[ CAS No. 94651-33-9 ] {[proInfo.proName]}

Name: 94651-33-9|2-(Trifluoromethoxy)benzaldehyde|98%
Brand: Ambeed
SKU: A199511
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Quality Control of [ 94651-33-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 94651-33-9 ]

CAS No. :	94651-33-9	MDL No. :	MFCD00042405
Formula :	C₈H₅F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	CPHXLFKIUVVIOQ-UHFFFAOYSA-N
M.W :	190.12	Pubchem ID :	2777192
Synonyms :

Calculated chemistry of [ 94651-33-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.51
TPSA :	26.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.38 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.86
Log Po/w (XLOGP3) :	2.93
Log Po/w (WLOGP) :	3.66
Log Po/w (MLOGP) :	1.59
Log Po/w (SILICOS-IT) :	2.54
Consensus Log Po/w :	2.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.01
Solubility :	0.187 mg/ml ; 0.000981 mol/l
Class :	Soluble
Log S (Ali) :	-3.14
Solubility :	0.136 mg/ml ; 0.000718 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.98
Solubility :	0.201 mg/ml ; 0.00106 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.37

Safety of [ 94651-33-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 94651-33-9 ]

* 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.

Upstream synthesis route of [ 94651-33-9 ]
Downstream synthetic route of [ 94651-33-9 ]

[ 94651-33-9 ] Synthesis Path-Upstream 1~5

1
[ 94651-33-9 ]
[ 136871-75-5 ]
[ 7035-09-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 3, p. 281 - 284

2
[ 456-55-3 ]
[ 68-12-2 ]
[ 94651-33-9 ]

Reference： [1] European Journal of Organic Chemistry, 2001, # 4, p. 691 - 695

3
[ 1262424-69-0 ]
[ 94651-33-9 ]

Reference： [1] Beilstein Journal of Organic Chemistry, 2010, vol. 6, p. 1061 - 1069

4
[ 100-52-7 ]
[ 659-28-9 ]
[ 94651-33-9 ]
[ 52771-21-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6

5
[ 100-52-7 ]
[ 659-28-9 ]
[ 94651-33-9 ]
[ 52771-21-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2018, vol. 57, # 42, p. 13784 - 13789[2] Angew. Chem., 2018, vol. 130, p. 13980 - 13985,6

[ 94651-33-9 ] Synthesis Path-Downstream 1~88

1
[ 94651-33-9 ]
protonated 2-(trifluoromethoxy)benzaldehyde [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1993,vol. 58,p. 1385 - 1392

2
[ 94651-33-9 ]
[ 136871-75-5 ]
[ 7035-09-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1998,vol. 8,p. 281 - 284

3
[ 38622-91-2 ]
[ 94651-33-9 ]
[ 887496-23-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2724 - 2728

4
[ 179556-97-9 ]
[ 94651-33-9 ]
4-[isobutyl-(2-trifluoromethoxy-benzyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2714 - 2718

5
[ 509142-63-6 ]
[ 94651-33-9 ]
N⁴,N⁴-dimethyl-N²-[cis-4-([2-(trifluoromethoxy)benzyl]amino}methyl)cyclohexyl]quinazoline-2,4-diamine dihydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3307 - 3319

6
[ 509142-67-0 ]
[ 94651-33-9 ]
N⁴-methyl-N²-[cis-4-([2-(trifluoromethoxy)benzyl]amino}methyl)cyclohexyl]quinazoline-2,4-diamine dihydrochloride [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 3307 - 3319

7
[ 866788-63-8 ]
[ 94651-33-9 ]
(E)-3-(2-trifluoromethoxyphenyl)acrylic acid 4'-[(E)-3-(2-trifluoromethoxyphenyl)acryloyloxymethyl]-[2,2']bipyridinyl-4-ylmethyl ester [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2005,vol. 3,p. 3140 - 3160

8
C₇H₇ClN₂S*HCl [ No CAS ]
[ 94651-33-9 ]
C₁₅H₁₀F₃ClN₂SO [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 4255 - 4259

9
[ 94651-33-9 ]
[ 314768-96-2 ]
2-(2-trifluoromethoxyphenyl)-6-pyrrolidinyl-4-quinazolinone [ No CAS ]

Reference： [1]Journal of the Chinese Chemical Society,2007,vol. 54,p. 785 - 790

10
[ 94651-33-9 ]
[ 887496-24-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2724 - 2728

11
[ 94651-33-9 ]
2-chloro-4-propyl-6-[4-(2-trifluoromethoxy-phenyl)-imidazol-1-yl]-pyrimidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2724 - 2728

12
[ 94651-33-9 ]
4-chloro-6-propyl-2-[4-(2-trifluoromethoxy-phenyl)-imidazol-1-yl]-pyrimidine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2724 - 2728

13
[ 94651-33-9 ]
(S)-4-Methyl-2-{6-propyl-2-[4-(2-trifluoromethoxy-phenyl)-imidazol-1-yl]-pyrimidin-4-ylamino}-pentanoic acid (3-ethoxy-propyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 2724 - 2728

14
[ 94651-33-9 ]
[ 561304-64-1 ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4693 - 4699

15
[ 94651-33-9 ]
[ 561304-65-2 ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4693 - 4699

16
[ 94651-33-9 ]
7-chloro-1,3-dihydro-3-hydroxy-5-[2-(trifluoromethoxy)phenyl]-2H-1,4-benzodiazepin-2-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4693 - 4699

17
[ 94651-33-9 ]
[ 561304-63-0 ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4693 - 4699

18
[ 94651-33-9 ]
[ 561304-66-3 ]

Reference： [1]Journal of Organic Chemistry,2003,vol. 68,p. 4693 - 4699

19
[ 94651-33-9 ]
[ 380902-21-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2255 - 2259

20
[ 94651-33-9 ]
N-[[(1-isopropyl-piperidin-4-ylmethyl)-carbamoyl]-(2-trifluoromethoxy-phenyl)-methyl]-4-methoxy-benzamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2255 - 2259

21
[ 94651-33-9 ]
[ 380902-11-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2255 - 2259

22
[ 94651-33-9 ]
C₁₅H₇BrCl₂F₆N₂O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1727 - 1732

23
[ 94651-33-9 ]
3-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(2-trifluoromethoxy-phenyl)-3H-[1,3,4]thiadiazol-2-ylideneamine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 1727 - 1732

24
[ 302523-50-8 ]
[ 94651-33-9 ]
4-[2-[N-methyl-N-(4-isopropoxyphenyl)amino]ethyl]-1-(2-trifluoromethoxyphenylmethyl)piperidin-4-ol [ No CAS ]

Reference： [1]Patent: EP1182192,2002,A1 .Location in patent: Example 97

25
[ 79-24-3 ]
[ 94651-33-9 ]
[ 636597-81-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-butylamine; In ethanol; for 18h;Heating / reflux;	solution of 1.9 g of [1- (2-TRIFLUOROMETHOXY)-BENZALDEHYDE,] 4 ml of EtOH, 1.3 ml of 96% 2-nitroethane and 0.10 ml of n-butylamine was stirred at reflux for 18 h. Afterwards, it was diluted with [H20,] extracted with EtOAc (2x30 ml), washed with [HA0] (2x30 ml), brine, dried [(NA2S04)] ed evaporated in vacuo to afford 2.47 g of an orange oil, which was purified by flash chromatography (PE-EtOAc 100: 5). Evaporation of the collected fractions yielded 1.60 g [OF 2-NITRO-3- (2-TRIFLUOROMETHOXYPHENYL)-PROP-2-ENE] as a pale yellow oil. 1H-NMR (CDL3, delta): 2.35 (s, 3H), 7.30-7. 55 (m, 4H), 8.10 (s, [LH)]
	With N-butylamine; In ethanol; for 18h;Heating / reflux;	1-(2-Trifluoromethoxyphenyl)propan-2-one (Compound 2a) A solution of 1.9 g of 1-(2-trifluoromethoxy)benzaldehyde, 4 ml of EtOH, 1.3 ml of 96% 2-nitroethane and 0.10 ml of n-butylamine was stirred at reflux for 18 h. Afterwards, it was diluted with H2O, extracted with EtOAc (2?30 ml), washed with H2O (2?30 ml), brine, dried (Na2SO4) ed evaporated in vacuo to afford 2.47 g of an orange oil, which was purified by flash chromatography (PE-EtOAc 100:5). Evaporation of the collected fractions yielded 1.60 g of 2-nitro-3-(2-trifluoromethoxyphenyl)prop-2-ene as a pale yellow oil. 1H-NMR (CDCl3, ?): 2.35 (s, 3H), 7.30-7.55 (m, 4H), 8.10 (s,1H) A mixture of 1.6 g of the above compound, 0.024 g of Fe(ClO4)3, 3.0 g of Fe, 6 ml of H2O was heated at reflux and stirred for 7.5 h. After overnight resting at r.t., was added 2.80 ml of 37% HCl, heating for 1 h. After cooling, the mixture was extracted with EtOAc (3?40 ml), which was dried (Na2SO4) ed evaporated in vacuo to give the title compound (g 1.28) as an orange oil. 1H-NMR (CDCl3, ?): 2.22 (s, 3H), 3.77 (s, 2H), 7.15-7.40 (m, 4H) 4-Oxo-3-(2-trifluoromethoxyphenyl)pentanal diethyl acetal (Compound 2b) To a suspension of 1.87 g of 60% NaH oil dispersion in 10 ml of anhydrous DMF was added dropwise during 6 min under a nitrogen stream, a solution of compound 2a in 15 ml of DMF and the reaction mixture was stirred at r.t. for 3 h. After overnight resting, was added 0.447 g of 2-bromoacetaldehyde diethyl acetal (97%) in 5 ml of DMF; the mixture was stirred at r.t. for 30?, then at 80 C. for 3 h. Afterwards, the mixture was diluted with H2O (250 ml), acidified with HCl 2N, extracted with Et2O (3?50 ml), washed with H2O (40 ml), dried (Na2SO4) and evaporated in vacuo, affording a crude (brownish oil), which was purified by flash chromatography (PE-EtOAc 100:2) to yield 1.44 g of compound 2b as a yellowish oil. 1H-NMR (CDCl3, ?): 1.08-1.32 (m, 6H), 1.75-1.95 (m, 1H), 2.08 (s, 3H), 2.35-2.60 (m, 1H), 3.20-3.80 (m, 4H), 4.20-4.40 (2H), 7.15-7.35 (4H) 4-Oxo-3-(2-trifluoromethoxyhenyl)pentanal (Compound 2c) The title compound was obtained following the procedure described for Compound 1e but using as a starting material Compound 2b instead of Compound 1d. After the usual work-up procedure, the title compound was obtained (99%) and used without further purification in the next step. 1H-NMR (CDCl3, ?): 2.12 (s, 3H), 2.58 (dd, 1H), 3.40 (dd, 1H), 4.61 (dd, 1H), 7.11-7.40 (m, 4H), 9.75 (s, 1H) 1-(4-Fluoro-2-methoxyphenyl)-4-[4-Oxo-3-(2-trifluoromethoxyphenyl)pentyl]piperazine The title compound was obtained following the procedure described for the Compound of Example 1, but using as a starting material Compound 2c instead of compound 1e and 1-(4-fluoro-2-methoxyphenyl)piperazine instead of 1-(2,2,2-trifluoroethoxyphenyl)piperazine. Purification by flash chromatography (PE-EtOAc 7:3) yielded the title compound (60%). Oil. 1H-NMR (CDCl3, ?): 1.65-1.85 (m, 1H), 2.10 (s, 3H), 2.25-2.45 (m, 3H), 2.50-2.70 (m, 4H), 2.85-3.10 (m, 4H), 3.82 (s, 3H), 4.15-4.31 (m, 1H), 6.50-6.68 (m, 2H), 6.78-6.90 (m, 1H), 7.20-7.35 (m, 4H)

Reference： [1]Patent: WO2003/106443,2003,A1 .Location in patent: Page 35-36
[2]Patent: US2004/72839,2004,A1 .Location in patent: Page/Page column 20

26
[ 369656-67-7 ]
[ 94651-33-9 ]
C₄₂H₄₅F₃N₆O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 20℃; for 1.5h;	The compound (31.6 mg) obtained in Example 1-5 was dissolved in methanol (0.3 ml), and the solution was added with <strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong> (9.0 mul) and stirred at room temperature for 1.5 hours. After completion of reaction, the solvent wasdistilledoff, and the residue was dried in vacuum and re-dissolved in methanol (0.6 ml). The solution was ice-cooled, and sodium borohydride (10mg) was added to the solution. The resultant solution was returned to room temperature and stirred for 60 minutes. After completion of reaction, the solvent was distilled off, and the residue was dissolved in chloroform. The resultant solution was washed with 0.5 mol/l sodium hydroxide and brine and dried with anhydrous sodium sulfate, and the solvent was distilled off. The residuewas dissolved in chloroform (0.9 ml), and methanesulfonic acid (40 mul) and methanol (40 mul) were added under ice-cooling, followed by stirring at room temperature for 2.5 hours. After completion of reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (chloroform/methanol/water = 7/3/0.5), to thereby obtain a methanesulfonate (29.9 mg) of the subject compound as a white solid. MS (FAB,Pos.) :m/z=673 [M+1]+1H-NMR(500MHz,DMSO-d6) : delta=1.52(3H,d,J=6.8Hz) ,1.60-1.81(4H,m) ,2.3 4(9H,s) ,2.92-3.07(2H,m) ,4.19(2H,t,J=5.6Hz) ,4.30(2H,br) ,4.42(2H ,br) ,4.53-4.61(1H,m) ,5.71(1H,quint. ,J=6.8Hz) ,7.45-7.68(12H,m), 7.83(1H,d,J=8.1Hz) ,7.95(1H,d,J=7.8Hz),7.97(2H,d,J=8.0Hz),8.09(1H,d,J=7.8Hz) ,8.54(1H,d,J=8.1Hz) ,8.71(1H,d,J=7.8Hz) ,8.84(2H,br s) .

Reference： [1]Patent: EP1431290,2004,A1 .Location in patent: Page 27-28

27
[ 675134-86-8 ]
[ 94651-33-9 ]
4-[bis(1H-imidazol-2-ylmethyl)-amino]-methyl}-N-[4-(2-trifluoromethoxy-benzylamino)-butyl]-benzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with <strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong> (manufactured by Avocado Co., Ltd.) (0.0290 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (39.7 mg) of the subject compound as a white solid. MS(FAB,Pos.):m/z=556[M+H]+1H-NMR(500MHz,DMSO-d6):delta=1.55-1.57(2H,m),1.68-1.70(2H,m),2.99(2H,br),3.26(2H,d,J=6.0Hz),3.71(2H,s),4.10(4H ,s),4.20(2H,s),7.45-7.53(4H,m),7.56-7.59(1H,m),7.77-7.82(3H,m),8.53(1H,t,J=5.5Hz),9.24(2H,br).

Reference： [1]Patent: EP1550657,2005,A1 .Location in patent: Page/Page column 41

28
[ 94651-33-9 ]
5-nitro-2-(trifluoromethoxy)benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.9%	With sulfuric acid; nitric acid; at 0℃; for 1.16667h;	Intermediate 14: tert-butyl methyl(5-nitro-2- (trifluoromethoxy)benzyl)carbamate; Intermediate 14A:; [00233] To a mixture of nitric acid (1.6 mL, 35.8 mmol) and sulfuric acid (8 mL, 150 mmol) at 0 0C, was added <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (1.881 mL, 13.15 mmol), dropwise over 10 min. The brown mixture was stirred at 0 0C for 1 h, then was poured onto 100 mL ice. The suspension was stirred, then the precipitate was collected by filtration, rinsed with H2O and sucked dry. The product was dissolved with EtOAc (20 mL), dried (Na2SO4) and concentrated to afford Intermediate 14A (2.10 g, 8.93 mmol, 67.9 % yield) as a yellow oil.
	With sulfuric acid; nitric acid;	A. To a mixture of concentrated sulfuric acid (81 mL) and concentrated nitric acid (15.5 mL), cooled to 0 C., was added <strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong> (25 g, 0.13 mol) portionwise while maintaining the temperature of the reaction below 0 C. After 1.5 hours, the reaction mixture was poured cautiously over 1000 mL of ice in a large beaker and left to stand for 0.5 hours. The resulting suspension was filtered, washed well with H2 O and air dried to give crude 5-nitro-<strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong>, m.p. 32-34 C.

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 7125 - 7137
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 169 - 196
[3]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 527 - 532
[4]Patent: WO2008/79836,2008,A2 .Location in patent: Page/Page column 86
[5]Patent: US5721255,1998,A

29
[ 10230-68-9 ]
octyl β-aminocrotonate [ No CAS ]
[ 94651-33-9 ]
octyl 4-(2-trifluoromethoxyphenyl)-1,4-dihydro-2,6-dimethyl-3-nitropyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid; In ethanol; ethyl acetate; toluene;	EXAMPLE 61 Octyl 4-(2-trifluoromethoxyphenyl)-1,4-dihydro-2,6-dimethyl-3-nitropyridine-5-carboxylate STR71 10.65 g (50 mmol) of octyl beta-aminocrotonate, 9 g (87.5 mmol) of nitroacetone and 3 ml (50 mmol) of acetic acid are added to 9.5 g (50 mmol) of <strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong> in 75 ml of ethanol and the mixture is boiled for 4 hours. It is then cooled and concentrated. The oily evaporation residue is taken up in ethyl acetate, washed with water, sodium hydrogen carbonate solution and again with water, dried and concentrated. The oil obtained is purified over a 600 ml silica gel column using toluene/ethyl acetate. The clean fractions are combined, concentrated and crystallized using ether. The crystals are filtered off with suction and washed with ether. 6.7 g (28.5% of theory) of yellow crystals of melting point 120-122 C. are obtained.

Reference： [1]Patent: US5008279,1991,A

30
[ 372-31-6 ]
[ 94651-33-9 ]
[ 57-13-6 ]
ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium hydrogen sulfate; silica gel; In acetonitrile;Heating / reflux;	EXAMPLE 22. Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate. Ethyl 2-oxo-4-(2-(trifluoromethoxy)phenyl)-6-(trifluoromethyl)-l,2,3,4 tetrahydropyrimidine-5- carboxylate: Ethyl 4,4,4,trifluoro-3-oxobutanoate (200mg, 1.08 mmol) was added to a solution of (trifluoromethoxy)benzaldehyde (103 mg, 0.54mmol) in CH3CN at room temperature. To this solution was added urea (64.8 mg, 1.08 mmol) followed SiO2-NaHSO4 (20mg, 0.1 mmol). The reaction mixture was stirred overnight at reflux. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with CHC13 (250 ml) and filtrate was concentrated to afford 3.9 g (87%) as a off- white solid. [M+H]+ calcd for C14H16FN2O3, 398.25, found 398.

Reference： [1]Patent: WO2007/101213,2007,A2 .Location in patent: Page/Page column 38-39

31
[ 22065-85-6 ]
[ 94651-33-9 ]
[ 614730-64-2 ]

Yield	Reaction Conditions	Operation in experiment
40%		Production Example 148 1-(1-Benzylpiperidin-4-yl)-2-[2-(trifluoromethoxy)phenyl]ethanone The title compound (1.12 g, 40% yield) was obtained in the same manner as Production Example 16 from 2.81 g of <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> and 1.50 g of 1-benzylpiperidine-4-carboxaldehyde. 1H-NMR (400 MHz, CDCl3); ((ppm) 1.69-1.81 (2H, m), 1.81-1.90 (2H, m), 1.97-2.06 (2H, m), 2.39-2.48 (1H, 111), 2.89-2.96 (2H, m), 3.50 (2H, s), 3.80 (2H, s), 7.15-7.33 (9H, m).

Reference： [1]Patent: US2004/167224,2004,A1

32
C₂₅H₃₉ClN₄O [ No CAS ]
[ 94651-33-9 ]
C₃₃H₄₂ClF₃N₄O₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 6825 - 6831

33
[ 94651-33-9 ]
[ 1383740-00-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 35℃; for 6h;	A solution of hydroxylamine hydrochloride (1.07 g, 15.40 mmol) and sodium hydroxide (0.67 g, 16.75 mmol) in water (10 mL) was added dropwise to a solution of <strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong> (2.00 mL, 14.01 mmol) in ethanol (20 mL). The mixture was stirred at 35 0C for 6 hours. Upon cooling, the mixture was concentrated. Water was added, and the mixture was extracted with ethyl acetate. The organic layer <n="103"/>was dried over anhydrous magnesium sulfate, filtered, and concentrated to give 2.55 g (89%) of <strong>[94651-33-9]2-[(trifluoromethyl)oxy]benzaldehyde</strong> oxime as a solid. 1H NMR (400 MHz, CDCl3): delta 8.41 (s, IH), 7.88 (dd, J = 8, 2 Hz, IH), 7.45-7.40 (m, IH), 7.33-7.27 (3H).
86%	With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 20℃; for 1h;	A solution of sodium hydroxide (3.75 g, 0.093 mol) in water (64 ml) was added to a stirred solution of hydroxylamine hydrochloride (6.3 g, 0.0907 mol) in water (64 ml) at 0 C. After 10 mins, a solution of 2-(trifluoromethoxy) benzaldehyde (15 g, 0.078 mol) in ethanol (64 ml) was added. The resulting solution was allowed to stir for an additional lh at room temperature. The resulting solution was diluted with ice water, extracted with ethyl acetate and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to afford the titled compound (16.5 g, 86%) as a solid. 1H NMR (400 MHz, d6-DMSO): d 11.75 (s, 1H), 8.22 (s, 1H), 7.60- 7.38 (m, 3H). 8.23 (S, 1H), 7.88 (dd, J = 8.0 Hz, J - 2 Hz, 1H), 7.59-7.51 (m, 1H), 7.49-7.42 (m, 2H).
	With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 0 - 20℃; for 1h;	To a solution of sodium hydroxide (7 g, 175.00 mmol, 1.19 equiv) in water(120 mL) was added a stirred solution of NH2OH.HCl (11.8 g, 169.78 mmol, 1.15 equiv) in water (120 mL) at 0C. The resulting solution was stirred for 10 min at 0 C. Then a solution of <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (28 g, 147.29 mmol, 1.00 equiv) in ethanol (120 mL) was added. The resulting solution was allowed to stir for an additional 1 h at room temperature. The resulting solution was diluted with 500 ml of H20, extracted with 2x700 mL of ethyl acetate and the organic layers were combined, washed with 2x300 mL of brine, dried over anhydrous sodium sulfate andconcentrated under vacuum to give (E)-<strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> oxime as an off-white crystalline solid.

	With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 20℃; for 1h;	A solution of sodium hydroxide (7.00 g, 175.0 mmol, 1.19 equiv) in water (120 mL) was added to a stirred solution ofNHzOH.HCl (11.80 g, 169.8 mmol, 1.15 equiv) in water (120 mL) at 0C. The resulting solution P A T E N TPAT054477-WO-PCT was stirred for 10 min at 0 C. Then a solution of <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (28.00 g, 147.3 mmol, 1.00 equiv) in ethanol (120 mL) was added. The resulting solution was allowed to stir for an additional 1 h at room temperature. The resulting solution was diluted with 500 ml of H20, extracted with 2x700 mL of ethyl acetate and the organic layers were combined, washed with 2x300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum, which gave (E)-<strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> oxime as an off-white crystal.
	With hydroxylamine hydrochloride; sodium hydroxide; In ethanol; water; at 20℃; for 1h;	A solution of sodium hydroxide (7.00 g, 175.0 mmol, 1.19 equiv) in water (120 mL) was added a stirred solution of NH2OH.HCl (11.80 g, 169.8 mmol, 1.15 equiv) in water (120 mL) at 0C. The resulting solution was stirred for 10 min at 0 C. Then a solution of <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (28.00 g, 147.3 mmol, 1.00 equiv) in ethanol (120 mL) was added. The resulting solution was allowed to stir for an additional 1 h at room temperature. The resulting solution was diluted with 500 ml of H20, extracted with 2 x 700 mL of ethyl acetate and the organic layers were combined, washed with 2 x 300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. (E)-2- (trifluoromethoxy)benzaldehyde oxime was obtained as an off-white crystal.
	With hydroxylamine hydrochloride;	4. Preparation of (E)-2-trifluoromethoxybenzaldoxime Hydroxylamine hydrochloride (5.88 g, 84.7 mmol) was dissolved in water (60 mL), and the solution was stirred at 0 C. NaOH (3.5 g, 87.6 mmol) was dissolved in water (60 mL), and then added dropwise to the reaction flask. <strong>[94651-33-9]2-trifluoromethoxybenzaldehyde</strong> (14 g, 73.6 mmol) was dissolved in an anhydrous ethanol solution (60 mL), and then added dropwise to the reaction flask. After the addition was completed, the mixture solution reacted at 25 C for 1 hr. The reaction solution was diluted with water (300 mL), and extracted with ethyl acetate (500 mL x 3). The organic phases were combined, dried and concentrated to obtain the crude product (15.4 g).

Reference： [1]Patent: WO2009/5998,2009,A1 .Location in patent: Page/Page column 101-102
[2]Patent: WO2020/33382,2020,A1 .Location in patent: Page/Page column 31
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[4]Patent: WO2012/87519,2012,A1 .Location in patent: Page/Page column 80; 81
[5]Patent: WO2012/87521,2012,A1 .Location in patent: Page/Page column 39; 40
[6]Patent: WO2012/87520,2012,A1 .Location in patent: Page/Page column 39
[7]Patent: EP3650449,2020,A1 .Location in patent: Paragraph 0272; 0279-0280

34
[ 3471-05-4 ]
[ 94651-33-9 ]
3-(2-trifluoromethoxybenzylidene)anabaseine bishydrochloride [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2433 - 2446

35
[ 1227461-26-8 ]
[ 94651-33-9 ]
[ 1227461-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; sodium tris(acetoxy)borohydride; In 1,2-dichloro-ethane; at 20℃; for 2h;	Compound 98; Quinolin-3-yl-[6-(2-trifluoromethoxy-benzyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl]-amine; [00448] A vial was charged with (6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-quinolin-3-yl-amine (15.0 mg, 0.0570 mmol), 2-Trifluoromethoxy-benzaldehyde (11.9 mg, 0.0627 mmol), 1 ,2-dichloroethane (0.8 mL, 10 mmol) and methanol (0.2 mL, 4 mmol). Sodium triacetoxyborohydride (36.2 mg, 0.171 mmol) was added, and the reaction stirred at room temperature for 2 hours. The reaction mixture was quenched with saturated NaHCtheta3 solution (5 mL) and extracted with DCM (5 mL). The organic layer was evaporated to dryness and redissolved in DMSO (ImL). Purification using reversed-phase HPLC (acetonitrile-water at pHIO) gave qumolm-3-yl-[6-(2-trifluoromethoxy-benzyl)-6,7-dihydro-5H- pyrrolo[3,4-d]pyrimidin-4-yl]-amine (0.7 mg) as a white solid.

Reference： [1]Patent: WO2010/59610,2010,A1 .Location in patent: Page/Page column 85-86

36
[ 1262424-69-0 ]
[ 94651-33-9 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2010,vol. 6,p. 1061 - 1069

37
[ 94651-33-9 ]
[ 914636-53-6 ]

Reference： [1]Patent: US2011/53974,2011,A1

38
[ 94651-33-9 ]
[ 1083090-91-8 ]

Reference： [1]Patent: US2011/53974,2011,A1

39
[ 94651-33-9 ]
[ 1202578-21-9 ]

Reference： [1]Patent: US2011/53974,2011,A1

40
[ 94651-33-9 ]
[ 1202576-64-4 ]

Reference： [1]Patent: US2011/53974,2011,A1

41
[ 94651-33-9 ]
[ 1202578-20-8 ]

Reference： [1]Patent: US2011/53974,2011,A1

42
[ 5927-18-4 ]
[ 94651-33-9 ]
[ 1202578-19-5 ]

Yield	Reaction Conditions	Operation in experiment
100%		(63A) Methyl (2E)-3-[2-(trifluoromethoxy)phenyl]acrylate A tetrahydrofuran (40 mL) solution of methyl dimethyl phosphonoacetate (7.3 mL, 50.6 mmol) was slowly added to a suspension of sodium hydride (about 63%, oily, 1.93 g, 50.6 mmol) and tetrahydrofuran (80 mL) at 0 C., and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. A tetrahydrofuran (40 mL) solution of <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (8.01 g, 42.1 mmol) was slowly added thereto, and the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. To the reaction solution, a saturated aqueous solution of ammonium chloride was added, and the organic matter was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 85:15 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (12.2 g, quantitative). 1H NMR (CDCl3, 500 MHz): delta3.83 (3H, s), 6.49 (1H, d, J=16.1 Hz), 7.35-7.28 (2H, m), 7.40-7.45 (1H, m), 7.66 (1H, dd, J=7.8, 1.5 Hz), 7.92 (1H, d, J=16.1 Hz)

Reference： [1]Patent: US2011/53974,2011,A1 .Location in patent: Page/Page column 80

43
[ 41391-54-2 ]
[ 94651-33-9 ]
(1SR,2SR)-2-methyl-1-(2-(trifluoromethoxy)phenyl)but-3-yn-1-ol [ No CAS ]
(1SR,2RS)-2-methyl-1-(2-(trifluoromethoxy)phenyl)but-3-yn-1-ol [ No CAS ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 3398 - 3405

44
[ 1308338-92-2 ]
[ 94651-33-9 ]
[ 1308337-91-8 ]

Yield	Reaction Conditions	Operation in experiment
33%		(S)-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)(1 ,2,3,4-tetrahydroisoquinolin-3- yl)methanone (30mg, 0.085mmol), <strong>[94651-33-9]2-(trifluoromethoxy)benzaldehyde</strong> (65mg, 0.34mmol) and sodium triacetoxyborohydride (72mg, 0.34mmol) were mixed in DMF (0.6ml) and heated in the microwave at 100C for 5 mins. LCMS analysis indicated good conversion. The reaction mixture was quenched with water (200muIota) and then purified by prep LCMS (XBridge column, 0.1 % TFA modifier). Fractions containing the desired product were treated on a 500mg SCX cartridge eluting with 2M NH3 in MeOH and then evaporated in vacuo, yielding (S)-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1 H)-yl)(2-(2-(trifluoromethoxy)benzyl)-1 ,2,3,4-tetrahydroisoquinolin-3-yl)methanone as a white solid (15mg, 0.028mmol, 33%) M.S. (ESI) (m/z): 527[M+H]+.

Reference： [1]Patent: WO2011/61318,2011,A1 .Location in patent: Page/Page column 24

45
[ 181227-48-5 ]
[ 598-45-8 ]
[ 5845-53-4 ]
[ 94651-33-9 ]
C₃₅H₄₆F₃N₃O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 783 - 796

46
[ 181227-48-5 ]
[ 5845-53-4 ]
[ 94651-33-9 ]
[ 1354788-97-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 783 - 796

47
[ 94651-33-9 ]
[ 1354566-97-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 169 - 196

48
[ 94651-33-9 ]
[ 1354567-25-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 169 - 196

49
[ 94651-33-9 ]
[ 1354567-62-6 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 169 - 196

50
[ 94651-33-9 ]
[ 937271-13-1 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 169 - 196

51
[ 858124-31-9 ]
[ 94651-33-9 ]
[ 1360060-27-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium tert-pentoxide; In N,N-dimethyl-formamide; at 20℃; for 1h;	General procedure: To a solution of benzaldehydes (1.2 equiv) and 26 (1.0 equiv) in DMF was added sodium tert-pentoxide (2.0 equiv). The mixture was stirred at room temperature for 1 h. Two workup procedures were used. Procedure A: Saturated aqueous solution of NH4Cl was added to the reaction mixture, and the resulting precipitate was filtered, washed with water, and dried in vacuo to give the desired products 27a-c, 27e-f, 27i-l, 27n-p, 27r. Procedure B: The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by flash chromatography (SiO2, n-hexane/EtOAc) to give the desired products 27d, 27g-h, 27m, 27q, 27s-u.

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1442 - 1460

52
[ 94651-33-9 ]
(5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)-methanol [ No CAS ]

Reference： [1]Patent: WO2012/87521,2012,A1
[2]Patent: WO2012/87520,2012,A1
[3]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[4]Patent: WO2012/87519,2012,A1
[5]Patent: WO2019/149158,2019,A1
[6]Patent: WO2020/33382,2020,A1
[7]Patent: EP3632910,2020,A1
[8]Patent: EP3650449,2020,A1

53
[ 94651-33-9 ]
[ 946427-86-7 ]

54
[ 94651-33-9 ]
[ 1103500-32-8 ]

55
[ 94651-33-9 ]
[ 1383740-01-9 ]

Reference： [1]Patent: WO2012/87520,2012,A1
[2]Patent: WO2012/87519,2012,A1
[3]Patent: WO2020/33382,2020,A1

56
[ 94651-33-9 ]
[ 1383816-28-1 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[2]Patent: WO2012/87519,2012,A1

57
[ 94651-33-9 ]
[ 1383816-29-2 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[2]Patent: WO2012/87519,2012,A1

58
[ 94651-33-9 ]
[ 1383816-32-7 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[2]Patent: WO2012/87519,2012,A1

59
[ 94651-33-9 ]
[ 1383816-33-8 ]

Reference： [1]Journal of Medicinal Chemistry,2017,vol. 60,p. 9960 - 9973
[2]Patent: WO2012/87519,2012,A1

60
[ 94651-33-9 ]
[ 1383816-38-3 ]