54109-16-9|2-Bromo-1-[2-(trifluoromethyl)phenyl]-1-ethanone| Ambeed

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Structure of 54109-16-9

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Quality Control of [ 54109-16-9 ] Purity: 98% SDS Specification

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Product Details of [ 54109-16-9 ]

CAS No. :	54109-16-9
Formula :	C₉H₆BrF₃O
M.W :	267.04
SMILES Code :	FC(F)(F)C1=C(C=CC=C1)C(=O)CBr
MDL No. :	MFCD03094304
InChI Key :	KWZCBMKXNYOQAK-UHFFFAOYSA-N
Pubchem ID :	2778430

Safety of [ 54109-16-9 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H314
Precautionary Statements:	P280-P305+P351+P338-P310
Class:	8
UN#:	3265
Packing Group:	Ⅱ

Computational Chemistry of [ 54109-16-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	49.51
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.07 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.86
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.28
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.44
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.24
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.75
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.31

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.68
Solubility	0.0556 mg/ml ; 0.000208 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.31
Solubility	0.13 mg/ml ; 0.000486 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.49
Solubility	0.00862 mg/ml ; 0.0000323 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.6 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.99

Application In Synthesis of [ 54109-16-9 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 54109-16-9 ]

[ 54109-16-9 ] Synthesis Path-Downstream 1~54

1
[ 54109-16-9 ]
[ 765-30-0 ]
[ 70522-43-9 ]

References: [1]Patent: US3225096,1965,A .
Chem.Abstr.,1966,vol. 64.
Chem.Abstr.,1966,vol. 64.

2
[ 908094-01-9 ]
[ 54109-16-9 ]
[ 121041-21-2 ]

References: [1]Australian Journal of Chemistry,1989,vol. 42,p. 1735 - 1748.

3
[ 54109-16-9 ]
[ 124583-55-7 ]
[ 129486-38-0 ]

References: [1]Journal of Medicinal Chemistry,1990,vol. 33,p. 2715 - 2720.

4
[ 54109-16-9 ]
[ 121041-65-4 ]
6-(3-Methoxy-benzylsulfanyl)-2-(2-trifluoromethyl-phenyl)-imidazo[1,2-b]pyridazin-3-ol [ No CAS ]

References: [1]Australian Journal of Chemistry,1989,vol. 42,p. 1735 - 1748.

5
[ 54109-16-9 ]
[ 122-52-1 ]
[ 42755-97-5 ]

References: [1]Bulletin de la Societe Chimique de France,1974,p. 1585 - 1590.

6
[ 100-54-9 ]
[ 54109-16-9 ]
3-[5-(2-trifluoromethyl-phenyl)-1<i>H</i>-imidazol-2-yl]-pyridine [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 3593 - 3596.

7
1-(3-Cyano-phenyl)-3-[1-dimethylamino-meth-(Z)-ylidene]-thiourea [ No CAS ]
[ 54109-16-9 ]
3-[5-(2-trilfuoromethylbenzoyl)thiazol-2-ylamino]benzonitrile [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1599 - 1603.

8
1-[1-Dimethylamino-meth-(Z)-ylidene]-3-(3-trifluoromethyl-phenyl)-thiourea [ No CAS ]
[ 54109-16-9 ]
(2-trifluoromethylphenyl)-[2-(3-trifluoromethylphenylamino)thiazol-5-yl]methanone [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 1599 - 1603.

9
[ 54109-16-9 ]
[ 518035-83-1 ]
C₁₆H₉F₃N₂O₄S [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3729 - 3732.

10
[ 593270-19-0 ]
[ 54109-16-9 ]
{3-[5-(2-Trifluoromethyl-benzoyl)-thiazol-2-ylamino]-propyl}-carbamic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		[0475] [CHEMMOL-00023] [0476] The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester and 2-trifluoromethyl phenacylbromide (literature: EP 432040) according to the procedure described for Example 25. MS (m/e): 429.9 (MH+, 100%).

References: [1]Patent: US2003/225141,2003,A1 .Location in patent: Page 21.

11
[ 593270-19-0 ]
[ 54109-16-9 ]
[ 593270-28-1 ]

Yield	Reaction Conditions	Operation in experiment
		[0487] [CHEMMOL-00029] [0488] The title compound was synthesised from [3-(3-Dimethylaminomethylene-thioureido)-propyl]-carbamic acid tert-butyl ester 2-Trifluoromethyl-phenacyl bromide (literature: EP432040) according to the procedure described for Example H. [0489] MS (m/e): 330.4 (MH+, 100%).

References: [1]Patent: US2003/225141,2003,A1 .Location in patent: Page 22.

13
[ 660857-55-6 ]
[ 54109-16-9 ]
3-[4-methyl-5-(2-trifluoromethylbenzoyl)thiazol-2-ylamino]benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With triethylamine; In ethanol; at 20℃; for 16h;	To a mixture of 801 mg (5 mmol) 3-cyanophenylthioisocyanate in 5 ml IN [NAOH] at [0C] was added 473 mg acetamidine hydrochloride in 10 ml THF and allowed to stirr at 0C for 16 h. The mixture was extracted with ethylacetate and the cornbined organic layers [ARERE] dried with [MGS04] and evaporated to dryness. The residue was purified by flash [COLUENN] chromatography on silica [ELUTINGWITH ETHYLACETATE/CYCLOHEX : ANE 1] : 2 to yield [510] mg (47%) of 1-(1-Amino-ethylidene)-3-(3-cyano-phenyl)-thiourea. (MS (m/e): 219.2 [(M+H,] 100%). A mixture of 50 mg (0.23 mrnol) [1- (1-AMINO-ETHYLIDENE)-3- (3-CYANO-PHENYZ)-] thiourea, 92 mg (0.345 mmol) [2-BROMO-1- (2-TRIFLUOROMETHYL-PHENYL)-ETHANONE AND-48] ul triethylamine in 1 ml ethanol was stirred for 16 h at room temperature. The mixtures were diluted with methanol and directly subjected to preparative HPLC separation on reversed phase eluting with an [ACETONITRILE/WATER] gradient. Evaporation of the product fractions yielded 10.4 mg (12%) of the title compound. (MS (m/e): 386.2 (M-H, 100%)

References: [1]Patent: WO2004/14884,2004,A1 .Location in patent: Page 34; 64.

14
[ 40760-22-3 ]
[ 54109-16-9 ]
5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	at 140 - 150℃; for 4.5h;	Combine 2-BROMO-1- (2-TRIFLUOROMETHYL-PHENYL)-ETHANONE (6.6 g, 24.7 mmol) with 5-carbamoyl-pentanoic acid methyl ester (7. 8 g, 49 mmol) and heat the neat mixture in a sealed vessel at 140-150C for about 4.5 hours. Cool the mixture, dilute with water, and extract with EtOAc. Dry the combined extracts over NA2S04 and concentrate. Chromatography over silica gel (CH2C12) allows for recovery of 5- [4- (2-TRIFLUOROMETHYL- PHENYL)-OXAZOL-2-YL]-PENTANOIC acid methyl ester (3.47 g, 43 %). MS (ES): (M+1) + 328. 2 M/Z.

References: [1]Patent: WO2005/19184,2005,A1 .Location in patent: Page/Page column 85-86.

15
[ 17408-14-9 ]
[ 54109-16-9 ]

Yield	Reaction Conditions	Operation in experiment
93%	With copper(ll) bromide; In chloroform; ethyl acetate; for 5h;Heating / reflux;	Dissolve 2'- (trifluoromethyl)-acetophenone (5.0 g, 26.6 mmol) in CHCl3 (25 ML) and add this mixture to a warmed slurry of CuBr2 (11.86 g, 53.2 mmol) in EtOAc (75 mL). Heat the resulting mixture near reflux for approx. 5 hours. Cool and filter the mixture and concentrate the resulting filtrate. Chromatograph the resulting residue over silica gel (CH2Cl2) to allow for isolation of 2-Bromo-1- (2-trifluoromethyl-phenyl)- ethanone (6.6 g, 93 %).
	With bromine; In diethyl ether; chloroform; at 20 - 25℃; for 1h;	Reference Example 5 ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate; 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25 C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45 C. for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2'-(trifluoromethyl)acetophenone, yield 66%). 1H-NMR (CDCl3) δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m).
	With bromine; In diethyl ether; at 0 - 20℃;	To a solution of l-[2-(trifluoromethyl)phenyl]ethanone (1 g) in diethyl ether (10 mL) cooled at 0 C was added bromine (0.288 mL) dropwise. The resulting mixture was allowed to warm to room temperature. After stirring for 2 hours, the reaction was complete. Solvent was removed in vacuo to afford 2-bromo-l-[2-(trifluoromethyl)phenyl]ethanone (1.488 g) as a yellow oil. MS(ES+) m/z 267 (MH+).

	With hydrogen bromide; bromine; acetic acid; In chloroform; for 0.5h;	To a solution of l-(2-(trifluoromethyl)phenyl)ethanone (71.0 g, 377.0 mmol)and HBr (2.0 mL, 45% solution of AcOH) in chloroform (500.0 mL) was added the solution of dibromide (60.3 g, 377.0 mmol) in chloroform (200.0 mL). After addition, the solution was stirred for 30 min, then the solvent was evaporated and the residue was used in the next step directly. MS (ESI) calcd for C9H6BrF30: 265.96.
	With bromine; In diethyl ether; chloroform; at 10 - 35℃; for 1h;	Reference Example 25 Ethyl 2-cyano-4-oxo-4-[(2-trifluoromethylphenyl)butanoate 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure to give crude 1-bromo-1-(2-trifluoromethylphenyl)ethanone.
	With bromine; In diethyl ether; at 20℃; for 0.5h;	General procedure: To a stirred solution of 2-methylacetophenone 8b (13.42 g, 100 mmol) in Et2O (100 mL) was added dropwise bromine (16.0 g, 100 mmol), and the mixture was stirred at room temperature for 30 min, poured into ice H2O, extracted with Et2O. The extract was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain an crude oil of 2-bromo-1-(2-methylphenyl)ethanone.
	With N-Bromosuccinimide; toluene-4-sulfonic acid; In water; acetonitrile; at 80℃; for 4h;Inert atmosphere;	A 200 mL flask was charged with 2′-trifluoromethylacetophenone (9.41 g, 50 mmol), N-bromosuccinimide (9.79 g, 55 mmol, 1.1 eq.), p-toluenesulfonic acid (10.46 g, 55 mmol, 1.1 eq.) and MeCN (100 mL) under nitrogen stream and the mixture was stirred for 4 hours at 80 C. The mixture was allowed to cool to room temperature and then MeCN was removed by an evaporator. CHCl3 (150 mL) and H2O (50 mL) were added to the residue and the lower layer was separated and then washed with saturated aqueous NaHCO3 (50 mL) twice and brine (50 mL). The solution was dried over anhydrous MgSO4 and filtered and then solvents were removed in an evaporator to obtain the crude product as yellow oil (13.66 g) in >99.9% yield. This product was identified as 2-Bromo-2′-trifluoromethylacetophenone contaminated with some dibromo compound. 1H-NMR (CDCl3), delta (ppm): 4.36 (s, 2H), 7.48-7.50 (m, 1H), 7.60-7.64 (m, 2H), 7.72-7.75 (m, 1H), 19F-NMR (CDCl3), delta in ppm, standard: C6F6=-162.2 ppm: -58.68.
	With bromine; In dichloromethane; for 1.5h;	2-Amino-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (V.17); Step 1; To a solution of 20.00 g (0.11 mole) of 2'-(trifluoromethyl)acetophenone in 200 mL of dichloromethane was added 5.5 mL (0.11 mole) of bromine over 90 minutes. A stream of nitrogen was bubbled through the reaction mixture for 15 minutes. The mixture solvent was removed under reduced pressure. The residue was dissolved with ethanol, and then concentrated under reduced pressure to give 27.25 g of 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone as a yellow oil, which was used in the next step without further purification.

References: [1]Patent: WO2005/19184,2005,A1 .Location in patent: Page/Page column 85.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 6572 - 6582.
[3]Patent: US2007/60623,2007,A1 .Location in patent: Page/Page column 20.
[4]Patent: WO2006/36024,2006,A1 .Location in patent: Page/Page column 109; 284.
[5]Patent: WO2012/27965,2012,A1 .Location in patent: Page/Page column 21.
[6]Journal of Medicinal Chemistry,2013,vol. 56,p. 84 - 96.
[7]Patent: WO2013/59594,2013,A1 .Location in patent: Page/Page column 74.
[8]Patent: EP2336107,2015,B1 .Location in patent: Paragraph 0199.
[9]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3298 - 3314.
[10]Patent: US2018/44284,2018,A1 .Location in patent: Paragraph 0178; 0179.
[11]Patent: US2010/160308,2010,A1 .Location in patent: Page/Page column 7.
[12]Molecules,2021,vol. 26.

16
(3R,4R;3S,4S)-4-(4-chloro-phenyl)-1-(4-hydroxy-pyrrolidin-3-yl)-piperidin-4-ol bistrifluoroacetate [ No CAS ]
[ 54109-16-9 ]
(3R,4R;3S,4S)-2-{3-[4-(4-chloro-phenyl)-4-hydroxy-piperidin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-1-(2-trifluoromethyl-phenyl)-ethanone bistrifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 1h;	Example 126. Mixture of (3R,4R; 3S. 4S)-f2-((3-r4-(4-Chloro-phenyl)-4-hvdroxy- piperidin-l-vn-4-hvdroxy-pyrrolidm-l-yl)-l-(2-trifluoromethyl-phenyl)-ethanone bistrifluoroacetat; [00366] A mixture of (3R.4R; 3S,4S)-4-(4-chloro-phenyl)-l-(4-hydroxy-pyrroridin-3-yl)- piperidin-4-ol bistrifluoroacetate (see Example 1 for preparation) (12.7 mg, 0.024 mmol), 2-Bromo-l- (2-trifluoromethyl-phenyl)-ethanone (8 mg, 1.2 eq.), diisopropyl ethyl amine (26 μL, 6 eq.) were dissolved into DMF (0.8 mL) at O0C. The solution was warmed to RT and stirred for Ih. The mixture was purified by preparative LC-MS to yield 15 mg of the title compound as the bistrifluoroacetate salt. ESDVIS ([M+H]*): 483.3 (100).

References: [1]Patent: WO2006/71958,2006,A1 .Location in patent: Page/Page column 106.

17
[ 6757-31-9 ]
[ 54109-16-9 ]
[ 254911-94-9 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; N,N-dimethyl-formamide;	EXAMPLE 15 A mixture of methyl 4-carbamoylbenzoate (896 mg), 2-trifluoromethylphenacyl bromide (2.22 g) and N,N-dimethylformamide (5 ml) was stirred at 130 C. for 2 hours. Hot ethanol was added to the reaction mixture, which was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was concentrated, and the residue was subjected to a silica gel column chromatography to obtain methyl 4-[4-(2-trifluoromethylphenyl)-2-oxazolyl]benzoate as an oil from a fraction eluted with ethyl acetate-hexane.

References: [1]Patent: US6545009,2003,B1 .

18
[ 145958-94-7 ]
[ 54109-16-9 ]
[ 10299-69-1 ]
[ 145933-93-3 ]

Yield	Reaction Conditions	Operation in experiment
0.44 g (36%)	In acetonitrile;	Example 15 2,3-Dimethyl -7(2-trifluoromethylphenacyl)-pyrrolo[2,3-b]pyridine hydrobromide The title compound was made according to the general method from Example 14. 2,3 -dimethyl-pyrrolo[2,3-b]pyridine (438 mg, 3 mmol), 2-trifluoromethylphenacyl bromide (798 mg, 3 mmol) in acetonitrile (5 ml). Yield 0.44 g (36%). (1 H-NMR, 300 MHz, DMSO-d6), 2.45(s,3H), 2.50(s,3H), 6.55(s,2H),7.65(t,1H), 7.95(t,1H), 8.05(m,2H), 8.40(d,2H), 8.65 (d, 1H).

References: [1]Patent: US5439917,1995,A .

19
[ 54109-16-9 ]
[ 881673-53-6 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 5 ethyl 2-cyano-4-oxo-4-[(2-trifluoromethyl)phenyl]butanoate; 2'-(Trifluoromethyl)acetophenone (10.0 g) was dissolved in chloroform (30 mL) and diethyl ether (30 mL), a solution of bromine (8.50 g) in chloroform (20 mL) was added dropwise while maintaining the reaction temperature at not higher than 25 C. After the dropwise addition, the mixture was stirred at room temperature for 1 hr, water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentration under reduced pressure to give crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone. Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45 C. for 1 hr. A solution of crude 2-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone (100 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2'-(trifluoromethyl)acetophenone, yield 66%). 1H-NMR (CDCl3) δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m).

References: [1]Patent: US2007/60623,2007,A1 .Location in patent: Page/Page column 20.

20
[ 54109-16-9 ]
[ 96-50-4 ]
[ 1015756-70-3 ]

References: [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 1592 - 1600.

21
[ 1207476-93-4 ]
[ 54109-16-9 ]
[ 1207477-02-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 108 - 111.

22
[ 1520-27-0 ]
[ 54109-16-9 ]
[ 1222343-52-3 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1677 - 1679.

23
potassium cyanide [ No CAS ]
[ 54109-16-9 ]
[ 40018-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water; at 20℃;	Step 2; A solution of 26.04 g (0.40 mole) of potassium cyanide in 30 mL of water was added to a stirring solution of 27.00 g (0.10 mole) of 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone in 500 mL of ethanol. The mixture was stirred at room temperature overnight. Water and dichloromethane were added to the mixture. The mixture was then acidified with acetic acid (pH=5-6). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Recrystallization of the residue with ether and hexane gave 14.97 g of 3-oxo-3(2-trifluoromethyl-phenyl)-propionitrile.

References: [1]Patent: US2010/160308,2010,A1 .Location in patent: Page/Page column 8.

24
[ 54109-16-9 ]
[ 105-56-6 ]
[ 881673-53-6 ]

Yield	Reaction Conditions	Operation in experiment
10.43 g		Potassium carbonate (13.82 g) was added to ethyl cyanoacetate (44.44 g), and the mixture was stirred at 45C for 1 hr. A solution (100 mL) of crude 1-bromo-1-(2-trifluoromethylphenyl)ethanone in acetone was added dropwise. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hr, and stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Excess ethyl cyanoacetate contained in the obtained oil was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→7:1) to give the title compound as an oil (yield 10.43 g, from 2'-(trifluoromethyl)acetophenone, 66%).1H-NMR (CDCl3)δ: 1.36 (3H, t, J=7.2 Hz), 3.34-3.46 (1H, m), 3.59-3.70 (1H, m), 4.08-4.22 (1H, m), 4.32 (2H, q, J=7.2 Hz), 7.57-7.80 (4H, m).
		General procedure: K2CO3 powder (27.6 g, 200 mmol) was added to ethyl cyanoacetate (79.2 g 700 mmol), and the mixture was stirred at 43-45 C for 45 min. To this stirred suspension was added a solution of crude 2-bromo-1-(2-methylphenyl)ethanone in acetone (150 mL) over a period of 30 min, and then the mixture was stirred at room temperature for 16 h, filtered and concentrated under reduced pressure. The residue was taken up with EtOAc, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (n-hexane/EtOAc = 10/1-8/1)to

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.
[2]Patent: WO2006/36024,2006,A1 .Location in patent: Page/Page column 109; 284.
[3]Patent: EP2336107,2015,B1 .Location in patent: Paragraph 0199.
[4]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3298 - 3314.

25
[ 1361413-53-7 ]
[ 54109-16-9 ]
[ 1361413-05-9 ]

References: [1]Patent: WO2012/27965,2012,A1 .

26
[ 1361413-53-7 ]
[ 54109-16-9 ]
[ 1361413-59-3 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 85℃; for 0.5h;Inert atmosphere;	A solution of 2-bromo-l-[2-(trifluoromethyl)phenyl]ethanone (intermediate 6a, 381 mg) and N- [(-(methyloxy)phenyl]methyl}amino)carbonothioyl]benzamide (intermediate lb, 400 mg) in NN-dimethylformamide (DMF) (4 mL) was stirred at 85 C under nitrogen for 30 mins. After cooling to room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine and dried over anhydrous Na2SC>4. After filtration, solvent was removed in vacuo and the residue was stirred in TFA (7 mL) at 80 C overnight. Most of TFA was removed under reduced pressure. The residue was neutralized with sat. NaHCC>3, and then extracted with EtOAc for 3 times. The combined organic layers were washed with brine and dried over anhydrous Na2S04. After filtration, the solution was concentrated and further purified by chromatography (EtOAc : PE = 0-70 %) to afford (2-amino-4-phenyl-l,3-thiazol-5-yl)[2-(trifluoromethyl)phenyl]methanone (336 mg) as a yellow solid. MS(ES+) m/z 349 (MH+).

References: [1]Patent: WO2012/27965,2012,A1 .Location in patent: Page/Page column 21-22.

27
[ 54109-16-9 ]
[ 881673-68-3 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3298 - 3314.

28
[ 54109-16-9 ]
[ 881673-54-7 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3298 - 3314.

29
[ 54109-16-9 ]
[ 881674-62-0 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.

30
[ 54109-16-9 ]
[ 881674-60-8 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.

31
[ 54109-16-9 ]
[ 881677-15-2 ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.

32
[ 54109-16-9 ]
N-methyl-1-{1-(pyridin-3-ylsulfonyl)-5-[2-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl}methanamine dihydrochloride [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 4446 - 4456.

33
Cu⁽¹⁺⁾*CF₃^(1-)*C₆H₁₅N*3FH [ No CAS ]
[ 54109-16-9 ]
[ 1400907-10-9 ]

References: [1]Journal of the American Chemical Society,2012,vol. 134,p. 16167 - 16170.

34
[ 54109-16-9 ]
[ 1415838-57-1 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 84 - 96.

35
[ 54109-16-9 ]
[ 1415838-66-2 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 84 - 96.

36
[ 54109-16-9 ]
[ 93703-24-3 ]
[ 1415838-45-7 ]

References: [1]Journal of Medicinal Chemistry,2013,vol. 56,p. 84 - 96.

37
[ 446273-59-2 ]
[ 54109-16-9 ]
[ 1431322-42-7 ]

Yield	Reaction Conditions	Operation in experiment
49.8%	In acetonitrile; for 24h;Reflux;	A mixture of 4-bromo-6-chloropyridazin-3-amine (30.0 g, 144.0 mmol) and 2-bromo-l- (2-(trifluoromethyl)phenyl)ethanone (96.0 g, 360.0 mmol) in MeCN (1000.0 mL) was refluxed for 24 h. After cooling, the mixture was filtered and the solid was washed with EtOAc. The solid was poured into bicarb, stirred for 1 h and extracted with EtOAc. The organic layers were combined and concentrated in vacuo to give 8-bromo-6-chloro-2-(2- (trifluoromethyl)phenyl)imidazo[l ,2-b]pyridazine (27.0 g, 71.7 mmol, 49.8 % yield). MS (ESI) calcd for Ci3H6BrClF3N3: 374.94.
	In acetonitrile; at 80℃; for 24h;	A mixture of 4-bromo-6-chloropyridazin-3-amine (207.0 mg, 0.99 mmol, 1.0 equiv.) and <strong>[54109-16-9]2-bromo-1-(2-(trifluoromethyl)phenyl)ethan-1-one</strong> (647.7 mg, 2.42 mmol, 2.5 equiv.) in MeCN (6.5 mL) in a sealed vessel was heated to 80C. After 24 h, the mixture was filtered through celite, rinsed with EtOAc, and the filtrate was concentrated in vacuo. Purification by column chromatography (0-100% DCM in hexanes) afforded 8-bromo-6-chloro-2-(2- (trifluoromethyl)phenyl)imidazo[1,2-b]pyridazine. ES/MS m/z: 377.90 [M+H].

References: [1]Patent: WO2013/59594,2013,A1 .Location in patent: Page/Page column 74-75.
[2]Patent: WO2021/222522,2021,A1 .Location in patent: Paragraph 0861.
[3]Patent: WO2021/222522,2021,A1 .Location in patent: Paragraph 0861.

38
[ 54109-16-9 ]
[ 1431322-43-8 ]

References: [1]Patent: WO2013/59594,2013,A1 .

39
[ 54109-16-9 ]
[ 1431322-44-9 ]

References: [1]Patent: WO2013/59594,2013,A1 .

40
[ 54109-16-9 ]
[ 1431322-45-0 ]

References: [1]Patent: WO2013/59594,2013,A1 .

41
[ 54109-16-9 ]
[ 1431321-35-5 ]

References: [1]Patent: WO2013/59594,2013,A1 .

42
[ 1392725-32-4 ]
[ 54109-16-9 ]
[ 1449199-49-8 ]

Yield	Reaction Conditions	Operation in experiment
38%	In 1,2-dichloro-ethane;Reflux;	A solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (0.30 g, 0.57 mmol) and <strong>[54109-16-9]2-(trifluoromethyl)phenacyl bromide</strong> (0.22 g, 0.85 mmol) in DCE (30 mL) was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (250 mL), washed with brine solution (125 mL), and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate concentrated, and the residue purified by flash chromatography (0-100% ethyl acetate/hexanes) to provide (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-4-(2-(trifluoromethyl)-phenyl)thiazolidin-4-ol as a yellow solid (0.15 g, 38% yield): mp 115-117.5 C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.86-7.77 (m, 5H), 7.73 (d, J=7.2 Hz, 1H), 7.62 (dt, J=21.6, 7.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.37-7.28 (m, 3H), 7.24-7.17 (m, 1H), 4.34 (s, 2H), 3.20 (dt, J=13.7, 6.8 Hz, 2H), 1.25 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ -57.99, -58.02; ESIMS m/z 711 ([M+H]+).
38%	In 1,2-dichloro-ethane;Reflux;	Example 30 Preparation of (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-4-(2-(trifluoromethyl)phenyl)thiazolidin-4-ol (Compound 263C) A solution of (E)-N-(2-isopropylphenyl)-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazinecarbothioamide (0.30 g, 0.57 mmol) and <strong>[54109-16-9]2-(trifluoromethyl)phenacyl bromide</strong> (0.22 g, 0.85 mmol) in DCE (30 mL) was heated to reflux and stirred overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (250 mL), washed with brine solution (125 mL), and dried over anhydrous sodium sulfate. The solution was filtered, the filtrate concentrated, and the residue purified by flash chromatography (0-100% ethyl acetate/hexanes) to provide (Z)-3-(2-isopropylphenyl)-2-((E)-(4-(1-(4-(trifluoromethoxy)-phenyl)-1H-1,2,4-triazol-3-yl)benzylidene)hydrazono)-4-(2-(trifluoromethyl)-phenyl)thiazolidin-4-ol as a yellow solid (0.15 g, 38% yield): mp 115-117.5 C.; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=8.4 Hz, 2H), 8.13 (s, 1H), 7.86-7.77 (m, 5H), 7.73 (d, J=7.2 Hz, 1H), 7.62 (dt, J=21.6, 7.2 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.37-7.28 (m, 3H), 7.24-7.17 (m, 1H), 4.34 (s, 2H), 3.20 (dt, J=13.7, 6.8 Hz, 2H), 1.25 (d, J=6.9 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ -57.99, -58.02; ESIMS m/z 711 ([M+H]+).

References: [1]Patent: US2013/203592,2013,A1 .Location in patent: Paragraph 0166; 0167.
[2]Patent: US2016/135464,2016,A1 .Location in patent: Paragraph 0166; 0167.

43
[ 262268-69-9 ]
[ 54109-16-9 ]

Yield	Reaction Conditions	Operation in experiment
61%	With water; silver fluoride; trifluoroacetic acid; at 40℃; for 6h;Green chemistry;	General procedure: A mixture of haloalkyne (0.5 mmol), AgF (5mol%) and water (1 equiv.) in TFA (1 mL) was stirred at 40C for 6h, after which TFA was distilled out for reuse. The residue was separated by column chromatography to give the pure sample.

References: [1]Tetrahedron Letters,2014,vol. 55,p. 1373 - 1375.

44
[ 108-94-1 ]
[ 54109-16-9 ]
[ 1668558-12-0 ]
C₁₅H₁₅F₃O₂ [ No CAS ]

References: [1]Chemical Science,2014,vol. 5,p. 2438 - 2442.

45
[ 14222-60-7 ]
[ 54109-16-9 ]
2-(2-propylpyridin-4-yl)-4-(2-(trifluoromethyl)phenyl)thiazole [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6572 - 6582.

46
C₂₁H₂₇N₅O₃*C₂H₄O₂ [ No CAS ]
[ 54109-16-9 ]
C₃₀H₃₀F₃N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In chloroform; at 70℃; for 7h;	Compound 1 (see Reference Example 7-11) (200 mg), Compound 2 (175 mg) and potassium carbonate (242mg) were added to a mixed solvent of chloroform (5 mL) and saturated brine (5 mL), and the mixture was stirred at 70C for 7 hours. The organic layer was separated from the reaction solution and dried over anhydrous sodium sulfate,and subsequently the solvent was distilled off under reduced pressure. The obtained residue was dissolved in methanol(7 mL) and tetrahydrofuran (7 mL), a 2N aqueous sodium hydroxide solution (2186 mL) was added, and the mixture wasstirred at 50 C for 5 hours. The reaction solution was concentrated under reduced pressure, and to the obtained residuewas added trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 7 hours. The reaction solutionwas concentrated under reduced pressure, and to the obtained residue was added a small amount of tetrahydrofuran,and neutralized with a 1N aqueous sodium hydroxide solution. After a few drops of acetic acid was added to the reactionsolution, ethyl acetate was added thereto to carry out a liquid separation. The organic layer was separated and driedover anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The obtainedresidue was purified by silica gel column chromatography (chloroform:methanol = 100:0 to 94:6), solidified from diethylether and collected by filtration to obtain Compound 3 (12.3 mg).MS (m/z): 510 [M+H]+

References: [1]Patent: EP2862856,2015,A1 .Location in patent: Paragraph 0468.

47
C₂₁H₂₇N₅O₃*C₂H₄O₂ [ No CAS ]
[ 54109-16-9 ]
C₂₆H₂₂F₃N₅O₃ [ No CAS ]

References: [1]Patent: EP2862856,2015,A1 .

48
[ 54109-16-9 ]
C₂₃H₂₀BF₃N₂O₄ [ No CAS ]