Name: 39971-65-8|Zinc(II) trifluoromethanesulfinate|98%
Brand: Ambeed
SKU: A814305
Rating: 95 (29 reviews)

1
[ 421-17-0 ]
[ 39971-65-8 ]
[ 358-15-6 ]

Yield	Reaction Conditions	Operation in experiment
	5 d;
	In diethyl ether byproducts: ZnCl2; 25-31°C;
	In diethyl ether byproducts: ZnCl2; 25-31°C;

Reference： [1]Haszeldine, R. N.; Kidd, J. M. [Journal of the Chemical Society][Journal of the Chemical Society, 1955, p. 2901 - 2910]
[2]Haszeldine, R. N.; Kidd, J. M. [Journal of the Chemical Society][Journal of the Chemical Society, 1955, p. 2901 - 2910]
[3]Block; Weidner [Nature, 1967, vol. 214, # 5087, p. 478 - 479] Weidner, J. P.; Block, S. S. [Journal of Medicinal Chemistry, 1967, vol. 10, p. 1167 - 1170]
[4][Gmelin Handbuch der Anorganischen Chemie, Gmelin Handbook: F: PerFHalOrg.1, 1.1.6.5.2, page 157 - 193]
[5][Gmelin Handbuch der Anorganischen Chemie, Gmelin Handbook: F: PerFHalOrg.2, 1.2, page 50 - 76]
[6][Gmelin Handbuch der Anorganischen Chemie, Gmelin Handbook: F: PerFHalOrg.2, 1.3.7, page 182 - 182]

2
[ 39971-65-8 ]
[ 6493-05-6 ]
[ 1346252-46-7 ]

Reference： [1]Nature,2012,vol. 491,p. 95 - 99
[2]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

3
C₁₁H₁₆BNO₂*ClH [ No CAS ]
[ 39971-65-8 ]
[ 1036990-42-7 ]

Reference： [1]Nature,2012,vol. 491,p. 95 - 99

4
[ 6622-91-9 ]
[ 39971-65-8 ]
[ 1008737-00-5 ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide; In dichloromethane; water; at 0 - 20℃; for 12h;	2- (2-(difluoromethyl)-6-(trifluoromethyl)pyridin-4-yl)acetic acid (33): To a vigorously stirred solution of 4-pyridylacetic acid hydrochloride (110 mg, 0.634 mmol, 1.0 equiv) and zinc trifluoromethanesulfinate (TFMS; 413 mg, 1.25 mmol, 2.0 equiv) in DCM (2.5 mL) and water (1.0 mL) at 0 C was added tert-butyl hydroperoxide (70% solution in water, 255 muL, 1.8 mmol, 2.8 equiv) dropwise via Eppendorf pipette. The reaction mixture was stirred at room temperature for 12 hours followed by removal of the organic layer by pipette. The organic layer was dried over magnesium sulfate, filtered, concentrated in vaouo, precipitated with hexanes, decanted, and further dried in vacuo. To a vigorously stirred, uniform suspension of the crude product and zinc difluoromethanesulfinate (DEMS; 92 mg, 0.31 mmol, 0.50 equiv) in perfluorotoluene (2.5 niL) and water (1.0 mL) at 0 C was added tert-butyl hydroperoxide (70% solution in water, 64 pL, 0.45 mmol, 0.70 equiv) dropwise via Eppendorf pipette. The reaction mixture was stirred at 50 C for 6 hours, cooled to 0 C then charged with a second addition of reagents DFMS (92 mg, 0.31 mmol, 0.50 equiv) and tert-butyl hydroperoxide (70% solution in water, 64 muL, 0.45 minol, 0.70 equiv) The reaction mixture was stirred for an additional 12 hours at 50 C followed by cooling to 0 C , charging with a third addition of DFMS (372 mg, 1.26 mmol, 2.0 equiv) and tert-butyl hydroperoxide (70% solution in water, 255 muL, 1.8 mmol, 2.8 equiv) then stirred an additional 6 hours at 50 C. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3 (15 nI), extracted with EtOAc (3 x 15 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC eluting with 50% Et20/hexanes to provide 33 (31 mg, 20%) as a white solid; Rf = 0.70 (50% Et2O/hexanes +1% AcOH); m.p. = 73-78 00; 1H-NMR (400 MHz, CDCl3) delta 7.79 (s, 1 H), 7.75 (s, 1 H), 6.69Ct, J = 54.9 Hz, 1 H), 3.85 (s, 2 H); 13C-NMR (150MHz, CDCl3) delta 174.2, 154.0 (t, JCF = 27.1 Hz), 148.6(q, JCF = 35.5 Hz), 146.0, 124.0, 123.4 (q, JCF = 2.7Hz), 121.1 (q, JCF = 274.3 Hz), 113.2 (t, JCF = 241.5Hz), 40.2; 19F-NMR (376 MHz, CDCl3) delta -68.3, -116.1; IR (neat) 3102, 1716, 1414, 1337, 1244, 1126,1037, 918 cm?; HRMS (ESI-TOF) calc?d for C9H7F5NO2 [M+H] 256.0391; found 256.0388.

Reference： [1]Nature,2012,vol. 491,p. 95 - 99
[2]Patent: WO2013/82028,2013,A1 .Location in patent: Page/Page column 50

5
[ 38940-62-4 ]
[ 39971-65-8 ]
[ 1346252-30-9 ]
[ 1260664-97-8 ]

Reference： [1]Nature,2012,vol. 491,p. 95 - 99

6
[ 14080-23-0 ]
[ 39971-65-8 ]
[ 1206459-86-0 ]
[ 944905-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In water at 25℃; Overall yield = 42 %;

Reference： [1]Fujiwara, Yuta; Dixon, Janice A.; O'Hara, Fionn; Funder, Erik Daa; Dixon, Darryl D.; Rodriguez, Rodrigo A.; Baxter, Ryan D.; Herle, Bart; Sach, Neal; Collins, Michael R.; Ishihara, Yoshihiro; Baran, Phil S. [Nature, 2012, vol. 491, # 7427, p. 95 - 99]

7
[ 1722-10-7 ]
[ 39971-65-8 ]
[ 1416821-58-3 ]

Yield	Reaction Conditions	Operation in experiment
45%	With tert.-butylhydroperoxide In dichloromethane; water at 25℃;

Reference： [1]Fujiwara, Yuta; Dixon, Janice A.; O'Hara, Fionn; Funder, Erik Daa; Dixon, Darryl D.; Rodriguez, Rodrigo A.; Baxter, Ryan D.; Herle, Bart; Sach, Neal; Collins, Michael R.; Ishihara, Yoshihiro; Baran, Phil S. [Nature, 2012, vol. 491, # 7427, p. 95 - 99]

8
[ 58-08-2 ]
[ 39971-65-8 ]
1,3,7-trimethyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With tert.-butylhydroperoxide In dichloromethane; water at 25℃;
66%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 8h; Electrochemical reaction;

Reference： [1]Fujiwara, Yuta; Dixon, Janice A.; O'Hara, Fionn; Funder, Erik Daa; Dixon, Darryl D.; Rodriguez, Rodrigo A.; Baxter, Ryan D.; Herle, Bart; Sach, Neal; Collins, Michael R.; Ishihara, Yoshihiro; Baran, Phil S. [Nature, 2012, vol. 491, # 7427, p. 95 - 99]
[2]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

9
[ 39971-65-8 ]
[ 3430-22-6 ]
[ 1010422-51-1 ]
[ 1448776-80-4 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

10
[ 1620-75-3 ]
[ 39971-65-8 ]
[ 1448776-81-5 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

11
[ 39971-65-8 ]
[ 29681-43-4 ]
[ 1448776-91-7 ]
[ 1448776-92-8 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

12
[ 39971-65-8 ]
[ 33252-29-8 ]
6-chloro-3-(trifluoromethyl)pyridine-2-carbonitrile [ No CAS ]
[ 1448776-89-3 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

13
[ 33252-28-7 ]
[ 39971-65-8 ]
[ 1245913-20-5 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

14
[ 39971-65-8 ]
[ 83164-33-4 ]
[ 1448777-09-0 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

15
[ 39971-65-8 ]
[ 738-70-5 ]
[ 1448777-10-3 ]

Yield	Reaction Conditions	Operation in experiment
35%	With tert.-butylhydroperoxide; bis-(((isopropyl)sulfinyl)oxy)zinc; zinc sulfinate In chloroform; water at 20 - 50℃; for 14h; regioselective reaction;

Reference： [1]O'Hara, Fionn; Blackmond, Donna G.; Baran, Phil S. [Journal of the American Chemical Society, 2013, vol. 135, # 32, p. 12122 - 12134]

16
[ 39971-65-8 ]
[ 59718-84-2 ]
[ 1448777-26-1 ]
[ 1360967-65-2 ]
[ 1448777-27-2 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

17
[ 39971-65-8 ]
[ 65719-09-7 ]
[ 198401-84-2 ]
[ 205582-88-3 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

18
[ 583-58-4 ]
[ 39971-65-8 ]
[ 1448776-76-8 ]
[ 100696-00-2 ]

Yield	Reaction Conditions	Operation in experiment
1: 36% 2: 22%	With tert.-butylhydroperoxide; bis-(((isopropyl)sulfinyl)oxy)zinc; zinc sulfinate In chloroform; water at 20 - 50℃; for 12h; Overall yield = 58 %; regioselective reaction;

Reference： [1]O'Hara, Fionn; Blackmond, Donna G.; Baran, Phil S. [Journal of the American Chemical Society, 2013, vol. 135, # 32, p. 12122 - 12134]

19
[ 3430-17-9 ]
[ 39971-65-8 ]
[ 1211525-93-7 ]
[ 1448776-78-0 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

20
[ 39971-65-8 ]
[ 26256-72-4 ]
[ 1448776-86-0 ]

Reference： [1]Journal of the American Chemical Society,2013,vol. 135,p. 12122 - 12134

21
2-[4-(1-hydroxy-1-methylethyl)phenyl]-7-methyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one [ No CAS ]
[ 39971-65-8 ]
2-[4-(1-hydroxy-1-methylethyl)phenyl]-7-trifluoromethyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In dichloromethane; water; dimethyl sulfoxide at 20℃; for 18h; Cooling with ice;	12 Example 12 Synthesis of 2-[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]-7-trifluoromethyl-3H- pyrrolo[2,1-f][1 ,2,4]triazin-4-one ("A20") Example 12 Synthesis of 2-[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]-7-trifluoromethyl-3H- pyrrolo[2,1-f][1 ,2,4]triazin-4-one ("A20") To a suspension of 2-[4-(1 -hydroxy-1 -methyl-ethyl)-phenyl]-3H-pyrrolo[2,1- f][1 ,2,4]triazin-4-one (135 mg, 0.50 mmol) and bis(trifluoromethylsulfinyloxy)- zinc (497 mg, 1.50 mmol) in a biphasic mixture of dichloromethane (2.0 ml) and water (0.8 ml) is added tert-butyl hydroperoxide (70% solution in water, 342 μΙ, 2.50 mmol) under external cooling with ice. The mixture is allowed to reach room temperature. Dimethyl sulfoxide (1.0 ml) is added and the mixture is stirred for 18 hours at room temperature. The reaction mixture is diluted with dichloromethane and saturated sodium hydrogen carbonate solution is added. The solid is filtered off and the organic phase of the filtrate is separated. The aqueous phase of the filtrate is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 2-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-7-trifluoromethyl-3H- pyrrolo[2,1-f][1 ,2,4]triazin-4-one as white powder; HPLC/MS 1.89 min (C), [M+H] 338; H N R (400 MHz, DMSO-d6) δ [ppm] 12.43 (s, 1H), 7.95 - 7.88 (m, 2H), 7.69 - 7.62 (m, 2H), 7.12 (d, J = 4.6 Hz, 1H), 7.03 (d, J = 4.6 Hz, 1H), 5.18 (s, 1H), 1.47 (s, 6H).

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2013/164061, 2013, A1 Location in patent: Page/Page column 71-72

22
4-[3-iodo-1-(1-phenylethyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethylisoxazole [ No CAS ]
[ 39971-65-8 ]
4-[3-iodo-1-(1-phenylethyl)-2-(trifluoromethyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethylisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6 mg	With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 50℃; Cooling with ice;	38 Preparation of 4-[3-iodo-l-(l-phenylethyl)-2-(trifluoromethyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5- dimethyl-isoxazole P-0245 To 4-[3-iodo- l-(l-phenylethyl)pyrrolo[3,2-b]pyridin-6-yl]-3,5-dimethyl-isoxazole (P-0224, 100 mg, 0.23 mmol) and zinc trifluoromethanesulfinate (149.58 mg, 0.45 mmol) was added DMSO (1 ml) followed by water (0.4 ml).The reaction was cooled in an ice bath and tert-butyl hydroperoxide (0.095 ml, 0.75 mmol) was added dropwise (1 min addition time). The reaction was removed from the ice bath and allowed to warm to room temperature and then placed in an oil bath at 50 °C and allowed to stir overnight. After overnight, a second addition of zinc trifluoromethanesulfinate (140 mg, 0.42 mmol) followed by the addition of tert-butyl hydroperoxide (0.095 ml, 0.75 mmol) was performed at room temperature. The reaction was placed in an oil bath at 50 °C for an additional 12 hours. The reaction was extracted with saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted 3 more times with 10 mL portions of ethyl acetate. The organic layers were combined and the volatiles were removed by rotary evaporation to provide the crude product that was purified by flash chromatography (5-60% ethyl acetate in hexanes). Fractions containing desired product were all impure, so they were combined and the desired product was purified by reverse phase HPLC. This provided 6 mg of desired product P-0245 as an off-white solid after lyophilization. MS (ESI) [M+H+]+ = 512.1

Reference： [1]Current Patent Assignee: OPNA IMMUNO-ONCOLOGY SA - WO2014/145051, 2014, A1 Location in patent: Paragraph 0284

23
[ 17289-19-9 ]
[ 39971-65-8 ]
methyl 1-methyl-5-(trifluoromethyl)-1H-imidazole-4-carboxylate [ No CAS ]
methyl 1-methyl-2-(trifluoromethyl)-1H-imidazole-4-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

24
[ 39971-65-8 ]
[ 66121-69-5 ]
1-methyl-5-(trifluoromethyl)-1H-imidazole-4-carbonitrile [ No CAS ]
1-methyl-2-(trifluoromethyl)-1H-imidazole-4-carbonitrile [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

25
[ 62366-53-4 ]
[ 39971-65-8 ]
methyl 1-methyl-5-(trifluoromethyl)-1H-imidazole-2-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

26
[ 62366-53-4 ]
[ 39971-65-8 ]
methyl 1-methyl-5-(trifluoromethyl)-1H-imidazole-2-carboxylate [ No CAS ]
methyl 1-methyl-4-(trifluoromethyl)-1H-imidazole-2-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

27
[ 3034-41-1 ]
[ 39971-65-8 ]
1-methyl-4-nitro-5-(trifluoromethyl)-1H-imidazole [ No CAS ]
1-methyl-2-(trifluoromethyl)-4-nitro-1H-imidazole [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

28
[ 39971-65-8 ]
[ 17289-20-2 ]
methyl 1-methyl-2-(trifluoromethyl)-1H-imidazole-5-carboxylate [ No CAS ]
methyl 1-methyl-4-(trifluoromethyl)-1H-imidazole-5-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

29
[ 39971-65-8 ]
[ 443-48-1 ]
C₇H₈F₃N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 8h; Electrochemical reaction;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

30
[ 39971-65-8 ]
[ 5952-93-2 ]
methyl 1-methyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

31
[ 146941-72-2 ]
[ 39971-65-8 ]
4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-amine [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

32
[ 1072-83-9 ]
[ 39971-65-8 ]
[ 1346252-16-1 ]
1-(3,5-bis(trifluoromethyl)-1H-pyrrol-2-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 60% 2: 12%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 6h; Electrochemical reaction;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

33
[ 39971-65-8 ]
[ 13138-76-6 ]
methyl 1-methyl-4-nitro-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 6h; Electrochemical reaction;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

34
[ 39971-65-8 ]
[ 433267-55-1 ]
ethyl 4-bromo-5-(trifluoromethyl)-1H-pyrrole-2-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

35
[ 932-62-7 ]
[ 39971-65-8 ]
[ 1416821-59-4 ]

Yield	Reaction Conditions	Operation in experiment
36%	With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 20℃; for 8h;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

36
[ 932-62-7 ]
[ 39971-65-8 ]
[ 1416821-59-4 ]
1-(1-methyl-2,5-bis(trifluoromethyl)-1H-pyrrol-3-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 55% 2: 7%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 6h; Electrochemical reaction; Overall yield = 62 %;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

37
[ 2199-43-1 ]
[ 39971-65-8 ]
[ 1414887-27-6 ]

Yield	Reaction Conditions	Operation in experiment
29%	With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 20℃; for 8h;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

38
[ 2199-43-1 ]
[ 39971-65-8 ]
[ 1414887-27-6 ]
ethyl 3,5-bis(trifluoromethyl)-1H-pyrrole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 65% 2: 27%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 6h; Electrochemical reaction; Overall yield = 92 %; Overall yield = 375 mg;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

39
[ 2199-49-7 ]
[ 39971-65-8 ]
C₉H₁₀F₃NO₂ [ No CAS ]
ethyl 4-methyl-5-(trifluoromethyl)-1H-pyrrole-3-carboxylate [ No CAS ]
ethyl 4-methyl-2,5-bis(trifluoromethyl)-1H-pyrrole-3-carboxylate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

40
[ 7461-50-9 ]
[ 39971-65-8 ]
[ 24101-09-5 ]

Yield	Reaction Conditions	Operation in experiment
36%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 8h; Electrochemical reaction;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

41
[ 39971-65-8 ]
[ 66-22-8 ]
[ 54-20-6 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

42
[ 3770-50-1 ]
[ 39971-65-8 ]
ethyl 3-(trifluoromethyl)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 8h; Electrochemical reaction;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

43
[ 39971-65-8 ]
[ 1196-57-2 ]
[ 58457-64-0 ]

Yield	Reaction Conditions	Operation in experiment
40%	With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 20℃; for 8h;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

44
[ 25676-75-9 ]
[ 39971-65-8 ]
4-bromo-1-methyl-5-(trifluoromethyl)-1H-imidazole hydrochloride [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 11868 - 11871
Angew. Chem.,2014,vol. 126,p. 12062 - 12065,4

45
[ 2386-25-6 ]
[ 39971-65-8 ]
1-(2,4-dimethyl-5-(trifluoromethyl)-1H-pyrrol-3-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With tetraethylammonium perchlorate In dimethyl sulfoxide at 20℃; for 6h; Electrochemical reaction;

Reference： [1]O-Brien, Alexer G.; Maruyama, Akinobu; Inokuma, Yasuhide; Fujita, Makoto; Baran, Phil S.; Blackmond, Donna G. [Angewandte Chemie - International Edition, 2014, vol. 53, # 44, p. 11868 - 11871][Angew. Chem., 2014, vol. 126, # 44, p. 12062 - 12065,4]

46
tasocitinib [ No CAS ]
[ 39971-65-8 ]
3-[(3R,4R)-4-methyl-3-{methyl[5-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidin-4 yl]amino}-piperidin-1-yl]-3-oxopropanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With tert.-butylhydroperoxide In dichloromethane; water at 0 - 55℃; Sealed tube;

Reference： [1]Gehringer, Matthias; Forster, Michael; Pfaffenrot, Ellen; Bauer, Silke M.; Laufer, Stefan A. [ChemMedChem, 2014, vol. 9, # 11, p. 2516 - 2527]

47
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.02,6]octadeca-1⁽¹⁸⁾,2⁽⁶⁾,4,14,16-pentaen-8-one trifluoroacetate [ No CAS ]
[ 39971-65-8 ]
(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3-triazol-1-yl)phenyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyrimidin-1-yl}-3,9-dimethyl-3,4,7,15-tetraazatricyclo[12.3.1.02,6]octadeca-1⁽¹⁸⁾,2⁽⁶⁾,4,14,16-pentaen-8-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With trifluoroacetic acid In water; dimethyl sulfoxide; <i>tert</i>-butyl alcohol for 3.5h;	120 Example 120Preparation of (9R, 135)- 13- {4-[5-chloro-2-( 1 H-i ,2,3-triazol- 1 -yl)phenyl]-6-oxo-5-(trifluoromethyl)- 1 ,6-dihydropyrimidin- 1 -yl} -3 ,9-dimethyl-3 ,4,7, 15 -tetraazatricyclo[12.3.1 .02’6]octadeca- 1(1 8),2(6),4, 14,1 6-pentaen-8-one A TFA/DMSO solution was prepared by dissolving TFA (10 iL) in DMSO (2.5 mL). To a separate vial containing a mixture of(9R,13S)-13-{4-[5-chloro-2-(1H-1,2,3- triazol- 1 -yl)phenyl]-6-oxo- 1 ,6-dihydropyrimidin- 1 -yl} -3 ,9-dimethyl-3 ,4,7,15-tetraazatricyclo [12.3.1 .02,6]octadeca- 1(1 8),2(6),4, 14,1 6-pentaen-8-one trifluoroacetate (0.0084 g, 0.013 mmol), prepared as described in Example 133, and Zn(SO2CF3)2 (8.31 mg, 0.025 mmol) was added DMSO (0.25 mL). Next, 0.25 mL of the TFA/DMSO solution was added to give a clear, yellow solution. Then, 70% aq t-BuOOH (5.21 tl, 0.03 8 mmol) was added. After 2 h, additional Zn(SO2CF3)2 (16.6 mg, 0.050 mmol) wasadded. After 30 mm, additional 70% aq t-BuOOH (10.4 tl, 0.076 mmol) was added. After 1 h, the reaction was stopped. MeOH (1.5 mL) was added to the reaction mixture and it was purified by reverse phase chromatography to provide (9R,13S)-13-{4-[5- chloro-2-( 1 H- 1,2,3 -triazol- 1 -yl)phenyl] -6-oxo-5 -(trifluoromethyl)- 1 ,6-dihydropyrimidin--yl} -3 ,9-dimethyl-3 ,4,7, 1 5-tetraazatricyclo[ 12.3.1 .02’6]octadeca- 1(1 8),2(6),4, 14,16-pentaen-8-one (0.0024 g, 30% yield) as a white solid. MS(ESI) m/z: 624.4 (M+H),626.4 (M+2+H). A mixture of atropisomers were observed by ‘H NMR and ‘9F NMR.NMR (500MHz, CD3OD) ö 9.09 - 9.06 (m, 0.5H), 9.03 - 9.00 (m, 0.5H), 8.75 (d, J=5.0 Hz, 0.5H), 8.72 (d, J=5.0 Hz, 0.5H), 8.33 (s, 0.5H), 8.25 (s, 0.5H), 7.87 (br. s., 0.5H), 7.80 (br. s., 0.5H), 7.76 - 7.67 (m, 3H), 7.64 (d, J=2.2 Hz, 0.5H), 7.61 (d, J2.2Hz, 0.5H), 7.55 - 7.48 (m, 2H), 6.06 - 5.97 (m, 1H), 4.06 (s, 1.5H), 4.05 (s, 1.5H), 2.772.68 (m, 1H), 2.33 - 2.24 (m, 1H), 2.14 - 1.99 (m, 2H), 1.65 - 1.56 (m, 1H), 1.56 - 1.44(m, 1H), 1.02-0.97 (m, 3H), 0.68-0.55 (m, 1H). ‘9FNMR(471MHz, CD3OD) ö -60.90iF), -60.94 (s, iF). Analytical HPLC (Method A): RT = 7.55 mm, purity = 97.9%;Factor XIa Ki= iiOnM.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - WO2015/116886, 2015, A1 Location in patent: Page/Page column 353; 354

48
(Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-5-methoxy-2-(pyridin-3-yl)pent-1-en-1-yl)phenol [ No CAS ]
[ 39971-65-8 ]
(Z)-4-(1-(4-(2-(dimethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-5-hydroxy-2-(pyridin-3-yl)pent-1-en-1-yl)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7%	With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water at 0 - 20℃; for 12h;	(Z)-4-(1-(4-(2-(Dimethylamino)ethoxy)-3-(trifluoromethyl)phenyl)-5-hydroxy-2-(pyridin-3-yl)pent-1-en-1-yl)phenol (16) To a solution of 13a (66.5 mg, 0.15 mmol) and zinc trifluoromethanesulfinate (127 mg,0.38 mmol) in CH2Cl2 (2.5 mL)/H2O (1.0 mL) was added TFA (12 L, 0.15 mmol) and tert-butylhydroperoxide (70% in H2O) (64 L, 0.46 mmol) at 0 °C. The reaction mixture was stirred at rt for 12 h.Upon consumption of the starting material, the reaction was partitioned between CH2Cl2 (2 mL) andsat. NaHCO3 solution (2 mL). The organic layer was separated, and the aqueous layer was extractedwith CH2Cl2 and dried over MgSO4. The crude product was purified by preparative HPLC usingeluent A (0.1% TFA H2O) and eluent B (0.1% TFA ACN) (A/B = 70/30) to give the desired product.(5 mg, 7% yield). 1H-NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 8.18 (s, 1H), 7.70 (d, J = 6.2 Hz, 1H), 7.28(m, 3H), 6.94 (d, J = 6.7 Hz, 1H), 6.83 (d, J = 6.8 Hz, 2H), 6.71 (d, J = 6.8 Hz, 2H), 4.11 (t, J = 4.0 Hz,2H), 3.28 (m, 2H), 3.21 (s, 3H), 3.16 (m, 2H), 2.65 (s, 6H), 2.57 (m, 2H), 1.58 (m, 2H). MS m/z (ESI)487.2 (M + 1)+ (calcd for C27H29F3N2O3H+ 487.54).

Reference： [1]Kim, Jina; Im, Chun Young; Yoo, Eun Kyung; Ma, Min Jung; Kim, Sang-Bum; Hong, Eunmi; Chin, Jungwook; Hwang, Hayoung; Lee, Sungwoo; Kim, Nam Doo; Jeon, Jae-Han; Lee, In-Kyu; Jeon, Yong Hyun; Choi, Hueng-Sik; Kim, Seong Heon; Cho, Sung Jin [Molecules, 2016, vol. 21, # 1]

49
[ 1428651-90-4 ]
[ 39971-65-8 ]
4-bromo-1-(trifluoromethyl)-5 , 6-dihydro-7H-cyclopenta[c]pyridin-7-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With tert.-butylhydroperoxide In dichloromethane; water at 0℃;	8.A j00538J Step A: Preparation of 4-bromo- 1 -(trifluoromethyl)-5 .6-dihydro-7H- cyclopenta[clpyridin-7-one: A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0 °C was treated with tert-butyl hydroperoxide (70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58mL, 18.86mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHCO3. Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2 x 20 mL CH2C12. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 3 0-90% CH2C12/hexane to afford 4-bromo- 1 -(trifluoromethyl)-5 , 6-dihydro-7H-cyclopenta[c]pyridin-7-one as an off- white solid (390 mg, 30%). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280/282.
30%	With tert.-butylhydroperoxide In dichloromethane; water at 0℃;	8.A Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichlorom ethane (30 mL) and water (15 mL) at 0 °C was treated with tert-butyl hydroperoxide (-70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58mL, 18.86mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHCO3. Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2 x 20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 30-90%) CH2Cl2/hexane to afford 4-bromo- l-(trifluorom ethyl)- 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one as an off-white solid (390 mg, 30%>). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280 / 282.
30%	With tert.-butylhydroperoxide In dichloromethane; water	8.A Step A: Preparation of 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0° C. was treated with tert-butyl hydroperoxide (˜70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58 mL, 18.86 mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHCO3. Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2*20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgSO4, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 30-90% CH2Cl2/hexane to afford 4-bromo-1-(trifluoromethyl)-5,6-dihydro-7H-cyclopenta[c]pyridin-7-one as an off-white solid (390 mg, 30%). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280/282.

30%	With tert.-butylhydroperoxide In dichloromethane; water at 0℃;	4.A Step A: Preparation of 4-bromo- l -(trifluoromethyl)-5,6-dihydro-7//- cyclopenta[c]pyridin-7-one: A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfmyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0 °C was treated with tert-butyl hydroperoxide (-70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfmyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58mL, l8.86mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHCO,. Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2 x 20 mL CH2Cl2. The combined organics were rinsed with 10 mL of brine, dried with MgS04, filtered, and concentrated to dryness. (0802) Purification was achieved by chromatography on silica using 30-90% CH2Cl2/hexane to afford 4-bromo-l-(trifluoromethyl)-5,6-dihydro-7iT-cyclopenta[c]pyridin-7-one as an off- white solid (390 mg, 30%). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280 / 282.
30%	With tert.-butylhydroperoxide In dichloromethane; water at 0℃;	1.A Step A: Preparation of 4-bromo- l-(trifluoromethyl)-5,6-dihydro-7H- cyclopenta\|^"c]pyridin-7-one: A suspension of 4-bromo-5,6-dihydrocyclopenta[c]pyridin-7-one (1.0 g, 4.72 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (4.69 g, 14.15 mmol) in a mixture of dichloromethane (30 mL) and water (15 mL) at 0 °C was treated with tert-butyl hydroperoxide (-70% in water, 2.58 mL, 18.86 mmol, added via pipette using a plastic tip) and stirred overnight. Additional portions of bis(((trifluoromethyl)sulfinyl)oxy)zinc (2.35 g, 7.07 mmol) and tert-butyl hydroperoxide (2.58mL, 18.86mmol) were added sequentially to drive the reaction to completion. After stirring for an additional day, the reaction vessel was placed into a water bath and carefully quenched by the addition of saturated NaHC03. Once effervescence ceased, the reaction mixture filtered through a pad of celite to remove. The pad of celite was rinsed with additional dichloromethane. The filtrate was separated and the aqueous portion extracted further with 2 x 20 mL CH2CI2. The combined organics were rinsed with 10 mL of brine, dried with MgS04, filtered, and concentrated to dryness. Purification was achieved by chromatography on silica using 30-90% CH^CVhexane to afford 4-bromo- 1 -(trifluorom ethyl)- 5,6-dihydro-7H-cyclopenta[c]pyridin-7-one as an off-white solid (390 mg, 30%). The desired regioisomer elutes first. LCMS ESI (+) (M+H) m/z 280 / 282.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2016/145032, 2016, A1 Location in patent: Paragraph 00538
[2]Current Patent Assignee: MERCK & CO INC - WO2016/145045, 2016, A1 Location in patent: Paragraph 00499
[3]Current Patent Assignee: MERCK & CO INC - US2018/140569, 2018, A1 Location in patent: Paragraph 0851
[4]Current Patent Assignee: MERCK & CO INC - WO2019/191227, 2019, A1 Location in patent: Paragraph 0266; 0267
[5]Current Patent Assignee: MERCK & CO INC - WO2016/144826, 2016, A1 Location in patent: Paragraph 0430

50
[ 5813-48-9 ]
[ 39971-65-8 ]
methyl trifluoromethanethiosulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	at -20℃; for 24h;	4.1. Synthesis Methyl trifluoromethanethiosulfonate, CF3SO2SCH3, wasobtained by reaction of CH3SCl and Zn(CF3SO2)2 based on the areported synthesis [11] with some modifications. CH3SCl (5 mmol)was condensed, through a vacuum line, into a flask containing Zn(CF3SO2)2 (2 mmol). The reaction mixture was cooled at 20 Cand stirred for 24 h. The product was isolated by trap to trap distillation,keeping the traps at 65, 100 and 196 C. CF3SO2SCH3was retained at 65 C, as a colorless liquid. The purity of the productwas checked by FT-IR spectroscopy. As methyl trifluoromethanesulfonateis quite sensitive to atmospheric conditionsand temperature, the pure compound was stored in flame-sealedglass ampoules under liquid nitrogen in a Dewar vessel.1H NMR (200 MHz, DMSO) d = 2.34 (s, 3H, CH3). 13C NMR(50 MHz, DMSO) d = 119.27 (d, J = 327.0 Hz, CF3), 17.92, CH3(s).1H NMR (200 MHz, DMSO) d = 2.34 (s, 3H, CH3). 13C NMR(50 MHz, DMSO) d = 119.27 (d, J = 327.0 Hz, CF3), 17.92, CH3(s)(see Table S1).

Reference： [1]Galván; Contreras Aguilar; Defonsi Lestard; Tuttolomondo; Ulic; Ben Altabef [Inorganica Chimica Acta, 2017, vol. 455, p. 254 - 261]

51
2-amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt [ No CAS ]
[ 39971-65-8 ]
2-amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2 mg	With tert.-butylhydroperoxide In chloroform; water at 0 - 20℃;	159 Example 159. 2-Amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)-1-(trifluoromethyl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (racemic mixture prepared) To 2-amino-N-{1-[8-chloro-5-(1,1-dioxido-1,2,5-thiadiazepan-5-yl)imidazo[1,5-a]pyridin-6-yl]ethyl}pyrazolo[1,5-a]pyrimidine-3-carboxamide trifluoroacetate salt (0.023 g, 0.037 mmol, from Example 149) and zinc bis(trifluoromethanesulfinate) (0.037 g, 0.11 mmol, Aldrich) in CHCl3 (0.6 mL) and H2O (0.150 mL) at 0° C. was added tert-butyl hydroperoxide (0.025 mL, 0.19 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was worked up by partition between EtOAc and water. The aqueous layer was extracted with two further portions of EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. DMF and MeOH were used to reconstitute the residue, which was purified by preparative HPLC/MS (pH=2). Yield: 2 mg. LCMS calculated for C21H22ClF3N9O3S monoisotopic (M+H)+: m/z=572.1; found 572.2. 1H NMR (400 MHz, CD3OD) δ 8.68 (dd, J=6.8, 1.4 Hz, 1H), 8.66 (s, 0.5H), 8.63 (s, 0.5H), 8.57-8.54 (m, 1H), 7.38 (s, 0.5H), 7.34 (s, 0.5H), 6.98 (dd, J=6.8, 4.7 Hz, 1H), 5.70 (q, J=6.8 Hz, 0.5H), 5.63 (q, J=6.9 Hz, 0.5H), 4.17-3.34 (m, 8H), 1.63 (d, J=7.4 Hz, 1.5H), 1.61 (d, J=7.3 Hz, 1.5H)

Reference： [1]Current Patent Assignee: INCYTE CORP - US2017/129899, 2017, A1 Location in patent: Paragraph 1130; 1131

52
(Z)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-5-methoxy-2-(pyridin-3-yl)pent-1-en-1-yl)phenol [ No CAS ]
[ 39971-65-8 ]
4-[(Z)-1-{4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)phenyl}-5-methoxy-2-(pyridin-3-yl)pent-1-en-1-yl]phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7%	With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; water at 0 - 20℃; for 24h;	11.1 4-[(Z)-1-{4-[2-(dimethylamino)ethoxy]-3-(trifluoromethyl)phenyl}-5-methoxy-2-(pyridin-3-yl)pent-1-en-1-yl]phenol (Z) -4- (1- (4- (2- (dimethylamino) ethoxy) phenyl) -5-methoxy-2- (pyridin- (Trifluoromethyl) sulfinyl) oxy) zinc (0.127 g, 0.284 mmol) in dichloromethane / water (2.5: 1) Dissolved in 3.5 mL of the mixed solution, and then cooled to 0 ° C or lower. (0.012 mL, 0.154 mmol) and a 70% aqueous solution of tert-butylhydroperoxide (0.064 mL, 0.461 mmol) were added in this order, followed by reaction at room temperature for 1 day. After diluting with dichloromethane and washing with sodium bicarbonate solution, brine, the organic layer was dried over anhydrous Na2SO4 and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by prep-HPLC to obtain 5.4 mg (yield: 7.0%) of the desired compound 14-1.

Reference： [1]Current Patent Assignee: KYUNGPOOK NATIONAL UNIVERSITY HOSPITAL; DAEGU GYEONGBUK MEDICAL INNOVATION FOUNDATION - KR101681041, 2016, B1 Location in patent: Paragraph 0363 - 0366

53
[ 2545-89-3 ]
[ 39971-65-8 ]
C₁₅H₁₇F₃N₂O₆ [ No CAS ]
C₁₆H₁₆F₆N₂O₆ [ No CAS ]

Reference： [1]Chemical Science,2018,vol. 9,p. 4168 - 4175

54
[ 658-79-7 ]
[ 39971-65-8 ]
C₁₂H₁₃F₃N₂O₄ [ No CAS ]
C₁₃H₁₂F₆N₂O₄ [ No CAS ]

Reference： [1]Chemical Science,2018,vol. 9,p. 4168 - 4175

55
[ 39971-65-8 ]
[ 19786-36-8 ]
C₁₅H₁₇F₃N₂O₄ [ No CAS ]
C₁₆H₁₆F₆N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide; acetic acid In aq. buffer at 37℃; Inert atmosphere; Glovebox;

Reference： [1]Ichiishi, Naoko; Caldwell, John P.; Lin, Melissa; Zhong, Wendy; Zhu, Xiaohong; Streckfuss, Eric; Kim, Hai-Young; Parish, Craig A.; Krska, Shane W. [Chemical Science, 2018, vol. 9, # 17, p. 4168 - 4175]

56
[ 38579-21-4 ]
[ 39971-65-8 ]
C₁₆H₂₁F₃N₂O₄ [ No CAS ]
C₁₇H₂₀F₆N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide; acetic acid In aq. buffer at 37℃; Inert atmosphere; Glovebox;

Reference： [1]Ichiishi, Naoko; Caldwell, John P.; Lin, Melissa; Zhong, Wendy; Zhu, Xiaohong; Streckfuss, Eric; Kim, Hai-Young; Parish, Craig A.; Krska, Shane W. [Chemical Science, 2018, vol. 9, # 17, p. 4168 - 4175]

57
[ 13589-04-3 ]
[ 39971-65-8 ]
(2S)-1-(((S)-1-carboxy-2-(4-hydroxy-3-(trifluoromethyl)phenyl)ethyl)amino)-4-(methylsulfinyl)-1-oxobutan-2-aminium [ No CAS ]
C₁₆H₁₈F₆N₂O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide; acetic acid In aq. buffer at 37℃; Inert atmosphere; Glovebox;

Reference： [1]Ichiishi, Naoko; Caldwell, John P.; Lin, Melissa; Zhong, Wendy; Zhu, Xiaohong; Streckfuss, Eric; Kim, Hai-Young; Parish, Craig A.; Krska, Shane W. [Chemical Science, 2018, vol. 9, # 17, p. 4168 - 4175]

58
2C₆H₁₄N₄O₂*C₁₇H₁₇F₂N₅O₃S [ No CAS ]
[ 39971-65-8 ]
N-(3-{4-[6-(difluoromethyl)-5-methoxypyridin-3-yl]-1H-1,2,3-triazol-1-yl}-2,4-difluorophenyl)propane-1-sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With tert.-butylhydroperoxide; iron(III)-acetylacetonate; trifluoroacetic acid In dichloromethane; dimethyl sulfoxide at 20℃; for 0.25h; regioselective reaction;

Reference： [1]Kuttruff, Christian A.; Haile, Margit; Kraml, Johannes; Tautermann, Christofer S. [ChemMedChem, 2018, vol. 13, # 10, p. 983 - 987]

59
1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-1H-benzo[d]imidazole [ No CAS ]
[ 39971-65-8 ]
1-cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)-1H-benzo[d]imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In dimethyl sulfoxide at 0 - 50℃; for 16h; Inert atmosphere;	56 1 -Cyclopropyl-5,6-difluoro-2-(pyridazin-4-yl)-4-(trifluoromethyl)- 1H-benzo[d]imidazole (Ex. 56) j1023] To a stirred solution of 1-cyclopropyl-5,6-difluoro- 2-(pyridazin-4-yl)-1H-benzo[d]imidazole Ex. 55 (100 mg,0.36 mmol) in DMSO (1.5 mE) under an inert atmosphere was added zinc trifluoromethanesulfinate (243 mg, 0.73 mmol) at room temperature. To this was added TI3HP (141 mg, 1.10 mmol) at 0° C. The reaction mixture was stirred at 500 C. for 16 h. Afier consumption of starting material (by TEC), the reaction mixture was basified with saturated sodium bicarbonate solution (20 mE) and extracted with CH2C12 (2x20 mE). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative HPEC to afford 1-cyclopropyl-5,6-difluoro-2- (pyridazin-4-yl)-4-(trifluoromethyl)- 1H-benzo[d]imidazole Ex. 56 (19 mg, 0.05 mmol, 15%) as an off-white solid.j1024] ‘H NMR (500 MHz, CD3OD): ö 9.85 (s, 1H), 9.44(dd, J5.2, 1.2 Hz, 1H), 8.38 (dd, J=5.2, 2.3 Hz, 1H), 8.06(dd, J9.3, 7.0 Hz, 1H), 3.92-3.86 (m, 1H), 1.38-1.20 (m,2H), 0.89-0.83 (m, 2H) j1025]purity)j1026]EC-MS: m/z 340.9 [M+H] at 2.75 RT (91.67% HPEC: 91.79%

Reference： [1]Current Patent Assignee: PHASEBIO PHARMACEUTICALS INC - US2018/185362, 2018, A1 Location in patent: Paragraph 1022; 1023; 1024; 1025; 1026

60
[ 39971-65-8 ]
[ 95-55-6 ]
2-amino-5-trifluoromethanesulfonylphenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With iron(III) chloride; acetic acid at 70℃; for 5h;	6-2 Example 6-2 General procedure: A mixture, obtained by adding 0.5 mmol (0.078 g) of sodium trifluoromethanesulfinate, 0.25 mmol (0.027 g) of 2-aminophenol and 0.5 mmol (0.081 g) of anhydrous iron (III) chloride to 1 mE of acetic acid, was heated and stirred at 70° C. for S hours. Apart of the reaction mixture was collected and analyzed using high performance liquid chromatography to confirm generation of 2-amino-5-trifluo- romethanesulfonylphenol. The same operation as described in Example 6-1 was carried out using the solvent, sulfinate and oxidizing agent described in Table 1 below. The results are shown below. In Table 1, Table 2 and Table 3, CF3S(O)ONa represents sodium trifluoromethanesulfinate, CF3 5(0)0K represents potassium trifluoromethanesulfinate, and (CF3 S (O)O)2Zn represents zinc bis(trifluoromethanesulfinate).

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2018/290970, 2018, A1 Location in patent: Paragraph 0077; 0078; 0079; 0080

61
[ 39971-65-8 ]
[ 18087-73-5 ]
3-bromo-6-(trifluoromethyl)imidazo[1,2-b]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	In dichloromethane; at 0 - 20℃; for 15h;	A solution of <strong>[18087-73-5]3-bromoimidazo[2,1-f]pyridazine</strong> (50 mg, 0.252 mmol) and zinc trifluoromethanesulfinate (168 mg, 0.507 mmol) in DCM (1 mL) and water (0.4 mL) was cooled to 0 C followed by the slow addition of t-BuOOH (100 muL of 70%w/v, 0.777 mmol). The solution was warmed to ambient temperature over 15 hours. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO3 and the layers separated. The aqueous layer was extracted with DCM (x 3) and the combined organic extracts dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica, 0 to 10% EtOAc/Petroleum Ether gradient elution) to give a mixture of two regioisomers (29.5 mg, 0.1109 mmol, 44%) that was used directly in the next reaction; MS m/z: (M+H)+.

Reference： [1]Patent: WO2019/148132,2019,A1 .Location in patent: Paragraph 00975; 00976

62
[ 39971-65-8 ]
[ 10168-00-0 ]
C₇H₅BrF₃N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In chloroform; water at 0 - 50℃; for 72h;	PREPARATION OF INTERMEDIATE 1-60 Zinc sulfinate (1.0 g, 3.00 mmol) was added to a solution of 3-bromo-4-methylpyridine (300 mg, 1.74 mmol) in a mixture of CHCh (9.8 mL) and FLO (3 mL) at 0 °C and the reaction mixture was stirred vigorously tert- Butyl hydroperoxide (70% purity, 0.72 mL, 5.23 mmol) was added dropwise and the reaction mixture was stirred at 50 °C for 48 h. Additional quantity of zinc sulfinate (1.00 g, 3.00 mmol) was added and the reaction mixture was stirred at 50 °C for another 24 h. The mixture was cooled to room temperature, and a saturated solution of NaHC03/EDTA was added until pH=7. The solution was diluted with DCM and washed with EDTA disodium salt/NaHC03 solution. The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried (MgS04), filtered and concentrated under reduced pressure. The crude mixture was purified by flash column chromatography (silica, DCM) to afford 1-60 (165 mg, 34%, 88% purity) as a white solid.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2019/243533, 2019, A1 Location in patent: Page/Page column 33; 34

63
6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-chloro-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3H)-one [ No CAS ]
[ 39971-65-8 ]
[ 76-05-1 ]
(x)C₂HF₃O₂*C₂₁H₂₃Cl₂F₃N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With tert.-butylhydroperoxide In 1,2-dichloro-ethane at 20℃; for 2h; Sonication; Cooling;	11 6-((3S,4S)-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(R_a)-(2,3-dichlorophenyl)-2-methyl-5-(trifluoromethyl)pyrimidin-4(3H)-one TFA salt A suspension of 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-chloro-3-(Ra)-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3H)-one (Example 9) (35 mg, 0.083 mmol), TFA (9.6 μL, 0.12 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (55 mg, 0.16 mmol) in DCE (591 μL) was sonicated to give a uniform suspension then cooled to ° C. and tert- butyl hydroperoxide (34 μL, 0.25 mmol) was added dropwise. The resulting mixture was warmed to rt and stirred for 2 h. Water (1 mL) was added, the layers were separated and the aqueous layer was extracted with DCM (1 mL×3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by mass-triggered preparative HPLC (Mobile phase: A=0.1% TFA/H2O, B=0.1% TFA/MeCN; Gradient: B=20-50%; 20 min; Column:)(Bridge C18, 5 μm, 19 mm×150 mm) to afford the title compound (15 mg, 30% yield) as a white solid (single diastereomer): MS (ES) C21H23Cl2F3N4O2 requires: 490, found: 491 [M+H]+; 1H NMR (600 MHz, DMSO-d6) δ 7.90 (s, 3H), 7.84 (dd, J=7.9, 1.8 Hz, 1H), 7.63-7.56 (m, 2H), 4.24-4.17 (m, 1H), 3.96 (d, J=14.0 Hz, 1H), 3.91-3.83 (m, 2H), 3.72 (d, J=9.0 Hz, 1H), 3.50-3.44 (m, overlap H2O, 1H), 3.32-3.16 (m, overlap H2O, 2H), 2.03 (s, 3H), 1.78 (d, J=13.8 Hz, 3H), 1.61 (d, J=13.2 Hz, 1H), 1.21 (d, J=6.5 Hz, 3H).

Reference： [1]Current Patent Assignee: BRIDGEBIO PHARMA LLC - US2020/48249, 2020, A1 Location in patent: Paragraph 0411-0412

64
2-Methyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ No CAS ]
[ 39971-65-8 ]
2-Methyl-3-(trifluoromethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.04 g	With tert.-butylhydroperoxide In dichloromethane; water at 20℃; for 16h; Cooling with ice;	R.41 2-Methyl-3-(trifluoromethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one Reference Example 41 2-Methyl-3-(trifluoromethyl)-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one To a mixture of the compound of Reference example 13 (100 mg), bis(((trifluoromethyl)sulfinyl)oxy)zinc (439 mg), dichloromethane (3.0 mL), and water (1.2 mL) was added dropwise 70% aqueous 2-hydroperoxide-2-methylpropane (0.362 mL) under ice temperature. After stirring at room temperature for 16 hours, aqueous 10% sodium thiosulfate was added to the reaction mixture. The mixture was extracted with chloroform, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the titled compound (0.0400 g). 1H-NMR (400 MHz, CDCl3) δ: 2.92 (2H, t, J=6.6 Hz), 3.56 (2H, td, J=6.6, 3.2 Hz), 4.04 (3H, q, J=1.4 Hz), 5.79 (1H, brs).

Reference： [1]Current Patent Assignee: Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2020/172543, 2020, A1 Location in patent: Paragraph 0507; 0508; 0509

65
(S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole [ No CAS ]
[ 39971-65-8 ]
(S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In water; dimethyl sulfoxide at 0 - 50℃;	3.2 Step 2 : Preparation of (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H- pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole 10: To (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H- pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (9, 0.91 g, 2.05 mmol) and zinctrifluoromethanesulfinate (1.36 g, 4.10 mmol) was added DMSO (10 ml) followed by water (4 ml). The reaction was cooled in an ice bath and tert-Butyl hydroperoxide (0.86 ml, 6.8 mmol) was added dropwise. The reaction was removed from the ice bath and allowed to warm to ambient temperature and then placed in an oil bath at 50 °C and allowed to stir overnight. After 22 hours, LCMS indicated ~10% product formation. An additional 1.27 g of zinc trifluoromethanesulfinate was added, followed by 1 ml of tert-Butyl hydroperoxide. The reaction was allowed to continue for an additional 17 hours at 50 °C. The reaction was extracted with saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted 3 more times with 5 mL portions of ethyl acetate. The organic layers were combined and volatiles removed by rotary evaporation to provide the crude product that was purified by silica gel column chromatography (10-60% ethyl acetate in hexanes). This provided (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5- dimethylisoxazole (10). MS (ESI) [M+H+]+= 512.1.

Reference： [1]Current Patent Assignee: OPNA IMMUNO-ONCOLOGY SA - WO2020/210366, 2020, A1 Location in patent: Paragraph 0406

66
methyl 7-bromothieno[3,2-b]pyridine-3-carboxylate [ No CAS ]
[ 39971-65-8 ]
methyl 7-bromo-2-(trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In dimethyl sulfoxide at 0 - 50℃; for 2.5h;	2.2B.2B.4 Methyl 7-bromothieno[3,2-b]pyridine-3-carboxylate (1, 68.0 mg, 0.25 mmol) and bis(trifluoromethylsulfinyloxy)zinc (1a, 139.8 mg, 0.50 mmol) are dissolved in dimethylsulfoxide (1.71 mL) in an oven-dried screw capped vial equipped with a stir bar. The mixture is stirred vigorously at 0 °C while tert-butyl hydroperoxide (0.09 mL, 0.92 mmol) is added slowly. After completion of addition the ice bath is removed and the reaction mixture is heated to 50 °C in a heating block for 2.5 h before being cooled to room temperature. The reaction mixture is diluted with saturated aqueous sodium bicarbonate and ethyl acetate. The layers are separated and the aqueous phase extracted with ethyl acetate three times. The combined organic material is washed with brine and dried over magnesium sulfate. The solids are filtered and solvent removed in vacuo to afford a crude residue that is purified via silica gel chromatography (5 to 40 % ethyl acetate in hexanes), affording methyl 7-bromo-2- (trifluoromethyl)thieno[3,2-b]pyridine-3-carboxylate (2).

Reference： [1]Current Patent Assignee: EFFECTOR THERAPEUTICS INC; EFFECT THERAPY STOCK LTD COMPANY; EFFECTOR THERAPEUTICS INC - WO2021/3157, 2021, A1 Location in patent: Paragraph 0311-0312; 0346

67
6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one [ No CAS ]
[ 39971-65-8 ]
6-chloro-2-methyl-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In dimethyl sulfoxide at 0 - 50℃; for 6.5h;	3.3A.3A.1 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one (2, 1.00 g, 5.1 mmol) is dissolved in DMSO (30 mL) in a round bottomed flask equipped with a stir bar. The reaction mixture is stirred at 10 °C while bis(trifluoromethylsulfonyl)zinc (4.23 g, 12.8 mmol) is added in 1 portion. tert-Butyl hydroperoxide (3.53 mL, 19.2 mmol) is then added dropwise via addition funnel. After 5 min the reaction mixture is warmed to room temperature and after an additional 5 min it is warmed to 50 °C for 6.5 h. The reaction mixture is cooled to room temperature and then the reaction mixture is diluted with saturated sodium bicarbonate and ethyl acetate. The layers are separated and the aqueous phase extracted with ethyl acetate three times. The combined organic material is washed with brine and dried over magnesium sulfate. The solids are filtered and solvent removed in vacuo to afford 6-chloro-2-methyl-7-(trifluoromethyl)pyrido[3,2- d]pyrimidin-4(3H)-one (3).

Reference： [1]Current Patent Assignee: EFFECTOR THERAPEUTICS INC; EFFECT THERAPY STOCK LTD COMPANY; EFFECTOR THERAPEUTICS INC - WO2021/3157, 2021, A1 Location in patent: Paragraph 0405; 0407

68
6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one [ No CAS ]
[ 39971-65-8 ]
6-chloro-2-methyl-8-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4(3H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In dimethyl sulfoxide for 6.5h;	3.3A.3A.3 6-chloro-2-methylpyrido[3,2-d]pyrimidin-4(3H)-one (1, 1.00 g, 5.1 mmol) is dissolved in dimethyl sulfoxide (30 mL) in a round bottomed flask equipped with a stir bar. The reaction mixture is stirred at 10 °C while bis(trifluoromethylsulfonyl)zinc (4.23 g, 12.8 mmol) is added in 1 portion. tert-Butyl hydroperoxide (3.53 mL, 19.2 mmol) is then added dropwise via addition funnel. After 5 min the reaction mixture is warmed to room temperature and after an additional 5 min it is warmed to 50 °C for 6.5 h. The reaction mixture is cooled to room temperature and then diluted with saturated aqueous sodium bicarbonate and ethyl acetate. The layers are separated and the aqueous phase extracted with ethyl acetate three times. The combined organic material is washed with brine and dried over magnesium sulfate. The solids are filtered and solvent removed in vacuo to afford a mixture of 6-chloro-2-methyl-8-(trifluoromethyl)pyrido[3,2-d]pyrimidin- 4(3H)-one (2).

Reference： [1]Current Patent Assignee: EFFECTOR THERAPEUTICS INC; EFFECT THERAPY STOCK LTD COMPANY; EFFECTOR THERAPEUTICS INC - WO2021/3157, 2021, A1 Location in patent: Paragraph 0405; 0410

69
2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile [ No CAS ]
[ 39971-65-8 ]
2,8-dimethyl-4-oxo-6-(trifluoromethyl)-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In chloroform; water at 0 - 20℃; for 15h;	1.1A.1A.15 A solution of 2,8-dimethyl-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidine-5-carbonitrile (1, 0.200 g, 0.99 mmol) and bis(((trifluoromethyl)sulfinyl)oxy)zinc (1a, 0.662 g 1.99 mmol) is stirred in chloroform (2.0 mL) and water (2.0 mL), tert-butyl hydrogen peroxide(70 %) (0.38 mL, 2.99 mmol) is added at 0 °C. The reaction mixture is stirred at room temperature for 15 h. After this time, the reaction mixture is diluted water and extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude is purified by silica gel (100-200 mesh) column chromatography using 70-80 % ethyl acetate in hexanes as eluent. The desired fractions are concentrated under reduced pressure to afford 2,8-dimethyl-4-oxo-6-(trifluoromethyl)-3,4-dihydropyrido[3,4-d]pyrimidine- 5-carbonitrile (2).

Reference： [1]Current Patent Assignee: EFFECTOR THERAPEUTICS INC; EFFECT THERAPY STOCK LTD COMPANY; EFFECTOR THERAPEUTICS INC - WO2021/3157, 2021, A1 Location in patent: Paragraph 0169; 0209

70
1-(cyclopropylmethyl)-4-((2-(2-ethyl-1H-benzimidazol-1-yl)-4-morpholinylthiophene[3,2-d]pyrimidine-6-yl)methyl)piperazin-2-one [ No CAS ]
[ 39971-65-8 ]
C₂₉H₃₂F₃N₇O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With peroxybutanol In dimethyl sulfoxide at 50℃; for 18h;	19 The compound 5 (0.15mmol) of Example 5 was dissolved in DMSO (1mL, 0.15mol/L), and zinc trifluoromethanesulfinate was added to it at room temperature (TFMS, 0.165g, 0.5mmol), after the two are completely dissolved, Slowly add to the reaction solution Tert-Butanol peroxy (TBHP, 70%, 0.064mL, 0.5mmol), The temperature of the reaction solution was raised to 50° C. and stirring was continued for 6 hours. TFMS (1.5eq) and TBHP (1.5eq) were added to the reaction solution again and the reaction was continued for 12 hours. After the reaction solution was cooled, it was extracted with ethyl acetate and water, the ethyl acetate layer was washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate and then subjected to silica gel column chromatography to obtain compound 19 (0.019g, 0.032mmol) , The yield is 21%.

Reference： [1]Current Patent Assignee: SICHUAN UNIVERSITY - CN112920199, 2021, A Location in patent: Paragraph 0357-0361

71
[ 39971-65-8 ]
1-(8-fluoro-3-quinolyl)spiro[4H-pyrrolo[1,2- a]pyrazine-3,1'-cyclopentane] [ No CAS ]
1-(8-fluoro-3-quinolyl)-6-(trifluoromethyl)spiro-[4H-pyrrolo[1,2-a]pyrazine-3,1'-cyclopentane] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide In nonane; dichloromethane; water at 0 - 35℃; for 3h;	A2.5 Step 5: To a solution of 1-(8-fluoro-3-quinolyl)spiro[4H-pyrrolo[1 ,2-a]pyrazine-3,T-cyclopentane] (0.06 g, 0.19 mmol) in DCM (1 ml_) / water (0.5 ml_) cooled to 0°C was added zinc trifluoromethanesulfinate (0.13 g, 0.38 mmol) and tertbutyl hydroperoxide (5M in nonanes, 0.10 ml_, 0.53 mmol). The resulting solution was gradually warmed to 35°C and was rapidly stirred at this temperature for 3 h. The reaction mixture was cooled to RT and partitioned between water and ethyl acetate. The organic phase was washed with brine, dried over MgSC , filtered and concentrated under vacuo. The residue was purified by flash chromatography (silica gel, cyclohexane :EtOAc) to afford 1-(8-fluoro-3-quinolyl)-6- (trifluoromethyl)spiro-[4H-pyrrolo[1 ,2-a]pyrazine-3,T-cyclopentane] as yellow gum. (0303) LC-MS (Method G), Rt = 1.19 min, MS: (M+H) = 388. (0304) NMR (400 MHz, CDCh) d ppm 9.33 (d, 1 H) 8.56 (t, 1 H) 7.71 (d, 1 H) 7.45 - 7.58 (m, 2 H) 7.26 (s, 1 H) 6.53 - 6.80 (m, 1 H) 6.35 (d, 1 H) 4.01 (s, 2 H) 1 .93 - 2.09 (m, 4 H) 1 .68 - 1 .93 (m, 4 H).

Reference： [1]Current Patent Assignee: Syngenta (in: Sinochem Holdings); SINOCHEM HOLDINGS CORPORATION LTD - WO2021/204855, 2021, A1 Location in patent: Page/Page column 55

72
[ 103260-65-7 ]
[ 39971-65-8 ]
trifluoromethyl 4-methoxy-1 H-indole-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
115 mg	With tert.-butylhydroperoxide; trifluoroacetic acid In water; dimethyl sulfoxide at 0 - 52℃; for 2.75h;	5.1; 6.1 Step 1. Synthesis of trifluoromethylated 4-methoxy-1H-indole-2-carboxylic acid (C24). A mixture of 4-methoxy-1H-indole-2-carboxylic acid (100 g, 0.523 mmol) and zinc(ll) trifluoromethanesulfinate (120 mg, 0.362 mmol) was treated with dimethyl sulfoxide (1.5 mL) followed by trifluoroacetic acid (56 μL, 0.727 mmol). After the reaction mixture had been cooled to 0 °C, tert- butyl hydroperoxide (70% in water; 143 μL, 1.03 mmol) was added, and stirring was continued at 0 °C for 20 minutes, then at room temperature for 25 minutes. The reaction mixture was subsequently heated at 52 °C for 2 hours, whereupon it was cooled to room temperature and treated in a drop- wise manner with aqueous sodium bicarbonate solution until bubbling had ceased. After the resulting mixture had been partitioned between aqueous sodium bicarbonate solution and ethyl acetate, the aqueous layer was extracted once with ethyl acetate and the organic layers were discarded. The aqueous layer was then acidified to pH 7 with 1 M hydrochloric acid; ethyl acetate was added, and the mixture was stirred while the pH was adjusted to 1 by addition of 1 M hydrochloric acid. After the biphasic mixture had been stirred for 10 minutes, the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. By LCMS analysis, the residue (115 mg) contained a mixture of starting material and mono-trifluoromethylated products, as well as a small amount of di- trifluoromethylated material. The bulk of this mixture was used in Step 4. Yield: 115 mg, <0.4 mmol. LCMS m/z 189.8, 257.8, 325.8 (minor) [M-H]-. 1H NMR (400 MHz, methanol-d4), characteristic peaks from the three major components: d 7.07 (br d, J = 8.4 Hz), 7.02 (br d, J = 8.4 Hz), 6.81 (d, J = 7.8 Hz), 6.66 (d, J = 7.8 Hz), 6.51 (d, J =7.7 Hz), 4.06 (s, -OMe), 3.93 (s, -OMe), 3.92 (s, -OMe).
115 mg	With tert.-butylhydroperoxide; trifluoroacetic acid In water; dimethyl sulfoxide at 0 - 52℃; for 2.75h;	5.1; 6.1 Step 1. Synthesis of trifluoromethylated 4-methoxy-1H-indole-2-carboxylic acid (C24). A mixture of 4-methoxy-1H-indole-2-carboxylic acid (100 g, 0.523 mmol) and zinc(ll) trifluoromethanesulfinate (120 mg, 0.362 mmol) was treated with dimethyl sulfoxide (1.5 mL) followed by trifluoroacetic acid (56 μL, 0.727 mmol). After the reaction mixture had been cooled to 0 °C, tert- butyl hydroperoxide (70% in water; 143 μL, 1.03 mmol) was added, and stirring was continued at 0 °C for 20 minutes, then at room temperature for 25 minutes. The reaction mixture was subsequently heated at 52 °C for 2 hours, whereupon it was cooled to room temperature and treated in a drop- wise manner with aqueous sodium bicarbonate solution until bubbling had ceased. After the resulting mixture had been partitioned between aqueous sodium bicarbonate solution and ethyl acetate, the aqueous layer was extracted once with ethyl acetate and the organic layers were discarded. The aqueous layer was then acidified to pH 7 with 1 M hydrochloric acid; ethyl acetate was added, and the mixture was stirred while the pH was adjusted to 1 by addition of 1 M hydrochloric acid. After the biphasic mixture had been stirred for 10 minutes, the organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. By LCMS analysis, the residue (115 mg) contained a mixture of starting material and mono-trifluoromethylated products, as well as a small amount of di- trifluoromethylated material. The bulk of this mixture was used in Step 4. Yield: 115 mg, <0.4 mmol. LCMS m/z 189.8, 257.8, 325.8 (minor) [M-H]-. 1H NMR (400 MHz, methanol-d4), characteristic peaks from the three major components: d 7.07 (br d, J = 8.4 Hz), 7.02 (br d, J = 8.4 Hz), 6.81 (d, J = 7.8 Hz), 6.66 (d, J = 7.8 Hz), 6.51 (d, J =7.7 Hz), 4.06 (s, -OMe), 3.93 (s, -OMe), 3.92 (s, -OMe).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2021/250648, 2021, A1 Location in patent: Page/Page column 104; 106-108
[2]Current Patent Assignee: PFIZER INC - WO2021/250648, 2021, A1 Location in patent: Page/Page column 104; 106-108

73
[ 39971-65-8 ]
N-[(2S)-1-({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-1H-indole-2-carboxamide [ No CAS ]
N-[(2S)-1-({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-7-(trifluoromethyl)-1H-indole-2-carboxamide [ No CAS ]
N-[(2S)-1-({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-3-(trifluoromethyl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 11% 2: 1.6%	With tert.-butylhydroperoxide; trifluoroacetic acid In water; dimethyl sulfoxide at 50℃;	5; 6 Examples 5 and 6 N-[(2S)-1-({(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1- oxopentan-2-yl]-4-methoxy-3-(trifluoromethyl)-1H-indole-2-carboxamide (5) and N- [(2S)-1-({(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan- 2-yl]-4-methoxy-7-(trifluoromethyl)-1H-indole-2-carboxamide (6) To a pressure release vial containing zinc(ll) trifluoromethanesulfinate (98%, 2.44 mg, 7.21 μmol) were sequentially added a solution of 4 (0.79 g, 1.8 μmol) in dimethyl sulfoxide (60 μL), trifluoroacetic acid (0.56 μL, 7.3 μmol), and tert- butyl hydroperoxide (70% in water; 1.25 uL, 9.03 μmol). The vial was capped and heated to 50 °C overnight, whereupon the reaction mixture was cooled and diluted with acetonitrile and a 1% solution of formic acid in water, to a volume of approximately 2 to 3 mL. The final solvent composition was such that the resulting mixture appeared clear, generally about 20% to 30% acetonitrile. The entire mixture was subjected to reversed- phase HPLC (Column: Phenomenex Luna C18 ,10 x 250 mm, 10 pm; Mobile phase A: 0.5% acetic acid in water; Mobile phase B: 9:1 acetonitrile / methanol; Gradient: 15% B for 5 minutes, then 15% to 70% B linear gradient over 84 minutes, then 70% to 95% B over 1 minute, then 95% B for 9 minutes; Flow rate: 2 mL/min). The eluate was passed through a UV/VIS detector and then was split at approximately 15:1 between a fraction collector and an ion trap mass spectrometer. Fractions were collected every 20 seconds and those potentially containing products of interest were evaluated by UHPLC-UV-HRMS before pooling. The two products eluted at approximately 71 and 75 minutes. The first-eluting product was 5 {N-[(2S)-1-({(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-3- (trifluoromethyl)-1H-indole-2-carboxamide}, and the second-eluting was 6 {N-[(2S)-1- ({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4- methoxy-7-(trifluoromethyl)-1H-indole-2-carboxamide}. 5 -Yield: 0.101 mg, 0.199 μmol, 11%. High-resolution MS m/z 508.2171 [M+H]+; calculated for C24H29F3N5O4, 508.2172. 1H NMR (600 MHz, DMSO-d6) δ 12.22 (br s, 1 H), 9.01 (d, J = 7.6 Hz, 1H), 8.96 (d, J= 7.9 Hz, 1H), 7.73 (s, 1H), 7.21 (dd, J= 8, 8 Hz, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 6.69 (d, J = 7.8 Hz, 1 H), 5.03 - 4.95 (m, 1 H), 4.49 - 4.40 (m, 1H), 3.87 (s, 3H), 3.22 - 3.08 (m, 2H), 2.43 - 2.34 (m, 1H), 2.23 - 2.10 (m, 2H), 1.82 (ddd, J = 13.7, 9.3, 6.8 Hz, 1H), 1.78 - 1.66 (m, 2H), 1.62 (ddd, J = 14.6, 9.7, 5.2 Hz, 1 H), 1.49 (ddd, J= 13.8, 8.8, 5.5 Hz, 1 H), 0.97 - 0.88 (m, 6H). Retention time: 8.43 minutes (Analytical conditions. Column: Phenomenex Kinetex XB-C18, 2.1 x 100 mm, 2.6 pm; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 5% B for 0.5 minutes, then 5% to 70% B over 10.5 minutes, then 70% to 95% B over 2 minutes; Flow rate: 0.4 mL/min). 6 - Yield: 14.7 pg, 0.029 μmol, 1.6%. High-resolution MS m/z 508.2178 [M+H]+; calculated for C24H29F3N5O4, 508.2172. 1H NMR (600 MHz, DMSO-d6) δ 11.47 (br s, 1 H), 9.00 (d, J = 7.9 Hz, 1H), 8.79 (d, J= 7.8 Hz, 1H), 7.70 (s, 1 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.35 (s, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 5.02 - 4.94 (m, 1 H), 4.56 - 4.48 (m, 1 H), 3.97 (s, 3H), 3.18 - 3.05 (m, 2H), 2.39 - 2.30 (m, 1 H), 2.18 - 2.08 (m, 2H), 1.86 - 1.77 (m, 1 H), 1.75 - 1.64 (m, 3H), 1.61 - 1.52 (m, 1H), 0.95 (d, J= 6.1 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H). Retention time: 8.92 minutes (Analytical conditions identical to those used for 5).
1: 11% 2: 1.6%	With tert.-butylhydroperoxide; trifluoroacetic acid In water; dimethyl sulfoxide at 50℃;	5; 6 Examples 5 and 6 N-[(2S)-1-({(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1- oxopentan-2-yl]-4-methoxy-3-(trifluoromethyl)-1H-indole-2-carboxamide (5) and N- [(2S)-1-({(1S)-1-Cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan- 2-yl]-4-methoxy-7-(trifluoromethyl)-1H-indole-2-carboxamide (6) To a pressure release vial containing zinc(ll) trifluoromethanesulfinate (98%, 2.44 mg, 7.21 μmol) were sequentially added a solution of 4 (0.79 g, 1.8 μmol) in dimethyl sulfoxide (60 μL), trifluoroacetic acid (0.56 μL, 7.3 μmol), and tert- butyl hydroperoxide (70% in water; 1.25 uL, 9.03 μmol). The vial was capped and heated to 50 °C overnight, whereupon the reaction mixture was cooled and diluted with acetonitrile and a 1% solution of formic acid in water, to a volume of approximately 2 to 3 mL. The final solvent composition was such that the resulting mixture appeared clear, generally about 20% to 30% acetonitrile. The entire mixture was subjected to reversed- phase HPLC (Column: Phenomenex Luna C18 ,10 x 250 mm, 10 pm; Mobile phase A: 0.5% acetic acid in water; Mobile phase B: 9:1 acetonitrile / methanol; Gradient: 15% B for 5 minutes, then 15% to 70% B linear gradient over 84 minutes, then 70% to 95% B over 1 minute, then 95% B for 9 minutes; Flow rate: 2 mL/min). The eluate was passed through a UV/VIS detector and then was split at approximately 15:1 between a fraction collector and an ion trap mass spectrometer. Fractions were collected every 20 seconds and those potentially containing products of interest were evaluated by UHPLC-UV-HRMS before pooling. The two products eluted at approximately 71 and 75 minutes. The first-eluting product was 5 {N-[(2S)-1-({(1S)-1-cyano-2-[(3S)-2- oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4-methoxy-3- (trifluoromethyl)-1H-indole-2-carboxamide}, and the second-eluting was 6 {N-[(2S)-1- ({(1S)-1-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl}amino)-4-methyl-1-oxopentan-2-yl]-4- methoxy-7-(trifluoromethyl)-1H-indole-2-carboxamide}. 5 -Yield: 0.101 mg, 0.199 μmol, 11%. High-resolution MS m/z 508.2171 [M+H]+; calculated for C24H29F3N5O4, 508.2172. 1H NMR (600 MHz, DMSO-d6) δ 12.22 (br s, 1 H), 9.01 (d, J = 7.6 Hz, 1H), 8.96 (d, J= 7.9 Hz, 1H), 7.73 (s, 1H), 7.21 (dd, J= 8, 8 Hz, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 6.69 (d, J = 7.8 Hz, 1 H), 5.03 - 4.95 (m, 1 H), 4.49 - 4.40 (m, 1H), 3.87 (s, 3H), 3.22 - 3.08 (m, 2H), 2.43 - 2.34 (m, 1H), 2.23 - 2.10 (m, 2H), 1.82 (ddd, J = 13.7, 9.3, 6.8 Hz, 1H), 1.78 - 1.66 (m, 2H), 1.62 (ddd, J = 14.6, 9.7, 5.2 Hz, 1 H), 1.49 (ddd, J= 13.8, 8.8, 5.5 Hz, 1 H), 0.97 - 0.88 (m, 6H). Retention time: 8.43 minutes (Analytical conditions. Column: Phenomenex Kinetex XB-C18, 2.1 x 100 mm, 2.6 pm; Mobile phase A: water containing 0.1% formic acid; Mobile phase B: acetonitrile; Gradient: 5% B for 0.5 minutes, then 5% to 70% B over 10.5 minutes, then 70% to 95% B over 2 minutes; Flow rate: 0.4 mL/min). 6 - Yield: 14.7 pg, 0.029 μmol, 1.6%. High-resolution MS m/z 508.2178 [M+H]+; calculated for C24H29F3N5O4, 508.2172. 1H NMR (600 MHz, DMSO-d6) δ 11.47 (br s, 1 H), 9.00 (d, J = 7.9 Hz, 1H), 8.79 (d, J= 7.8 Hz, 1H), 7.70 (s, 1 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.35 (s, 1 H), 6.72 (d, J = 8.3 Hz, 1 H), 5.02 - 4.94 (m, 1 H), 4.56 - 4.48 (m, 1 H), 3.97 (s, 3H), 3.18 - 3.05 (m, 2H), 2.39 - 2.30 (m, 1 H), 2.18 - 2.08 (m, 2H), 1.86 - 1.77 (m, 1 H), 1.75 - 1.64 (m, 3H), 1.61 - 1.52 (m, 1H), 0.95 (d, J= 6.1 Hz, 3H), 0.90 (d, J = 6.1 Hz, 3H). Retention time: 8.92 minutes (Analytical conditions identical to those used for 5).

Reference： [1]Current Patent Assignee: PFIZER INC - WO2021/250648, 2021, A1 Location in patent: Page/Page column 104; 105
[2]Current Patent Assignee: PFIZER INC - WO2021/250648, 2021, A1 Location in patent: Page/Page column 104; 105

74
[ 1446001-92-8 ]
[ 39971-65-8 ]
7-bromo-5-(trifluoromethyl)-2,3-dihydro-1H-pyrido[3,4-b][1,4]oxazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; lithium hydroxide monohydrate at 60℃; for 12h;	Intermediate 74: 7-Bromo-5-(trifluoromethyl)-2,3-dihydro-1H- pyrido[3,4-b][1,4] oxazine To a suspension of Intermediate 1 (200 mg, 1.0 eq.) in DCM (1.0 mL), TFA (2.0 eq.), zinc trifluoromethanesulfinate (1.0 eq.) and water (1.0 mL) were added. Then, 2-hydroperoxy-2-methylpropane (2.0 eq.) was added and the resulting suspension was heated to 60 °C and stirred for 12h. Volatiles were removed under reduced pressure and Intermediate 74 was used as such in the next step. LC-MS (ESI): m/z (M+1): 282.7 - 284.7 (Method 1).
	With tert.-butylhydroperoxide; trifluoroacetic acid In dichloromethane; lithium hydroxide monohydrate at 60℃; for 12h;	Intermediate 74: 7-Bromo-5-(trifluoromethyl)-2,3-dihydro-1H- pyrido[3,4-b][1,4] oxazine To a suspension of Intermediate 1 (200 mg, 1.0 eq.) in DCM (1.0 mL), TFA (2.0 eq.), zinc trifluoromethanesulfinate (1.0 eq.) and water (1.0 mL) were added. Then, 2-hydroperoxy-2-methylpropane (2.0 eq.) was added and the resulting suspension was heated to 60 °C and stirred for 12h. Volatiles were removed under reduced pressure and Intermediate 74 was used as such in the next step. LC-MS (ESI): m/z (M+1): 282.7 - 284.7 (Method 1).

Reference： [1]Current Patent Assignee: Valline SRL - WO2022/13311, 2022, A1 Location in patent: Page/Page column 101
[2]Current Patent Assignee: Valline SRL - WO2022/13311, 2022, A1 Location in patent: Page/Page column 101

75
[ 39971-65-8 ]
3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)propanamide [ No CAS ]
[ 76-05-1 ]
3-(4-chlorophenyl)-N-[3-(pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]propanamide trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	Stage #1: bis(((trifluoromethyl)sulfinyl)oxy)zinc; 3-(4-chlorophenyl)-N-(3-(pyridin-4-yl)-1H-pyrazol-5-yl)propanamide With tert.-butylhydroperoxide In water monomer; dimethyl sulfoxide at 50℃; for 2h; Stage #2: trifluoroacetic acid	125 3-(4-Chlorophenyl)-N-[3-(pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]propanamide To a solution of 3-(4-chlorophenyl)-N-[3-(pyridin-4-yl)-1H-pyrazol-5-yl]propanamide (Example 98, 16 mg, 0.040 mmol, 1.0 equiv) in DMSO (300 µL,0.13 M) was added zinc(II) bis(trifluoromethyl)-λ-sulfanoylolate (48 mg, 0.18 mmol, 5.0 equiv), followed by TBHP (70 wt. % in water, 32 µL, 0.36, 10 equiv). Thereaction mixture was heated to 50 °C and stirred for 2 h, after which it was cooled to rt and diluted with MeCN:water (1:1, 1 mL). The material was directly purified byRP-HPLC (Method A, 10-100% MeCN in H2O + 0.1% TFA). Fractions containing the desired product were combined and concentrated by lyophilization to afford 3-(4-chlorophenyl)-N-[3-(pyridin-4-yl)-4-(trifluoromethyl)-1H-pyrazol-5-yl]propanamide (2.0 mg, 0.030 mmol, 11% yield) as white solid, trifluoroacetic acid salt. LCMS: ESI-MS m/z: 463.1 [M+H]+.

Reference： [1]Current Patent Assignee: NURA BIO - WO2022/31736, 2022, A1 Location in patent: Page/Page column 128

76
[ 39971-65-8 ]
[ 106-51-4 ]
[ 577-10-6 ]

Yield	Reaction Conditions	Operation in experiment
66 %Spectr.	With lithium hydroxide monohydrate In acetonitrile at 20℃; for 2h; Irradiation; Inert atmosphere;

Reference： [1]Lee, Da Seul; Soni, Vineet Kumar; Heo, Seunga; Hwang, Ho Seong; You, Youngmin; Cho, Eun Jin [Green Chemistry, 2022]

77
[ 1400683-18-2 ]
[ 39971-65-8 ]
8-oxo-4-(trifluoromethyl)-5,6,7,8-tetrahydroquinoline-3-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With tert.-butylhydroperoxide In dichloromethane; lithium hydroxide monohydrate at 20℃; Cooling with ice;	174.1 A solution of 8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (130.0 mg, 0.76 mmol) and zinc trifluoromethanesulfinate (750.92 mg, 2.27 mmol) in DCM (6 mL) and H2O (3 mL) was cooled in ice water. The mixture was stirred vigorously while adding tert-butyl hydroperoxide (0.42 mL, 3.02 mmol, 70% solution in H2O). The solution was warmed to r.t. and stirred overnight. An additional eqivalent of zinc trifluoromethanesulfinate and 1.3 equivalent of tert-butyl hydroperoxide (70% solution in H2O) were added at r.t. and the mixture was stirred for 2 hrs. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The residue was purified by silica gel chromatography on a 10 g silica gel column, using a 0-60% EtOAc/cyclohexane gradient eluent to afford the title compound (55 mg, 30%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.30 (1 H, s) 3.18 (2 H, t, J=5.39 Hz) 2.79 - 2.85 (2 H, m) 2.16 (2 H, quin, J=6.33 Hz). MS-ESI (m/z) calc’d for C11H8F3N2O [M+H]+: 241.1. Found 241.1.
30%	With tert.-butylhydroperoxide In dichloromethane; lithium hydroxide monohydrate at 20℃; Cooling with ice;	174.1 A solution of 8-oxo-6,7-dihydro-57/-quinoline-3-carbonitrile (130.0 mg, 0.76 mmol) and zinc trifluoromethanesulfinate (750.92 mg, 2.27 mmol) in DCM (6 mL) and H2O (3 mL) was cooled in ice water. The mixture was stirred vigorously while adding tert-butyl hydroperoxide (0.42 mL, 3.02 mmol, 70% solution in H2O). The solution was warmed to r.t. and stirred overnight. An additional eqivalent of zinc trifluoromethanesulfinate and 1.3 equivalent of tert-butyl hydroperoxide (70% solution in H2O) were added at r.t. and the mixture was stirred for 2 hrs. The reaction mixture was partitioned between H2O and DCM, the phases were separated, and the aqueous layer was extracted with DCM (2x). The combined organic phases were washed with H2O (lx), passed through a phase separator, and evaporated to dryness. The residue was purified by silica gel chromatography on a 10 g silica gel column, using a 0-60% EtOAc/cyclohexane gradient eluent to afford the title compound (55 mg, 30%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) δ 9.30 (1 H, s) 3.18 (2 H, t, J=5.39 Hz) 2.79 - 2.85 (2 H, m) 2.16 (2 H, quin, J=6.33 Hz). MS-ESI (m/z) calc’d for C11H8F3N2O [M+H]+: 241.1. Found 241.1.

Reference： [1]Current Patent Assignee: E SCAPE BIO - WO2022/155419, 2022, A1 Location in patent: Page/Page column 330-331
[2]Current Patent Assignee: E SCAPE BIO - WO2022/155419, 2022, A1 Location in patent: Page/Page column 330-331

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

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{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	39971-65-8	MDL No. :	MFCD25978123
Formula :	C₂F₆O₄S₂Zn	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	UANOWFITUWBPCF-UHFFFAOYSA-L
M.W :	331.55	Pubchem ID :	14174735
Synonyms :

Num. heavy atoms :	15
Num. arom. heavy atoms :	0
Fraction Csp3 :	1.0
Num. rotatable bonds :	2
Num. H-bond acceptors :	10.0
Num. H-bond donors :	0.0
Molar Refractivity :	30.22
TPSA :	118.68 Å²

GI absorption :	Low
BBB permeant :	No
P-gp substrate :	Yes
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.5 cm/s

[ CAS No. 39971-65-8 ] {[proInfo.proName]}

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Lipophilicity

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Medicinal Chemistry

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Application In Synthesis of [ 39971-65-8 ]

[ 39971-65-8 ] Synthesis Path-Upstream 1~6

[ 39971-65-8 ] Synthesis Path-Downstream 1~77

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[ 39971-65-8 ]

Fluorination Reagents

Precautionary Statements-General

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Log Po/w (iLOGP) :	-34.0
Log Po/w (XLOGP3) :	1.16
Log Po/w (WLOGP) :	5.02
Log Po/w (MLOGP) :	-0.13
Log Po/w (SILICOS-IT) :	1.62
Consensus Log Po/w :	-5.27

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Log S (ESOL) :	-2.49
Solubility :	1.06 mg/ml ; 0.0032 mol/l
Class :	Soluble
Log S (Ali) :	-3.25
Solubility :	0.188 mg/ml ; 0.000566 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.18
Solubility :	221.0 mg/ml ; 0.667 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	3.0

Signal Word:	Danger	Class:	8
Precautionary Statements:	P302+P352-P304+P340+P312-P305+P351+P338+P310-P332+P313-P403+P233-P405-P501	UN#:	3261
Hazard Statements:	H315-H318-H335	Packing Group:	Ⅱ
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
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P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
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P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
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P270	Do not eat, drink or smoke when using this product.
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P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
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P311	Call a POISON CENTER or doctor/physician.
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P315	Get immediate medical advice/attention.
P320
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P321
P322
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P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

[ CAS No. 39971-65-8 ] {[proInfo.proName]}

Quality Control of [ 39971-65-8 ]

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[ 39971-65-8 ] Synthesis Path-Upstream 1~6

[ 39971-65-8 ] Synthesis Path-Downstream 1~77

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Fluorination Reagents

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[ 39971-65-8 ]