[ CAS No. 454-73-9 ] {[proInfo.proName]}

Name: 454-73-9|3-Fluoro-5-nitro-1-trifluoromethylbenzene|98%
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Quality Control of [ 454-73-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 454-73-9 ]

Product Details of [ 454-73-9 ]

CAS No. :	454-73-9	MDL No. :	MFCD07779168
Formula :	C₇H₃F₄NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RKLBCPTURHSIOJ-UHFFFAOYSA-N
M.W :	209.10	Pubchem ID :	15272400
Synonyms :

Calculated chemistry of [ 454-73-9 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	6.0
Num. H-bond donors :	0.0
Molar Refractivity :	40.22
TPSA :	45.82 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) :	-5.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.44
Log Po/w (XLOGP3) :	2.74
Log Po/w (WLOGP) :	4.33
Log Po/w (MLOGP) :	2.38
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	2.41

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.05
Solubility :	0.187 mg/ml ; 0.000896 mol/l
Class :	Soluble
Log S (Ali) :	-3.36
Solubility :	0.092 mg/ml ; 0.00044 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.95
Solubility :	0.235 mg/ml ; 0.00112 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 454-73-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 454-73-9 ]

* 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 [ 454-73-9 ]
Downstream synthetic route of [ 454-73-9 ]

[ 454-73-9 ] Synthesis Path-Upstream 1~3

1
[ 454-73-9 ]
[ 401-99-0 ]
[ 133532-73-7 ]

Reference： [1] Russian Journal of Organic Chemistry, 1996, vol. 32, # 9, p. 1325 - 1331

2
[ 401-99-0 ]
[ 454-73-9 ]

Reference： [1] Russian Journal of Organic Chemistry, 1996, vol. 32, # 9, p. 1325 - 1331
[2] Journal of Labelled Compounds and Radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S27-S29
[3] Patent: WO2009/49028, 2009, A1, . Location in patent: Page/Page column 107
[4] Patent: WO2016/49774, 2016, A1, . Location in patent: Paragraph 0124; 0125

3
[ 3819-88-3 ]
[ 454-73-9 ]

Reference： [1] Patent: US2002/45749, 2002, A1,

[ 454-73-9 ] Synthesis Path-Downstream 1~88

1
[ 454-73-9 ]
[ 402-02-8 ]

Reference： [1]Journal of the American Chemical Society,1944,vol. 66,p. 1972

2
[ 401-99-0 ]
[ 454-73-9 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutyl ammonium fluoride; In dimethyl sulfoxide; at 100 - 110℃; for 4h;	Tetramethylammonium fluoride (200 g, 2.15 mol) was added to a solution of 1,3- dinitro-5-trifluoromethyl-benzene (200 g, 0.847 mol) in DMSO (2 L). The mixture was heated to 100-110 0C for 4 h. TLC (Petroleum ether: EtOAc=20:l) showed -50% of starting material has been converted into mono fluoro substituted intermediate. 4-Methyl- IH- imidazole (200 g, 2.43 mol) was added to the reaction mixture, and the resulting solution was heated to 140 0C overnight. TLC (Petroleum ether: EtOAc=20:l) showed the aforementioned intermediate disappeared. The reaction mixture was cooled to room temperature, and then added with water (10 L). The resulting mixture was extracted with DCM (2 L x 2). The combined organic layers were concentrated to give a crude product, which was purified by chromatography (silica, elute; Petroleum ether: EtOAc = 5:1?3:1) to give the title compound (34 g, 15%) as a yellow solid.
	With potassium fluoride; phthalic anhydride; In dimethyl sulfoxide; at 150℃; for 4h;	General procedure: Referring to Scheme 1.7 above, a suspension of compound 1 (5.0 mmol), KF (6.0 mmol) and phthalic anhydride (4.0 mmol) in 8.0 mL DMSO. The mixture was stirred at 150C for 4h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 2, which were purified through flash chromatography on silica gel (Hexane/EtOAc 50:1 to 15:1 as the eluent). Marpholine (6.0 mmol) was added to a solution of compound 2 (3.0 mmol) in 20.0 ml. DMSO. The mixture was stirred at 100C for 4h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 3, which were purified through flash chromatography on silica gel (Hexane/EtOAc 10:1 to 4:1 as the eluent). Compound 3 (2.0 mmol) was dissolved in EtOH (10.0 mL), Fe powder (200 mg) was added followed by 1.0 ml. 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:1 to 1 :1 as the eluent) to afford compound 4. To a solution of triphosgene (2.0 mmol) in dry DCM (4.0 mL), amine 5 (2.0 mmol) in DCM (8.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.6 mL) in DCM (2.0 mL) over 5 min at room temperature. The mixture was stirred for 20 min. Then amine 4 (2.0 mmol) in DCM (4.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 6. Compound 6 (1.0 mmol) was dissolved in EtOH (8.0 mL), Fe powder (100 mg) was added followed by 1.0 mL 5% aqueous solution of NH4CL. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 7. Compound 7 (0.1 mmol) was dissolved in dry THF (5.0 mL). Triethylamine (0.2 mmol) was added followed by acyl chloride 8 (0.15 mmol) at 0C. The reaction mixture was stirred at 0C for 30 min. Then the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 5:1 to 1 :1 as the eluent) to afford compound 861 or 862.

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331
[2]Journal of labelled compounds and radiopharmaceuticals,1999,vol. 42,p. S27-S29
[3]Patent: WO2009/49028,2009,A1 .Location in patent: Page/Page column 107
[4]Patent: WO2016/49774,2016,A1 .Location in patent: Paragraph 0124; 0125

3
[ 454-73-9 ]
[ 401-99-0 ]
[ 133532-73-7 ]

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331

4
[ 454-73-9 ]
4-[(3-Fluoro-5-trifluoromethylphenyl)amino]-6,7-dimethoxyquinazoline [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,1999,vol. 42,p. S27-S29

5
[ 393-75-9 ]
[ 454-73-9 ]

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331

6
[ 454-73-9 ]
[ 349-57-5 ]

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331
[2]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331
[3]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331

7
[ 454-73-9 ]
3-nitro-5-trifluoromethyldiphenyl ether [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331

8
[ 454-73-9 ]
3-nitro-5-thiophenoxybenzotrifluoride [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331

9
[ 454-73-9 ]
2,2-bis-[4-(3-nitro-5-trifluoromethylphenoxy)phenyl]propane [ No CAS ]

Reference： [1]Russian Journal of Organic Chemistry,1996,vol. 32,p. 1325 - 1331

10
FSO₂CF₂CO₂Me [ No CAS ]
[ 3819-88-3 ]
[ 454-73-9 ]

Yield	Reaction Conditions	Operation in experiment
82%	In ethyl acetate; N,N-dimethyl-formamide;	Step a. A mixture of 1-fluoro-3-iodo-5-nitrobenzene (2.733 g, 10.24 mmol), FSO2CF2CO2Me (3.26 mL, 25.6 mmol), Cul (2.342 g, 12.3 mmol) in DMF (30 mL) was heated to 90 C for 2 days under an nitrogen atmosphere. It was then poured into water and extracted with EtOAc. The organic layer was separated, washed with brine, dried with anhydrous Na2SO4, concentrated by rotary evaporation and purified by flash chromatography on silica gel with a gradient elution of 10-30% EtOAc/hexanes to yield 3-fluoro-5-nitrobenzotrifluoride as an oil (1.76 g, 82%).

Reference： [1]Patent: US2002/45749,2002,A1

11
[ 822-36-6 ]
[ 454-73-9 ]
[ 916975-92-3 ]

Yield	Reaction Conditions	Operation in experiment
30.8%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	A suspension of 4-methyl-1H-imidazole (1.178 g, 14.35 mmol) in DMF (15 mL) was added to a solution of <strong>[454-73-9]1-fluoro-3-nitro-5-(trifluoromethyl)benzene</strong> (2 g, 9.56 mmol) in DMF (15 mL). Cs2CO3 (6.23 g, 19.13 mmol) was added and the mixture was stirred at 80 C. for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA=5:1). All fractions found to contain product by TLC (PE/EA=1:1, Rf=0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-imidazole (800 mg, 2.95 mmol, 30.8% yield): 1H NMR (400 MHz, CD3OD) delta 8.61-8.78 (m, 1H), 8.44-8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H); ES-LCMS m/z 272.0 (M+H).
30.8%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	A suspension of 4-methyl-lH-imidazole (1.178 g, 14.35 mmol) in DMF (15 mL) was added to a solution of l-fluoro-3-nitro-5-(trifluoromethyl)benzene (2 g, 9.56 mmol) in DMF (15 mL). CS2CO3 (6.23 g, 19.13 mmol) was added and the mixture was stirred at 80 C for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHC03 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The crude material was purified by silica column chromatography (PE/EA = 5: 1). All fractions found to contain product by TLC (PE/EA = 1: 1, Rf = 0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-l-(3-nitro-5- (trifluoromethyl)phenyl)-lH-imidazole (800 mg, 2.95 mmol, 30.8% yield): l NMR (400 MHz, CD3OD) delta 8.61-8.78 (m, 1H), 8.44-8.51 (m, 1H), 8.31-8.39 (m, 2H), 7.55 (s, 1H), 2.27 (s, 3H); ES-LCMS m/z 272.0 (M+H).
30.8%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	A suspension of 4-methyl-1H-imidazole (1.178 g 14.35 mmol) in DMF (15 mL) was added to a solution of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (2 g 9.56 mmol) in DMF (15 mL) . Cs2CO3(6.23 g 19.13 mmol) was added and the mixture was stirred at 80 for 8 h. The mixture was cooled to rt and then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over MgSO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 51) . All fractions found to contain product by TLC (PE/EA 11 Rf 0.5) were combined and concentrated to yield a light yellow solid of 4-methyl-1- (3-nitro-5- (trifluoromethyl) phenyl) -1H-imidazole (800 mg 2.95 mmol 30.8yield) 1HNMR(400 MHz CD3OD) delta 8.61-8.78 (m 1H) 8.44-8.51 (m 1H) 8.31-8.39 (m 2H) 7.55 (s 1H) 2.27 (s 3H) ES-LCMS rn/z 272.0 (M+H)

	In dimethyl sulfoxide; at 140℃;	Tetramethylammonium fluoride (200 g, 2.15 mol) was added to a solution of 1,3- dinitro-5-trifluoromethyl-benzene (200 g, 0.847 mol) in DMSO (2 L). The mixture was heated to 100-110 0C for 4 h. TLC (Petroleum ether: EtOAc=20:l) showed -50% of starting material has been converted into mono fluoro substituted intermediate. 4-Methyl- IH- imidazole (200 g, 2.43 mol) was added to the reaction mixture, and the resulting solution was heated to 140 0C overnight. TLC (Petroleum ether: EtOAc=20:l) showed the aforementioned intermediate disappeared. The reaction mixture was cooled to room temperature, and then added with water (10 L). The resulting mixture was extracted with DCM (2 L x 2). The combined organic layers were concentrated to give a crude product, which was purified by chromatography (silica, elute; Petroleum ether: EtOAc = 5:1?3:1) to give the title compound (34 g, 15%) as a yellow solid.
	With potassium carbonate;	: In post-3-nitro-5-trifluoromethyl-fluorophenyl and 4-methylimidazole,obtained by stannous chloride reduction of the nitro

Reference： [1]Patent: US2014/275111,2014,A1 .Location in patent: Paragraph 0252; 0253
[2]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 48
[3]Patent: WO2016/37578,2016,A1 .Location in patent: Page/Page column 79; 80
[4]Patent: WO2009/49028,2009,A1 .Location in patent: Page/Page column 107
[5]Patent: CN103739550,2016,B .Location in patent: Paragraph 0197-0200

12
[ 454-73-9 ]
[ 123-30-8 ]
[ 1613588-48-9 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In N,N-dimethyl-formamide; at 110 - 120℃; for 48h;	To a solution of 4-aminophenol (164 mg, 1.50 mmol) in DMF (3.00 mL) was added K2CO3 (228 mg, 1.65 mmol), followed <strong>[454-73-9]1-fluoro-3-(trifluoromethyl)-5-nitrobenzene</strong> (314 mg, 1.50 mmol). The resulted mixture was heated at 110-120 C. for 48 hours, and then cooled to ambient temperature, and filtered through Celite. The Celite was washed with EtOAc (5 mL*3). The filtrate and washings were combined, concentrated to dryness, and partitioned between H2O and EtOAc. The aqueous phase was separated and back-extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography on a silica gel column, eluting with DCM/haxanes (50-100%) to give the product (358 mg, 80% yield) as a yellow solid. LCMS cal'd. for C13H10F3N2O3 (MH+): 299.1; found 299.2

Reference： [1]Patent: US2014/171438,2014,A1 .Location in patent: Paragraph 0503; 0504

13
[ 454-73-9 ]
[ 1613588-49-0 ]

Reference： [1]Patent: US2014/171438,2014,A1

14
[ 454-73-9 ]
[ 1613588-51-4 ]

Reference： [1]Patent: US2014/171438,2014,A1

15
[ 454-73-9 ]
[ 1613588-62-7 ]

Reference： [1]Patent: US2014/171438,2014,A1

16
[ 454-73-9 ]
[ 1613588-47-8 ]

Reference： [1]Patent: US2014/171438,2014,A1

17
[ 454-73-9 ]
[ 1613588-57-0 ]

Reference： [1]Patent: US2014/171438,2014,A1

18
[ 454-73-9 ]
[ 1613588-56-9 ]

Reference： [1]Patent: US2014/171438,2014,A1

19
[ 454-73-9 ]
[ 1613588-61-6 ]

Reference： [1]Patent: US2014/171438,2014,A1

20
[ 454-73-9 ]
[ 641571-11-1 ]

Reference： [1]Patent: US2014/275111,2014,A1
[2]Patent: WO2014/141187,2014,A1
[3]Patent: WO2016/37578,2016,A1
[4]Patent: CN103739550,2016,B

21
[ 108-01-0 ]
[ 454-73-9 ]
[ 900254-38-8 ]

Yield	Reaction Conditions	Operation in experiment
50.7%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	To a suspension of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (2 g 9.56 mmol) in DMF (10 mL) was added 2- (dimethylamino) ethanol (2.56 g 28.7 mmol) and K2CO3(2.64 g 19.13 mmol) . The mixture was stirred at 80 for 8 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over MgSO4 filtered and concentrated. The residue was purified by silica column chromatography (10EA 90PE 3 g silica column) . All fractions found to contain product by TLC (PE/EA 51 Rf 0.5) to yield a light yellow solid of N N-dimethyl-2- (3-nitro-5- (trifluoromethyl) phenoxy) ethanamine (1.35g 4.85 mmol 50.7yield) 1HNMR(400 MHz CDCl3) delta 8.08 (s 1H) 7.94 (s 1H) 7.51 (s 1H) 4.20-4.17 (t J 5.6 Hz 2H) 2.81-2.78 (t J 5.6 Hz 2H) 2.36 (s 6H) ES-LCMS m/z 279.1 (M+H)
28.2%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	A suspension of 2-(dimethylamino)ethanol (128 mg, 1.435 mmol) in DMF (5 inL) was added to a solution of l-fluoro-3 -nitro-5 -(trifluoromethyl)benzene (200 mg, 0.956 mmol) in DMF (5 mL). K2CO3 (264 mg, 1.913 mmol) was added and the mixture was stirred at 80 C for 8 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between ethyl acetate and saturated NaHC03 solution. The combined organic extracts were washed with brine, dried over MgS04, filtered and concentrated. The crude material was purified by preparative TLC (PE/EA = 5: 1, Rf = 0.6) to yield a light yellow solid of N,N-dimethyl-2-(3 -nitro-5 - (trifluoromethyl)phenoxy)ethanamine (75 mg, 0.270 mmol, 28.2% yield): lH NMR (400 MHz, CD3OD) delta 8.22-8.02 (m, 2H), 7.72 (s, 1H), 4.43 (t, J= 5.1 Hz, 2H), 3.26 (t, J= 4.9 Hz, 2H), 2.78- 2.60 (m, 6H). ES-LCMS m/z 279 (M+H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	Step 1 : N,N-dimethyl-2-(3 -nitro-5 -(trifluoromethyl)phenoxy)ethanamine To a suspension of l-fluoro-3 -nitro-5 -(trifluoromethyl)benzene (2 g, 9.56 mmol) in DMF (15 mL) were added 2-(dimethylamino)ethanol (2.56 g, 28.7 mmol) and K2CO3 (2.64 g, 19.13 mmol). The mixture was stirred at 80 C for 8 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA (10 mL) and a saturated NaHCC>3 solution (10 mL). The organic extract was washed with brine (10 mL), dried over MgSO/i, filtered, and concentrated. The crude material was purified by flash column chromatography (PE/EA = 1 : 1). All fractions found to contain product by TLC (PE/EA = 1 : 1, Rf = 0.5) were combined and concentrated to yield a light yellow solid of N,N-dimethyl-2-(3-nitro-5-(trifluoromethyl)phenoxy)ethanamine (1.8 g, 5.18 mmol, 54.1%): l NMR (400 MHz, CDC13) delta 8.07 (s, 1H), 7.94 (s, 1H), 7.50 (s, 1H), 4.18 (t, J = 5.4 Hz, 2H), 2.79 (t, J= 5.4 Hz, 2H), 2.36 (s, 6H); ES-LCMS m/z 279.0 (M+H).

Reference： [1]Patent: WO2016/37578,2016,A1 .Location in patent: Page/Page column 256; 257
[2]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 166
[3]Patent: WO2016/38552,2016,A1 .Location in patent: Page/Page column 56

22
[ 7554-65-6 ]
[ 454-73-9 ]
4-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.2%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 15h;Inert atmosphere;	To a solution of l-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2C03 (496 mg, 3.59 mmol) in DMF (3 inL) was added 4-methyl- lH-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110 C and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo. The residue was dissolved in DCM (60 inL) and washed with H20 (20 mL) and brine (20 mL). The organic layer was dried over Na2S04, filtered and concentrated to give crude material which was purified by silica column chromatography (PE/EA = 10/1 to 5/1) to afford pure product 4-methyl- 1 -(3 -nitro-5 -(trifluoromethyl)phenyl)-lH-pyrazole (500 mg, 1.678 mmol, 70.2% yield): NMR (400 MHz, CD3OD): delta 8.83 (s, IH), 8.46 (s, IH), 8.35 (s, IH), 8.30 (s, IH), 7.64 (s, IH), 2.18 (s, 3H). ES-LCMS: m/z 272.2 (M+H).

Reference： [1]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 137

23
[ 1453-58-3 ]
[ 454-73-9 ]
3-methyl-1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42.1%	With potassium carbonate; In N,N-dimethyl-formamide; at 110℃; for 15h;Inert atmosphere;	To a solution of l-fluoro-3-nitro-5-(trifluoromethyl)benzene (500 mg, 2.391 mmol) and K2CO3 (496 mg, 3.59 mmol) in DMF (10 mL) was added 3 -methyl- IH-pyrazole (196 mg, 2.391 mmol) in one portion. Then the mixture stirred under N2 was heated to 110 C and reacted for 15 h. LCMS analysis showed the starting material disappeared. The solvent was removed in vacuo and the residue obtained was dissolved in DCM (40 mL) and washed with H20 (15 mL) and brine (15 mL). The organic layer was dried over NaaSOzi, filtered and concentrated to give a residue which was purified by silica column chromatography (PE/EA = 8/1 to 3/1) to afford pure product 3- methyl-l-(3-nitro-5-(trifluoromethyl)phenyl)-lH-pyrazole (300 mg, 1.007 mmol, 42.1% yield). l NMR (400 MHz, CD3OD): delta 8.84 (s, 1H), 8.47 (s, 1H), 8.41 (d, J= 2.4 Hz, 1H), 8.35 (s, 1H), 6.42 (d, J= 2.4 Hz, 1H), 2.36 (s, 3H). ES-LCMS: m/z 272.0 (M+H).

Reference： [1]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 139

24
[ 622-40-2 ]
[ 454-73-9 ]
4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46.5%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 10h;	A mixture of l-fluoro-3 -nitro-5 -(trifluoromethyl)benzene (800 mg, 3.83 mmol), 2- morpholinoethanol (552 mg, 4.21 mmol) and K2C03 (1586 mg, 11.48 mmol) in DMF (20 mL) was stirred at 90 C for 10 h. The mixture was concentrated. To the residue was added DCM (150 mL) and the mixture was stirred for 10 min and then filtered. The filtrate was concentrated. The residue was purified by silica column chromatography (PE/EA = 10: 1-5: 1). All fractions found to contain product by TLC (PE/EA = 5: 1, Rf = 0.6) were combined and concentrated to yield a yellow solid of 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)mophiholine (600 mg, 1.780 mmol, 46.5% yield): lH NMR (400 MHz, CDC13): delta 8.02 (s, 1H), 7.87 (s, 1H), 7.43 (s, 1H), 4.16 (t, J = 5.6 Hz, 2H), 3.72-3.63 (m, 4H), 2.79 (t, J = 5.6 Hz, 2H), 2.58-2.47 (m, 4H). ES-LCMS m/z: 321 (M+H).

Reference： [1]Patent: WO2014/141187,2014,A1 .Location in patent: Page/Page column 149

25
[ 454-73-9 ]
2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

26
[ 454-73-9 ]
[ 1234820-86-0 ]

Reference： [1]Patent: WO2014/141187,2014,A1

27
[ 454-73-9 ]
2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

28
[ 454-73-9 ]
2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(4-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

29
[ 454-73-9 ]
3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)aniline [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

30
[ 454-73-9 ]
2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

31
[ 454-73-9 ]
2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(3-methyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)phenyl)acetamide hydrochloride [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

32
[ 454-73-9 ]
[ 900254-39-9 ]

Reference： [1]Patent: WO2014/141187,2014,A1

33
[ 454-73-9 ]
2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

34
[ 454-73-9 ]
2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

35
[ 454-73-9 ]
[ 900254-37-7 ]

Reference： [1]Patent: WO2014/141187,2014,A1
[2]Patent: WO2016/37578,2016,A1
[3]Patent: WO2016/38552,2016,A1

36
[ 454-73-9 ]
N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

37
[ 454-73-9 ]
N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2014/141187,2014,A1

38
[ 288-88-0 ]
[ 454-73-9 ]
1-(3-nitro-5-(trifluoromethyl)phenyl)-1H-1,2,4-triazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.9%	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 8h;	To a solution of 1-fluoro-3-nitro-5- (trifluoromethyl) benzene (1 g 4.78 mmol) in DMF (15 mL) was added 1H-1 2 4-triazole (0.396 g 5.74 mmol) . Cs2CO3(3.12 g 9.56 mmol) was added and the mixture was at 80 for 8 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3solution. The combined organic extract was washed with brine dried over MgSO4 filtered and concentrated. The residue was purified by silica column chromatography (PE/EA 5/1) . All fractions found to contain product by TLC (PE/EA 1/1 Rf 0.5) were combined and concentrated to yield a light yellow solid of 1- (3-nitro-5- (trifluoromethyl) phenyl) -1H-1 2 4-triazole (690 mg 2.67 mmol 55.9yield) 1HNMR(400 MHz CD3OD) delta 9.43 (s 1H) 9.01 (s 1H) 8.65 (s 1H) 8.55 (s 1H) 8.26 (s 1H) ES-LCMS m/z 259.0 (M+H)

Reference： [1]Patent: WO2016/37578,2016,A1 .Location in patent: Page/Page column 251; 252

39
[ 454-73-9 ]
1-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

40
[ 454-73-9 ]
1-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

41
[ 454-73-9 ]
1-(2-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-methylpyrimidin-5-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

42
[ 454-73-9 ]
1-(2-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-4-methylpyrimidin-5-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

43
[ 454-73-9 ]
1-(2-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-4,6-dimethylpyrimidin-5-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

44
[ 454-73-9 ]
1-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-ethylpyrimidin-5-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

45
[ 454-73-9 ]
1-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-methylpyrimidin-5-yl)-3-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

46
[ 454-73-9 ]
[ 1220630-55-6 ]

Reference： [1]Patent: WO2016/37578,2016,A1

47
[ 454-73-9 ]
1-(3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

48
[ 454-73-9 ]
1-(3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)urea hydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

49
[ 454-73-9 ]
1-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-4-methylpyrimidin-5-yl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

50
[ 454-73-9 ]
1-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-4-methylpyrimidin-5-yl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

51
[ 454-73-9 ]
1-(2-chloropyrimidin-5-yl)-3-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)-phenyl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

52
[ 454-73-9 ]
1-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)pyrimidin-5-yl)urea [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

53
[ 454-73-9 ]
1-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-5-yl)urea dihydrochloride [ No CAS ]

Reference： [1]Patent: WO2016/37578,2016,A1

54
[ 454-73-9 ]
5-(4-morpholinyl)-3-(trifluoromethyl)benzenamine [ No CAS ]

Reference： [1]Patent: WO2016/49774,2016,A1

55
[ 454-73-9 ]
C₁₉H₁₆F₆N₄O₄ [ No CAS ]

Reference： [1]Patent: WO2016/49774,2016,A1

56
[ 110-91-8 ]
[ 454-73-9 ]
[ 1529769-94-5 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide; at 100℃; for 4h;	General procedure: Referring to Scheme 1.7 above, a suspension of compound 1 (5.0 mmol), KF (6.0 mmol) and phthalic anhydride (4.0 mmol) in 8.0 mL DMSO. The mixture was stirred at 150C for 4h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 2, which were purified through flash chromatography on silica gel (Hexane/EtOAc 50:1 to 15:1 as the eluent). Marpholine (6.0 mmol) was added to a solution of compound 2 (3.0 mmol) in 20.0 ml. DMSO. The mixture was stirred at 100C for 4h. The mixture was diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4. Solvents were removed under reduced pressure to afford the crude products 3, which were purified through flash chromatography on silica gel (Hexane/EtOAc 10:1 to 4:1 as the eluent). Compound 3 (2.0 mmol) was dissolved in EtOH (10.0 mL), Fe powder (200 mg) was added followed by 1.0 ml. 5% aqueous solution of NH4Cl. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by flash chromatography on silica gel (Hexane/EtOAc 3:1 to 1 :1 as the eluent) to afford compound 4. To a solution of triphosgene (2.0 mmol) in dry DCM (4.0 mL), amine 5 (2.0 mmol) in DCM (8.0 mL) was added dropwise followed by the dropwise addition of triethylamine (0.6 mL) in DCM (2.0 mL) over 5 min at room temperature. The mixture was stirred for 20 min. Then amine 4 (2.0 mmol) in DCM (4.0 mL) was added dropwise into the mixture. Stirring was continued for 30 min. The reaction was quenched with dilute Na2CO3. The organic layer was washed with water and brine, and dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 6. Compound 6 (1.0 mmol) was dissolved in EtOH (8.0 mL), Fe powder (100 mg) was added followed by 1.0 mL 5% aqueous solution of NH4CL. The mixture was refluxed for 1 h. The solvent was removed in wacuo and the residue was dissolved in acetone. After filtration and concentration in vacuo, the residue was purified by recrystallization (solvent: DCM) to afford compound 7. Compound 7 (0.1 mmol) was dissolved in dry THF (5.0 mL). Triethylamine (0.2 mmol) was added followed by acyl chloride 8 (0.15 mmol) at 0C. The reaction mixture was stirred at 0C for 30 min. Then the reaction was quenched with water and diluted with EtOAc. The organic layer was washed with brine, and dried over Na2SO4. After filtration and concentration, the residue was purified by flash chromatography in silica gel (Hexane/EtOAc 5:1 to 1 :1 as the eluent) to afford compound 861 or 862.

Reference： [1]Patent: WO2016/49774,2016,A1 .Location in patent: Paragraph 0124; 0125

57
[ 454-73-9 ]
C₃₄H₃₆F₃N₇O₂Si [ No CAS ]

Reference： [1]Patent: WO2016/33304,2016,A1
[2]Chimia,2019,vol. 73,p. 561 - 570

58
[ 454-73-9 ]
[1-[3-amino-5-(trifiuoromethyl)phenyl]imidazol-4-yl]methanol [ No CAS ]

Reference： [1]Patent: WO2016/33304,2016,A1

59
[ 454-73-9 ]
3-[4-[[tert-butyl(dimethyl)silyl]oxymethyl]imidazol-1-yl]-5-(trifluoromethyl)aniline [ No CAS ]

Reference： [1]Patent: WO2016/33304,2016,A1
[2]Chimia,2019,vol. 73,p. 561 - 570

60
[ 822-55-9 ]
[ 454-73-9 ]
[1-[3-nitro-5-(trifluoromethyl)phenyl]imidazol-4-yl]methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.5 g	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 10h;	Step 1:[0122] First, l-fluoro-3-nitro-5-(trifluoromethyl)benzene (3, 10.0 g, 47.8 mmol, 1 equiv) and 1H- imidazol-4-ylmethanol (12.9 g, 95.7 mmol, 2 equiv) were dissolved in DMSO (60 mL). Then, K2CO3(9.91 g, 71.7 mmol, 1.5 equiv) was added and the mixture was heated to 80C and stirred at this temperature for 10 hrs. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined and evaporated to remove the solvent, further purified by column chromatography, resulting in compound 4 as a yellow solid (3.5 g)

Reference： [1]Patent: WO2016/33304,2016,A1 .Location in patent: Paragraph 0122

61
[ 454-73-9 ]
N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2016/38552,2016,A1

62
[ 454-73-9 ]
N-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethyl)phenyl)-2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetamide [ No CAS ]

Reference： [1]Patent: WO2016/38552,2016,A1

63
[ 454-73-9 ]
[ 652-67-5 ]
C₂₀H₁₄F₆N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60 mmol		(1) at the normal temperature, to is equipped with a mechanical stirrer, condenser and nitrogen inlet and outlet 500 ml three-necked round bottom flask is added 100 mmol different mountain ash alcohol and 150 mmol N, N - dimethyl formamide, after stir added to the solution 230 mmol calcium silicide, heating to 60 C and stirring 11 hours; slowly adding 215 mml of 3 - fluoro -5 - nitro-benzotrifluoride, for 70 C reaction 14 hours; after cooling to room temperature, the reaction mixture is slowly poured into rapidly stirred in the distilled water, filtered, the solid separated out for washing by deionized water 3 times, for 80 C drying 10 hours recrystallization with methanol, to obtain the isosorbide derivative containing trifluoromethyl benzene structure of the dinitro monomer: brown 2, 5 - di (3 - trifluoromethyl -5 - nitrophenoxy) -1: 4; 3:6 - second dehydration - D - sorbitol 60 mmol

Reference： [1]Patent: CN107129504,2017,A .Location in patent: Paragraph 0043; 0047; 0051

64
[ 454-73-9 ]
[ 652-67-5 ]
C₂₀H₁₈F₆N₂O₄ [ No CAS ]

Reference： [1]Patent: CN107129504,2017,A

65
[ 454-73-9 ]
[ 150-76-5 ]
1-(4-methoxyphenoxy)-3-nitro-5-(trifluoromethyl)benzene [ No CAS ]