[ CAS No. 35375-74-7 ] {[proInfo.proName]}

Name: 35375-74-7|5-Chloro-2-nitro-4-(trifluoromethyl)aniline|98%
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Quality Control of [ 35375-74-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 35375-74-7 ]

Product Details of [ 35375-74-7 ]

CAS No. :	35375-74-7	MDL No. :	MFCD01312277
Formula :	C₇H₄ClF₃N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AAMCWLIPRMIPBN-UHFFFAOYSA-N
M.W :	240.57	Pubchem ID :	2773813
Synonyms :

Calculated chemistry of [ 35375-74-7 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	2
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	49.68
TPSA :	71.84 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.55 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.38
Log Po/w (XLOGP3) :	3.13
Log Po/w (WLOGP) :	4.01
Log Po/w (MLOGP) :	1.95
Log Po/w (SILICOS-IT) :	0.72
Consensus Log Po/w :	2.24

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.47
Solubility :	0.082 mg/ml ; 0.000341 mol/l
Class :	Soluble
Log S (Ali) :	-4.31
Solubility :	0.0118 mg/ml ; 0.0000492 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-2.93
Solubility :	0.284 mg/ml ; 0.00118 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	3.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.03

Safety of [ 35375-74-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 35375-74-7 ]

* 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 [ 35375-74-7 ]
Downstream synthetic route of [ 35375-74-7 ]

[ 35375-74-7 ] Synthesis Path-Upstream 1~5

1
[ 400-70-4 ]
[ 35375-74-7 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 262 - 272
[2] MedChemComm, 2013, vol. 4, # 7, p. 1118 - 1123
[3] Journal of Medicinal Chemistry, 1992, vol. 35, # 23, p. 4455 - 4463

2
[ 1026318-97-7 ]
[ 35375-74-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379

3
[ 445-13-6 ]
[ 35375-74-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379

4
[ 546434-30-4 ]
[ 35375-74-7 ]

Reference： [1] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379

5
[ 35375-74-7 ]
[ 157590-59-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With water; tin(ll) chloride In ethanol at 80℃;	To a solution of 5-chloro-2-nitro-4-(trifluoromethyl)aniline (2g, 8.3lmmol) in EtOH:H20 (5:1, lOmL) was added SnCl2 (4.73g, 24.9mmol) at rt. The reaction mixture was stirred at 800 C for 3h. The TLC showed reaction to be complete. The reaction mixture was filtered through celite bed and concentrated under reduced pressure to afford 4-chloro-5-(trifluoromethyl)benzene-1,2-diamine as yellow semi solid. Yield:1.7 g (97percent);1H NMR (400 MHz, DMSO-d6): 6.95 (5, 1H), 6.88 (5, 1H), 4.68-5.08 (bs, 4H), MS (ESI-) for CHNOS m/z 209.15 [M-H].

Reference： [1] Patent: WO2018/37223, 2018, A1, . Location in patent: Page/Page column 118; 119
[2] Journal of Medicinal Chemistry, 1995, vol. 38, # 22, p. 4367 - 4379
[3] Patent: WO2004/35549, 2004, A1, . Location in patent: Page 105
[4] Patent: WO2008/56150, 2008, A1, . Location in patent: Page/Page column 182

[ 35375-74-7 ] Synthesis Path-Downstream 1~63

1
[ 288-32-4 ]
[ 35375-74-7 ]
[ 131885-50-2 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272
[2]Journal of Medicinal Chemistry,1992,vol. 35,p. 4455 - 4463

2
[ 400-70-4 ]
[ 35375-74-7 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272
[2]MedChemComm,2013,vol. 4,p. 1118 - 1123
[3]Journal of Medicinal Chemistry,1992,vol. 35,p. 4455 - 4463

3
[ 35375-74-7 ]
[ 157590-59-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With water; tin(ll) chloride; In ethanol; at 80℃;	To a solution of <strong>[35375-74-7]5-chloro-2-nitro-4-(trifluoromethyl)aniline</strong> (2g, 8.3lmmol) in EtOH:H20 (5:1, lOmL) was added SnCl2 (4.73g, 24.9mmol) at rt. The reaction mixture was stirred at 800 C for 3h. The TLC showed reaction to be complete. The reaction mixture was filtered through celite bed and concentrated under reduced pressure to afford 4-chloro-5-(trifluoromethyl)benzene-1,2-diamine as yellow semi solid. Yield:1.7 g (97%);1H NMR (400 MHz, DMSO-d6): 6.95 (5, 1H), 6.88 (5, 1H), 4.68-5.08 (bs, 4H), MS (ESI-) for CHNOS m/z 209.15 [M-H].
	With tin(ll) chloride; In ethanol; ethyl acetate; at 70℃; for 1h;	Example 84 [5-CHLORO-6-TRIFLUOROMETHYL-2- [4- (3-TRIFLUOROMETHYL-PYRIDIN-2-YL)-PIPERAZIN-1-YL]-] 1H-benzoimidazole. (a) [5-CHLORO-4- (TRIFLUOROMETHYL)] benzene-1,2-diamine. To a solution of 5-chloro-2-nitro-4- (trifluoromethyl) phenylamine (2 g, 8. 3 mmol, Oakwood) in EtOAc (26 mL) and [ETOH] (13 [ML) WAS] added tin [(II)] chloride dihydrate (13.1 g, 45 mmol, Aldrich). The reaction mixture was stirred at [70C] for 1 h. The light-yellow reaction solution was poured to crushed ice (50 mL) and carefully neutralized using saturated aqueous solution [OF NAHC03.] The resulting suspension was extracted with EtOAc (3 x 60 mL). The combined organic extracts were dried over [MGS04,] filtered and the filtrate evaporatedcon in vacuo to give the title compound as white solid, which was used in the next step without additional purification. MS (ESI, pos. ion) [INLZ] : 211.4 (M+1).
		Starting material Iu:4-chloro-5-(trifluoromethyl)benzene-l,2-diamine<strong>[35375-74-7]5-chloro-2-nitro-4-(trifluoromethyl)aniline</strong> was combined with 5% iron(III)chloride on silica gel (6.692g, .2063mmol), activated carbon (3.2g, 2x wt. of SM), and 2OmL MeOH. This reaction mixture was stirred and heated at 800C for lOmin. Hydrazine monohydrate was then added (4.0ImL, 82.51mmol) slowly, drop wise at first to avoid foaming, then quickly. The reaction was stirred and heated for an additional 15min, then filtered hot. The solids were washed with MeOH and EtOAc. The filtrates were combined and concentrated to yield1.4276g product as a light yellow solid. 1H NMR (300 MHz, DMSO-D6) 4.95 (s, 2 H) 5.41 (s, 2 H) 6.63 (s, 1 H) 6.85 (s, 1 H).

Reference： [1]Patent: WO2018/37223,2018,A1 .Location in patent: Page/Page column 118; 119
[2]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379
[3]Patent: WO2004/35549,2004,A1 .Location in patent: Page 105
[4]Patent: WO2008/56150,2008,A1 .Location in patent: Page/Page column 182

4
[ 1026318-97-7 ]
[ 35375-74-7 ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

6
[ 67-56-1 ]
[ 35375-74-7 ]
[ 473537-32-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium hydroxide; In dimethyl sulfoxide; at 23℃; for 168h;	1) 5-Methoxy-2-nitro-4-trifluoromethyl-phenylamine [CAS-no. 473537-32-5]: Commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> (30.0 g, 125 mmol) was dissolved in DMSO (250 mL) and MeOH (125 mL), then potassium hydroxide (85%, 18.1 g, 274 mmol) was added and the resulting deep red solution was stirred at 23 C. for 7 days. The mixture was poured onto 1 N HCl (350 mL) and water (1500 mL), this suspension was stirred for 1 h, then the precipate was filtered off, washed with cold water and the crystals were dried in air at 60 C. overnight to get 5-methoxy-2-nitro-4-trifluoromethyl-phenylamine (28.98 g, 98%) as a yellow solid. MS (ISN) 235.1 [(M-H)-]; mp 56 C.

Reference： [1]Patent: US2007/232583,2007,A1 .Location in patent: Page/Page column 38
[2]MedChemComm,2013,vol. 4,p. 1118 - 1123

7
[ 1007374-16-4 ]
[ 35375-74-7 ]
[ 1007374-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 55 - 70℃; for 17.25h;	To a mixture of compound 3c1 (38 mg, 0.16 mmol) and dry DMSO (1 mL) is successively added K2CO3 (55 mg, 0.4 mmol) and phenol 1a9 (Example 1A) (53 mg, 0.16 mmol). The reaction mixture is stirred at 55 C. for 1 h 15 min and then at 70 C. for 16 h. The reaction mixture is poured into water and extracted with EtOAc (3×). The combined organic extract is successively washed with water (4×) and brine, dried with MgSO4, filtered and concentrated to afford intermediate 3c2.

Reference： [1]Patent: US2008/45516,2008,A1 .Location in patent: Page/Page column 33-34

8
[ 35375-74-7 ]
[ 74-88-4 ]
[ 61286-98-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In acetone; at 20℃; for 48h;	To a solution of <strong>[35375-74-7]5-chloro-2-nitro-4-(trifluoromethyl)aniline</strong> (2g, 8.31 mmol) in acetone (5OmL) were added K2003 (3.45g, 24.94mmol) and Mel (11.8g, 83.l4mmol) at rt. The reaction mixture was stirred at rt for 48h. The TLC showed reaction to be complete. The reaction was diluted with H20 (5OmL) and extracted with EtOAc (3x5OmL). The organic layer was washed with brine (5OmL), dried (Na2SO4), filtered and concentrated under reduced pressure to afford 5-chloro-N-methyl-2-nitro-4- (trifluoromethyl)aniline as a yellow solid. Yield: 2 g (95%);1H NMR (400 MHz, DMSO-d6): 8.63 (d, J= 2.7 Hz, 1H), 8.35 (5, 1H), 7.27 (5, 1H), 3.01 (d, J= 4.9 Hz, 3H); MS (ESI-) for CHNOS m/z 253.13 [M-H].
	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1h;	To a mixture of compound 3e1 (100 mg, 0.45 mmol) and dry DMF (2 mL) are successively added Cs2CO3 (218 mg, 0.67 mol) and CH3I (0.042 mL, 0.67 mmol). The mixture is stirred for 1 hour at ambient temperature, poured into water and extracted with EtOAc. The organic extract is washed with water (4×) and brine, dried with MgSO4, filtered and concentrated to afford compound 3e2.

Reference： [1]Patent: WO2018/37223,2018,A1 .Location in patent: Page/Page column 117; 118
[2]Patent: US2008/45516,2008,A1 .Location in patent: Page/Page column 36

9
[ 35375-74-7 ]
[ 647836-00-8 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272

10
[ 35375-74-7 ]
[ 647836-01-9 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272

11
[ 35375-74-7 ]
8-imidazol-1-yl-4-oxo-7-trifluoromethyl-4,5-dihydro-[1,2,4]triazolo[1,5-<i>a</i>]quinoxaline-2-carboxylic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272

12
[ 35375-74-7 ]
[ 647836-13-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272

13
[ 35375-74-7 ]
[ 647836-02-0 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272

14
[ 35375-74-7 ]
5-imidazol-1-yl-2-nitro-4-trifluoromethyl-benzenediazonium; hydrogen sulfate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 262 - 272

15
[ 35375-74-7 ]
[ 153505-38-5 ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

16
[ 35375-74-7 ]
6-chloro-5-nitro-7-trifluoromethyl-1,4-dihydroquinoxaline-2,3-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

17
[ 445-13-6 ]
[ 35375-74-7 ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

18
[ 546434-30-4 ]
[ 35375-74-7 ]

Reference： [1]Journal of Medicinal Chemistry,1995,vol. 38,p. 4367 - 4379

19
[ 35375-74-7 ]
[ 131885-99-9 ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4455 - 4463

20
[ 35375-74-7 ]
5-Imidazol-1-yl-2-pyridin-4-yl-6-trifluoromethyl-1H-benzoimidazole [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1992,vol. 35,p. 4455 - 4463

21
[ 24424-99-5 ]
[ 35375-74-7 ]
[ 473537-41-6 ]

Yield	Reaction Conditions	Operation in experiment
70.7%	With dmap; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere;	[00473] To a stirred solution of <strong>[35375-74-7]5-chloro-2-nitro-4-(trifluoromethyl)aniline</strong> (1.3 g, 5.42 mmol) in THF (20 mL) was added Boc anhydride (1.77 g, 8.12 mmol) followed by DMAP (198 mg, 1.62 mmol) at 0 C under inert atmosphere. The resulting reaction mixture was allowed to warm to RT and stirred for 2 hr. After the consumption of starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 5% EtOAc/Hexane to afford tert-butyl 5-chloro-2-nitro-4- (trifluoromethyl)phenylcarbamate (1.3 g, 70.7%) as a pale yellow solid. 1H NMR (500 MHz, CDC13): delta 9.88 (bs, 1H), 8.91 (s, 1H), 8.56 (s, 1H), 1.54 (d, J= 9.5 Hz, 9H). MS (ESI): 339 [M- 1]·
		Compound Al was prepared via the di-Boc-compound from commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (22.61 g, 94 mmol) and Boc2O (42.06 g, 193 mmol), followed by treatment with 2 eq. TFA in CH2CL2 according to the general procedure A (method c). Method c (from 2-nitroanilines): To a solution of the 2-nitroaniline (550 mmol) and DMAP (1.22 g, 10 mmol) in THF (1000 mL) at 23C WAS dropwise added within 70 min a solution OF 30C20 (246 g, 1128 mmol) in THF (500 mL) and stirring was continued at 23C for 75 min. The entire mixture was evaporated to dryness and dried at HV to leave a dark brown solid. This material was dissolved in DCM (1100 mL), cooled to 0C and TFA (84 mL, 1100 mmol) was added dropwise. The mixture was stirred at 0C for 2 h, poured into icecold sat. NAHCO3-SOLUTION, extracted with DCM, washed with brine and dried over MGS04. Removal of the solvent in vacuum left a dark brown solid which was coated on silica gel and purified by silica gel column chromatography with hexane/EtOAc to give the (2-nitro-phenyl) -carbamic acid tert-butyl ester as a yellow solid.
	With trifluoroacetic acid; In dichloromethane;	Example A1 (5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester The title compound was prepared via the di-Boc-compound from commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (22.61 g, 94 mmol) and Boc2O (42.06 g, 193 mmol), followed by treatment with 2 eq. TFA in CH2Cl2 according to the general procedure A (method c). Obtained as a yellow solid (31.82 g, 99%). MS (ISN) 339.1 [(M-H)-] and 341 [(M+2-H)-]; mp 113-115 C.

	With trifluoroacetic acid; In dichloromethane;	Example A11 (5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester The title compound was prepared via the di-Boc-compound from commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (22.61 g, 94 mmol) and Boc2O (42.06 g, 193 mmol), followed by treatment with 2 eq. TFA in CH2Cl2 according to the general procedure A (method c). Obtained as a yellow solid (31.82 g, 99%). MS (ISN) 339.1 [(M-H)-]and 341 [(M+2-H)-]; mp 113-115 C.
	With trifluoroacetic acid; In dichloromethane;	Example B5 (5-Chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester The title compound was prepared via the di-Boc-compound from commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (22.61 g, 94 mmol) and Boc2O (42.06 g, 193 mmol), followed by treatment with 2 eq. TFA in CH2Cl2 according to the general procedure B (method c). Obtained as a yellow solid (31.82 g, 99%). MS (ISN) 339.1 [(M-H)-] and 341 [(M+2-H)-]; mp 113-115 C.

Reference： [1]Patent: WO2015/191630,2015,A1 .Location in patent: Paragraph 00473
[2]Patent: WO2005/14002,2005,A1 .Location in patent: Page/Page column 29; 33
[3]Patent: US2003/166639,2003,A1
[4]Patent: US2002/198197,2002,A1
[5]Patent: US6544985,2003,B2

22
[ 64-17-5 ]
[ 35375-74-7 ]
[ 473537-36-9 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium; at 55 - 60℃; for 96h;	To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol), and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7 (57.74 g, 240 mmol) was added in one portion, and the resulting dark red mixture was stirred at 55-60 C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HCl to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60 C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M-H].
96%		To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available 5-chloro-2-nitro-4-trifluoromethyl- phenylamine [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion and the resulting dark red mixture was stirred at 55-60 C for 4 days. The warm reaction mixture was slowly poured into H20 (ca. 2000 mL), adjusted pH with conc. HCl to pH 2, the yellow precipitate was filtered off, washed with H20 and dried in air at 60 C to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M-H]
96%		To ethanol (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol, ca. 2.24 equiv) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> (57.74 g, 240 mmol, 1.0 equiv, [CAS RN 35375-74-7]) was added in one portion and the resulting dark red mixture was stirred at 55-60 C. for 4 d. The warm reaction mixture was slowly poured into water (ca. 2000 mL), the pH adjusted with a solution of 1 M HCl to 2, the yellow precipitate filtered off, washed with water and dried in air at 60 C. to give 57.81 g (96%) of the title compound as a yellow solid which was used without further purification. MS (ISN): 249.0 [M-H]-.

Reference： [1]Patent: US2006/217387,2006,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2005/123738,2005,A1 .Location in patent: Page/Page column 27-28
[3]Patent: US2006/205718,2006,A1 .Location in patent: Page/Page column 29

23
[ 35375-74-7 ]
[ 1813-24-7 ]

Yield	Reaction Conditions	Operation in experiment
91%		Step 1: 5-Methyl-2-nitro-4-trifluoromethyl-phenylamine Under argon atmosphere, a suspension of potassium tert-butanolate (71.6 g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with a mechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was added drop wise at 20-30 C. under ice bath cooling. To the thick white suspension was the added solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO (100 mL) and the red solution warmed up to 60 C. and stirred for 20 h at 60 C. The mixture was cooled to 23 C. and a solution of potassium hydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise. The mixture was then heated to 100 C. and stirred for further 4 h. The mixture was cooled to 23 C., diluted with water (ca. 1000 mL), acidified with 37% HCl 3 to pH 3, and extracted three times with tert-butyl methyl ether (TBME) The organic layers were washed with brine, dried over MgSO4 and evaporated to give a brown solid, which was triturated with hot heptane, filtered off and washed with heptane to give the title compound as a brown solid (50.0 g, 91%), which was used without further purification. MS (ISN) 218.9 [M-H].
91%		Under argon atmosphere, a suspension of potassium tert-butanolate (71.6 g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with a mechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was added drop wise at 20-30 C. under ice bath cooling. To the thick white suspension was the added solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO (100 mL) and the red solution warmed up to 60 C. and stirred for 20 h at 60 C. The mixture was cooled to 23 C. and a solution of potassium hydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise. The mixture was then heated to 100 C. and stirred for further 4 h. The mixture was cooled to 23 C., diluted with water (ca. 1000 mL), acidified with 37% HCl 3 to pH 3, and extracted three times with tert-butyl methyl ether (TBME) The organic layers were washed with brine, dried over MgSO4 and evaporated to give a brown solid, which was triturated with hot heptane, filtered off and washed with heptane to give the title compound as a brown solid (50.0 g, 91%), which was used without further purification. MS (ISN) 218.9 [M-H].
91%		Example A.4 3-Methyl-4-trifluoromethyl-acetophenone; The 1-(3-methyl-4-trifluoromethyl-phenyl)-ethanone was prepared by the following sequence: Step 1: 5-Methyl-2-nitro-4-trifluoromethyl-phenylamine Under argon atmosphere, a suspension of potassium tert-butanolate (71.6 g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with a mechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was added drop wise at 20-30 C. under ice bath cooling. To the thick white suspension was the added solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO (100 mL) and the red solution warmed up to 60 C. and stirred for 20 h at 60 C. The mixture was cooled to 23 C. and a solution of potassium hydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise. The mixture was then heated to 100 C. and stirred for further 4 h. The mixture was cooled to 23 C., diluted with water (ca. 1000 mL), acidified with 37% HCl 3 to pH 3, and extracted three times with tert-butyl methyl ether (TBME) The organic layers were washed with brine, dried over MgSO4 and evaporated to give a brown solid, which was triturated with hot heptane, filtered off and washed with heptane to give the title compound as a brown solid (50.0 g, 91%), which was used without further purification. MS (ISN) 218.9 [M-H].

Reference： [1]Patent: US2006/183756,2006,A1 .Location in patent: Page/Page column 10
[2]Patent: US2006/217387,2006,A1 .Location in patent: Page/Page column 22
[3]Patent: US2007/72879,2007,A1 .Location in patent: Page/Page column 10-11

24
[ 75-89-8 ]
[ 35375-74-7 ]
[ 119115-61-6 ]

Yield	Reaction Conditions	Operation in experiment
98%		Step 1: 2-Nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenylamine Commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL) and 2,2,2-trifluoroethanol (270 mL) were added at 23 C., the slightly exothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500 mmol) were added slowly and the dark red reaction mixture was stirred at 23 C. for 4 days. Transferred into a 3 L flask and 1500 ml H2O were added under ice bath cooling, acidified with 3 N HCl and stirred at 23 C. for 3 h, filtered off the yellow precipitate, washed with H2O and dried in air at 60 C. to give the title compound as a yellow solid (89.47 g, 98%). MS (ISN) 303.1 [M-H].
98%	With potassium hydroxide; In water; dimethyl sulfoxide; at 23℃; for 4h;	Commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL) and 2,2,2-trifluoroethanol (270 mL) were added at 23 C., the slightly exothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500 mmol) were added slowly and the dark red reaction mixture was stirred at 23 C. for 4 days. Transferred into a 3 L flask and 1500 mL H2O were added under ice bath cooling, acidified with 3 N HCl and stirred at 23 C. for 3 h, filtered off the yellow precipitate, washed with H2O and dried in air at 60 C. to give the title compound as a yellow solid (89.47 g, 98%). MS (ISN) 303.1 [M-H].
98%		Example A.6 3-(2,2,2-Trifluoro-ethoxy)-4-trifluoromethyl-acetophenone; The 1-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-ethanone was prepared by the following sequence: Step 1: 2-Nitro-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenylamine Commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL) and 2,2,2-trifluoroethanol (270 mL) were added at 23 C., the slightly exothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500 mmol) were added slowly and the dark red reaction mixture was stirred at 23 C. for 4 days. Transferred into a 3 L flask and 1500 ml H2O were added under ice bath cooling, acidified with 3 N HCl and stirred at 23 C. for 3 h, filtered off the yellow precipitate, washed with H2O and dried in air at 60 C. to give the title compound as a yellow solid (89.47 g, 98%). MS (ISN) 303.1 [M-H].

98%

Commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (72.2 g, 300 mmol) was dissolved in DMSO (600 mL) and 2,2,2- trifluoroethanol (270 mL) were added at 23 C, the slightly exothermic reaction was cooled with a ice bath. KOH (85%, 99.0 g, 1500 mmol) were added slowly and the dark red reaction mixture was stirred at 23 C for 4 days. Transferred into a 3 L flask and 1500 ml H20 were added under ice bath cooling, acidified with 3 N HCI and stirred at 23 C for 3 h, filtered off the yellow precipitate, washed with H20 and dried in air at 60 C to give the title compound as a yellow solid (89.47 g, 98%). MS (ISN) 303.1 [M-H].

Reference： [1]Patent: US2006/183756,2006,A1 .Location in patent: Page/Page column 12
[2]Patent: US2006/217387,2006,A1 .Location in patent: Page/Page column 24
[3]Patent: US2007/72879,2007,A1 .Location in patent: Page/Page column 12-13
[4]Patent: WO2005/123738,2005,A1 .Location in patent: Page/Page column 29

25
[ 35375-74-7 ]
[ 124-40-3 ]
[ 893444-22-9 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate; In tetrahydrofuran; N,N-dimethyl-formamide; at 100 - 120℃; for 0.583333h;Heating in the microwave;	A mixture of <strong>[35375-74-7]5-chloro-2-nitro-4-(trifluoromethyl)aniline</strong>(101.5 mg, 0.42 mmol), potassium carbonate (59.0 mg, 0.43 mmol), and dimethylamine (2 M/THF, 220 muL, 0.44 mmol) in DMF (150 muL) was heated in the microwave at 100 0C for 15 minutes, then at 120 C for 20 minutes. The reaction mixture was concentrated and the crude residue was purified using silica gel column chromatography (5-> 10-^20% EtOAc / hexanes) to afford compound 7.1 (61.7 mg,59%) as a yellow solid.

Reference： [1]Patent: WO2006/65703,2006,A1 .Location in patent: Page/Page column 110

26
[ 35375-74-7 ]
[ 473537-36-9 ]

Yield	Reaction Conditions	Operation in experiment
96%		Step 1: 5-Ethoxy-2-nitro-4-trifluoromethyl-phenylamine To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion and the resulting dark red mixture was stirred at 55-60 C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HCl to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60 C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M-H].
96%		Example A.5 3-Ethoxy-4-trifluoromethyl-acetophenone; The 1-(3-ethoxy-4-trifluoromethyl-phenyl)-ethanone was prepared by the following sequence: Step 1: 5-Ethoxy-2-nitro-4-trifluoromethyl-phenylamine To EtOH (500 mL) was added potassium metal (ca. 21 g, ca. 537 mmol) and the vigorous reaction had to be cooled with an ice bath. Stirring was continued until all potassium metal was dissolved. Solid commercially available <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (57.74 g, 240 mmol) was added in one portion and the resulting dark red mixture was stirred at 55-60 C. for 4 days. The warm reaction mixture was slowly poured into H2O (ca. 2000 mL), adjusted pH with conc. HCl to pH 2, the yellow precipitate was filtered off, washed with H2O and dried in air at 60 C. to give a yellow solid (57.81 g, 96%), which was used without further purification. MS (ISN) 249 [M-H].
	With potassium hydroxide; In ethanol; dimethyl sulfoxide;	Example D4 5-Ethoxy-2-nitro-4-trifluoromethyl-phenylamine The title compound was prepared from <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7] (7.06 g, 29.3 mmol) and KOH (4.26 g, 64.6 mmol) in EtOH (30 mL) and DMSO (60 mL) according to the general procedure E. Obtained as a yellow solid (4.20 g). MS (ISN) 249 [(M-H)-]; mp 95 C.

Reference： [1]Patent: US2006/183756,2006,A1 .Location in patent: Page/Page column 11
[2]Patent: US2007/72879,2007,A1 .Location in patent: Page/Page column 12
[3]Patent: US2002/198197,2002,A1

27
[ 35375-74-7 ]
[ 473537-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In methanol; dimethyl sulfoxide;	Example D3 5-Methoxy-2-nitro-4-trifluoromethyl-phenylamine The title compound was prepared from <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> [CAS-No. 35375-74-7](4.61 g, 19.2 mmol) and KOH (2.78 g, 42.2 mmol) in MeOH (20 mL) and DMSO (40 mL) according to the general procedure E. Obtained as a yellow solid (4.18 g). MS (ISN) 235 [(M-H)-]; mp 56 C.

Reference： [1]Patent: US2002/198197,2002,A1

28
[ 110-89-4 ]
[ 35375-74-7 ]
8-Piperidino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 8 8-Piperidino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and piperidine by a method analogous to the method described in example 4. M.p.>300 C. (decomp.). 1 H-NMR (DMSO-d6): delta13.0 (2H, broad s), 8.75 (1H, s), 7.50 (1H, s), 2.80 (4H, m), 1.65 (4H, m), 1.55 (2H,m).

Reference： [1]Patent: US5532236,1996,A

29
[ 110-91-8 ]
[ 35375-74-7 ]
8-Morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 7 8-Morpholino-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and morpholine by a method analogous to the method described in example 4. M.p.>300 C. 1 H-NMR (DMSO-d6): delta13.0 (1H, broad s), 12.0 (broad s), 8.75 (1H, s), 7.50 (1H, s), 3.70 (4H, m), 2.80 (4H, m). MS (m/e): 355 (M+, 70%).

Reference： [1]Patent: US5532236,1996,A

30
[ 109-01-3 ]
[ 35375-74-7 ]
8-(4-Methylpiperazin-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 9 8-(4-Methylpiperazin-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and 1-methylpiperazine by a method analogous to the method described in example 4. M.p.>300 C. 1 H-NMR (DMSO-d6): delta13.0 (2H, broad s), 8.65 (1H, s), 7.50 (1H, s), 2.70 (4H, m), 2.45 (4H, m), 2.20 (3H, s).

Reference： [1]Patent: US5532236,1996,A

31
[ 288-32-4 ]
[ 35375-74-7 ]
8-(1H-Imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 6 8-(1H-Imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and imidazole by a method analogous to the method described in example 4. (M.p. 350 C. (decomp.). 1 H-NMR (DMSO-d6): delta13.1 (1H, broad s), 12.1 (1H, broad s), 8.50 (1H, s), 7.85 (1H, s), 7.70 (1H, s), 7.40 (1H, s), 7.10 (1H, s). MS (m/e): 336 (M+, 100%).

Reference： [1]Patent: US5532236,1996,A

32
[ 930-62-1 ]
[ 35375-74-7 ]
8-(2,4-Dimethyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		a. 8-(2,4-Dimethyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo-[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and 2,4-dimethylimidazole by a method analogous to the method described in example 4. M.p.>330 C. 1 H-NMR (DMSO-d6): delta2.02 (s, 3H), 2.11 (s, 3H), 6.91 (s, 1H), 7.69 (s, 1H), 8.44 (s, 1H), 12.15 (br.s, 1H), 13.15 (br. s, 1H). MS (m/e): 364 (M+, 100%).

Reference： [1]Patent: US5532236,1996,A

33
[ 822-36-6 ]
[ 35375-74-7 ]
8-(4-Methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo[4,3-a]quinoxaline-1,4(2H,5H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 5 8-(4-Methyl-1H-imidazol-1-yl)-7-trifluoromethyl[1,2,4]triazolo-[4,3-a]quinoxaline-1,4(2H,5H)-dione The title compound was prepared from 4-amino-2-chloro-5-nitrobenzotrifluoride and 4-methylimidazole by a method analogous to the method described in example 4. M.p. 320 C. (decomp.). 1 H-NMR (DMSO-d6): delta12.5 (2H, broad s), 8.50 (1H, s), 7.70 (1H, s), 7.65 (1H, s), 7.10 (1H, s), 2.20 (3H, s). MS (m/e): 350 (M+, 100%).

Reference： [1]Patent: US5532236,1996,A

34
[ 693-98-1 ]
[ 35375-74-7 ]
4-amino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	In N,N-dimethyl-formamide;	a. 4-Amino-2-(2-methyl-1H-imidazol-1-yl)-5-nitrobenzotrifluoride To a solution of 20.0 g (~83 mmol) 4-amino-2-chloro-5-nitrobenzotrifluoride in 50 ml dry N,N-dimethylformamide was added 30 g (~370 mmol) 2-methylimidazole, and stirring was continued at 180 C. for 30 h. The reaction mixture was poured into 400 ml water to give the title compound (14.7 g; 62%). M.p. 222-225 C.

Reference： [1]Patent: US5532236,1996,A

35
[ 626-64-2 ]
[ 35375-74-7 ]
[ 172455-31-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; dimethyl sulfoxide;	REFERENCE EXAMPLE 6 STR14 4-Amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride First, a mixture containing 2.40 g of 4-amino-2-chloro-5-nitrobenzotrifluoride, 2.0 g of 4-hydroxypyridine, 684 mg of 86% potassium hydroxide, 15 ml of dimethylsulfoxide was heated in an oil bath at 70 C. for 2 hours. The mixture was cooled and ice water was added to the mixture. Precipitated crude crystals were filtered and recrystallized with methanol/ethyl acetate to give 2.69 g of crystals of 4-amino-5-nitro-2-(4-oxo-4H-pyridin-1-yl)-benzotrifluoride. Melting point: 274-275 C. Elemental analysis (analyzed as C12 H8 N3 O3 F3) Calculated: C,48.17; H,2.70; N,14.04; F,19.05 (%) Found: C,48.12; H,2.78; N,13.98; F,19.11 (%) H1 -NMR (d6 -DMSO)delta: 6.19 (2H, d, J=8 Hz), 7.17 (1H, s), 7.74 (2H, d, J=8 Hz), 8.17 (2H, br.s), 8.38 (1H, s).

Reference： [1]Patent: US5677305,1997,A

36
[ 35375-74-7 ]
N-(3-amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium hydrogencarbonate; In methanol; water;	PREPARATION 20 N-(3-Amino-6-chloro-7-trifluoromethyl-2-methoxyquinoxalin-5-yl)methanesulphonamide STR83 (a) 1,2-Diamino-4-chloro-5-trifluoromethyl benzene A solution of sodium dithionite (51.0 g, 293 mmol) in water (700 ml) was added to a stirred mixture of <strong>[35375-74-7]5-chloro-4-trifluoromethyl-2-nitroaniline</strong> ?Khim Geterotsikl Soedin, 1136[(1976)] (23.5 g, 97.7 mmol) and potassium bicarbonate (51.0 g) in methanol (700 ml) at room temperature. After 30 minutes, the mixture was concentrated under reduced pressure, and the residue was partitioned between dichloromethane and water. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure to give an orange solid (13.3 g, 65%). 1 H NMR (300 MHz, CDCl3) delta=3.37 (2H, br s), 3.70 (2H, br s), 6.78 (1H,s), 6.98 (1H,s).

Reference： [1]Patent: US5852016,1998,A

37
[ 35375-74-7 ]
[ 123-08-0 ]
[ 934765-59-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 6h;	Step 1: 4-[5-Amino-4-nitro-2-(trifluoromethyl)phenyl]oxy}benzaldehyde Preparation A solution of <strong>[35375-74-7]5-chloro-2-nitro-4-(trifluoromethyl)aniline</strong> (0.240 g, 1.00 mmol), potassium t-butoxide (0.135 g, 1.2 mmol), and 4-hydroxybenzaldehyde (0.147 g, 1.2 mmol) in dimethylformamide (5 mL) was heated to 80 degrees Centigrade for 6 hours and then cooled. Water was added and the organics extracted using ethyl acetate (2*50 mL). The combined organics were then washed once in brine and then dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using a gradient of 30%-40% ethyl acetate/hexanes eluted the product to give 0.243 g of 4-[5-amino-4-nitro-2-(trifluoromethyl)phenyl]oxy}benzaldehyde as an yellowish solid. (M+H) 327.1, 2.66 min (LC/MS method A)

Reference： [1]Patent: US2009/54431,2009,A1 .Location in patent: Page/Page column 32-33

38
[ 35375-74-7 ]
[ 811-51-8 ]
4-chloro-5-ethylsulfanyl-2-nitro-phenylamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In N,N-dimethyl-formamide; at 100℃; for 18h;	To a solution of 5- chloro-2-nitro-4-trifluoromethyl-phenylamine (2.23 g, 9.25 mmol) and DMF (46 ml_) was added sodium thioethoxide (2.16 g, 23.1 mmol). The reaction mixture was heated at 100 0C for 18 h, cooled, and poured into ice/brine (350 ml_). The resulting precipitate was collected to yield the titled compound (2.1 O g, 85% yield). This compound did not yield MS data. 1H NMR (400 MHz, CDCI3): 8.41 (s, 1 H), 6.59 (s, 1 H), 6.38 (s, 3H), 3.02 (q, J = 7.4 Hz, 2H), 1.43 (t, J = 7.4 Hz, 3H).

Reference： [1]Patent: WO2009/134750,2009,A1 .Location in patent: Page/Page column 164

39
[ 35375-74-7 ]
[ 5188-07-8 ]
[ 1193384-47-2 ]

Yield	Reaction Conditions	Operation in experiment
95%	In N,N-dimethyl-formamide; at 90℃; for 0.833333h;	To a solution of <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> (2.02 g, 8.40 mmol) and DMF (40 ml_) was added sodium thiomethoxide (0.618 g, 8.82 mmol). The mixture was heated to 90 0C for 50 min, then poured into brine. Water was added to bring the total volume to 300 ml_ and the orange precipitate was collected to yield the titled compound (2.02 g, 95%). 1H NMR (400 MHz, CDCI3): 8.42 (s, 1 H), 6.51 (s, 1 H),6.39 (br s, 2H), 2.53 (s, 3H).

Reference： [1]Patent: WO2009/134750,2009,A1 .Location in patent: Page/Page column 107

40
[ 95-77-2 ]
[ 35375-74-7 ]
[ 1193384-26-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; In ISOPROPYLAMIDE; at 85℃; for 18h;	To a mixture of 5-chloro-2-nitro-4-trifluoronnethyl-phenylannine (LOO g, 4.16 mmol) and DMA (21 ml_) was added K2CO3 (1.15 g, 8.32 mmol) and 3,4-dichloro-phenol (1.36 g, 8.32 mmol). The mixture was heated to 85 0C for 18 h. The mixture was cooled to 23 0C and poured into ice water. The precipitate was collected, dissolved in EtOAc (150 ml_) and washed with brine (2 x 30 ml_). The organic layers were combined, dried, filtered, and concentrated under reduced pressure to yield the titled compound (1.51 g, 99%). 1H NMR (500 MHz, CDCI3): 8.52 (s, 1 H), 7.53 (d, J = 8.7 Hz, 1 H), 7.26 (d, J = 3.2 Hz, 1 H), 7.00 (dd, J = 8.7, 2.7 Hz, 1 H), 6.37 (s, 2H), 6.06 (s, 1 H).

Reference： [1]Patent: WO2009/134750,2009,A1 .Location in patent: Page/Page column 89

41
[ 107-03-9 ]
[ 35375-74-7 ]
[ 1193384-49-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 16h;	To a mixture of <strong>[35375-74-7]5-chloro-2-nitro-4-trifluoromethyl-phenylamine</strong> (1.5O g, 6.26 mmol), potassium carbonate (1.72 g, 12.5 mmol), and DMF (31 ml_) was added 1 -propanediol (0.620 ml_, 6.86 mmol). The reaction mixture was heated at 90 0C for 16 h, then allowed to cool to 23 0C and poured into ice/brine (300 ml_). The resulting yellow precipitate was collected to yield the titled compound (1.67 g, 95%). MS (ESI/CI): mass calcd. for CiOHnF3N2O2S, 280.1 ; m/z found, 281.0 [M+H]+. 1H NMR (400 MHz, CDCI3): 8.41 (s, 1 H), 6.58 (s, 1 H), 6.36 (br s, 2H), 2.97 (t, J = 7.3 Hz, 2H), 1.87-1.72 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H).

Reference： [1]Patent: WO2009/134750,2009,A1 .Location in patent: Page/Page column 108

42
[ 35375-74-7 ]
[ 105-53-3 ]
[ 1813-24-7 ]

Yield	Reaction Conditions	Operation in experiment
91%		Under argon atmosphere, a suspension of potassium tert-butanolate (71.6 g, 625 mmol) in DMSO (150 mL) was placed in a 1.5 L flask, fitted with a mechanical stirrer. Then diethyl malonate (97.9 mL, 625 mmol) was added drop wise at 20 - 30 C under ice bath cooling. To the thick white suspension was the added solid commercially available 5- chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (60.14 g, 250 mmol) in one portion, the mixture was diluted with DMSO (100 mL) and the red solution warmed up to 60 C and stirred for 20 h at 60 C. The mixture was cooled to 23 C and a solution of potassium hydroxide (85%, 65.24 g, 1 mol) in water (100 mL) was added drop wise. The mixture was then heated to 100 C and stirred for further 4 h. The mixture was cooled to 23 C, diluted with water (ca. 1000 mL), acidified with 37% HCI 3 to pH 3, and extracted three times with tert-butyl methyl ether (TBME) The organic layers were washed with brine, dried over MgS04 and evaporated to give a brown solid, which was triturated with hot heptane, filtered off and washed with heptane to give the title compound as a brown solid (50.0 g, 91%), which was used without further purification. MS (ISN) 218.9 [M-H].

Reference： [1]Patent: WO2005/123738,2005,A1 .Location in patent: Page/Page column 25

43
[ 35375-74-7 ]
1-(tert-butoxycarbonylamino)-5-methoxy-2-nitro-4-(trifluoromethyl)benzene [ No CAS ]