 ,3-dione (1.01 g, 8.0 mmol) in CH2CI2 (15 mL) was added . triethylamine (1.2 mL, 8.6 mmol) followed by acetyl chloride (0.6 mL, 8.4 mmol). The mixture was stirred at room temperature for 3 hours before washing with water (2x). The aqueous phase was back extracted with EtOAc. The combined organic extracts were concentrated and purified by Biotage (4OS column, 15% acetone/heptane) to provide 5-methyl-3-oxocyclohex-1-enyl acetate (1.2 g, 89%).A mixture of δ-methyl-S-oxocyclohex-i-enyl acetate (1.2 g, 7.1 mmol), CH3CN (15 ml_), triethylamine (2.1 mL) and sodium cyanide (7 mg, 0.1 mmol) was stirred at room temperature overnight. The mixture was concentrated, re-dissolved in EtOAc and acidified with 1 N HCI. The organic phase was isolated , concentrated and purified by Biotage chromatography (4OS column, 8% acetone/heptane) to afford 2- acetyl-5-methylcyclohexane-1 ,3-dione (0.96 g, 96%).A solution of 2-acetyl-5-methylcyclohexane-1 ,3-dione (0.96 g, 5.7 mmol) in methanol (28 mL) containing iodine (2.90 g, 11.4 mmol) was heated at reflux overnight. The mixture was cooled to room temperature and concentrated. The material was dissolved in CH2CI2 and washed with aqueous Na2S2O3 and the aqueous phase was back extracted with CH2CI2 (2x). The combined organic extracts were - concentrated and purified by Biotage chromatography (40 M column, 10% acetone/heptane) to provide the title compound as a pale yellow solid (550 mg, 53%).
75%	With pyridine In chloroform at 20℃; for 16h;	3-Oxocyclohex-1-en-1-yl Acetate (15a). General procedure for the formation of 3-acyloxy-2-cyclohexenones. General procedure: (Compounds 15a-15e are also commercially available.) Acetyl chloride (1.02mL, 14.3mmol) was added to a solution of cyclohexane-1,3-dione (14a, 1.00g, 8.92mmol) and pyridine (1.08ml, 13.4mmol) in CHCl3 (31mL). The reaction mixture was stirred at room temperature for 16h. The mixture was then washed with H2O (30mL), 0.1N HCl (30mL), saturated NaHCO3 (30mL) and H2O (30mL), dried over anhydrous Na2SO4, and evaporated. The residue was purified by silica column chromatography (EtOAc:hexanes 1:2) to afford compound 15a as a yellowish oil (790mg, 58%).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2008/65508, 2008, A1 Location in patent: Page/Page column 24-25
[2]Lee, Jae Chul; Hong, Kwon Ho; Becker, Andreas; Tash, Joseph S.; Schönbrunn, Ernst; Georg, Gunda I. [European Journal of Medicinal Chemistry, 2021, vol. 214]

28
[ 4341-24-6 ]
[ 90-02-8 ]
[ 59666-27-2 ]

Yield	Reaction Conditions	Operation in experiment
82%	With diethylamine In ethanol at 20℃; for 6h;	General procedure: To a well stirred solution of salicylaldehyde, 1 (2 mmol) and appropriate 1,3-dione (2/3/4, 4 mmol) in ethanol (4 mL) was added diethylamine (20 mol%) and stirring continued. Upon completion of the reaction (TLC), the resultant solid was filtered, washed with water, dried, again washed with a hexane-chloroform mixture (9:1 ,v/v) and dried. The resultant product, 5/6/7, was found to be pure for all practical purposes.
	With acetic acid In water at 100℃; for 1h;

Reference： [1]Kupwade, Ravindra V.; Pandit, Kapil S.; Desai, Uday V.; Kulkarni, Makarand A.; Wadgaonkar, Prakash P. [Research on Chemical Intermediates, 2016, vol. 42, # 7, p. 6313 - 6325]
[2]Location in patent: experimental part Sato, Nagaaki; Jitsuoka, Makoto; Shibata, Takunobu; Hirohashi, Tomoko; Nonoshita, Katsumasa; Moriya, Minoru; Haga, Yuji; Sakuraba, Aya; Ando, Makoto; Ohe, Tomoyuki; Iwaasa, Hisashi; Gomori, Akira; Ishihara, Akane; Kanatani, Akio; Fukami, Takehiro [Journal of Medicinal Chemistry, 2008, vol. 51, # 15, p. 4765 - 4770]

29
[ 4341-24-6 ]
[ 358-23-6 ]
[ 1187055-93-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	Synthesis of 5-methyl-3-oxocyclohex-1-enyltrifluoromethanesulfonate Synthesis of 5-methyl-3-oxocyclohex-1-enyltrifluoromethanesulfonate To a solution of 5-methylcyclohexane-1,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2CO3 (1.1 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHCO3 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2SO4, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.86 min, LC=3.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 11H), 2.53 (dd, J=16.6, 3.7, 11H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;	To a solution of 5-methylcyclohexane-1,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2CO3 (1.1 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHCO3 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2SO4, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.86 min, LC=3.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	To a solution of 5-methylcyclohexane-1,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2CO3 (1.1 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHCO3 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2SO4, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.86 min, LC=3.84 min. 1H-NMR (400 MHz, CDCl3) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).

78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	Synthesis of 5-methyl-3-oxocyclohex- 1 -enyltrifluoromethanesulfonate Synthesis of 5-methyl-3-oxocyclohex- 1 -enyltrifluoromethanesulfonate To a solution of 5-methylcyclohexane-l,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2C03 (1.1 equiv.) and cooled to 0 °C. Added Tf20 (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0°C under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHC03 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2S04, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3- oxocyclohex-l-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt = 0.86 min, LC = 3.84 min. 1H-NMR (400 MHz, CDC13) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	Synthesis of 5-methyl-3-oxocvclohex- 1 -enyltrifluoromethanesulfonate Synthesis of 5-methyl-3-oxocvclohex- 1 -enyltrifluoromethanesulfonate To a solution of 5-methylcyclohexane-l,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2C03 (1.1 equiv.) and cooled to 0 °C. Added Tf20 (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0°C under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHC03 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2S04, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3- oxocyclohex-l-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt = 0.86 min, LC = 3.84 min. 1H-NMR (400 MHz, CDC13) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	Synthesis of 5-methyl-3-oxocyclohex- 1 -enyltrifluoromethanesulfonate To a solution of 5-methylcyclohexane-l,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2C03 (1.1 equiv.) and cooled to 0 °C. Added Tf20 (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0°C under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHC03 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2S04, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3- oxocyclohex-l-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt = 0.86 min, LC = 3.84 min. 1H-NMR (400 MHz, CDC13) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	Synthesis of 5-methyl-3-oxocyclohex- 1 -enyltrifluoromethanesulfonate Synthesis of 5-methyl-3-oxocyclohex- 1 -enyltrifluoromethanesulfonate To a solution of 5-methylcyclohexane-l,3-dione (1.0 equiv.) in DCM (0.5M) was added Na2C03 (1.1 equiv.) and cooled to 0 °C. Added Tf20 (1.0 equiv.) in DCM (5.0 M) dropwise over 1 hr at 0°C under a nitrogen atmosphere. Upon addition, the reaction was stirred for 1 hr at room temperature (dark red solution). The solution was filtered and the filtrate was quenched by careful addition of saturated NaHC03 with vigorous stirring until pH=7. The solution was transferred to a separatory funnel and the layers were separated. The organic layer was washed with brine, dried with Na2S04, filtered, concentrated under vacuo and dried under high vacuum for 15 min to yield 5-methyl-3- oxocyclohex-l-enyl trifluoromethanesulfonate as light yellow oil in 78% yield. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt = 0.86 min, LC = 3.84 min. 1H-NMR (400 MHz, CDC13) δ ppm: 6.05 (s, 1H), 2.70 (dd, J=17.2, 4.3, 1H), 2.53 (dd, J=16.6, 3.7, 1H), 2.48-2.31 (m, 2H), 2.16 (dd, J=16.4, 11.7, 1H), 1.16 (d, J=5.9, 3H).
78%	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;
67%	With sodium carbonate In dichloromethane at 0 - 20℃; Inert atmosphere;	Synthesis of 5-methyl-3-oxocyclohex-1-enyltrifluoromethanesulfonate To a solution of 5-methylcyclohexane-1,3-dione (1 equiv) in DCM (0.4M) was added Na2CO3 (1.0 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 2 hr at room temperature (dark red solution). The solution was filtered and to the filtrate was added saturated NaHCO3 (carefully), then extracted the organics, dried with brine, then Na2SO4, and concentrated. The crude was purified via SiO2 column chromatography eluting with DCM and hexanes (1:1) or alternatively via a neutral alumina plug eluting with DCM to afford 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate in 30% or 67% yield respectively. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.94 min, LC=3.84 min
67%	With sodium carbonate In dichloromethane at 0 - 20℃; for 3h;	To a solution of S-methylcyclohexane-l^-dione (1 equiv) in DCM (0.4M) was added Na2CO3 (1.0 equiv.) and cooled to O0C. Added Tf2O (1.0 equiv.) in DCM (5M) dropwise over 1 hr at O0C under a nitrogen atmosphere. Upon addition, the reaction was stirred for 2 hr at room temperature (dark red solution). The solution was filtered and to the filtrate was added saturated NaHCO3 (carefully), then extracted the organics, dried with brine, then Na2SO4, and concentrated. The crude was purified via SiO2 column chromatography eluting with DCM and hexanes (1 : 1) or alternatively via a neutral alumina plug eluting with DCM to afford 5-methyl-3-oxocyclohex-l-enyl trifluoromethanesulfonate in 30% or 67% yield respectively. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt = 0.94 min, LC = 3.84 min.
	With sodium carbonate In dichloromethane at 0 - 30℃; for 2h;	83.1 Step 1. 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate Step 1. 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate To a mixture of 5-methylcyclohexane-1,3-dione (8.00 g, 63.4 mmol) in DCM (100 mL) was added sodium carbonate (7.39 g, 69.8 mmol). The mixture was cooled at 0° C. and a solution of trifluoromethanesulfonic anhydride (10.7 mL, 63.4 mmol) in DCM (100 mL) was added dropwise over 1 h at 0° C. The reaction mixture was stirred at room temperature for 1 h. The solution was filtered and the filtrate was quenched by careful addition of saturated NaHCO3 until pH=7. The organic layer was washed with water and brine and dried over Na2SO4, then filtered. The filtrate was concentrated under reduced pressure to afford the sub-title compound as a light yellow oil. The material was used for the next step without further purification. LCMS calc. for C8H10F3O4S (M+H)+ m/z: 259.0. found: 259.1.
	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h;	1 Step 1. 5-Methyl-3-oxocyclohex-l-en-l-yl trifluoromethanesulfonate To a solution of 5-methylcyclohexane-l,3-dione (50.1 g, 397 mmol) in DCM (700 mL) was added a2C03 (46.3 g, 437 mmol) and the resulting mixture was cooled to 0 °C. A solution of trifluoromethanesulfonic anhydride (66.8 mL, 397 mmol) in DCM (600 mL) was added dropwise over 1 h at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solution was filtered and the filtrate was quenched by careful addition of saturated aq. NaHC03 to pH = 7. The organic layer was washed with water, brine, dried over a2S04 and concentrated under reduced pressure to give the sub-title product as light yellow oil, which was used for next step without further purification. LCMS calc. for C8H10F3O4S (M+H)+: m/z = 259.0; Found: 259.1.
	With sodium carbonate In dichloromethane at 0 - 20℃; for 3h;	5.1 Step 1. 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate To a solution of 5-methylcyclohexane-l,3-dione (50.1 g, 397 mmol) in DCM (700 mL) was added Na2C03 (46.3 g, 437 mmol) and the resulting mixture was cooled to 0 °C. A solution of trifluoromethanesulfonic anhydride (66.8 mL, 397 mmol) in DCM (600 mL) was added dropwise over 1 h at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solution was filtered and the filtrate was quenched by careful addition of saturated aq. NaHCC to pH = 7. The organic layer was washed with water, brine, dried over Na2S04 and concentrated under reduced pressure to give the sub-title product as light yellow oil, which was used for next step without further purification. LCMS calc. for CsHioFsC S (M+H)+: m/z = 259.0; Found: 259.1.
	With sodium carbonate In dichloromethane at 0 - 20℃; for 3h;	1 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate To a solution of 5-methylcyclohexane-l ,3-dione (50.1 g, 397 mmol) in dichloromethane (DCM) (700 mL) was added sodium carbonate (46.3 g, 437 mmol) and the resulting mixture was cooled to 0 °C. A solution of trifluoromethanesulfonic anhydride (66.8 mL, 397 mmol) in DCM (600 mL) was added to the reaction flask drop wise over 1 h at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The solution was filtered and the filtrate was quenched by careful addition of saturated NaHC03 (aq) to reach pH=7. The organic layer was washed with water, brine, then dried over Na2S04 and concentrated to give product as a light yellow oil which was used in the next step without purification. LCMS calculated for C8H10F3O4S (M+H)+: m/z = 259.0; Found: 259.1
	With sodium carbonate In dichloromethane at 0 - 20℃; for 2h; Inert atmosphere;	22 5-Methyl-3-oxocyclohex-1-en-1-yl trifluoromethanesulfonate: At 0 °C, to a solution of 5-methylcyclohexane-1,3-dione (4.90 g, 38.84 mmol) in dichioromethane (100 mL) was added sodium carbonate (4.39 g, 41.41 mmol), to which was added a solution of Tf20 (11.73 g, 41.58 mmol) in dichloromethane (10 mL) dropwise over 30 mm period. The resulting solution was stirred for 2 h at room temperature. When the reaction was done, it was quenched by the addition of sat. sodium bicarbonate solution (500 mL). The resulting mixture was extracted with DCM (300 mL x 3). The organic phases were combined, washed with brine and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography eluting with DCM in hexane (0% to 50% gradient) to yield 5-methyl-3- oxocyclohex-1-en-1-yl trifluoromethanesulfonate as yellow oil (5.00 g, crude). MS: m/z = 258.8 [M+Hj .

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2010/56576, 2010, A1 Location in patent: Page/Page column 23
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2012/225062, 2012, A1 Location in patent: Page/Page column 18
[3]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2012/225061, 2012, A1 Location in patent: Page/Page column 14
[4]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2013/175388, 2013, A1 Location in patent: Page/Page column 86-87
[5]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - WO2014/33631, 2014, A1 Location in patent: Page/Page column 31-32
[6]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2014/33630, 2014, A1 Location in patent: Page/Page column 28; 38
[7]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2014/99880, 2014, A1 Location in patent: Page/Page column 113
[8]Burger, Matthew T.; Nishiguchi, Gisele; Han, Wooseok; Lan, Jiong; Simmons, Robert; Atallah, Gordana; Ding, Yu; Tamez, Victoriano; Zhang, Yanchen; Mathur, Michelle; Muller, Kristine; Bellamacina, Cornelia; Lindvall, Mika K.; Zang, Richard; Huh, Kay; Feucht, Paul; Zavorotinskaya, Tatiana; Dai, Yumin; Basham, Steve; Chan, Julie; Ginn, Elaine; Aycinena, Alex; Holash, Jocelyn; Castillo, Joseph; Langowski, John L.; Wang, Yingyun; Chen, Min Y.; Lambert, Amy; Fritsch, Christine; Kauffmann, Audry; Pfister, Estelle; Vanasse, K. Gary; Garcia, Pablo D. [Journal of Medicinal Chemistry, 2015, vol. 58, # 21, p. 8373 - 8386]
[9]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2010/216839, 2010, A1 Location in patent: Page/Page column 34
[10]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2009/109576, 2009, A1 Location in patent: Page/Page column 79
[11]Current Patent Assignee: INCYTE CORP - US2015/57265, 2015, A1 Location in patent: Paragraph 1145; 1146
[12]Current Patent Assignee: INCYTE CORP - WO2016/10897, 2016, A1 Location in patent: Page/Page column 91
[13]Current Patent Assignee: INCYTE CORP - WO2016/196244, 2016, A1 Location in patent: Page/Page column 76
[14]Current Patent Assignee: INCYTE CORP - WO2017/59251, 2017, A1 Location in patent: Page/Page column 47
[15]Current Patent Assignee: MERCK KGAA - WO2018/31434, 2018, A1 Location in patent: Paragraph 00198; 00419

30
[ 4341-24-6 ]
[ 17356-08-0 ]
[ 375825-03-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 5-methylcyclohexan-1,3-dione With bromine; sodium acetate; acetic acid at 15 - 20℃; Stage #2: thiourea at 100℃; for 1h;	A.04.B 5-Methyl-cyclohexane- 1,3-dione (70.0 g, 0.555 mol) and NaOAc (68.3 g, 0.832 mol) are suspended in AcOH (700 mL) and Br2 (88.7 g, 0.555 mol) is added drop-wise while maintaining the reaction temperature between 15 and 20 0C. After complete addition, the reaction is stirred at RT overnight. Thiourea (42.2 g, 0.555 mol) is added in portions and the reaction mixture is heated to 100 0C for 1 h. After cooling to RT, the AcOH is removed in vacuo. The resulting crude product is diluted with water (1 L), adjusted to pH = 7 with NaHCO3 solution (3 M) and the resulting mixture is extracted with EtOAc (3 x 1 L). The organic phase is washed with brine and dried over anhydrous Na2SO4. The solvent is evaporated in vacuo and the residue is recrystallized from hexane to give 2-amino-5- methyl-5,6-dihydro-4H-benzothiazol-7-one (87.2 g, 86 % yield).1H NMR: (400 MHz, DMSO-J6) δ 8.09 (br s, 2H), 2.77-2.72 (m, IH), 2.39-2.13 (m, 4H), 1.03 (d, J= 6.0 Hz, 3H).

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2010/122091, 2010, A1 Location in patent: Page/Page column 15

31
[ 4341-24-6 ]
[ 895042-86-1 ]
[ 903458-25-3 ]

Reference： [1]Russian Chemical Bulletin,2009,vol. 58,p. 1034 - 1040

32
[ 4341-24-6 ]
[ 895042-86-1 ]
[ 1241965-82-1 ]

Reference： [1]Russian Chemical Bulletin,2009,vol. 58,p. 1034 - 1040

33
[ 87212-60-0 ]
[ 4341-24-6 ]
[ 1313876-93-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With PEG-stabilized Ni nanoparticles In ethylene glycol at 20℃; for 0.166667h;	General procedure for the enol lactonization of 3 with active methylenes (4) to yield the corresponding enol lactone derivatives (5-8) General procedure: In a typical experiment, 5-arylidene Meldrum's acid (3, 2 mmol) was added to a well stirred dispersion of nickel nanoparticles in ethylene glycol [2 mL of dispersion (0.0235 wt % of Ni)/0.1 g of 1] in a 25 mL R.B. flask. Dimedone (4a, 2 mmol) was added and the stirring was continued. The progress of the reaction was monitored by TLC using petroleum ether/ethyl acetate (60:40, v/v) as eluent. Upon complete formation of 5, the solid product was filtered at pump, washed with water, dried and recrystallised from hot ethanol. 7,7-Dimethyl-4-aryl-4,6,7,8-tetrahydro-3H-chromene-2,5-dione was obtained as identified by its mp and spectral data.