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[ CAS No. 445-13-6 ] {[proInfo.proName]}

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Chemical Structure| 445-13-6

Chemical Structure| 445-13-6

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Quality Control of [ 445-13-6 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 445-13-6 ]

CAS No. :	445-13-6	MDL No. :	MFCD00278479
Formula :	C₇H₅ClF₃N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KZAMRRANXJVDCD-UHFFFAOYSA-N
M.W :	195.57	Pubchem ID :	67962
Synonyms :

Calculated chemistry of [ 445-13-6 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	40.86
TPSA :	26.02 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) :	-5.54 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.65
Log Po/w (XLOGP3) :	2.75
Log Po/w (WLOGP) :	4.1
Log Po/w (MLOGP) :	3.15
Log Po/w (SILICOS-IT) :	2.77
Consensus Log Po/w :	2.88

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.09
Solubility :	0.159 mg/ml ; 0.000815 mol/l
Class :	Soluble
Log S (Ali) :	-2.95
Solubility :	0.219 mg/ml ; 0.00112 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.54
Solubility :	0.0558 mg/ml ; 0.000285 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.24

Safety of [ 445-13-6 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P280-P305+P351+P338	UN#:
Hazard Statements:	H317-H319	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 445-13-6 ]

* 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 [ 445-13-6 ]
Downstream synthetic route of [ 445-13-6 ]

[ 445-13-6 ] Synthesis Path-Upstream 1~11

1
[ 445-13-6 ]
[ 35375-74-7 ]

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

2
[ 75-63-8 ]
[ 108-42-9 ]
[ 445-14-7 ]
[ 445-13-6 ]
[ 432-21-3 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 8, p. 2293 - 2299

3
[ 75-63-8 ]
[ 108-42-9 ]
[ 445-14-7 ]
[ 445-13-6 ]
[ 432-21-3 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 8, p. 2293 - 2299

4
[ 100-34-5 ]
[ 445-13-6 ]

Reference： [1] Patent: US4162329, 1979, A,

5
[ 7587-89-5 ]
[ 445-13-6 ]

Reference： [1] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 25, p. 119
[2] Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 25, p. 119
[3] Patent: US2093115, 1936, ,

6
[ 151504-80-2 ]
[ 445-13-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2929 - 2932

7
[ 41252-96-4 ]
[ 445-13-6 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2003, vol. 13, # 17, p. 2929 - 2932

8
[ 75-63-8 ]
[ 108-42-9 ]
[ 445-14-7 ]
[ 445-13-6 ]
[ 432-21-3 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 8, p. 2293 - 2299

9
[ 445-13-6 ]
[ 37900-81-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	at 0 - 110℃; for 3 h; Heating / reflux	To a sulfuric acid (14 ml) -H₂O (14 ml) solution of 3-chloro-4-(trifluoromethyl)aniline (1.96 g, 10 mmol) was added a H₂O (10 mL) solution of sodium nitrite (828 mg,12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was poured into 10 M sulfuric acid (50 mL). The stirred mixture was refluxed at 110 ° C. for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a ethyl acetate/hexane= to furnish 945 mg (48percent yield) of the title compound as a brown oil. ¹H NMR (CDCl₃, 270 MHz) δ ppm 5.99 (1H, brs), 6.80 (1H, dd, J=2.6, 8.6 Hz), 7.00 (1H, d, J=2.6 Hz), 7.56 (1H, d, J=8.6 Hz). MS (ESI) m/z: 195[M-H^-.

Reference： [1] Patent: US2006/100460, 2006, A1, . Location in patent: Page/Page column 22

10
[ 445-13-6 ]
[ 157590-59-5 ]

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

11
[ 445-13-6 ]
[ 467435-07-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	With tert.-butylnitrite; copper(ll) bromide In acetonitrile at 45℃; for 3 h;	A solution of 4-amino-2-chlorobenzotrifluoride (9.780 g; 50.007 mmol) in MeCN (65 ml) was treated with copper(ll) bromide (1 1.169 g; 50.007 mmol), and the green heterogeneous mixture was heated to 45°C. A solution of tert-butyl nitrite (6.53 ml; 55.008 mmol) in MeCN (10 ml) was then added dropwise over 30 min., and the resulting mixture was further stirred at 45°C for 2h20. The dark heterogeneous reaction mixture was allowed to cool to rt, and was directly purified by FC (DCM). After concentration to dryness under reduced pressure, the expected product 4-bromo-2-chloro-1-trifluoromethyl-benzene was obtained as a yellow oil (12.82O g; 50percent). LC-MS: t_R = 1.10 min.; [M+H]⁺: no ionisation.

Reference： [1] Patent: WO2008/78291, 2008, A1, . Location in patent: Page/Page column 42

[ 445-13-6 ] Synthesis Path-Downstream 1~80

1
[ 7587-89-5 ]
[ 445-13-6 ]

Reference： [1]Patent: DE672371,1935,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 25,p. 119

2
[ 445-13-6 ]
[ 546434-30-4 ]

Reference： [1]Patent: DE672371,1935,
Fortschr. Teerfarbenfabr. Verw. Industriezweige,vol. 25,p. 119

3
[ 2401-85-6 ]
[ 445-13-6 ]
[ 68105-69-1 ]

Reference： [1]Patent: DE2708440,1978,
Chem.Abstr.,1978,vol. 89

4
[ 654-55-7 ]
[ 445-13-6 ]
[ 72781-79-4 ]

Reference： [1]Patent: DE2815290,1979,
Chem.Abstr.,1980,vol. 92

5
[ 445-13-6 ]
[ 2375-97-5 ]
[ 72773-12-7 ]

Reference： [1]Patent: DE2815290,1979,
Chem.Abstr.,1980,vol. 92

6
[ 445-13-6 ]
[ 27738-96-1 ]
[ 35631-27-7 ]
[ 39886-32-3 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1972,vol. 765,p. 78 - 93

7
[ 445-13-6 ]
[ 39893-50-0 ]
[ 23794-99-2 ]

Reference： [1]Patent: DE1802739,1969,
Chem.Abstr.,1969,vol. 71

8
[ 75-63-8 ]
[ 108-42-9 ]
[ 445-14-7 ]
[ 445-13-6 ]
[ 432-21-3 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1990,p. 2293 - 2299

9
[ 445-13-6 ]
[ 108-24-7 ]
[ 546434-30-4 ]

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

10
[ 445-13-6 ]
[ 742097-64-9 ]
thiazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2929 - 2932

11
[ 445-13-6 ]
pyridine-2-carboxylic acid (4-isothiocyanato-phenyl)-amide [ No CAS ]
pyridine-2-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2929 - 2932

12
[ 445-13-6 ]
oxazole-4-carboxylic acid (4-isothiocyanato-phenyl)-amide [ No CAS ]
oxazole-4-carboxylic acid {4-[3-(3-chloro-4-trifluoromethyl-phenyl)-thioureido]-phenyl}-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2929 - 2932

13
[ 151504-80-2 ]
[ 445-13-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; In water; at 55℃; for 3h;Green chemistry;	General procedure: To the corresponding nitro aromatic compound (1 mmol) in3mL water, 40 mg catalyst was added and the suspension wasstirred vigorously at ambient temperature. Subsequently, 2 mmolNaBH4 was added and the mixture heated to 55 C. Afterwards, theprogress of reduction process was monitored using thin layerchromatography until the complete reduction of nitro groups. After the reduction reaction completed, the catalyst was removed withan external magnet and washed with ethanol. The products werepurified by a short column chromatography over silica gel to obtainthe corresponding compounds in high purity. 1H NMR spectra andcomparison of melting points to authentic samples were used forrecognizing of the reaction products.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2929 - 2932
[2]Journal of Molecular Structure,

14
[ 61982-14-7 ]
[ 445-13-6 ]
[ 929910-69-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375

15
[ 1006962-20-4 ]
[ 445-13-6 ]
2-methyl-4-nitro-2<i>H</i>-pyrazole-3-carboxylic acid (3-chloro-4-trifluoromethyl-phenyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375

16
potassium 1H-[1,2,4]triazole-3-selenoxide [ No CAS ]
[ 445-13-6 ]
[ 873576-69-3 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2006,vol. 54,p. 7724 - 7728

17
[ 445-13-6 ]
[ 105-56-6 ]
<i>N</i>-(3-chloro-4-trifluoromethyl-phenyl)-2-cyano-acetamide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375
[2]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1195 - 1198

18
[ 951134-40-0 ]
[ 445-13-6 ]
Example 45 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		Example 45 N4-(3-Chloro-4-trifluoromethyl-phenyl)-N2,N2-dimethyl-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine The title compound was synthesized like Example 39 with modifications to Step C as follows: Step C. A mixture of [4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-2-yl]-dimethyl-amine (50 mg, 0.14 mmol), 3-chloro-4-trifluoro-methylaniline (40 mg, 0.20 mmol), and p-toluenesulfonic acid (51 mg, 0.27 mmol) in toluene (2 mL) was heated in a sealed tube at 120 C. for 18 h. The mixture was cooled, diluted with satd. aq. NaHCO3, and extracted with CH2Cl2. The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound (55 mg, 78%). MS (ESI): mass calcd. for C23H21ClF6N6, 530.14; m/z found, 531.8 [M+H]+. 1H NMR (CD3OD): 8.43-8.40 (m, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.08-7.98 (m, 1H), 7.66-7.62 (m, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.11-7.08 (m, 1H), 3.45-3.39 (m, 4H), 3.33-3.31 (m, 1H), 3.13 (s, 6H), 3.06-3.03 (m, 2H), 2.97-2.93 (m, 2H).

Reference： [1]Patent: US2007/225275,2007,A1 .Location in patent: Page/Page column 26-27

19
C₁₁H₁₁N₃O₂ [ No CAS ]
[ 445-13-6 ]
C₁₈H₁₄F₃ClN₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3550 - 3557

20
C₁₁H₁₁N₃O₂ [ No CAS ]
[ 445-13-6 ]
C₁₈H₁₄ClF₃N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3550 - 3557

21
C₁₅H₁₃N₃O₂ [ No CAS ]
[ 445-13-6 ]
C₂₂H₁₆ClF₃N₄O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3550 - 3557

22
C₉H₉N₅O₂ [ No CAS ]
[ 445-13-6 ]
C₁₆H₁₂ClF₃N₆O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 3550 - 3557

23
[ 445-13-6 ]
5-amino-3-methyl-isoxazole-4-carboxylic acid (3-chloro-4-trifluoromethyl-phenyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375

24
[ 445-13-6 ]
2-cyano-3-ethoxy-but-2-enoic acid (3-chloro-4-trifluoromethyl-phenyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375

25
[ 445-13-6 ]
3-methyl-5-[(pyridin-4-ylmethylene)-amino]-isoxazole-4-carboxylic acid (3-chloro-4-trifluoromethyl-phenyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375

26
[ 445-13-6 ]
3-methyl-5-[(pyridin-4-ylmethyl)-amino]-isoxazole-4-carboxylic acid (3-chloro-4-trifluoromethyl-phenyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 1369 - 1375

27
[ 41252-96-4 ]
[ 445-13-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 2929 - 2932

28
[ 445-13-6 ]
[ 35375-74-7 ]

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

29
[ 445-13-6 ]
[ 157590-59-5 ]

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

30
[ 445-13-6 ]
[ 153505-38-5 ]

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

31
[ 445-13-6 ]
[ 1026318-97-7 ]

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

32
[ 445-13-6 ]
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

33
[ 445-13-6 ]
[ 32333-53-2 ]

Yield	Reaction Conditions	Operation in experiment
		Following the procedure of N. Ikemoto et al. (Tetrahedron, 59:1317 (1998)), <strong>[445-13-6]3-chloro-4-trifluoromethylaniline</strong> (890 mg, 4.6 mmol, Ryan Scientific) in CH3CN (37 mL) was added to a 250 mL round-bottomed flask. The flask was cooled in an ice bath, and HOAc (3.7 mL) and HCl (12 M, 1.8 mL) were added. Sodium nitrite (380 mg, 5.5 mmol, Aldrich) in 0.77 mL of H2O was added in 0.15 mL portions every 2 min until all of the solution had been added (total time ca. 9 min). After 25 min, sulfur dioxide (Aldrich) was bubbled into the reaction mixture for 1.25 h. Copper(II)chloride (780 mg, 5.8 mmol, Aldrich) in 1.5 mL of water was then added to the reaction mixture. Gas evolution occurred, and the reaction was warmed to RT and stirred overnight. After the lower boiling solvents were removed in vacuo, water was added, and the mixture was extracted with CH2Cl2 (3×). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated in vacuo to give the crude material as a brownish oil with solid in it. The compound did not ionize well, but an aliquot, when treated with propylamine, provided the propylarylsulfonamide adduct with a ESI-MS, -ion, m/z=300.2 (M-1).

Reference： [1]Patent: US2005/234044,2005,A1 .Location in patent: Page/Page column 42-43

34
[ 445-13-6 ]
[ 37900-81-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With sulfuric acid; water; sodium nitrite; at 0 - 110℃; for 3h;Heating / reflux;	To a sulfuric acid (14 ml) -H2O (14 ml) solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (1.96 g, 10 mmol) was added a H2O (10 mL) solution of sodium nitrite (828 mg,12 mmol) at 0 ° C. The reaction mixture was stirred at ambient temperature for 1 hour. The mixture was poured into 10 M sulfuric acid (50 mL). The stirred mixture was refluxed at 110 ° C. for 2 hours. The reaction mixture was then quenched with saturated aqueous solution of sodium bicarbonate and then crude products were extracted with ethyl acetate The organic layer was then washed with brine, dried over sodium sulfate. After the filtration to separate solvent and sodium sulfate, the solvent was removed under reduced pressure to give the residue, which was applied to a silica gel chromatography column and eluted with a ethyl acetate/hexane= to furnish 945 mg (48percent yield) of the title compound as a brown oil. 1H NMR (CDCl3, 270 MHz) delta ppm 5.99 (1H, brs), 6.80 (1H, dd, J=2.6, 8.6 Hz), 7.00 (1H, d, J=2.6 Hz), 7.56 (1H, d, J=8.6 Hz). MS (ESI) m/z: 195[M-H-.

Reference： [1]Patent: US2006/100460,2006,A1 .Location in patent: Page/Page column 22

35
[ 445-13-6 ]
[ 1885-14-9 ]
[ 894801-69-5 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine; In tetrahydrofuran; for 18h;	Phenyl [3-chloro-4-(trifluoromethyl)phenyl]carbamate; Phenyl chloroformate (0.86 mL) was added slowly to a stirring solution of 3-chloro-4- trifluoromethyl aniline (933 mg) in THF (10 mL) containing pyridine (1.07 mL) under an argon atomosphere. The reaction was stirred for 18 h then diluted with ethyl acetate (35 mL) and IM HCl (20 mL). The organic layer was separated and washed with saturated aqueous NaHCO3 then dried (MgSO4), filtered and evaporated. Trituration with 1:9 EPO <DP n="183"/>EtOAc dsohexanes (10 mL) at reflux followed by cooling to RT afforded a solid which was filtered to afford 1.15 g of the title compound.

Reference： [1]Patent: WO2006/67401,2006,A1 .Location in patent: Page/Page column 181-182

36
[ 445-13-6 ]
[ 76-02-8 ]
[ 894801-68-4 ]

Yield	Reaction Conditions	Operation in experiment
69%	With pyridine; In dichloromethane; for 2h;	l^^-Trichloro-N-tS-chloro^^trifluoromethy^phenyllacetaiiiide; To a solution of 4-amino-2-chlorobenzotrifluoride (300 mg) and pyridine (243 mg) in dichloromethane (1OmL) was added a solution of trichloro acetyl chloride (279 mg) in dichloromethane (5mL) dropwise. The solution was stirred for 2hrs and then concentrated at reduced pressure. The residue was purified by silica gel chromatography eluting with 0-10% ethyl acetate in hexane to give the title compound as a white solid (360mg, 69%).

Reference： [1]Patent: WO2006/67401,2006,A1 .Location in patent: Page/Page column 179

37
[ 496808-03-8 ]
[ 445-13-6 ]
N-[3-chloro-4-(trifluoromethyl)phenyl]-4-[(1-methylpiperidin-3-yl)methyl]piperazine-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		iV-tS-CIiloro^-CtrifluoromethylJphenyy^-fCl-methylpiperidin-S- yl)methyl]pipera-ne-l-carboxaniotaide; To a solution of di-tert-butyl dicarbonate (114.6 mg) in chloroform (2 ml) was added 4-dimethylaminopyridine (6 mg). A solution of 4-amino-2-chlorobenzotrifluoride(98.1 mg) in chloroform (2 ml) was added and the reaction mixture stirred for 20 minutes at room temperature. A solution of l-[(l-methylpiperidm-3-yl)methyl]piperazine (98.5 mg) in chloroform (2 ml) was added and the resulting solution was stirred at reflux for 18 hours. The reaction mixture was purified by column chromatography on silica gel (20 g) using a gradient of 100% dichloromethane through to 20% methanolic ammonia in dichloromethane to give the title compound (14 mg).

Reference： [1]Patent: WO2006/67401,2006,A1 .Location in patent: Page/Page column 46; 176

38
[ 445-13-6 ]
[ 1885-14-9 ]
[ 371-40-4 ]
[ 78015-62-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With triethylamine; In 1,2-dichloro-benzene;	Example 2 (variant b) STR11 0.5 mol of chloroformic acid phenyl ester is added to a solution of 0.5 mol of p-fluoroaniline in 300 ml of dichlorobenzene and 70 ml (0.5 mol) of triethylamine, whilst cooling (0-10 C.). The reaction mixture is then left to stand at room temperature for 24 hours. The triethylamine hydrochloride which has formed is filtered off and 0.5 mol of <strong>[445-13-6]3-chloro-4-trifluoromethylaniline</strong> is added to the filtrate. The reaction solution is heated to 180 C. for 6 hours, the solvent is stripped off in vacuo and the residue is boiled up in 250 ml of ether and filtered off again. N-4-Fluorophenyl-N'-3-chloro-4-trifluoromethylphenylurea of melting point 212 to 214 C. is obtained. Yield: 67% of theory.

Reference： [1]Patent: US4405644,1983,A

39
[ 100-34-5 ]
[ 445-13-6 ]

Yield	Reaction Conditions	Operation in experiment
		It was prepared by diazotizing of 3-chloro-4-trifluoromethylaniline and subsequent reduction of the corresponding phenyldiazonium chloride with tin(II) chloride.

Reference： [1]Patent: US4162329,1979,A

40
[ 445-13-6 ]
[ 932374-43-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With Iodine monochloride; In methanol; dichloromethane; at 0℃;	Step 1 5-Chloro-2-iodo-4-(trifluoromethyl)phenylamine A 250 mL 3-necked round bottom flask was charged with <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (4.5 g, 0.02 mol) and MeOH (50 mL). To the above was added dropwise a solution of IC1 (4.8 g, 0.03 mol) in CH2Cl2 (100 mL) at 0 C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtOAc/Petroleum ether=1:20, Rf=0.6). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2Cl2, washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo, to give 6.9 g (93%) of the product. MS m/z: 320 (M-H+).
93%	With Iodine monochloride; In methanol; dichloromethane; at 0 - 20℃; for 1h;	A 250 mL 3-necked round bottom flask was charged with 3-chloro-4- (trifluoromethyl)aniline (4.5 g, 0.02 mol) and MeOH (50 mL). To the above was added dropwise a solution of ICl (4.8 g, 0.03 mol) in CH2C12 (100 mL) at 0 C. The resulting mixture was stirred at room temperature for 1 h. Reaction progress was monitored by TLC (EtO Ac/Petroleum ether = 1 :20, Rf = 0.6). Work-up: the mixture was concentrated in vacuo. The residue was re-dissolved in CH2C12, washed with water, dried over anhydrous Na2SC>4 and concentrated in vacuo, to give 6.9 g (93%) of the product. MS m/z: 320 (M-H+).
	With sodium acetate; Iodine monochloride; In acetic acid; at 20℃; for 0.5h;	Iodine monochloride (1.5 g) was added in one portion to a mixture of 3-chloro-4- trifluoromethylaniline (1.7 g), sodium acetate trihydrate (2.2 g), and acetic acid (10 ml) at room temperature. After 30 min aqueous sodium bicarbonate / sodium sulfite was added and the mixture extracted with diethyl ether. The organic phase was dried over Na2SO4, filtered and evaporated. The residue was purified by chromatography (ethyl acetate - hexane) to afford the title compound, 2.2 g.

Reference： [1]Patent: US2010/120741,2010,A1 .Location in patent: Page/Page column 70
[2]Patent: WO2011/112731,2011,A2 .Location in patent: Page/Page column 161-162
[3]Patent: WO2007/36718,2007,A2 .Location in patent: Page/Page column 48

41
[ 445-13-6 ]
[ 467435-07-0 ]

Yield	Reaction Conditions	Operation in experiment
50%	With tert.-butylnitrite; copper(ll) bromide; In acetonitrile; at 45.0℃; for 3.0h;	A solution of 4-amino-2-chlorobenzotrifluoride (9.780 g; 50.007 mmol) in MeCN (65 ml) was treated with copper(ll) bromide (1 1.169 g; 50.007 mmol), and the green heterogeneous mixture was heated to 45C. A solution of tert-butyl nitrite (6.53 ml; 55.008 mmol) in MeCN (10 ml) was then added dropwise over 30 min., and the resulting mixture was further stirred at 45C for 2h20. The dark heterogeneous reaction mixture was allowed to cool to rt, and was directly purified by FC (DCM). After concentration to dryness under reduced pressure, the expected product 4-bromo-2-chloro-1-trifluoromethyl-benzene was obtained as a yellow oil (12.82O g; 50%). LC-MS: tR = 1.10 min.; [M+H]+: no ionisation.

Reference： [1]Patent: WO2008/78291,2008,A1 .Location in patent: Page/Page column 42

42
[ 1000709-42-1 ]
[ 445-13-6 ]
Example 4 [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 40 - 46

43
[ 1051372-42-9 ]
[ 445-13-6 ]
[ 1051372-37-2 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5019 - 5034

44
[ 445-13-6 ]
[ 7446-09-5 ]
[ 32333-53-2 ]

Yield	Reaction Conditions	Operation in experiment
		Following the procedure of N. Ikemoto et al. (Tetrahedron, 59 : 1317 (1998)), <strong>[445-13-6]3-chloro-4-trifluoromethylaniline</strong> (890 mg, 4.6 mmol, Ryan Scientific) in CH3CN (37 mL) was added to a 250 mL round-bottomed flask. The flask was cooled in an ice bath, and HOAc (3.7 mL) and HCl (12 M, 1.8 mL) were added. Sodium nitrite (380 mg, 5.5 mmol, Aldrich) in 0.77 mL of H2O was added in 0.15 mL portions every 2 min until all of the solution had been added (total time ca. 9 min). After 25 min, sulfur dioxide (Aldrich) was bubbled into the reaction mixture for 1.25 h. Copper (II) chloride (780 mg, 5.8 mmol, Aldrich) in 1.5 mL of water was then added to the reaction mixture. Gas evolution occurred, and the reaction was warmed to RT and stirred overnight. After the lower boiling solvents were removed in vacuo, water was added, and the mixture was extracted with CH2Cl2 (3x). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated in vacuo to give the crude material as a brownish oil with solid in it. The compound did not ionize well, but an aliquot, when treated with propylamine, provided the propylarylsulfonamide adduct with a ESI-MS,-ion, M/Z = 300.2 (M-1).

Reference： [1]Patent: WO2004/92164,2004,A1 .Location in patent: Page 123; 124

45
[ 445-13-6 ]
[ 1206599-46-3 ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid; potassium iodide; sodium nitrite; In water; acetonitrile; at 10℃;	Intermediate 19 (S)-2-(4-Chloro-3-trifluoromethoxy-phenylamino)-propionic AcidA) 2-Chloro-4-iodo-1-trifluoromethyl-benzene; To a solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (450 mg, 2.30 mmol) and toluene 4-sulfonic acid (1.19 g, 6.92 mmol) in CH3CN (10 mL) was added a solution of potassium iodide (955 mg, 5.76 mmol) and sodium nitrite (318 mg, 4.61 mmol) in water (1.8 mL) over 15 min at 10 C., then after 20 min the reaction mixture was poured onto water, neutralized with sat. aq. NaHCO3 solution, treated with 2 M aq. sodium thiosulfate solution (6 mL), and extracted with EtOAc. The organic layer was dried (MgSO4), filtered, and evaporated to afford the title compound (517 mg) as a light brown oil, which was directly used in the next step.

Reference： [1]Patent: US2010/22518,2010,A1 .Location in patent: Page/Page column 24-25

46
[ 32315-10-9 ]
[ 1282532-16-4 ]
[ 445-13-6 ]
[ 1282532-17-5 ]

Yield	Reaction Conditions	Operation in experiment
47%		Example 13 (3S,6S)-3-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-6,8a-dimethyl-5- hexahydro-oxazolo[3,2-a]pyrazine-7-carboxylic acid (3-chloro^t-trifluoromethyl- phenyl)-amide OH A solution of 4-amino-2-chlorobenzotrifiuoride (30 mg, 0.15 mmol) in acetonitrile (0.5 mL) was added dropwise at 0C to a solution of bis-(trichloromethyl)-carbonate (17 mg, 50 muetaiotaomicron) in acetonitrile (0.5 mL) and pyridine (13 mg, 0.16 mmol). The ice bath was removed, then after 30 min a solution of (3S,6S)-3-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)- propyl]-6,8a-dimethyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (example 12G) in acetonitrile (0.5 mL) was added. After 3 h the reaction mixture was evaporated and the residue purified by chromatography (Si02; DCM? DCM/MeOH/25% aq. ammonia solution 90:10:0.25) to pruduce the title compound (39 mg, 47%). White solid, MS: 559.4 (M+H)+.
47%		A solution of 4-amino-2-chlorobenzotrifluoride (30 mg, 0.15 mmol) in acetonitrile (0.5 mL) was added dropwise at 0 C. to a solution of bis-(trichloromethyl)-carbonate (17 mg, 50 mumol) in acetonitrile (0.5 mL) and pyridine (13 mg, 0.16 mmol). The ice bath was removed, then after 30 min a solution of (3S,6S)-3-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-6,8a-dimethyl-hexahydro-oxazolo[3,2-a]pyrazin-5-one (example 12G) in acetonitrile (0.5 mL) was added. After 3 h the reaction mixture was evaporated and the residue purified by chromatography (SiO2; DCM?DCM/MeOH/25% aq. ammonia solution 90:10:0.25) to produce the title compound (39 mg, 47%). White solid, MS: 559.4 (M+H)+.

Reference： [1]Patent: WO2011/42399,2011,A1 .Location in patent: Page/Page column 52-53
[2]Patent: US2011/82294,2011,A1 .Location in patent: Page/Page column 22

47
[ 445-13-6 ]
[ 1217302-11-8 ]

Reference： [1]Patent: WO2011/112731,2011,A2

48
[ 7677-24-9 ]
[ 445-13-6 ]
[ 56-81-5 ]
[ 1375604-42-4 ]

Yield	Reaction Conditions	Operation in experiment
38.4%		To a stirred solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (AS) (10 g, 51.2 mmol) in glycerol(120 mL) were added sulfamix (17.3 g, 76.8 mmol), FeSO4.7H20 (2.9 g, 10.7 mmol) followedby boric acid (5.06 g, 81.9 mmol) at RT. The reaction mixture was cooled to 0 C;Conc.H2S04 (35 mL) was added to the reaction mixture and heated at 145 C for 3 h. Afterconsumption of the starting material (by TLC), the reaction was quenched with cold water and neutralized with NaHCO3. The aqueous layer was extracted with CH2C12 (3 x 500 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The obtained crude material waspurified by silica gel column chromatography eluting with 30% EtOAc/hexane to afford AT(mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol, 34%) as syrup.To a stirred solution of AT (mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol) in EtOAc(20 mL) was added m-CPBA (7.4 g, 43 mmol) at 0 C and the reaction mixture was stirred atRT for 12 h. After consumption of the starting material (by TLC), the reaction mixture wasconcentrated under reduced pressure. The crude material was purified by silica gel columnchromatography eluting with 10% MeOH/CH2C12 to afford AU (mixture of 5,6- and 6,7-regio isomers) (2 g, 8.06 mmol, 47.6%) as yellow solid.To a stirred solution of AU (mixture of 5,6- and 6,7-regio isomers) (5.0 g, 20.1 mmol) in ACN (50 mL) was added Et3N (7.1 g, 70.3 mmol) followed by TMSCN (6.9 g, 70.3 mmol) at 0 Cunder an inert atmosphere. The reaction mixture was stirred at RT for 14 h. The volatiles were evaporated under reduced pressure and the crude material was purified by silica gel column chromatography eluting with 8% EtOAc/Hexane to afford AV (6,7-isomer) (2.0 g, 7.75 mmol, 38.4%) as a brown solid.
		To a stirred solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (AS) (10 g, 51.2 mmol) in glycerol (120 mL) were added sulfamix (17.3 g, 76.8 mmol), FeS04.7H20 (2.9 g, 10.7 mmol) followed by boric acid (5.06 g, 81.9 mmol) at RT. The reaction mixture was cooled to 0 C; Conc.H2S04 (35 mL) was added to the reaction mixture and heated at 145 C for 3 h. After consumption of the starting material (by TLC), the reaction was quenched with cold water and neutralized with NaHC03. The aqueous layer was extracted with CH2CI2 (3 x 500 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04> filtered and concentrated in vacuo. The obtained crude material was purified by silica gel column chromatography eluting with 30% EtOAc/hexane to afford AT (mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol, 34%) as syrup.To a stirred solution of AT (mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol) in EtOAc (20 mL) was added m-CPBA (7.4 g, 43 mmol) at 0 C and the reaction mixture was stirred at RT for 12 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% MeOH/CH2Ci2 to afford AU (mixture of 5,6- and 6,7-regio isomers) (2 g, 8.06 mmol, 47.6%) as yellow solid.To a stirred solution of AU (mixture of 5,6- and 6,7-regio isomers) (5.0 g, 20.1 mmol) in ACN (50 mL) was added Et3N (7.1 g, 70.3 mmol) followed by TMSCN (6.9 g, 70.3 mmol) at 0 C under an inert atmosphere. The reaction mixture was stirred at RT for 14 h. The volatiles were evaporated under reduced pressure and the crude material was purified by silica gel column chromatography eluting with 8% EtOAc/Hexane to afford AV (6,7-isomer) (2.0 g, 7.75 mmol, 38.4%) as a brown solid.

Reference： [1]Patent: WO2019/182743,2019,A1 .Location in patent: Page/Page column 56
[2]Patent: WO2012/64943,2012,A2 .Location in patent: Page/Page column 69-71

49
[ 445-13-6 ]
[ 1375604-44-6 ]

Reference： [1]Patent: WO2012/64943,2012,A2
[2]Patent: WO2019/182743,2019,A1

50
[ 445-13-6 ]
[ 1375604-46-8 ]

Reference： [1]Patent: WO2012/64943,2012,A2
[2]Patent: WO2019/182743,2019,A1

51
[ 445-13-6 ]
[ 1375603-52-3 ]

Reference： [1]Patent: WO2012/64943,2012,A2
[2]Patent: WO2019/182743,2019,A1

52
[ 445-13-6 ]
[ 56-81-5 ]
[ 1375604-48-0 ]
[ 1375604-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ferrous(II) sulfate heptahydrate; sulfuric acid; boric acid; at 0 - 145℃;	To a stirred solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (AS) (10 g, 51.2 mmol) in glycerol (120 mL) were added sulfamix (17.3 g, 76.8 mmol), FeS04.7H20 (2.9 g, 10.7 mmol) followed by boric acid (5.06 g, 81.9 mmol) at RT. The reaction mixture was cooled to 0 C; Conc.H2S04 (35 mL) was added to the reaction mixture and heated at 145 C for 3 h. After consumption of the starting material (by TLC), the reaction was quenched with cold water and neutralized with NaHC03. The aqueous layer was extracted with CH2CI2 (3 x 500 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04> filtered and concentrated in vacuo. The obtained crude material was purified by silica gel column chromatography eluting with 30% EtOAc/hexane to afford AT (mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol, 34%) as syrup.

Reference： [1]Patent: WO2012/64943,2012,A2 .Location in patent: Page/Page column 69-71

53
[ 445-13-6 ]
[ 56-81-5 ]
[ 1375604-50-4 ]
[ 1375604-40-2 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (AS) (10 g, 51.2 mmol) in glycerol (120 mL) were added sulfamix (17.3 g, 76.8 mmol), FeS04.7H20 (2.9 g, 10.7 mmol) followed by boric acid (5.06 g, 81.9 mmol) at RT. The reaction mixture was cooled to 0 C; Conc.H2S04 (35 mL) was added to the reaction mixture and heated at 145 C for 3 h. After consumption of the starting material (by TLC), the reaction was quenched with cold water and neutralized with NaHC03. The aqueous layer was extracted with CH2CI2 (3 x 500 mL). The combined organic phases were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04> filtered and concentrated in vacuo. The obtained crude material was purified by silica gel column chromatography eluting with 30% EtOAc/hexane to afford AT (mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol, 34%) as syrup.To a stirred solution of AT (mixture of 5,6- and 6,7-regio isomers) (4 g, 17.2 mmol) in EtOAc (20 mL) was added m-CPBA (7.4 g, 43 mmol) at 0 C and the reaction mixture was stirred at RT for 12 h. After consumption of the starting material (by TLC), the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography eluting with 10% MeOH/CH2Ci2 to afford AU (mixture of 5,6- and 6,7-regio isomers) (2 g, 8.06 mmol, 47.6%) as yellow solid.

Reference： [1]Patent: WO2012/64943,2012,A2 .Location in patent: Page/Page column 69-71

54
[ 445-13-6 ]
[ 100-28-7 ]
[ 23745-41-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,2012,vol. 60,p. 1046 - 1054

55
[ 40465-45-0 ]
[ 445-13-6 ]
[ 1446482-93-4 ]

Reference： [1]Molecules,2013,vol. 18,p. 2904 - 2923

56
[ 463-71-8 ]
[ 445-13-6 ]
[ 30613-71-9 ]

Yield	Reaction Conditions	Operation in experiment
79%	With calcium carbonate; In dichloromethane; water; at 0 - 20℃; under 760.051 Torr;Inert atmosphere;	To a suspension of calcium carbonate (1.04 g, 10.4 mmol, Eq: 2.03) and thiophosgene (645 mg, 430 mu, 5.61 mmol, Eq: 1.1) in dichloromethane (13.2 g, 10.0 ml, 155 mmol, Eq: 25.3)/water (10.0 g, 10.0 ml, 555 mmol, Eq: 90.2) at 0, was added 3-chloro-4- (trifluoromethyl)aniline (1 g, 5.11 mmol, Eq: 1.00) The reaction was gradually warmed to room temperature and stirred overnight. Added 10 mL IN HC1. Separated organic layer, dried over sodium sulfate, and chromatographed (60 g Analogix, 100% hex) to give 962 mg (79%) of desired product as colorless oil.

Reference： [1]Patent: WO2014/6066,2014,A1 .Location in patent: Paragraph 0165

57
[ 445-13-6 ]
[ 1533434-70-6 ]

Reference： [1]Patent: WO2014/6066,2014,A1

58
[ 445-13-6 ]
[ 1533424-03-1 ]

Reference： [1]Patent: WO2014/6066,2014,A1

59
[ 1423915-00-7 ]
[ 445-13-6 ]
2-(5-tert-butylisoxazol-3-yl)-N'-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxoacetohydrazonoyl cyanide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6033 - 6047

60
6-[bis(4-chlorophenyl)methyl]-4-chloroquinazoline [ No CAS ]
[ 445-13-6 ]
6-(bis(4-chlorophenyl)methyl)-N-(3-chloro-4-(trifluoromethyl)phenyl)quinazolin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In isopropyl alcohol; Petroleum ether; at 25℃;	Into a 25-mL round-bottom flask, was placed 6-[bis(4-chlorophenyl)methyl]-4-chloroquinazoline (100 mg, 0.25 mmol, 1.00 equiv), <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (59 mg, 0.30 mmol, 1.20 equiv), propan-2-ol (10 mL) and triethylamine (0.1 mL). The resulting solution was stirred overnight at 25 C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1), to yield 6-[bis(4-chlorophenyl)methyl]-N-[3-chloro-4-(trifluoromethyl)phenyl]quinazolin-4-amine as a white solid. LC-MS (ES, m/z): 558 [M+H]+ 1H-NMR: (400 MHz, DMSO, ppm) delta 10.127 (s, 1H), 8.745 (s, 1H), 8.464 (s, 1H), 8.357 (s, 1H), -8.031 (m, 1H), 7.889-7.832 (m, 2H), 7.652 (d, J=7.5 Hz, 1H), 7.442-7.414 (m, 4H), 7.219-7.191 (m, 4H).

Reference： [1]Patent: US2016/68512,2016,A1 .Location in patent: Paragraph 0365-0367

61
[ 445-13-6 ]
N-(3-trifluoromethyl-4-chlorophenyl)-4-methylbenzenesulfonamide [ No CAS ]

Reference： [1]Synthetic Communications,2017,vol. 47,p. 771 - 778

62
[ 445-13-6 ]
2-(4-chloro-3-trifluoromethyl-phenyl)-1,2-benzisothiazol-3(2H)-one 1,1-dioxide [ No CAS ]

Reference： [1]Synthetic Communications,2017,vol. 47,p. 771 - 778

63
tetrafluoroboric acid [ No CAS ]
[ 445-13-6 ]
[ 95445-68-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite; In water; at 0℃; for 3.33333h;	General procedure: Aniline (50 mmol) was dissolved in the 40% (V/V) fluoroboric acid (200 mmol). After cooling to 0 C, an aqueous solution of sodium nitrite (3.6 g, 51 mmol) in 15 mL H2O was added dropwise for 20 min. The mixture was stirred for 3 h and the thick precipitate was collected and washed with diethyl ether (2×10 mL). The arenediazonium tetrafluoroborate was dried in vacuo (10-3 mbar) for 10 minutes and was then directly used without further purification.

Reference： [1]Synthetic Communications,2017,vol. 47,p. 771 - 778

64
C₁₀H₆N₂O₂ [ No CAS ]
[ 445-13-6 ]
2-(benzo[d]isoxazol-3-yl)-N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxoacetohydrazonoyl cyanide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of 3-chloroaniline 5a (37mg, 0.33mmol) in H2O (10mL cooled to-5C) was added 0.2mL of 2N HCl (aq.). To the resulting acidic aniline solution, 1N solution of sodium nitrite (0.33mL, 0.33mmol) was added dropwise to generate the aryldiazonium salt solution 6a. To the aryldiazonium salt solution was added sodium acetate (54mg, 0.66mmol), followed by 1mL solution of crude 3-oxo-3-(3-phenylisoxazol-5-yl)propanenitrile 4a (88mg, 0.33mmol) in ethanol. The reaction mixture was stirred at 0C for 5min, and then poured onto H2O (10mL) and extracted with ethyl acetate (20mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by short column chromatography on silica gel, eluting with hexane/ethyl acetate (2/1) to provide the desired product 7 (67mg, 50% for two steps from 3a) as a yellow solid.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 134,p. 62 - 71

65
C₁₆H₁₆N₂O₂ [ No CAS ]
[ 445-13-6 ]
N-(3-chloro-4-(trifluoromethyl)phenyl)-2-oxo-2-(5-(4-(tert-butyl)phenyl)isoxazol-3-yl)acetohydrazonoyl cyanide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of 3-chloroaniline 5a (37mg, 0.33mmol) in H2O (10mL cooled to-5C) was added 0.2mL of 2N HCl (aq.). To the resulting acidic aniline solution, 1N solution of sodium nitrite (0.33mL, 0.33mmol) was added dropwise to generate the aryldiazonium salt solution 6a. To the aryldiazonium salt solution was added sodium acetate (54mg, 0.66mmol), followed by 1mL solution of crude 3-oxo-3-(3-phenylisoxazol-5-yl)propanenitrile 4a (88mg, 0.33mmol) in ethanol. The reaction mixture was stirred at 0C for 5min, and then poured onto H2O (10mL) and extracted with ethyl acetate (20mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by short column chromatography on silica gel, eluting with hexane/ethyl acetate (2/1) to provide the desired product 7 (67mg, 50% for two steps from 3a) as a yellow solid.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 134,p. 62 - 71

66
[ 445-13-6 ]
[ 39528-62-6 ]
C₂₀H₁₇ClF₃N₃O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 5163 - 5166

67
[ 32315-10-9 ]
(S)-methyl 1-((4-aminophenyl)sulfonyl)pyrrolidine-2-carboxylate [ No CAS ]
[ 445-13-6 ]
methyl ((4-(3-(3-chloro-4-(trifluoromethyl)phenyl)ureido)phenyl)sulfonyl)-L-prolinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%		To a solution of triphosgene (50 mg, 0.17 mmol) in 5 mL tolene under N2, <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (98 mg, 0.5 mmol) was added. After stirring at 120 C for 2 h, methyl ((4-aminophenyl)sulfonyl)-L-prolinate (50 mg, 0.175 mmol) was added. Then the solution was allowed to stir at 120 C for overnight before concentration. The residue was purified by PTLC to get ZL0924 (35 mg, 41%) as a white solid. NMR (300 MHz, MeOD) delta 7.91 (d, J = 2.1 Hz, 1H), 7.85 - 7.79 (m, 2H), 7.74 - 7.66 (m, 3H), 7.49 (dd, J = 8.6, 2.0 Hz, 1H), 4.26 (dd, J = 8.0, 4.0 Hz, 1H), 3.75 (s, 3H), 3.54 - 3.43 (m, 1H), 3.29 (d, J = 2.8 Hz, 1H), 2.07 - 1.91 (m, 3H), 1.73 (dd, J = 7.2, 5.0 Hz, 1H). 13C NMR (75 MHz, MeOD) delta 173.13, 152.39, 143.71, 143.65, 132.24, 130.89, 128.42, 128.03, 127.93, 127.86, 127.79, 127.72, 124.97, 121.49, 121.37, 121.07, 120.24, 1 18.30, 1 16.08, 60.51, 51.51, 48.41, 30.49, 24.21.

Reference： [1]Patent: WO2018/112037,2018,A1 .Location in patent: Paragraph 0197

68
[ 32315-10-9 ]
[ 445-13-6 ]
3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione trifluoroacetate [ No CAS ]
1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20.7%		To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) was added a solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (100 mg, 0.51 mmol) and the mixture was refluxed at 80 C. for 0.5 h. After cooling to RT, the mixture was concentrated under vacuum and dissolved in THF (4 mL), then 3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)piperidine-2,6-dione 2,2,2-trifluoroacetic acid (51.5 mg, 0.18 mmol) was added, followed by TEA (36 mg, 0.36 mmol). The solution was stirred at RT for 2 h then concentrated under vacuum and purified by prep-HPLC to give 1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,6-dioxopiperidin-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea (18.6 mg, yield: 20.7%) as a white solid. MS (ESI) m/z 500.7, 502.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) delta 10.98 (s, 1H), 9.35 (s, 1H), 7.87 (s, 1H), 7.69 (d, J=9.2 Hz, 1H), 7.43 (dd, J=7.2, 8.4 Hz, 1H), 7.11 (t, J=6.0 Hz, 1H), 5.01 (dd, J=8.0, 13.2 Hz, 1H), 4.40 (d, J=6.0 Hz, 2H), 4.28 (q, J=41.6 Hz, 2H), 2.93-2.84 (m, 1H), 2.73-2.60 (m, 1H), 2.37-2.26 (m, 1H), 2.07-1.97 (m, 1H).

Reference： [1]Patent: US2018/170948,2018,A1 .Location in patent: Paragraph 0578-0579

69
[ 445-13-6 ]
(S)-1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea [ No CAS ]

Reference： [1]Patent: US2018/170948,2018,A1

70
[ 32315-10-9 ]
[ 445-13-6 ]
[ 39893-50-0 ]

Yield	Reaction Conditions	Operation in experiment
7.1%	In toluene; at 80℃; for 0.5h;	To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) was added dropwise a solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (100 mg, 0.51 mmol) and refluxed at 80 C. for 0.5 h. Then the mixture was concentrated to give 2-chloro-4-isocyanato-1-(trifluoromethyl)benzene. To the solution of 2-chloro-4-isocyanato-1-(trifluoromethyl)benzene in THF was added (S)-3-(1-(aminomethyl)-4-oxo-4H-thieno[3,4-c]pyrrol-5(6H)-yl)azepane-2,7-dione 2,2,2-trifluoroacetic acid salt (52.2 mg, 0.18 mmol), followed by TEA (34 mg, 0.34 mmol). The mixture was stirred at RT for 2 h. The mixture was concentrated to give crude product, which was purified by prep-HPLC with 5% to 95% ACN in 0.02% NH4Ac on a C18, 4.6×50 mm column to give (S)-1-(3-chloro-4-(trifluoromethyl)phenyl)-3-((5-(2,7-dioxoazepan-3-yl)-4-oxo-5,6-dihydro-4H-thieno[3,4-c]pyrrol-1-yl)methyl)urea (6.5 mg, 7.1%) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 10.70 (s, 1H), 9.34 (s, 1H), 7.88 (s, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.11 (t, J=6.0 Hz, 1H), 5.14 (dd, J=7.6, 12.4 Hz, 1H), 4.46 (d, J=5.2 Hz, 2H), 4.40 (d, J=4.8 Hz, 2H), 3.07-3.01 (m, 1H), 2.57-2.49 (m, 1H), 2.19-1.96 (m, 3H), 1.88-1.76 (m, 1H). MS (ESI) m/z 515.0, 517.0 [M+H]+.
	In toluene; at 80℃; for 0.5h;	To a solution of triphosgene (609 mg, 2.14 mmol) in toluene (5 mL) was added dropwise a solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (100 mg, 0.51 mmol) and refluxed at 80 C for 0.5 h. Then the mixture was concentrated to give crude 2-chloro-4- isocyanato-l-(trifluoromethyl)benzene used in the next step without purification. To the solution of 2-chloro-4-isocyanato-l-(trifluoromethyl)benzene in THF was added (S)-3-(5- (aminomethyl)-l-oxoisoindolin-2-yl)azepane-2,7-dione (TFA salt) (59.1 mg, 0.21 mmol), followed by TEA (42 mg, 0.42 mmol). The mixture was stirred at RT for 2 h. The mixture was concentrated and purified by silica gel chromatography eluting with MeOH/DCM from 0% to 8% to give Compound 12 (29.4 mg, 28%) as a white solid. MS (ESI) m/z 509.0 [M+H]+. MR (400 MHz, DMSO-d6) delta 10.72 (s, 1 H), 9.36 (s, 1 H), 7.91 (s, 1 H), 7.70- 7.68 (m, 2 H), 7.54 (s, 1 H), 7.45-7.41 (m, 2 H), 7.06 (t, J =14 Hz, 1 H), 5.23 (dd, J =7.6, 12.8 Hz, 1 H), 4.52 (s, 2 H), 4.43 (d, J =6.0 Hz, 2 H), 3.12-3.04 (m, 1 H), 2.61-2.55 (m, 1 H), 2.28-2.22 (m, 1 H), 2.12-1.96 (m, 2 H), 1.84-1.76 (m, 1 H).

Reference： [1]Patent: US2018/170948,2018,A1 .Location in patent: Paragraph 0503-0504
[2]Patent: WO2018/169777,2018,A1 .Location in patent: Paragraph 0225

71
[ 445-13-6 ]
1-[3-chloro-4-(trifluoromethyl)phenyl]-3-({2-[(3S)-2,7-dioxoazepan-3-yl]-1-oxo-2,3-dihydro-1H-isoindol-5-yl}methyl)urea [ No CAS ]

Reference： [1]Patent: WO2018/169777,2018,A1

72
[ 445-13-6 ]
methyl 16-[[3-chloro-4-(trifluoromethyl)phenyl]carbamoylamino]hexadecanoate [ No CAS ]

Reference： [1]European Journal of Pharmaceutical Sciences,2019,vol. 129,p. 87 - 98

73
[ 445-13-6 ]
16-[[3-chloro-4-(trifluoromethyl)phenyl]carbamoylamino]hexadecanic acid [ No CAS ]

Reference： [1]European Journal of Pharmaceutical Sciences,2019,vol. 129,p. 87 - 98

74
[ 445-13-6 ]
[ 530-62-1 ]
C₁₁H₇ClF₃N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 20℃;Inert atmosphere;	General procedure: A substituted aniline (3.0 mmol) and CDI (3.0 mmol) were dissolvedin anhydrous dichloromethane (15 mL) and the reaction was stirred atroom temperature for 1 h under a nitrogen atmosphere. The solvent wasthen removed under reduced pressure, yielding the crude carbamoylimidazolesas solids. The carbamoylimidazoles were then dissolved indichloromethane (5 mL), and added to a solution of amine 13a or 13b(2.0 mmol) in dichloromethane (15 mL). The reaction was then left tostir for 1 h at room temperature. Dichloromethane (50 mL) was thenadded, and the organic layer was washed with water (3×100 mL). Theorganic layer was dried over Na2SO4 and concentrated under reducedpressure. The product was purified on silica gel by step-wise gradientelution with dichloromethane/ethyl acetate (100:0 to 90:10).

Reference： [1]European Journal of Pharmaceutical Sciences,2019,vol. 129,p. 87 - 98

75
[ 445-13-6 ]
2-cyanobenzofuran-6-carbonyl chloride [ No CAS ]
N-(3-chloro-4-(trifluoromethyl)phenyl)-2-cyanobenzofuran-6-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98 mg	With triethylamine; In dichloromethane; at 20℃;	To the solution of 2-cyanobenzofuran-6-carboxylic acid (200 mg, 1.069 mmol) in 4.5 mL of toluene was added pyridine (519 pL, 6.41 mmol), 2 drops of DMF, followed by oxalyl chloride (187 pL, 2.137 mmol mmol). After the reaction was stirred at RT for6 hr, the mixture was filtered to remove solid, which was washed with toluene. The combined toluene solution was concentrated to give the crude intermediate, 2-cyanobenzofuran-6-carbonyl chloride. The solution of crude 2-cyanobenzofuran-6-carbonyl chloride (105 mg, 0.535 mmol) in I mL of DCM was added to the solution of <strong>[445-13-6]3-chloro-4-(trifluoromethyl)aniline</strong> (105 mg, 0.535 mmol) and TEA (186 pL, 1.338 mmol) in 1 .7 mL of DCM. After the reaction was stirred at RT overnight, the mixture was diluted with DCM, washed with H20, brine, dried over Na2504, and concentrated. The residue was purified by silica gel flash chromatography (100% heptane - 50% ethyl acetate/heptane) to give N-(3-chloro-4-(trifluoromethyl)phenyl)-2-cyanobenzofuran-6-carboxamide (98 mg). LCMS retention time = 1.60 minutes (LC method 3); MS (m+1) = 364.9.

Reference： [1]Patent: WO2019/87162,2019,A1 .Location in patent: Page/Page column 59

76
[ 15216-81-6 ]
[ 445-13-6 ]
5-chloro-N-[3-chloro-4-(trifluoromethyl)phenyl]-2-hydroxy-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; at 25℃;Inert atmosphere;	General procedure: A dry, 50 mL round bottom flask was charged with a magnetic stir bar then sealed with a septum and flushed with nitrogen. To this was added the salicylic acid derivative (2.0 mmol) and dichloromethane (10 mL). While stirring, SOCl2 (10 mmol) was added dropwise, followed by dimethylformamide (0.05 mmol), and the mixture was allowed to stir at room temperature under nitrogen for 12 hours. At this point, the mixture was concentrated under vacuum to afford the solid acid chloride derivative which was used immediately without further purification. The flask containing the acid chloride was then re-sealed with a septum and placed under a nitrogen atmosphere, and its contents were re-suspended in fresh dichloromethane (20 mL). While stirring, the aniline derivative (4.0 mmol) was added and the resulting opaque mixture was stirred for an additional 18 h. At this point, the mixture was quenched with ice water (5 mL) and phases were separated using a separatory funnel. The aqueous layer was extracted twice with dichloromethane (20 mL) then the organic layers were combined and washed with brine (40 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum to afford a crude solid residue. This residue was then re-suspended in dichloromethane (10 mL) and adsorbed onto silica gel (1 g), then chromatographed on a 12 g silica gel column using a solvent gradient of 0-40% ethyl acetate in hexanes over 25 min. The product-containing fractions were combined then concentrated under vacuum to afford the purified salicylamide derivative.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2307 - 2315

77
7-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester [ No CAS ]
[ 445-13-6 ]
4-((3-chloro-4-trifluoromethylphenyl)amino)-7-fluoro-1H-indole-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51.8%	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In water; toluene;Reflux; Inert atmosphere;	4-Bromo-7-fluoro-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.7 mmol) was dissolved in toluene (16 mL), and Pd2 (dba) 3 (64 mg, 0.07 mmol) and Davephos (55 mg) were sequentially added. , 0.14 mmol) and K3PO4 (401 mg, 2.1 mmol, 2.1 mL of H2O), and after stirring, add a solution of <strong>[445-13-6]3-chloro-4-trifluoromethylaniline</strong> (411 mg, 2.10 mmol) in toluene (4 mL), and protect it with argon. The reaction was refluxed overnight with a small amount of starting material remaining. Cool to room temperature, concentrate, add EA (30mL) to dissolve the residue, 6N hydrochloric acid (10mL × 2), wash with saturated brine (20mL × 3), wash with water (20mL × 2), column chromatography (P / E = 20: 1 ~ 10: 1) to obtain 145 mg of a white solid with a yield of 51.8% and a melting point of 201-203 C.
	With potassium phosphate; tris-(dibenzylideneacetone)dipalladium(0); DavePhos; In water; toluene; at 80℃;Inert atmosphere;	General procedure: To a solution of ethyl 4-bromo-1H-indole-2-carboxylate in toluene underargon atmosphere was added Pd2(dba)3 (0.1 eq), DavePhos (0.2 eq), K3PO4 (3 eq, 1Maqueous solution) and aryl amine (3 eq), and then the mixture was reacted at 80 Cuntil the starting material disappeared. The mixture was cooled to room temperatureand concentrated. Ethyl acetate was added to dissolve the residue and the mixture waswashed with saturated brine and water, dried over anhydrous Na2SO4, andconcentrated in vacuo. The crude product was purified by column chromatography toafford the target compound. Compounds 8a-8f, 8i-8l, 8a-1, 8a-6 ~ 8a-11, 8a-14 wereprepared with method 1.

Reference： [1]Patent: CN110483366,2019,A .Location in patent: Paragraph 1046-1051
[2]European Journal of Medicinal Chemistry,2020,vol. 188

78
[ 445-13-6 ]
[ 13149-00-3 ]
C₁₅H₁₅ClF₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; for 16h;Sealed tube; Reflux;	General procedure: To a solution of 6 (0.13 mmol, 1 eq) in THF (0.5 mL, 0.26M) in a 1-dram vial at room temperature aniline/heterocyclic amine (0.13 mmol, 1 eq) was added in one portion. The vial was sealed and the mixture heated to reflux for 16 hours to yield crude 7. For compounds 8, after cooling to room temperature, N,N-Diisopropylethylamine (0.143 mmol, 1.1 eq) and isobutyl chloroformate (0.143 mmol, 1.1 eq) were added and the reaction was stirred for 30 minutes at room temperature. For primary carboxamide congeners, ammonium hydroxide (1mL) was added and the reaction was stirred for an additional hour at room temperature. For substituted amide analogs, desired amine (0.26, 2 eq) was added instead of ammonium hydroxide and stirring was continued for an additional 2 hours. The reaction was then diluted with ether (1mL), the layers were separated and the aqueous layer was extracted with ether (3x2mL). The organic layers were passed through a phase separator and concentrated in vacuo, and then crude product was purified using preparative HPLC (30x50mm column, MeCN/0.1% TFA: Water, 4 min gradient) to yield desired compounds 8.

Reference： [1]Letters in drug design and discovery,2019,vol. 16,p. 1387 - 1394

79
[ 445-13-6 ]
[ 13149-00-3 ]
C₁₅H₁₆ClF₃N₂O₂ [ No CAS ]

Reference： [1]Letters in drug design and discovery,2019,vol. 16,p. 1387 - 1394

80
[ 445-13-6 ]
N-(3-morpholinopropyl) 2-chlorothiazole-4-carboxamide [ No CAS ]
N-(3-morpholinopropyl) 2-((3-chloro-4-(trifluoromethyl)phenyl)amino)thiazole-4-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019

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Technical Information

• 1,4-Addition of an Amine to a Conjugated Enone • 1,4-Addition of an Amine to a Conjugated Enone • Acid-Catalyzed α -Halogenation of Ketones • Add Hydrogen Cyanide to Aldehydes and Ketones to Produce Alcohols • Addition of a Hydrogen Halide to an Internal Alkyne • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alkyl Halide Occurrence • Alkylation of an Alkynyl Anion • Amides Can Be Converted into Aldehydes • Amine Synthesis from Nitriles • Amine Synthesis from Nitriles • Amines Convert Acyl Chlorides into Amides • Amines Convert Esters into Amides • An Alkane are Prepared from an Haloalkane • Azide Reduction by LiAlH4 • Azide Reduction by LiAlH4 • Basicity of Amines • Benzylic Oxidation • Birch Reduction • Birch Reduction of Benzene • Blaise Reaction • Blanc Chloromethylation • Buchwald-Hartwig C-N Bond and C-O Bond Formation Reactions • Catalytic Hydrogenation • Chan-Lam Coupling Reaction • Chichibabin Reaction • Chloroalkane Synthesis with SOCI2 • Complete Benzylic Oxidations of Alkyl Chains • Complete Benzylic Oxidations of Alkyl Chains • Complex Metal Hydride Reductions • Conversion of Amino with Nitro • Convert Haloalkanes into Alcohols by SN2 • Cyanohydrins can be Convert to Carbonyl Compounds under Basic Conditions • Deprotonation of Methylbenzene • Diazotization Reaction • DIBAL Attack Nitriles to Give Ketones • Directing Electron-Donating Effects of Alkyl • Electrophilic Chloromethylation of Polystyrene • Enamine Formation • Formation of an Amide from an Amine and a Carboxylic Acid • Formation of an Amide from an Amine and a Carboxylic Acid • Friedel-Crafts Alkylation of Benzene with Acyl Chlorides • Friedel-Crafts Alkylation of Benzene with Carboxylic Anhydrides • Friedel-Crafts Alkylation of Benzene with Haloalkanes • Friedel-Crafts Alkylation Using Alkenes • Friedel-Crafts Alkylations of Benzene Using Alkenes • Friedel-Crafts Alkylations Using Alcohols • Friedel-Crafts Reaction • General Reactivity • Grignard Reaction • Groups that Withdraw Electrons Inductively Are Deactivating and Meta Directing • Halogenation of Alkenes • Halogenation of Benzene • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hemiaminal Formation from Amines and Aldehydes or Ketones • Hiyama Cross-Coupling Reaction • Hofmann Elimination • Hofmann Rearrangement • Hydride Reductions • Hydrogenation to Cyclohexane • Hydrogenolysis of Benzyl Ether • Hydrolysis of Imines to Aldehydes and Ketones • Imine Formation from Amines and Aldehydes or Ketones • Ketone Synthesis from Nitriles • Kinetics of Alkyl Halides • Kumada Cross-Coupling Reaction • Leuckart-Wallach Reaction • Mannich Reaction • Methylation of Ammonia • Methylation of Ammonia • Nitration of Benzene • Nitriles Hydrolyze to Carboxylic Acids • Nitrosation of Amines • Nucleophilic Aromatic Substitution • Nucleophilic Aromatic Substitution with Amine • Oxidation of Alkyl-substituted Benzenes Gives Aromatic Ketones • Peptide Bond Formation with DCC • Petasis Reaction • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Preparation of Amines • Preparation of LDA • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reduction of an Amide to an Amine • Reduction of an Amide to an Amine • Reductive Amination • Reductive Amination • Reductive Removal of a Diazonium Group • Reverse Sulfonation——Hydrolysis • Ring Opening of Azacyclopropanes • Ring Opening of Azacyclopropanes • Ring Opening of Oxacyclobutanes • Ritter Reaction • Specialized Acylation Reagents-Vilsmeier Reagent • Stille Coupling • Strecker Synthesis • Substitution and Elimination Reactions of Alkyl Halides • Sulfonation of Benzene • Suzuki Coupling • Synthesis of 2-Amino Nitriles • The Acylium Ion Attack Benzene to Form Phenyl Ketones • The Claisen Rearrangement • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • The Nitro Group Conver to the Amino Function • Thorpe-Ziegler Reaction • Ugi Reaction • Vilsmeier-Haack Reaction

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P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

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