[ CAS No. 367-86-2 ] {[proInfo.proName]}

Name: 367-86-2|4-Fluoro-3-Nitrobenzotrifluoride|98%
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2D 3D

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Quality Control of [ 367-86-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 367-86-2 ]

Product Details of [ 367-86-2 ]

CAS No. :	367-86-2	MDL No. :	MFCD00007059
Formula :	C₇H₃F₄NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HLDFCCHSOZWKAA-UHFFFAOYSA-N
M.W :	209.10	Pubchem ID :	67778
Synonyms :

Calculated chemistry of [ 367-86-2 ]

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) :	-5.99 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	2.24
Log Po/w (WLOGP) :	4.33
Log Po/w (MLOGP) :	2.38
Log Po/w (SILICOS-IT) :	1.17
Consensus Log Po/w :	2.3

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.73
Solubility :	0.387 mg/ml ; 0.00185 mol/l
Class :	Soluble
Log S (Ali) :	-2.84
Solubility :	0.304 mg/ml ; 0.00145 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 :	1.86

Safety of [ 367-86-2 ]

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 [ 367-86-2 ]

* 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 [ 367-86-2 ]
Downstream synthetic route of [ 367-86-2 ]

[ 367-86-2 ] Synthesis Path-Upstream 1~15

1
[ 367-86-2 ]
[ 400-98-6 ]

Reference： [1] Tetrahedron, 2010, vol. 66, # 38, p. 7642 - 7650

2
[ 367-86-2 ]
[ 1496-40-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 627 - 640
[2] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 97 - 109

3
[ 121-17-5 ]
[ 367-86-2 ]

Reference： [1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6406 - 6411
[2] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6406 - 6411
[3] Advanced Synthesis and Catalysis, 2008, vol. 350, # 17, p. 2677 - 2682
[4] Tetrahedron Letters, 1987, vol. 28, # 1, p. 111 - 114
[5] Journal of the American Chemical Society, 1956, vol. 78, p. 6034,6037
[6] Tetrahedron Letters, 1987, vol. 28, # 1, p. 111 - 114
[7] Patent: US4424396, 1984, A,

4
[ 402-44-8 ]
[ 367-86-2 ]

Reference： [1] Journal of the Chemical Society, 1949, p. Spl. 113
[2] Journal of the American Chemical Society, 1956, vol. 78, p. 6034,6037
[3] Journal of the American Chemical Society, 1961, vol. 83, p. 4564 - 4571

5
[ 121-17-5 ]
[ 367-86-2 ]
[ 346-41-8 ]

Reference： [1] Journal of the American Chemical Society, 1956, vol. 78, p. 6034,6037

6
[ 121-17-5 ]
[ 367-86-2 ]
[ 32137-19-2 ]
[ 394-25-2 ]
[ 40700-38-7 ]
[ 400-99-7 ]

Reference： [1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6406 - 6411

7
[ 352-32-9 ]
[ 367-86-2 ]

Reference： [1] Journal of the Chemical Society, 1949, p. Spl. 113

8
[ 402-42-6 ]
[ 367-86-2 ]

Reference： [1] Journal of the Chemical Society, 1949, p. Spl. 113

9
[ 367-86-2 ]
[ 535-52-4 ]

Yield	Reaction Conditions	Operation in experiment
73.4%	With hydrogenchloride; stannous chloride; sodium hydrogencarbonate In methanol	[Reference example 16] Synthesis of Compound 16 12 N HCl (3.89 mL, 46.6 mmol) and SnCl₂ (4.76 g, 25.1 mmol) were added sequentially at 0°C to a methanol (5 mL) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.50 g, 7.17 mmol). The mixture was left to room temperature and then stirred overnight. A saturated aqueous solution of sodium bicarbonate was added to the mixture, followed by suction filtration. The mixture was subjected to extraction three times with ethyl acetate. The thus extracted organic mixture was washed with saturated sodium chloride solution, dried on anhydrous sodium sulfate, subjected to suction filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1), so that 2-fluoro-5-(trifluoromethyl)aniline (942 mg, 73.4percent) was obtained as orange oil. The results of TLC and ¹H NMR (CDCl₃, 400 MHz) are as follows. TLC R_f 0.37 (hexane/ethyl acetate = 10/1); ¹H NMR (CDCl₃ 400 MHz) δ 3.90 (s, 2H, NH₂), 6.96-7.26 (m, 3H, aromatic).

Reference： [1] Chemistry - A European Journal, 2016, vol. 22, # 46, p. 16513 - 16521
[2] Patent: EP2279750, 2011, A1,
[3] Journal of the Chemical Society, 1949, p. Spl. 113
[4] Journal of the American Chemical Society, 1956, vol. 78, p. 6034,6037
[5] Journal of Agricultural and Food Chemistry, 1996, vol. 44, # 11, p. 3643 - 3652

10
[ 367-86-2 ]
[ 7439-89-6 ]
[ 535-52-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogenchloride; sodium hydrogencarbonate In methanol; diethyl ether	Reference Example 1 Production of 2-fluoro-5-trifluoromethylaniline Twenty grams of 3-nitro-4-fluorobenzotrifluoride was dissolved in 50 ml of methanol. An iron powder (16 g) was added and concentrated hydrochloric acid was added dropwise with stirring. The reaction mixture was stirred overnight, followed by addition of sodium bicarbonate for neutralization. Then diethyl ether was added, and the insolubles were filtered off with cerite. The ether phase was separated, dried and concentrated under reduced pressure, giving 14 g of the contemplated product (yield 82percent).

Reference： [1] Patent: EP1243584, 2002, A1,

11
[ 121-17-5 ]
[ 367-86-2 ]
[ 32137-19-2 ]
[ 394-25-2 ]
[ 40700-38-7 ]
[ 400-99-7 ]

Reference： [1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6406 - 6411

12
[ 367-86-2 ]
[ 349-65-5 ]

Reference： [1] Journal of the Chemical Society, 1949, p. Spl. 113

13
[ 367-86-2 ]
[ 78068-85-6 ]

Reference： [1] Patent: EP163230, 1996, B2,

14
[ 367-86-2 ]
[ 182289-81-2 ]

Reference： [1] Journal of Agricultural and Food Chemistry, 1996, vol. 44, # 11, p. 3643 - 3652

15
[ 367-86-2 ]
[ 218156-96-8 ]

Reference： [1] European Journal of Medicinal Chemistry, 2017, vol. 134, p. 97 - 109

[ 367-86-2 ] Synthesis Path-Downstream 1~81

1
[ 367-86-2 ]
[ 535-52-4 ]

Yield	Reaction Conditions	Operation in experiment
73.4%	With hydrogenchloride; stannous chloride; sodium hydrogencarbonate; In methanol;	[Reference example 16] Synthesis of Compound 16 12 N HCl (3.89 mL, 46.6 mmol) and SnCl2 (4.76 g, 25.1 mmol) were added sequentially at 0C to a methanol (5 mL) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.50 g, 7.17 mmol). The mixture was left to room temperature and then stirred overnight. A saturated aqueous solution of sodium bicarbonate was added to the mixture, followed by suction filtration. The mixture was subjected to extraction three times with ethyl acetate. The thus extracted organic mixture was washed with saturated sodium chloride solution, dried on anhydrous sodium sulfate, subjected to suction filtration, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1), so that 2-fluoro-5-(trifluoromethyl)aniline (942 mg, 73.4%) was obtained as orange oil. The results of TLC and 1H NMR (CDCl3, 400 MHz) are as follows. TLC Rf 0.37 (hexane/ethyl acetate = 10/1); 1H NMR (CDCl3 400 MHz) delta 3.90 (s, 2H, NH2), 6.96-7.26 (m, 3H, aromatic).

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 16513 - 16521
[2]Patent: EP2279750,2011,A1
[3]Journal of the Chemical Society,1949,p. Spl. 113
[4]Journal of the American Chemical Society,1956,vol. 78,p. 6034,6037
[5]Journal of Agricultural and Food Chemistry,1996,vol. 44,p. 3643 - 3652

2
[ 367-86-2 ]
[ 394-25-2 ]

Reference： [1]Journal of the Chemical Society,1949,p. Spl. 113

3
[ 21230-43-3 ]
[ 367-86-2 ]
[ 79291-41-1 ]

Reference： [1]Journal of Medicinal Chemistry,1989,vol. 32,p. 2573 - 2582

4
[ 121-17-5 ]
[ 367-86-2 ]
[ 32137-19-2 ]
[ 394-25-2 ]
[ 40700-38-7 ]
[ 400-99-7 ]
C₁₄H₆F₇NO₃ [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1991,vol. 56,p. 6406 - 6411

5
[ 2039-66-9 ]
[ 367-86-2 ]
2-[2-(2-Nitro-4-trifluoromethyl-phenylamino)-ethyl]-phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In acetonitrile Heating; other solvent;

Reference： [1]Meanwell, Nicholas A.; Sit, Sing-Yuen; Gao, Jinnian; Boissard, Christopher G.; Lum-Ragan, Janet; Dworetzky, Steven I.; Gribkoff, Valentin K. [Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 14, p. 1641 - 1646]

6
[ 367-86-2 ]
rac-phenylalaninol [ No CAS ]
[ 2040-76-8 ]
3-benzyl-7-trifluoromethyl-3,4-dihydro-2<i>H</i>-quinoxaline-1-carboxylic acid phenylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multistep reaction;

Reference： [1]Krchnak, Viktor; Smith, Jennifer; Vagner, Josef [Collection of Czechoslovak Chemical Communications, 2001, vol. 66, # 7, p. 1078 - 1106]

7
[ 7651-83-4 ]
[ 367-86-2 ]
7-(2-nitro-4-trifluoromethyl-phenoxy)-isoquinoline [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 1657 - 1661

8
[ 367-86-2 ]
[ 62-53-3 ]
[ 2715-01-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine In N,N-dimethyl-formamide at 125℃; for 16h;

Reference： [1]Yun, Young K.; Porco Jr., John A.; Labadie, Jeff [Synlett, 2002, # 5, p. 739 - 742]

9
[ 367-86-2 ]
[ 149270-12-2 ]
[ 440634-04-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium hydrogencarbonate In ethanol; water for 6h; Heating;

Reference： [1]Amblard, Muriel; Calmes, Monique; Roques, Virginie; Tabet, Samuel; Loffet, Albert; Martinez, Jean [Organic Preparations and Procedures International, 2002, vol. 34, # 4, p. 405 - 415]

10
[ 367-86-2 ]
[ 74-89-5 ]
[ 20200-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dichloromethane; water at 20℃; for 14h;
	In ethanol Heating;
	In 1-methyl-pyrrolidin-2-one; water at 20℃; Cooling with ice;	1 Reference Production Example 1; To a mixture of 2.09 g of 4-fluoro-3-nitrobenzo trifluoride and 20 ml of N-methylpyrrolidone was added 2.33 g of a 40% methylamine aqueous solution under ice cool, and the mixture was heated up to room temperature and stirred for 1 hour. Water was poured, and the deposited precipitate was filtrated, then, washed with water, then, dried under reduced pressure to obtain 2.0 g of N-methyl-2-nitro-4-trifluoromethylaniline .1H-NMR (CDCl3) δ: 8.48 (s, IH), 8.28(br s, IH), 7.65 (dd, J=9.0, 2.1Hz, IH), 6.94 (d, J=9.0Hz, IH), 3.09 (d, J=5.1Hz, 3H)

In dimethyl sulfoxide at 20℃; for 3h; Inert atmosphere;

Reference： [1]Seth, Punit P.; Robinson, Dale E.; Jefferson, Elizabeth A.; Swayze, Eric E. [Tetrahedron Letters, 2002, vol. 43, # 41, p. 7303 - 7306]
[2]Gong, Baoqing; Hong, Feng; Kohm, Cory; Bonham, Lynn; Klein, Peter [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 6, p. 1455 - 1459]
[3]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - WO2010/125985, 2010, A1 Location in patent: Page/Page column 236
[4]Dong, Yaxi; Breit, Bernhard [Organic Letters, 2021, vol. 23, # 17, p. 6765 - 6769]

11
[ 367-86-2 ]
[ 402-54-0 ]
[ 7205-98-3 ]
phenyl (5'-trifluoromethyl-2'-nitrophenyl)(4''-trifluoromethyl-2''-nitrophenyl)methyl sulfone [ No CAS ]

Reference： [1]Organic Letters,2004,vol. 6,p. 4957 - 4960

12
[ 367-86-2 ]
[ 7205-98-3 ]
[ 100-00-5 ]
phenyl (5'-chloro-2'-nitrophenyl)(4''-trifluoromethyl-2''-nitrophenyl)methyl sulfone [ No CAS ]

Reference： [1]Organic Letters,2004,vol. 6,p. 4957 - 4960

13
[ 109-01-3 ]
[ 367-86-2 ]
[ 315239-67-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran at 70℃; for 14h;
	With sodium hydrogencarbonate In tetrahydrofuran at 20℃;	18.1 Step 1. Preparation of 1-Methyl-4-(2-nitro-4- trifluoromethyl-phenyl) -piperazine; Example 18 was prepared in accordance to a procedure described in Collins, et. al. , Tetrahedron, 48, No. 37, pp 7887-7898,1992. To a solution of I-Fluoro-2-nitro-4- trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added 1-Methyl-piperazine (0.64 mL, 5.74 mmol). The solution turned bright yellow. NaHC03 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS. The reaction was filtered and concentrated before being taken up in CH2Cl2 and H20. The organic layer was separated, dried with MgS04, filtered, and concentrated to afford the title compound as an orange-brown oil.
	With potassium carbonate In N,N-dimethyl-formamide at 120℃; for 6h; Inert atmosphere;

With potassium carbonate In N,N-dimethyl-formamide at 0 - 80℃; for 4h;

General Protocol D. General procedure: N,N-Diethylbenzene-1,2-diamine (73). K2CO3 (1.47g, 12.0mmol) was added to 1-fluoro-2-nitrobenzene 8a (0.22mL, 2.13mmol) and N,N-diethylamine (0.99mL, 9.6mmol) in DMF (7.5mL) at 0°C. The reaction was stirred at 80°C for 4h. The reaction was diluted with EtOAc (20mL), washed with water (2×10mL) and then saturated brine (20mL). The organic layers were separated and dried with MgSO4 and concentrated in vacuo. The orange crude residue was added to a stirred solution of EtOH (20mL). The reaction atmosphere was evacuated and backfilled three times with nitrogen gas before the addition of zinc (1.4g, 21mmol) and ammonium chloride (1.14g, 21mmol). The reaction was heated to reflux for 16h before being filtered through Celite and washed with EtOH (30mL). The reaction mixture was concentrated to dryness and purified using silica chromatography eluting with 25% EtOAc/heptane to obtain 73 as a brown oil (107.5mg, 49%). 1H NMR (CDCl3, 300MHz) δ 7.02 (d, J 7.7Hz, 1H), 6.93 (t, J 7.6Hz, 1H), 6.79-6.66 (m, 2H), 2.95 (q, J 6.9Hz, 4H), 0.98 (t, J 7.0Hz, 6H). MS m/z (%) [M+H]+ 165 (100).

Reference： [1]Cee, Victor J.; Albrecht, Brian K.; Geuns-Meyer, Stephanie; Hughes, Paul; Bellon, Steve; Bready, James; Caenepeel, Sean; Chaffee, Stuart C.; Coxon, Angela; Emery, Maurice; Fretland, Jenne; Gallant, Paul; Gu, Yan; Hodous, Brian L.; Hoffman, Doug; Johnson, Rebecca E.; Kendall, Richard; Kim, Joseph L.; Long, Alexander M.; McGowan, David; Morrison, Michael; Olivieri, Philip R.; Patel, Vinod F.; Polverino, Anthony; Powers, David; Rose, Paul; Wang, Ling; Zhao, Huilin [Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 627 - 640]
[2]Current Patent Assignee: AMGEN INC - WO2005/113494, 2005, A2 Location in patent: Page/Page column 95-96
[3]Maben, Zachary; Arya, Richa; Rane, Digamber; An, W. Frank; Metkar, Shailesh; Hickey, Marc; Bender, Samantha; Ali, Akbar; Nguyen, Tina T.; Evnouchidou, Irini; Schilling, Roger; Stratikos, Efstratios; Golden, Jennifer; Stern, Lawrence J. [Journal of Medicinal Chemistry, 2020, vol. 63, # 1, p. 103 - 121]
[4]Bailey, Brodie L.; Nguyen, William; Ngo, Anna; Goodman, Christopher D.; Gancheva, Maria R.; Favuzza, Paola; Sanz, Laura M.; Gamo, Francisco-Javier; Lowes, Kym N.; McFadden, Geoffrey I.; Wilson, Danny W.; Laleu, Benoît; Brand, Stephen; Jackson, Paul F.; Cowman, Alan F.; Sleebs, Brad E. [Bioorganic Chemistry, 2021, vol. 115]

14
[ 367-86-2 ]
[ 4543-96-8 ]
[ 926277-94-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium hydrogencarbonate In tetrahydrofuran at 20℃; for 1h;
	With sodium hydrogencarbonate In tetrahydrofuran at 20℃;	6.1 Example 6Synthesis of V-β-fdimethylamino^propyO-λ^-methvM-ftrifluoromethvQbenzene-1,2-diamineStep 1 : The title compound was made using a procedure described in Collins, et. al., Tetrahedron, Vol. 48, No. 37, pp 7887-7898, 1992. To a solution of 1 -fluoro-2-nitro-4- EPO trifluoromethyl-benzene (1.0 g, 4.78 mmol) in dry THF (24 mL) was added N'.N'.N3- trimethylpropane- 1,3 -diamine (0.64 mL, 5.7 mmol). The solution turned bright yellow. NaHCO3 (1.1 g, 13 mmol) was added and the reaction was stirred at room temperature and monitored by LCMS. The reaction was filtered and concentrated before being taken up in CH2CU and H2O. The organic layer was separated, dried with MgSO4, filtered, and concentrated to afford the title compound as an orange-brown oil.

Reference： [1]Hodous, Brian L.; Geuns-Meyer, Stephanie D.; Hughes, Paul E.; Albrecht, Brian K.; Bellon, Steve; Bready, James; Caenepeel, Sean; Cee, Victor J.; Chaffee, Stuart C.; Coxon, Angela; Emery, Maurice; Fretland, Jenne; Gallant, Paul; Gu, Yan; Hoffman, Doug; Johnson, Rebecca E.; Kendall, Richard; Kim, Joseph L.; Long, Alexander M.; Morrison, Michael; Olivieri, Philip R.; Patel, Vinod F.; Polverino, Anthony; Rose, Paul; Tempest, Paul; Wang, Ling; Whittington, Douglas A.; Zhao, Huilin [Journal of Medicinal Chemistry, 2007, vol. 50, # 4, p. 611 - 626]
[2]Current Patent Assignee: AMGEN INC - WO2008/57280, 2008, A1 Location in patent: Page/Page column 34-35

15
[ 367-86-2 ]
[ 1496-40-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 627 - 640
[2]European Journal of Medicinal Chemistry,2017,vol. 134,p. 97 - 109
[3]Journal of Medicinal Chemistry,2020,vol. 63,p. 103 - 121

16
[ 367-86-2 ]
[ 35203-49-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1455 - 1459
[2]Tetrahedron Letters,2002,vol. 43,p. 7303 - 7306
[3]Organic Letters,2021,vol. 23,p. 6765 - 6769

17
[ 367-86-2 ]
[ 1651-43-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N-methylmorpholine / dimethylformamide / 16 h / 125 °C 2: H₂ / 10 percent Pd/C / 2-methoxy-ethanol

Reference： [1]Yun, Young K.; Porco Jr., John A.; Labadie, Jeff [Synlett, 2002, # 5, p. 739 - 742]

18
[ 367-86-2 ]
[ 349-65-5 ]

Reference： [1]Journal of the Chemical Society,1949,p. Spl. 113

19
anhydrous calcium chloride [ No CAS ]
[ 367-86-2 ]
[ 78068-85-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 6 Into a 200 ml glass reactor, 200 g of 4-fluoro-3-nitrobenzotrifluoride and 5.3 g of anhydrous calcium chloride were charged, and chlorine gas was introduced at a rate of 27 g/hr at 180C under a pressure of 7 kg/cm2for 6 hours, whereby the conversion of the starting material was 94.6%, and the selectivity for 3-chloro-4-fluorobenzotrifluoride was 98.5%. Then, the reaction solution was washed with water and then distilled to obtain 149 g of 3-chloro-4-fluorobenzotrifluoride having a purity of 99.8%.

Reference： [1]Patent: EP163230,1996,B2

20
[ 367-86-2 ]
[ 151103-08-1 ]
3-(2-nitro-4-trifluoromethyl-phenoxy)-4-difluoromethoxy benzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride; In dimethyl sulfoxide; at 160℃; for 18h;	A solution of <strong>[151103-08-1]4-difluoromethoxy-3-hydroxybenzaldehyde</strong> (2.0 gm, 10.63 mmol) in DMSO (5 ml) was added to a stirred suspension of potassium fluoride (0.740 gm, 12.76 mmol) in dry DMSO (10 ml). A solution of 4-fluoro-3-nitrobenzotrifluoride (3.22 gm, 10.63 mmol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 160C for 18 h. The reaction mixture was cooled to room temperature and the contents were poured into water (100 ml) and extracted with ethyl acetate (25 ml x 3). The organic extracts were combined and washed with 1N sodium hydroxide (25 ml x 2), water and brine and dried over anhydrous sodium sulfate. The dried organic layer was concentrated in vacuo to obtain the product as a pale yellow solid (2. 2GM). IR (KBr) 3092,2878, 1697,1629, 1537,1352, 1331,1280, 1158,1134, 1075, 827 CM-1 'H NMR (300 MHz, DMSO) 8 7.23 (d, 1 H, J= 8.7 Hz), 7.35 (t, 1 H, J= 72.6 Hz), 7.63 (d, 1H, J= 8.1 Hz), 7.86 (d, 1 H, J= 2.1 Hz), 7.93 (dd, 1H, J= 8.4 Hz, 1.8 Hz), 7.99 (dd, 1H, J= 8.7 Hz, 2.4 Hz), 8.48 (d, 1H, J= 2.4 Hz), 9.94 (s, 1H).

Reference： [1]Patent: WO2004/37805,2004,A1 .Location in patent: Page 48

21
[ 2955-88-6 ]
[ 367-86-2 ]
[ 862873-84-5 ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 50℃;	5 mmol 4-Fluoro-3-nitrobenzotrifluoride, 5-7.5 mmol substituted 2-amino ethanol (R (CH2) 2OH) and 11. 5-12.5 mmol cesiumcarbonate are dissolved in DMF and stirred at room temperature or 50-80 °C until a full conversion is achieved. Depending from from the reaction route chosen, the reaction mixture is worked up according the following variants: Variant A : the reaction mixture is filtered and the residue rinsed with ethyl acetate. The filtrate is diluted with ethyl acetate, washed 3x with water and 1 x with brine, dried over Na2SO4, filtered and evaporated. The residue is purified by column chromatography (silica gel, eluent : DCM/MeOH 0-5% in 45min). Variant B: the reaction mixture is filtered by suction and rinsed with little DMF. The filtrate is evaporated. The oily residue is taken up in 100 mi water and extracted 3x with acyl acetate. The combined organic phases are washed 2x with water and 1x with brine, dried over Na2SO4, and evaporated. The residue is purified by column chromatography (silica gel, eluent : DCM/MeOH 0-5% in 45min). Variant C: the reaction mixture is filtered by suction and rinsed with little DMF. The filtrate is evaporated. The all the residue is taken up in 100 ml water and extracted 3x with acyl acetate. The combined organic phases are washed 2x with water and 1x with brine, dried over Na2SO4, and evaporated. Substituents, reaction conditions and yields : 4b: R = (CH2) 2N (CH2) 4; 50 °C, over night, working up procedure: A, 71 %, yellow oil 4c: R = (CH2) 2N (CH3) 2; room temperature, over night, working up procedure: A, 85 %, yellow oil 4d: R = (CH2) 2N (C2H5) 2; 70 °C, 2 h, working up procedure: A, 90 %, yellow oil 4e: R (CH2) 2N (CH2) 20 (CH2) 2; 50 °C, over night, working up procedure: B, 74 %, red-brown oil 4f: R = (CH2) 2N (CH2) 2NBoc (CH2) 2 ; 50 °C, over night, working up procedure: A, 84 %, yellow oil 4g: R = (CH2) 2NBocCH (CH3) 2; 80 °C, 4 h, working up procedure : C, 65 %, yellow oil 4h: R = CH2C (CH3) 2NBoc; 50 °C, 2.5 h, working up procedure: B, 78 %, yellow crystals Manufacture according to the general working procedure for the compounds 4b-4h: 4i : 80 °C, 5 h, working up procedure: A, 62 %, yellow oil
	Stage #1: 1-pyrrolidineethanol With sodium hydride In tetrahydrofuran for 0.0833333h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In tetrahydrofuran	29.1 Step 1. Preparation of 1-[2-(2-Nitro-4-trifluoromethyl- phenoxy) -ethyl]-pyrrolidine; To a suspension of NaH (60%, 248 mg, 6.21 mmol) in dry THF was added 2-Pyrrolidin-1-yl-ethanol (0.68 mL, 5.74 mmol). Bubbling was observed. The reaction was stirred for 5 minutes, at which time I-Fluoro-2-nitro-4-trifluoromethyl- benzene (0.67 mL, 4.79 mmol) was added. The solution turned red, and LCMS indicated completion of the reaction. The reaction was quenched by addition of H20, and the mixture was extracted with EtOAc, dried with MgS04, filtered, and concentrated to afford the title compound as an orange oil.

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2005/75425, 2005, A2 Location in patent: Page/Page column 181-182
[2]Current Patent Assignee: AMGEN INC - WO2005/113494, 2005, A2 Location in patent: Page/Page column 100-101

22
[ 3891-07-4 ]
[ 367-86-2 ]
[ 862873-98-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With caesium carbonate In DMF (N,N-dimethyl-formamide) at 50℃; for 5.5h;	0.67 ml (4.6 mmol) 4-Fluoro-3-nitrobenzotrifluoride are dissolved in DMF, treated with 1. 08 g (5.6 mmol) N- (2-Hydroxyethyl) phthalimide and 3.82 g (11.6 mmol) cesium carbonate and stirred for 5.5 h at 50 °C. The reaction mixture is filtered by suction and the filtrate is evaporated to dryness. The residue is taken up in ethyl acetate and washed several times with water. The organic phase is dried over Na2SO4, filtered and evaporated to dryness. Yield : 1. 15 g (61 %) 4k, yellow solid

Reference： [1]Current Patent Assignee: MERCK KGAA - WO2005/75425, 2005, A2 Location in patent: Page/Page column 184

23
[ 367-86-2 ]
[ 143-33-9 ]
[ 778-94-9 ]

Yield	Reaction Conditions	Operation in experiment
47%	tetrabutylammomium bromide; In acetonitrile; at 20 - 80℃; for 13h;Product distribution / selectivity;	The above experimental procedure was repeated at 80[deg.] C. but in the presence of a catalyst (0.2 equivalent) and acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol). The catalysts used were hexabutylguanidinium chloride or tetrabutylammonium bromide. The results (shown in Table 3) indicate that the use of hexabutylguanidinium chloride as catalyst gave very good selectivity especially in tetrahydrofuran or benzonitrile.
45%	In acetonitrile; at 20 - 80℃; for 6h;Product distribution / selectivity;	EXAMPLE 1; Preparation of 4-cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using an Alkali Metal Cyanide (Process (a)); [0071] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide or potassium cyanide (1 mmol), and acetonitrile or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours at 80[deg.] C. to give the title product. The results are shown in Table 1, from which it can me seen that the use of sodium cyanide gives good selectivity.; EXAMPLE 2; Preparation of 4-Cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using Sodium Cyanide: Effect of Solvent, Temperature and Catalyst (Process (a)); [0072] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide (1 mmol) and N,N-dimethylformamide, acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours to give the title product. The results are shown in Table 2, from which it may be observed that benzonitrile (PhCN) gave the highest selectivity.
40%	1,1,2,2,3,3-Hexabutylguanidiniumchlorid; In tetrahydrofuran; at 20 - 80℃; for 6h;Product distribution / selectivity;	The above experimental procedure was repeated at 80[deg.] C. but in the presence of a catalyst (0.2 equivalent) and acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol). The catalysts used were hexabutylguanidinium chloride or tetrabutylammonium bromide. The results (shown in Table 3) indicate that the use of hexabutylguanidinium chloride as catalyst gave very good selectivity especially in tetrahydrofuran or benzonitrile.

40%	1,1,2,2,3,3-Hexabutylguanidiniumchlorid; In benzonitrile; at 20 - 80℃; for 6h;Product distribution / selectivity;	The above experimental procedure was repeated at 80[deg.] C. but in the presence of a catalyst (0.2 equivalent) and acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol). The catalysts used were hexabutylguanidinium chloride or tetrabutylammonium bromide. The results (shown in Table 3) indicate that the use of hexabutylguanidinium chloride as catalyst gave very good selectivity especially in tetrahydrofuran or benzonitrile.
39%	In tetrahydrofuran; at 20 - 80℃; for 6h;Product distribution / selectivity;	EXAMPLE 2; Preparation of 4-Cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using Sodium Cyanide: Effect of Solvent, Temperature and Catalyst (Process (a)); [0072] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide (1 mmol) and N,N-dimethylformamide, acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours to give the title product. The results are shown in Table 2, from which it may be observed that benzonitrile (PhCN) gave the highest selectivity.
36%	In benzonitrile; at 20 - 80℃; for 6h;Product distribution / selectivity;	EXAMPLE 1; Preparation of 4-cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using an Alkali Metal Cyanide (Process (a)); [0071] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide or potassium cyanide (1 mmol), and acetonitrile or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours at 80[deg.] C. to give the title product. The results are shown in Table 1, from which it can me seen that the use of sodium cyanide gives good selectivity.; EXAMPLE 2Preparation of 4-Cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using Sodium Cyanide: Effect of Solvent, Temperature and Catalyst (Process (a)); [0072] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide (1 mmol) and N,N-dimethylformamide, acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours to give the title product. The results are shown in Table 2, from which it may be observed that benzonitrile (PhCN) gave the highest selectivity.
33%	1,1,2,2,3,3-Hexabutylguanidiniumchlorid; In acetonitrile; at 20 - 80℃; for 13h;Product distribution / selectivity;	The above experimental procedure was repeated at 80[deg.] C. but in the presence of a catalyst (0.2 equivalent) and acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol). The catalysts used were hexabutylguanidinium chloride or tetrabutylammonium bromide. The results (shown in Table 3) indicate that the use of hexabutylguanidinium chloride as catalyst gave very good selectivity especially in tetrahydrofuran or benzonitrile.
31 - 38%	In N,N-dimethyl-formamide; at 20 - 80℃; for 6h;Product distribution / selectivity;	EXAMPLE 2; Preparation of 4-Cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using Sodium Cyanide: Effect of Solvent, Temperature and Catalyst (Process (a)); [0072] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide (1 mmol) and N,N-dimethylformamide, acetonitrile, tetrahydrofuran or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours to give the title product. The results are shown in Table 2, from which it may be observed that benzonitrile (PhCN) gave the highest selectivity.

Reference： [1]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 7
[2]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 6-7
[3]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 7
[4]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 7
[5]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 7
[6]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 6-7
[7]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 7
[8]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 7

24
[ 367-86-2 ]
[ 151-50-8 ]
[ 778-94-9 ]

Yield	Reaction Conditions	Operation in experiment
38%	In acetonitrile; at 20 - 80℃; for 6h;Product distribution / selectivity;	EXAMPLE 1; Preparation of 4-cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using an Alkali Metal Cyanide (Process (a)); [0071] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide or potassium cyanide (1 mmol), and acetonitrile or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours at 80[deg.] C. to give the title product. The results are shown in Table 1, from which it can me seen that the use of sodium cyanide gives good selectivity.
26%	In benzonitrile; at 20 - 80℃; for 6h;Product distribution / selectivity;	EXAMPLE 1; Preparation of 4-cyano-3-nitrobenzotrifluoride from 4-Fluoro-3-nitrobenzotrifluoride Using an Alkali Metal Cyanide (Process (a)); [0071] A mixture of 4-fluoro-3-nitrobenzotrifluoride (1 mmol) and sodium cyanide or potassium cyanide (1 mmol), and acetonitrile or benzonitrile (1 ml/mmol) were mixed at 20[deg.] C. and heated for 6 hours at 80[deg.] C. to give the title product. The results are shown in Table 1, from which it can me seen that the use of sodium cyanide gives good selectivity.

Reference： [1]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 6-7
[2]Patent: US6635780,2003,B1 .Location in patent: Page/Page column 6-7

25
[ 367-86-2 ]
[ 51605-32-4 ]
4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-trifluoromethylphenyl)-1H-imidazole [ No CAS ]
4-Ethoxycarbonyl-5-methyl-1-(2-nitro-4-trifluoromethylphenyl)-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
42 g (84%)	With potassium carbonate; In acetonitrile;	Step a. 4-Ethoxycarbonyl-5-methyl-1-(2-nitro-4-trifluoromethylphenyl)-1H-imidazole A mixture of 4-fluoro-3-nitrobenzotrifluoride (20.5 ml, 146.5 mmol), ethyl 4-methyl-5-imidazolecarboxylate (23 g, 149.0 mmol), potassium carbonate (20.5 g, 148.5 mmol) and acetonitrile (200 ml) was stirred at 70° C. for 16 h. The solvent was removed under reduced pressure, and the residue submitted to flash chromatography on silica gel 60 eluding with toluene graduated to toluene/ethyl acetate (1:19) to give 42 g (84percent) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-trifluoromethylphenyl)-1H-imidazole. M.p. 139.5°-140.5° C. 1 H NMR (CDCl3): delta1.45 (t, 3H), 2.35 (s, 3H), 4.40 (q, 2H), 7.50 (s, 1H), 7.65 (d, 1H), 8.10 (dd, 1H), 8.45 (d, 1H).
42 g (84%)	With potassium carbonate; In acetonitrile;	Step a. 4-Ethoxycarbonyl-5-methyl-1-(2-nitro-4-trifluoromethylphenyl)-1H-imidazole A mixture of 4-fluoro-3-nitrobenzotrifluoride (20.5 ml, 146.5 mmol), ethyl 4-methyl-5-imidazolecarboxylate (23 g, 149.0 mmol), potassium carbonate (20.5 g, 148.5 mmol) and acetonitrile (200 ml) was stirred at 70°C for 16 h. The solvent was removed under reduced pressure, and the residue submitted to flash chromatography on silica gel 60 eluding with toluene graduated to toluene/ethyl acetate (1:19) to give 42 g (84percent) of 4-ethoxycarbonyl-5-methyl-1-(2-nitro-5-trifluoromethylphenyl)-1H-imidazole. M.p. 139.5-140.5°C.1H NMR (CDCl3): delta 1.45 (t, 3H), 2.35 (s, 3H), 4.40 (q, 2H), 7.50 (s, 1H), 7.65 (d, 1H), 8.10 (dd, 1H), 8.45 (d, 1H).

Reference： [1]Patent: US5741785,1998,A
[2]Patent: EP743945,2002,B1

26
[ 367-86-2 ]
[ 27532-96-3 ]
[ 877628-58-5 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium hydrogencarbonate; In dimethyl sulfoxide; at 50 - 100℃;	A mixture of 4-fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol), glycineester hydrochloride (201 mg, 1 .2 mmol) and NaHCO3 (128 mg, 2 mmol) in dry DMSO(1 ml) is stirred overnight at 50 or 65 C. In case the reaction is not complete a furtherheating at 85C to 100C for 3 h is necessary. The reaction is then cooled to rt andwater is added. The yellow to orange solid formed is filtered over a fritted funnel,rinsed thoroughly with water and dried under high vacuum. This yields the titlecompound (254 mg) in 79% as a yellow solid: ?R = 1.08 min (LC-3), ESI-MS (pos.):m/z 403.2 [M+2AcCN]+, m/z 321.56 [M+H]+, 'H-NMR (DMSO-d6): 5 (ppm) 1.44 (s,9H, ffiu), 4.23 (d, 2H, NHQkCOz), 7.08 (d, 1H, Har0m), 7.80 (dd, 1H, Ramm), 8.34 (br.s, lH,Harom),8.65(t, 1H,NH).

Reference： [1]Patent: WO2006/21418,2006,A1 .Location in patent: Page/Page column 162
[2]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4660 - 4664

27
[ 62414-68-0 ]
[ 367-86-2 ]
[ 1240200-66-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate In tetrahydrofuran at 75℃; for 14h;	77-V-1.1 To a 100-mL round bottom flask (RBF) was added (R)- piperidin-3-ol hydrochloride (1.29 g, 9.37 iranol), sodium bicarbonate (2.76 g, 32.8 iranol) , THF and 1-fluoro-2-nitro-4- (trifluoromethyl)benzene (1.31 ml, 9.37 mmol) . The yellow mixture was heated to 75°C. with a water-cooled reflux condensor and allowed to stir 14 h. The reaction- was EPO - Ill -filtered through a glass frit, rinsing with EtOAc, and concentrated in vacuo to give (R) -1- (2-nitro-4- (trifluoromethyl)phenyl)piperidin-3-ol as an orange oil.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2006/44823, 2006, A2 Location in patent: Page/Page column 110-111

28
[ 367-86-2 ]
[ 32673-41-9 ]
[ 1239985-88-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; In N,N-dimethyl-formamide; at 70℃;	To a solution of 1-fluoro-2-nitro-4- (trifluoromethyl)benzene (1.04 mL, 7.43 mmol) and (IH- pyrrol-3-yl)methanol hydrochloride salt (1.0 g, 7.43 mmol) in DMF (10 mL) was added Na2CO3 (2.36 g, 22.3 mmol) . The resulting mixture was heated at 7O0C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. The mixture was reconstituted in EtOAc (50 mL) and washed with 9% aq. Na2CO3 (10 mL) , brine (10 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (1- (2-nitro-4- (trifluoromethyl)phenyl) -IH-imidazol-4-yl)methanol .

Reference： [1]Patent: WO2006/44823,2006,A2 .Location in patent: Page/Page column 129

29
[ 367-86-2 ]
[ 3197-42-0 ]
[ 858126-24-6 ]

Yield	Reaction Conditions	Operation in experiment
99.2%	In N,N-dimethyl-formamide at 20℃; for 2h;	2-1 (S)-2-methylpiperidine (270 µl, 2.24 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (211 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate = 12/1). Thus, (S)-1-[2-nitro-4-(trifluoromethyl)phenyl]-2-methylpiperidine (286 mg, 99.2%) was yielded as an orange-colored oily material. TLC Rf 0.44 (hexane/ethyl acetate = 16/1).
94%	With triethylamine In dichloromethane at 20 - 35℃;	239.1 Step 1: (S)-2-methyl-1-(2-nitro-4-(trifluoromethyl)phenyl)piperidine: A mixture of 1-fluoro-2- nitro-4-(trifluoromethyl)benzene (250 µl, 1.79 mmol), (S)-2-methylpiperidine (250 µl, 2.13 mmol) and Et3N (0.6 ml, 4.30 mmol) in DCM (8 ml) was stirred at RT for 2 h and then at 35 °C overnight. The mixture was washed with 1 M HCl(aq) (10 ml), dried by passage through a phase separator and concentrated onto silica. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% DCM/isohexane) to afford the title compound (503 mg, 1.68 mmol, 94% yield, 96% purity) as an orange oil. UPLC-MS (Method 1) m/z 289.2 (M+H)+ at 1.87 min.1H NMR (500 MHz, DMSO-d6) d 8.14 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.8, 2.3 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 3.58 - 3.50 (m, 1H), 3.16 (ddd, J = 12.5, 8.5, 4.0 Hz, 1H), 2.82 (dt, J = 12.5, 4.6 Hz, 1H), 1.80 - 1.63 (m, 2H), 1.63 - 1.46 (m, 3H), 1.45 - 1.37 (m, 1H), 0.99 (d, J = 6.5 Hz, 3H).

Reference： [1]Current Patent Assignee: HAGIWARA (inventors) - EP1712242, 2006, A1 Location in patent: Page/Page column 32
[2]Current Patent Assignee: GREY WOLF THERAPEUTICS - WO2020/104822, 2020, A1 Location in patent: Page/Page column 94; 208-209

30
[ 367-86-2 ]
[ 4876-59-9 ]
[ 882679-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 75℃; for 12h;	To l-benzyl-<strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> (6.7 g, 23 mmol) was added Pd/C (10%, 2.4 g) under argon. Methanol (100 ml) was added via syringe, and H2 gas was introduced and the mixture stirred vigorously under an atmosphere of H2. After 48 h, the mixture was flushed with nitrogen, filtered through celite and concentrated to afford a mixture of starting material and <strong>[4876-59-9]N,N-dimethylpiperidin-4-amine dihydrochloride</strong> as a white solid. This solid was treated with l-Fluoro-2-nitro-4- trifluoromethyl-benzene (3.2 ml, 22.9 mmol), triethylamine (12.7 ml, 92 mmol), and 50 ml dry THF. The mixture was heated to 75 0C with a water-cooled reflux condenser for 12 h. The mixture was allowed to cool to ambient temperature, was filtered through a fritted funnel, and concentrated to an orange oil. The residue was purified by silica gel chromatography (MC/MeOH/cone. NH4OH) to give the desired product as an orange oil. MS (m/z) : 318.1 (M+H)+. Calc'd for C14H18F3N3O2: 317.31.

Reference： [1]Patent: WO2006/44823,2006,A2 .Location in patent: Page/Page column 147-148

31
[ 109-83-1 ]
[ 367-86-2 ]
[ 20200-22-0 ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; water	237.1 Synthesis of 3-{(2S,4S)-4-[4-(5-trifluoromethyl-1-methyl-2-benzimidazolyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine trihydrochloride (1) 4-Fluoro-3-nitrobenzotrifluoride (25 g) was dissolved in ethanol (50 mL), and 30% methylamine-ethanol solution (97.9 g)was gradually added dropwise under ice-cooling, and the mixture was stirred at room temperature for 40 min. The reaction mixture was added to water, and the precipitated solid was collected by filtration to give 4-methylamino-3-nitrobenzotrifluoride (25.5 g) as yellow crystals.

Reference： [1]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - EP1308439, 2003, A1

32
[ 367-86-2 ]
[ 7439-89-6 ]
[ 535-52-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With hydrogenchloride; sodium hydrogencarbonate; In methanol; diethyl ether;	Reference Example 1 Production of 2-fluoro-5-trifluoromethylaniline Twenty grams of 3-nitro-4-fluorobenzotrifluoride was dissolved in 50 ml of methanol. An iron powder (16 g) was added and concentrated hydrochloric acid was added dropwise with stirring. The reaction mixture was stirred overnight, followed by addition of sodium bicarbonate for neutralization. Then diethyl ether was added, and the insolubles were filtered off with cerite. The ether phase was separated, dried and concentrated under reduced pressure, giving 14 g of the contemplated product (yield 82%).

Reference： [1]Patent: EP1243584,2002,A1

33
[ 7311-95-7 ]
[ 367-86-2 ]
ethyl 2-(2-nitro-4-trifluoromethylanilino)benzo[b]thiophene-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		STARTING MATERIAL SYNTHESIS EXAMPLE 47 In the same manner as in Starting Material Synthesis Example 4 and using <strong>[7311-95-7]ethyl 2-aminobenzo[b]thiophene-3-carboxylate</strong> (5.0 g), 4-fluoro-3-nitrobenzotrifluoride (5.1 g) and dirnethyl sulfoxide (65 ml), ethyl 2-(2-nitro-4-trifluoromethylanilino)benzo[b]thiophene-3-carboxylate (12 g) was obtained.

Reference： [1]Patent: US6271225,2001,B1

34
[ 288-13-1 ]
[ 367-86-2 ]
[ 923945-86-2 ]

Yield	Reaction Conditions	Operation in experiment
81%	With N-ethyl-N,N-diisopropylamine In ethanol at 120℃; for 0.5h; Microwave irradiation;	10-1 Example 10-1: Procedure for introduction of substituted pyrazoles in ortho-position, exemplified with synthesis of l-(2-Nitro-4-trifluoromethylphenyl)-lH-pyrazole (41).; EPO l-Fluoro-2-nitro-4-trifluoromethylbenzene (209 mg, 1 mmol) was dissolved in ethanol (4.5 ml) in a 5 ml microwave reaction vessel. lH-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μL, 2 mmol) and a stir bar were added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave oven for 30 min at 120°C. TLC (Silica; Ηexanes/ethyl acetate, 4:1): Rf= 0.5 (40), 0.3 (41). The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Ηexanes/ethyl acetate) to afford compound 41 (206 mg, 81%). LC/MS (Method F): tR= 2.26 min, >95%, m/z (ESI+)= 258(MH+).
81%	With N-ethyl-N,N-diisopropylamine In ethanol	62 Example 62 Example 62 1-(2-Nitro-4-trifluoromethyl-phenyl)-1H-pyrazole (62) 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (209 mg, 1 mmol) was dissolved in EtOH (4.5 mL) in a 5 mL microwave reaction vessel. 1H-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μL, 2 mmol) and a stirrbar were added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave for 30 min at 120°C. The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Hexane: EtOAc) to afford the title compound 62 (206 mg, 81%). LC/MS >95%, m/z (ESI+)= 258(MH+).
81%	With N-ethyl-N,N-diisopropylamine In ethanol	51 1-(2-Nitro-4-trifluoromethyl-phenyl)-1H-pyrazole (51) Example 51 1-(2-Nitro-4-trifluoromethyl-phenyl)-1H-pyrazole (51) 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (209 mg, 1 mmol) was dissolved in EtOH (4.5 ml) in a 5 ml microwave reaction vessel. 1H-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μl, 2 mmol) and a stirrbar were added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave for 30 min at 120°C. The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Hexane: EtOAc) to afford the title compound 51 (206 mg, 81%). LC/MS >95%, m/z (ESI+)= 258(MH+).

81%	With N-ethyl-N,N-diisopropylamine In ethanol at 120℃; for 0.5h; microwave;	73 1-(2-Nitro-4-trifluoromethyl-phenyl)-1H-pyrazole (73) 1-Fluoro-2-nitro-4-trifluoromethyl-benzene (209 mg, 1 mmol) was dissolved in EtOH (4.5 mL) in a 5 mL microwave reaction vessel. 1H-pyrazole (83.5 mg, 1.2 mmol), DIPEA (329 μL, 2 mmol) and a stirrbar was added followed by sealing of the reaction vessel. The reaction mixture was then heated in the microwave for 30 min at 120° C. The reaction was concentrated in vacuo and the residue purified by flash chromatography (Silica, Hexane: EtOAc) to afford the title compound (206 mg, 81%). LC/MS>95%, m/z (ESI+)=258 (MH+).
62%	With potassium carbonate In N,N-dimethyl-formamide at 0 - 80℃; for 4h;	1-[2-Nitro-4-(trifluoromethyl)phenyl]pyrazole (104). K2CO3 (1.47g, 12.0mmol) was added to 1-fluoro-2-nitro-4-(trifluoromethyl)benzene 8b (0.14mL, 1mmol) and pyrazole (306mg, 1mmol) in DMF (7.5mL) at 0°C. The reaction was stirred at 80°C for 4h. The reaction was diluted with EtOAc (20mL), washed with water (2×10mL) and then saturated brine (20mL). The organic layers were separated and dried with MgSO4 and concentrated in vacuo. The crude residue was purified using silica chromatography eluting with DCM to obtain 104 as an orange crystalline solid (153mg, 62%). 1H NMR (CDCl3, 300MHz) δ 7.93 (d, J 8.5Hz, 1H), 7.83-7.72 (m, 3H), 6.54 (q, J 2.1Hz, 1H), 5.29 (d, J 1.7Hz, 1H). MS m/z (%) [M+H]+ 228 (100).
25%	With N-ethyl-N,N-diisopropylamine In acetonitrile Reflux;	30.1 Step 1: 1-(2-nitro-4-(trifluoromethyl)phenyl)pyrazole: A mixture of 1-fluoro-2-nitro-4- (trifluoromethyl)benzene (0.5 ml, 3.57 mmol), pyrazole (268 mg, 3.93 mmol) and DIPEA (1.3 ml, 7.44 mmol) in MeCN (15 ml) was heated underrefluxand stirred overnight. The mixture was concentrated onto silica and purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc/isohexane) to afford the title compound (237 mg, 0.908 mmol, 25% yield, 99% purity) as a light yellow oil. UPLC-MS (Method 1) m/z 258.1 (M+H)+at 1.38 min.1H NMR (500 MHz, DMSO-cfe) d 8.51 - 8.46 (m, 2H), 8.22 (dd, J = 8.5, 2.2 Hz, 1 H), 8.09 (d, J = 8.5 Hz, 1 H), 7.84 (d, J = 1.7 Hz, 1 H), 6.65 (t, J = 2.2 Hz, 1 H).
0.43 g	Stage #1: NH-pyrazole With potassium <i>tert</i>-butylate In dimethyl sulfoxide at 20℃; for 0.666667h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In dimethyl sulfoxide for 1.5h;	1 Example 1 1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-pyrazole Example 1 1-(2-nitro-4-(trifluoromethyl)phenyl)-1H-pyrazole To a solution of 1H-pyrazole (0.39 g) in dimethylsulfoxide (hereinafter abbreviated as DMSO) (5.2 mL) was added potassium tert-butoxide (0.7 g). The reaction mixture was stirred at room temperature for 40 minutes. To the reaction mixture was gradually added 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.1 g) and the reaction mixture was further stirred for 90 minutes. The reaction mixture was poured with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was purified on silica gel column chromatography (hexane : ethyl acetate = 10:1 → 2:1) to give the titled compound having the following physical characteristics (0.43 g). TLC : Rf 0.43 (Hexane : Ethyl Acetate = 3 : 1); 1H-NMR (DMSO-d6) : δ 6.61-6.64 (m, 1H), 7.82 (d, 1H), 8.07 (d, 1H), 8.20 (dd, 1H), 8.45-8.49 (m, 2H).

Reference： [1]Current Patent Assignee: MEDIVIR AB; JOHNSON & JOHNSON INC - WO2007/14922, 2007, A1 Location in patent: Page/Page column 75-76
[2]Current Patent Assignee: JOHNSON & JOHNSON INC; MEDIVIR AB - EP1881001, 2008, A1
[3]Current Patent Assignee: MEDIVIR AB; JOHNSON & JOHNSON INC - EP1881002, 2008, A1
[4]Current Patent Assignee: MEDIVIR AB - US2009/23758, 2009, A1 Location in patent: Page/Page column 61
[5]Bailey, Brodie L.; Nguyen, William; Ngo, Anna; Goodman, Christopher D.; Gancheva, Maria R.; Favuzza, Paola; Sanz, Laura M.; Gamo, Francisco-Javier; Lowes, Kym N.; McFadden, Geoffrey I.; Wilson, Danny W.; Laleu, Benoît; Brand, Stephen; Jackson, Paul F.; Cowman, Alan F.; Sleebs, Brad E. [Bioorganic Chemistry, 2021, vol. 115]
[6]Current Patent Assignee: GREY WOLF THERAPEUTICS - WO2020/225569, 2020, A1 Location in patent: Page/Page column 120
[7]Current Patent Assignee: ONO PHARMACEUTICAL CO LTD - EP2960234, 2015, A1 Location in patent: Paragraph 0181

35
[ 367-86-2 ]
[ 97-50-7 ]
C₁₅H₁₂ClF₃N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium fluoride; In ISOPROPYLAMIDE; at 150℃; for 0.166667h;Microwave irradiation;	EXAMPLE 1A A suspension of 1-fluoro-2-nitro-4-trifluoromethylbenzene (0.3 mL), 5-chloro-2,4-dimethoxyphenylamine (0.4 g) and potassium fluoride (0.2 g) in DMA (1.5 mL) at 150 C. was stirred under microwaves for 10 minutes, diluted with ethyl acetate, washed with water and concentrated. The concentrate was recrystallized from ethanol.

Reference： [1]Patent: US2007/105862,2007,A1 .Location in patent: Page/Page column 13

36
[ 367-86-2 ]
[ 290825-52-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: malonic acid dimethyl ester With sodium hydride In dimethyl sulfoxide at 100℃; for 1h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In dimethyl sulfoxide at 20 - 100℃; for 1h;	1 To prepare 6-trifluoromethyloxindole, first a 2L flask with a stir bar was charged with 45.8 ml (400 mmol) of dimethylmalonate and 500 ml of anhydrous DMSO. Next, 15.6 grams (391 mmol) of NaH was added in portions over 10 minutes to the vigorously stiring solution under an atmosphere of N2. That solution was heated to 1000C and stirred for lhour and then allowed to cool to ambient temperature. Next, 26 ml (186 mmol) of 4-fluoro-3-nitrobenzotrifluoride (CASNo. 367-86-2) was added using a syringe in one portion, which resulted in the previously colorless solution becoming dark brown/red. That colored solution was again heated to 1000C5 stirred for 1 hour and allowed to cool to ambient temperature. The solution was then poured into 1.3 L of saturated NH4Cl solution. The resulting mixture was Extracted with ethyl acetate followed by drying (using MgSO4) and concentration in vacuo, resulting in a red/orange oil that crystallized on standing overnight. Some of the excess dimethylmalonate was removed by decanting from the crystallized solid product. The crystallized solid product was then pulverized using a mortar and pestle, suspended in hexanes and filtered to remove the remaining dimethylmalonate.[0138] The resulting 2-(2-Nitro-4-trifluoromethyl-phenyl)-malonic acid dimethyl ester (56.1 g) was suspended in 200 ml of 6N HCl and stirred at reflux overnight. That solution was cooled, diluted with 500 ml of water, and filtered. The filtered solids were pulverized using mortar and pestil and suspended in water and filtered again, washing with copious water to remove traces of HCl. After drying in vacuo, the resuting solid (2-Nitro-4-trifluoromethyl-phenyl)-acetic acid was dissolved in 200 ml of AcOH to which was then added 5.4 grams of Palladium (10%) on Carbon. The resulting suspension was placed under one atmosphere of hydrogen (60 psi, Parr apparatus) for 4 hours. The suspenson was filtered through celite, washed with MeOH and CH2CI2, and concentrated in vacuo. Recrystallization from ethyl acetate/hexanes gave 27.19 g from the first crop, and 1.1 g from a second crop for a total yield of 28.29 g (76%, 3 steps) of 6-trifluoromethyloxindole (CASNo. 1735-89-3) as white prisms.

Reference： [1]Current Patent Assignee: LIGAND PHARMACEUTICALS INC - WO2007/106564, 2007, A2 Location in patent: Page/Page column 49-50

37
[ 288-32-4 ]
[ 367-86-2 ]
[ 25373-61-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 1H-imidazole With potassium <i>tert</i>-butylate In dimethyl sulfoxide for 0.0833333h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In dimethyl sulfoxide at 20℃; for 0.341667h;	171 Synthesis 1711 -(2-nitro-4-(trifluoromethyl)phenyl)-1 H-imidazoleA mixture of imidazole (0.997 g, 14.65 mmol) and terf-BuOK (1.722 g, 15.35 mmol) was put under Ar in a 100 mL and dissolved in dry DMSO (15 ml_) to give a colorless solution. After 5 min, 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.04 mL, 14.58 mmol) was added within 30 s, immediately leading to a darkening of the rm to black. A temperature rise was also noted. The black solution was stirred at RT for 20 min. Ice water (60 mL) and EtOAc (50 mL) were added, the organic layer was isolated, and the aqueous phase was extracted twice with 20 mL EtOAc. The organic layer was washed with H2O (2 x 30 mL), brine, dried, filtered and evaporated to give the title compound as an orange oil. Yield: 3.66 g (97%).1H-NMR (DMSO-d6), δ (ppm), J (Hz): 7.14 (s, 1 H, Harom), 7.49 (s, 1 H, Harom), 7.97 (d, J=8.4, 1 H1 Harom), 7.99 (s, 1 H, Haroϖi), 8.28 (d, J=8.4, 1 H, Harom), 8.59 (s, 1 H, HarOm); 13C- NMR (DMSO-d6), δ (ppm), J (Hz): 120.4, 122.7 (d, JFC=274), 122.9, 129.5 (d, JFC=34), 129.9, 130.0, 130.9, 133.4, 137.4, 144.5; 19F-NMR (DMSO-d6), δ (ppm): -60.8; LC-MS {m/z): 258.1 (M+H, 100), rt=1.37 min.
96%	With N-ethyl-N,N-diisopropylamine In acetonitrile for 20h; Heating / reflux;	1.1 Step 1: Synthesis of 1-[2-nitro-4-(trifluoromethyl)phenyl]-1 H-imidazole [Show Image] To a solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (15.00 g; 71.8 mmol; 1 eq) and diisopropylethylamine (12.5 mL; 71.8 mmol; 1 eq) in anhydrous acetonitrile (650 mL), imidazole (4.88 g ; 71,8 mmol ; 1 eq) is added under argon. The reaction mixture is allowed to stir under reflux for 20 hours until 1-fluoro-2-nitro-4-(trifluoromethyl)benzene has completely reacted. The crude mixture is concentrated under vacuum and the resulting powder dissolved in ethyl acetate (250 mL). The organic phase is then washed with water (100 mL), brine (100 mL) and dried over sodium sulfate to provide an orange powder after concentration under vacuum. Further purification by flash chromatography on silica gel (ethyl acetate/cyclohexane 5:5) afforded the title compound (17.7 g; 68.5 mmol; 96%) as a brown powder. 1H NMR (CDCl3), δ (ppm): 8.59 (s, 1H), 8.29 (dd, J = 8.3 and 1 Hz, 1 H), 7.99 (s, 1H), 7.97 (d, J = 8.3 Hz, 1 H), 7.49 (d, J = 1 Hz, 1 H), 7.14 (s, 1 H).
94%	With sodium hydroxide In dimethyl sulfoxide at 20℃; for 19h;

Reference： [1]Current Patent Assignee: CANCER RESEARCH UK; UNIVERSITY OF LONDON - WO2009/77766, 2009, A1 Location in patent: Page/Page column 196
[2]Current Patent Assignee: PHARMA OMNIUM INTERNATIONAL P O I - EP1972629, 2008, A1 Location in patent: Page/Page column 14
[3]Fauché, Kévin; Nauton, Lionel; Jouffret, Laurent; Cisnetti, Federico; Gautier, Arnaud [Chemical Communications, 2017, vol. 53, # 15, p. 2402 - 2405]

38
[ 10576-12-2 ]
[ 367-86-2 ]
[ 99907-59-2 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium Hydride 60% dispersion in mineral oil (2. [00G,] 49. [9MMOL)] was added to a stirred solution of ethyl [HYDROXYACETIMIDATE] (2) (4.29g, 41.6mmol) in DMF [(LOOML)] at OC under dry nitrogen atmosphere. After stirring at OC for 15 minutes, 4-fluoro-2-nitrobenzotrifluoride (1) (8.70g, 41. [6MMOL)] was added drop wise. The solution was stirred for an additional hour at OC and allowed to slowly warm to room temperature. Ethyl acetate and water were added to quench the reaction. The layers were separated and the organic layer was washed with sat. [NACL] solution, dried over sodium sulfate and concentrated. Purification on ISCO chromatography system using ethyl acetate/hexanes gradient gave 10.45g of 3. NMR (CDCL3) 8 s, [1H,] 8.3 ; d, 1H, 7.9 ; d, [1H,] 7.8 ; q, 2H, [4.] 2; s, 3H, 2.3 ; t, 3H, 1.4.

Reference： [1]Patent: WO2004/7462,2004,A1 .Location in patent: Page 3-4

39
[ 367-86-2 ]
[ 79069-14-0 ]
[ 1073176-29-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium hexamethylsilazane In tetrahydrofuran; toluene at 0℃; for 1h;

Reference： [1]Jones, Christopher R.; Qureshi, M. Khurram N.; Truscott, Fiona R.; Hsu, Shang-Te Danny; Morrison, Angus J.; Smith, Martin D. [Angewandte Chemie - International Edition, 2008, vol. 47, # 37, p. 7099 - 7102]

40
[ 367-86-2 ]
[ 153645-26-2 ]
[ 1073176-41-6 ]
[ 1073176-30-3 ]

Reference： [1]Angewandte Chemie - International Edition,2008,vol. 47,p. 7099 - 7102

41
[ 367-86-2 ]
[ 60-34-4 ]
[ 120940-43-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	In ethanol; water at 80℃;

Reference： [1]Location in patent: scheme or table Tomaszewski, Mirosław J.; Boisvert, Luc; Jin, Shujuan [Tetrahedron Letters, 2009, vol. 50, # 13, p. 1435 - 1437]

42
[ 109-00-2 ]
[ 367-86-2 ]
[ 361998-38-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	173 Synthesis 1733-(2-nitro-4-(trifluoromethy[)phenoxy)pyridineA brown solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (2.01 g, 9.61 mmol) and 3- 5 hydroxypyridine (0.923 g, 9.71 mmol) in dry DMF (15 ml) under Ar was treated with cesium carbonate (3.28 g, 10.07 mmol) at once and the brown mixture was stirred at RT for 2h. H2O (50 mL) and EtOAc (50 mL) were added and the organic layer was isolated. The water layer was extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with H2O (3 x 40 mL), brine (40 mL), dried (MgSO4), filtered and concentrated to 0 dryness to give a light yellow solid. Yield: 2.62 g (96%).1H-NMR (DMSO-d6), δ (ppm), J (Hz): 7.33 (d, J=8.7, 1H, Harom), 7.53 (m, 1H, Harom), 7.71 (m, 1H, Harom), 8.04 (dd, J=8.9, 4JFH=2.3, 1H, Harom), 8.49 (d, 4JFH=2.2, 1 H, Harom), 8.52 (m, 1H, Ha), 8.55 (d, J=2.9, 1H, Haram); 13C-NMR (DMSO-d6), δ (ppm), J (Hz): 120.7, 122.9 5 (d, JFc=274), 123.4, 124.3 (d, JFC=33.9), 125.0, 127.2, 131.7, 140.6, 141.6, 146.6, 151.3, 152.1; 19F-NMR (DMSO-d6), δ (ppm): -60.4; LC-MS (m/z): 285.0 (M+H, 100), rt=2.40 min.

Reference： [1]Current Patent Assignee: UNIVERSITY OF LONDON; CANCER RESEARCH UK - WO2009/77766, 2009, A1 Location in patent: Page/Page column 197

43
[ 367-86-2 ]
[ 22265-37-8 ]
[ 1224442-19-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 110℃; for 0.5h; Microwave irradiation;

Reference： [1]Location in patent: experimental part Gupta, Sahaj; Agarwal, Piyush K.; Kundu, Bijoy [Tetrahedron Letters, 2010, vol. 51, # 14, p. 1887 - 1890]

44
[ 107-10-8 ]
[ 367-86-2 ]
[ 2078-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one at 20℃; Cooling with ice;	207 Reference Production Example 207; To a mixture of 5.23 g of 4-fluoro-3-nitro-benzo trifluoride and 25 ml of N-methylpyrrolidone was added 3.69 g of n-propylamine under ice cool, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water, and the deposited solid was collected by filtration. This solid was washed with water, then, dried under reduced pressure to obtain 2.78 g of N-propyl-2-nitro~4- trifluoromethylaniline .1H-NMR (CDCl3) δ: 8.47 (d, IH), 8.29 (brs, IH), 7.61 (dd, IH), 6.94 (d, IH), 3.36-3.30 (m, 2H), 1.84-1.74 (m, 2H), 1.07 (t, 3H) .
	With potassium carbonate In water at 100℃; for 4h;

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - WO2010/125985, 2010, A1 Location in patent: Page/Page column 249
[2]Anh, Le Duc; De, Tran Quang; Duc Thanh, Danh La; Dupont-Rouzeyrol, Myrielle; Grailhe, Regis; Hue, Bui Thi Buu; Jo, Eunji; Nguyen, Phuong Hong; Son, Nguyen Hoang; Thoa, Than Thi; Van Hieu, Mai; Van Tuan, Nguyen; Windisch, Marc P. [ChemMedChem, 2020, vol. 15, # 15, p. 1453 - 1463]

45
[ 169120-70-1 ]
[ 367-86-2 ]
[ 1261167-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.17 h 1.2: 1 h / 20 °C 2.1: hydrogenchloride; iron(III) chloride; water; zinc / 1 h / 100 °C

Reference： [1]Wang, Kan; Herdtweck, Eberhardt; Doemling, Alexander [ACS Combinatorial Science, 2011, vol. 13, # 2, p. 140 - 146]

46
[ 169120-70-1 ]
[ 367-86-2 ]
C₁₇H₁₁F₄N₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-Cyano-N-(4-fluoro-benzyl)-acetamide With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.166667h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h;

Reference： [1]Location in patent: experimental part Wang, Kan; Herdtweck, Eberhardt; Doemling, Alexander [ACS Combinatorial Science, 2011, vol. 13, # 2, p. 140 - 146]

47
[ 367-86-2 ]
[ 717858-21-4 ]
[ 1261167-36-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; mineral oil / 0.17 h 1.2: 1 h / 20 °C 2.1: hydrogenchloride; iron(III) chloride; water; zinc / 1 h / 100 °C

Reference： [1]Wang, Kan; Herdtweck, Eberhardt; Doemling, Alexander [ACS Combinatorial Science, 2011, vol. 13, # 2, p. 140 - 146]

48
[ 367-86-2 ]
[ 717858-21-4 ]
C₂₂H₂₁F₃N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: C₁₅H₁₉N₃O With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.166667h; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h;

Reference： [1]Location in patent: experimental part Wang, Kan; Herdtweck, Eberhardt; Doemling, Alexander [ACS Combinatorial Science, 2011, vol. 13, # 2, p. 140 - 146]

49
[ 1694-31-1 ]
[ 367-86-2 ]
[ 1358722-09-4 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: tert-butyl acetoacetate With sodium hydride In tetrahydrofuran; mineral oil at 0℃; Inert atmosphere; Stage #2: 1-fluoro-2-nitro-4-trifluoromethyl-benzene In tetrahydrofuran; mineral oil for 7h; Inert atmosphere; Reflux;	Typical procedure for tert-Butyl 1-hydroxy-2-methyl-6-trifluoromethyl-1H-indole-3-carboxylate (NHI-1): At 0 °C, tert-butyl acetoacetate (6.62 mL, 40 mmol) was added dropwise to a suspension of NaH (60%) (1.68 g, 42 mmol) in dry THF (200 mL) under a nitrogen atmosphere. The mixture was left to stir at 0 °C until a clear solution formed. 1-Fluoro-2-nitro-4-trifluoromethylbenzene (2.8 mL, 20 mmol) was added dropwise and the mixture was allowed to stir under reflux. After consumption of the starting material (7 h), the mixture was cooled to room temperature and quenched with H2O (300 mL) and extracted with EtOAc (50 mL × 3). The extracts were dried over anhydrous MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash column chromatography (silica gel; hexane-EtOAc = 250: 1) to give (E)-tert-butyl 3-hydroxy-2-(2-nitro-4-trifluoromethylphenyl)but-2-enoate (14a) as a yellow oil (6.47 g, 18.6 mmol, 93% yield) as a mixture of enol (major) and ketone (minor) isomers as determined from the NMR spectrum. Yellow oil, 1H NMR (400 MHz, CDCl3) δ 13.26 (0.94H, OH, s), 8.30 (0.06H, s), 8.23 (0.94H, s), 7.88 (0.06H, dd, J = 1.2 Hz, 8.0 Hz), 7.82 (0.94H, dd, J = 1.2 Hz, 8.0 Hz), 7.66 (0.06H, d, J = 8.0 Hz), 7.44 (0.94H, d, J = 8.0 Hz), 5.30 (0.06H, s), 2.44 (0.18H, s), 1.90 (2.82H, s), 1.49 (0.54H, s), 1.34 (8.46H, s); 13C NMR (100 MHz, CDCl3) δ 173.27, 169.95, 149.69, 134.72, 134.51, 130.72 (q, J = 34 Hz), 128.97 (q, J = 3 Hz), 124.21, 121.56 (q, J = 4 Hz), 101.35, 83.12, 27.82 (3 C), 20.02; IR (KBr) ν 3020, 2982, 1645, 1539, 1354, 1323, 1152 cm-1; HRMS (ESI) calcd for C15H17F3NO5 [M+H]+: 348.1059, found: 348.1055.

Reference： [1]Location in patent: experimental part Shen, Shu-Su; Kartika, Vita; Tan, Ying Shan; Webster, Richard D.; Narasaka, Koichi [Tetrahedron Letters, 2012, vol. 53, # 8, p. 986 - 990]

50
[ 40263-57-8 ]
[ 367-86-2 ]
C₁₂H₆F₃IN₂O₃ [ No CAS ]

Reference： [1]Organic Letters,2012,vol. 14,p. 1892 - 1895

51
[ 13275-42-8 ]
[ 367-86-2 ]
[ 1449011-37-3 ]

Reference： [1]RSC Advances,2013,vol. 3,p. 1862 - 1870

52
[ 199175-10-5 ]
[ 367-86-2 ]
[ 1301189-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 80℃;Product distribution / selectivity;	Example 535-{4-[l-[(3S)-l-(Cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-5-(trifluoromethyl)- lH-benzimidazol-2-yl]phenyl}-lH-indazole(a) 1,1-Dimethylethyl (3S)-3-([2-nitro-4-(trifluoromethyl)phenyl]amino}methyl)-l- pyrrolidinecarboxylatel-Fluoro-2-nitro-4-(trifluoromethyl)benzene (5 g) was dissolved in 50 mL DMSO. To this was added 1,1-dimethylethyl (35)-3-(aminomethyl)-l-pyrrolidinecarboxylate (5.75 g) and DIEA (6.17 g) and the reaction mixture was heated to 80 C and stirred overnight. After cooling, the reaction mixture was diluted with 50 mL water and extracted with EtOAc (2 x 150 mL). The combined extracts were dried over sodium sulfate and evaporated to dryness to afford the titled compound, which was used without further purification.

Reference： [1]Patent: WO2011/56635,2011,A1 .Location in patent: Page/Page column 79-80

53
[ 367-86-2 ]
[ 1464025-91-9 ]
C₁₆H₁₉F₃N₂O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(2S,3S)-3-Amino-2-methyl-7-(trifluoromethyl)-2,3-dihydrobenzo[b][l,4]oxazepin- 4(5H)-one trifluoroacetate In a similar manner to that described for the preparation of (S)-3-amino-8-methyl-2,3- dihydrobenzo[b][l,4]oxazepin-4(5H)-one trifluoroacetate except in Step 1 the mixture was stirred overnight and in Step 2 the mixture was stirred 3 h, (2S,3S)-2-(tert- butoxycarbonylamino)-3-hydroxybutanoic acid discyclohexylamine salt (2.0 g, 5.00 mmol) and l-fluoro-2-nitro-4-(trifluoromethyl)benzene (1.04 g, 5.00 mmol) were converted to the title compound (58 mg) which was used without purification.

Reference： [1]Patent: WO2014/23708,2014,A1 .Location in patent: Page/Page column 63; 65-66

54
[ 367-86-2 ]
[ 1464025-91-9 ]
C₁₆H₂₁F₃N₂O₅ [ No CAS ]

Reference： [1]Patent: WO2014/23708,2014,A1

55
[ 367-86-2 ]
[ 54660-00-3 ]
3,6-diphenylbis(2-nitro-4-trifluoromethyl)-1,4-dioxopyrrole[3,4-c]pyrrole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 22h;
53%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 22h;	1 Preparation of compound 2a A mixture of DPP 3a (400 mg, 1 .39 mmol), 2-fluoro-5-trifluoromethyl-nitrobenzene (0.78 mL, 5.56 mmol) and K2C03 (770 mg, 5.56 mmol) in DMF (200 mL) was stitrred at 70 °C for 22 h, and the suspension became clear when the reaction is finished. Afterwards K2CO3 was removed by filtration and the solvent was removed by reduced pressure to get the crude product. Methanol (10 mL) was added to the crude product and the precipitate was filtered, washed with methanol (10 mL) until it became colorless, and dried under vacuum to get compound 2a as a yellow solid (490 mg, 53%). (0165) 1H NMR ([D6]DMSO, 400 MHz, 300 K): δ = 8.60 (d, 4 J = 1 .8 Hz, 0.9 H), 8.53 (d, 4 J = 1 .8 Hz, 1.1 H) , 8.25 (dd, 4J = 1.8 Hz, 3J = 8.7 Hz, 1.1 H), 8.18 (dd, 4J = 1 .6 Hz, 3J = 8.4 Hz, 0.9 H), 7.86 (d, 3J = 8.1 Hz , 1 .1 H), 7.62-7.44 (m, 10.9 H); the ratio of the isomers is = 0.9/1.1. 13C NMR (0166) ([D6]DMSO, 150 MHz, 343 K): δ = 161.9, 159.4, 159.3, 146.5, 145.9, 145.7, 132.7, 132.0, 131 .9, 131 .8, 131.5, 131.4, 130.6, 130.54, 130.52, 129.8, 129.5, 128.9, 128.75, 128.67, 128.6, 125.7, 125.6, 125.0, 123.2, 122.8, 122.7, 122.54, 122.51 , 121 .4, 109.84, 109.79. MS (MALDI TOF, neg. mode, CHCI3): mlz. calculated for C32H16F6N4O6: 666.105 [M] , found: 666.039. HRMS (ESI, pos. mode, acetonitrile/chloroform 1 :1 ): m/z. calculated for C32H17F6N4O6: 667.1052 [M+H]+, found: 667.1050. CV (CH2CI2, 0.1 M TBAHFP, vs. Fc/Fc+): £red (X/X )= -1 .43 V, £i 2ox (X X+) = 1 .04 V. UV-Vis (CHCI3): (ε) = 464 (23800 M 1 cm 1).

Reference： [1]Yue, Wan; Suraru, Sabin-Lucian; Bialas, David; Mueller, Matthias; Wuerthner, Frank [Angewandte Chemie - International Edition, 2014, vol. 53, # 24, p. 6159 - 6162][Angew. Chem., 2014, vol. 126, # 24, p. 6273 - 6276,4]
[2]Current Patent Assignee: BASF SE; SCREEMO LTD - WO2015/145315, 2015, A1 Location in patent: Page/Page column 24; 25

56
[ 367-86-2 ]
[ 153645-26-2 ]
[ 1073176-30-3 ]

Reference： [1]Chemistry - A European Journal,2016,vol. 22,p. 16513 - 16521

57
[ 367-86-2 ]
[ 784-57-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 1.5 h / 0 - 20 °C 2: tin(ll) chloride; hydrogenchloride / methanol / 42 h / 0 - 20 °C
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 0 - 80 °C 2: zinc; ammonium chloride / ethanol / 16 h / Inert atmosphere; Reflux

Reference： [1]Siqueira, Raoni Pais; Barros, Marcus Vinícius de Andrade; Barbosa, Éverton de Almeida Alves; Onofre, Thiago Souza; Gonçalves, Victor Hugo Sousa; Pereira, Higor Sette; Silva Júnior, Abelardo; de Oliveira, Leandro Licursi; Almeida, Márcia Rogéria; Fietto, Juliana Lopes Rangel; Teixeira, Róbson Ricardo; Bressan, Gustavo Costa [European Journal of Medicinal Chemistry, 2017, vol. 134, p. 97 - 109]
[2]Bailey, Brodie L.; Nguyen, William; Ngo, Anna; Goodman, Christopher D.; Gancheva, Maria R.; Favuzza, Paola; Sanz, Laura M.; Gamo, Francisco-Javier; Lowes, Kym N.; McFadden, Geoffrey I.; Wilson, Danny W.; Laleu, Benoît; Brand, Stephen; Jackson, Paul F.; Cowman, Alan F.; Sleebs, Brad E. [Bioorganic Chemistry, 2021, vol. 115]

58
[ 367-86-2 ]
[ 218156-96-8 ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 134,p. 97 - 109

59
[ 367-86-2 ]
[ 27798-60-3 ]
methyl 2-(2-methoxyphenyl)-2-(2-nitro-4-(trifluoromethyl)phenyl)acetate [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 2572 - 2575

60
[ 41365-75-7 ]
[ 367-86-2 ]
[ 79-08-3 ]
[ 105496-31-9 ]
C₁₈H₂₅F₃N₃O₆Pol [ No CAS ]