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[ CAS No. 133115-72-7 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 133115-72-7

Chemical Structure| 133115-72-7

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Quality Control of [ 133115-72-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 133115-72-7 ]

CAS No. :	133115-72-7	MDL No. :	MFCD00053033
Formula :	C₇H₈ClF₃N₂O	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	KQXZVSQCMVKMBK-UHFFFAOYSA-N
M.W :	228.60	Pubchem ID :	2777328
Synonyms :

Calculated chemistry of [ 133115-72-7 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	2.0
Molar Refractivity :	47.3
TPSA :	47.28 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.47 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.0
Log Po/w (XLOGP3) :	3.14
Log Po/w (WLOGP) :	3.74
Log Po/w (MLOGP) :	1.88
Log Po/w (SILICOS-IT) :	0.92
Consensus Log Po/w :	1.94

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.35
Solubility :	0.101 mg/ml ; 0.000442 mol/l
Class :	Soluble
Log S (Ali) :	-3.8
Solubility :	0.036 mg/ml ; 0.000158 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.72
Solubility :	0.436 mg/ml ; 0.00191 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.65

Safety of [ 133115-72-7 ]

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 [ 133115-72-7 ]

* 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.

Downstream synthetic route of [ 133115-72-7 ]

[ 133115-72-7 ] Synthesis Path-Downstream 1~50

1
[ 336186-19-7 ]
[ 133115-72-7 ]
[ 900182-98-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	In acetic acid at 100℃; for 4h;
58%	With acetic acid	R.5.2 2-[2-Methyl-5-(trifluoromethoxy)-1H-indol-3-yl]thio}benzoic acid Reference example 5-2 2-[2-Methyl-5-(trifluoromethoxy)-1H-indol-3-yl]thio}benzoic acid To the compound of Reference example 5-1 (920 mg, 4.37 mmol) were added acetic acid (20 ml) and 4-(trifluoromethoxy)phenylhydrazine hydrochloride (1 g, 4.37 mmol), and the mixture was stirred for 4 hours at 100°C. After being cooled to room temperature, the solvent was removed in vacuo. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography to give the subject compound (931 mg, 58 %). 1H NMR (CDCl3, 400 MHz) δ 8.48 (brs, 1H), 8.17 (dd, 1H, J = 8.0, 1.6 Hz), 7.35 (d, 1H, J = 8.0 Hz), 7.35 (brs, 1H), 7.20 (ddd, 1H, J = 8.0, 7.4, 1.6 Hz), 7.12 (ddd, 1H, J = 7.4, 7.4, 1.1 Hz), 7.08 (brd, 1H, J = 8.8 Hz), 6.71 (dd, 1H, J = 8.1, 1.1 Hz), 2.51 (s, 3H).

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - WO2006/75638, 2006, A1 Location in patent: Page/Page column 64-65
[2]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); Sumitomo Pharma (in: Sumitomo Chemical); SUMITOMO CHEMICAL COMPANY LIMITED - EP1837329, 2007, A1

2
[ CAS Unavailable ]
[ 123-76-2 ]
[ 133115-72-7 ]
[ 378802-41-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With sulfuric acid In dichloromethane; water; ethyl acetate	R.81 Synthesis of 2-(2-methyl-5-trifluoromethoxy-1H-indol-3-yl)acetic acid Reference Example 81 Synthesis of 2-(2-methyl-5-trifluoromethoxy-1H-indol-3-yl)acetic acid A mixture of 4-trifluoromethoxyphenylhydrazine hydrochloride (1 g), levulinic acid (1.3 g) and 10% aqueous sulfuric acid (20 ml) was stirred for 6 hours under a nitrogen atmosphere at 80° C. The reaction mixture was allowed to cool, water was added, and then extraction was performed with ethyl acetate and the organic layer was concentrated under reduced pressure. Saturated sodium bicarbonate water was added to the obtained residue and vigorously stirred therewith, and then dichloromethane was added and the mixture was again vigorously stirred. The aqueous layer was collected, rendered acidic with concentrated aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure, to obtain 0.40 g of the title compound as a colorless powder (31% yield). The NMR data for the obtained compound were as follows. NMR: (300 MHz, DMSO-d6) δ: 2.33 (3H,s), 3.57 (2H,s), 6.94 (1H,dd), 7.2-7.4 (2H,m), 11.13 (1H,s), 11.9-12.3 (1H,m)

Reference： [1]Current Patent Assignee: Chugai Pharmaceutical (in: Roche); ROCHE HOLDING AG - US2003/162724, 2003, A1

3
[ 17159-79-4 ]
4-(trifluoromethoxy)phenylhydrazine hydrochloride [ No CAS ]
ethyl 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: ethyl 4-oxocyclohexane-1-carboxylate; 4-(trifluoromethoxy)phenylhydrazine hydrochloride In ethanol Heating / reflux; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate	110.1 Step 1: Ethyl 6-(trifluoromethoxy)-2,3,4,9-tetrahydro-lH-carbazole-3-carboxylate [0383] A mixture of 4-oxocyclohexane carboxylic acid ethyl ester (3.75 g5 0.022 mol), 4-trifluoromethoxy phenylhydrazine hydrochloride (5 g, 0.0218 mol) and anhydrous ethanol (68 mL) was refluxed overnight under nitrogen. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic extracts were washed with 1 : 1 water/brine and dried over anhydrous magnesium sulfate. Removal of the solvent provided a yellow solid that was dried in vacuo (7.15 g). The material from two runs (11. 64 g) was chromatographed on silica gel Merck 60 using a 5 to 15 % gradient of ethyl acetate in hexane to yield the title compound as a pale tan solid (10.54 g, 92%), m.p. 131-132 0C. MS [(+)ES, m/z}: 328.1 [M+H]+. MS [(-)ES, m/z]: 326.1 (M-H]". HPLC: Chromolith Monolith column, 0.46x10 cm, gradient of acetonitrile in water (0.01% TFA), 4 mL/min, detection at 280 nm; Rt 2.45 min.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2006/89053, 2006, A2 Location in patent: Page/Page column 80

4
[ 1191-99-7 ]
[ 133115-72-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
92%	In THF-H₂ O	2 Step (2) Step (2) Preparation of 4-(4-Trifluoromethoxyphenylhydrazono)-1-butanol A solution of 4-trifluoromethoxyphenylhydrazine hydrochloride (5.4 g, 23.7 mmol), and 2,3-dihydrofuran (1.65 g, 23.7 mmol) in 75 mL of THF-H2 O (1:1, v/v) was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between Et2 O and water. The organic phase was washed with brine and dried. Removal of the solvent afforded fairly pure product as a yellow oil (5.67 g, 92%, mixture of E/Z isomers). 1 H NMR (CDCl3, 400 MHz): δ1.8 (m, 2H, CCH2 C), 3.85 (m, 2H, CH2 CH2 O), 6.9-7.2 (m, 5H, Ar-H+CCH=N) MS (EI, m/z): 262 (M)+, 176 (b.p., STR8

Reference： [1]Current Patent Assignee: PFIZER INC - US4960902, 1990, A

5
[ 1195951-24-6 ]
[ 133115-72-7 ]
[ 1195951-25-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	In ethanol at 50℃; for 3.5h; Reflux;	6.1 A solution of the ketoester (206 mg, 0.79 mmol, 1 eq) and (4-(trifluoromethoxy) phenyl)hydrazine hydrochloride (180 mg, 0.79 mmol, 1 eq) in EtOH (3 ml_) was heated 30 min at 500C then 3h at reflux. The volatiles were removed in vacuo and the resulting residue was purified via silica gel chromatography (Gradient elution: 0% to 100% EtOAc in hexanes) to afford the desired pyrazolone (181 mg, 60%) as a clear film.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2009/140342, 2009, A1 Location in patent: Page/Page column 103

6
[ 30708-54-4 ]
[ 133115-72-7 ]
[ 1220278-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-aza-bicyclo[3.2.2]nonan-4-one; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With hydrogenchloride; acetic acid In 1,4-dioxane at 150℃; for 0.25h; microwave irradiation; Stage #2: With sodium hydroxide In water	175 In a 30 mL microwave reaction tube were combined 4-(trifluoromethoxy)phenyl- hydrazine hydrochloride (1143 mg, 5.0 mmol; Alfa Aesar), l-azabicyclo[3.2.2]nonan-4-one (696 mg, 5.0 mmol; Example 2A), 4 NHCl in dioxane (2.5 mL, 10.0 mmol; Aldrich), and acetic acid (15 mL). The reaction mixture was heated in a microwave to 150 0C (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was basified with 5 N sodium hydroxide and extracted with ethyl acetate (3x50 mL). The combined organic phases were concentrated in vacuo and purified by reverse-phase HPLC [Waters XBridge RP 18 column, 5 μm, 30x100 mm, flow rate 40 niL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to afford the title compound: 1H ΝMR (300 MHz, methanol-^) δ ppm 2.08 (td, J=I, 4 Hz, 4 H), 2.99 - 3.13 (m, 3 H), 3.23 (dd, J=14, 7 Hz, 2 H), 4.21 (s, 2 H), 6.92 (ddd, J=9, 2, 1 Hz, 1 H), 7.16 (d, J=I Hz, 1 H), 7.28 (d, J=8 Hz, 1 H); MS (DCI/ΝH3) m/z 297 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2010/36998, 2010, A2 Location in patent: Page/Page column 205-206

7
[ 72761-60-5 ]
4-(trifluoromethoxy)phenylhydrazine hydrochloride [ No CAS ]
[ 1220279-07-1 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 9-azabicyclo<3.3.1>nonan-3-one hydrochloride; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With hydrogenchloride; acetic acid at 150℃; for 0.25h; microwave irradiation; Stage #2: With potassium carbonate In water	140A In a 30 mL microwave reaction tube were combined 4-(trifluoromethoxy)phenyl- hydrazine hydrochloride (1062 mg, 5.0 mmol; Maybridge), 9-azabicyclo[3.3.1]nonan-3-one hydrochloride (878 mg, 5.0 mmol; Accela ChemBio), and 1 iVΗCl in acetic acid (15 mL, 15 mmol; Aldrich). The reaction mixture was microwaved at 150 0C (Biotage Personal Chemistry, maximum 300 W) for 15 minutes, then cooled to room temperature. The solvent was removed, and the residue was dissolved in water (20 mL) and basifed with solid potassium carbonate to ~pΗ 12. This solution was extracted with dichloromethane (3x50 mL), and the combined organic phases were dried over magnesium sulfate. After removing the solvent under vacuum, the residue was purified by flash chromatography (silica gel, CH2CVCH3OH, 3:1) to afford the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 1.33 - 1.52 (m, 2 H), 1.64 - 1.78 (m, 2 H), 1.89 - 2.06 (m, 2 H), 2.68 (d, J=17 Hz, 1 H), 3.25 - 3.34 (m, 1 H), 3.62 (t, J=5 Hz, 1 H), 4.43 (t, J=3 Hz, 1 H), 6.93 (ddd, J=9, 2, 1 Hz, 1 H), 7.22 (d, J=I Hz, 1 H), 7.31 (d, J=9 Hz, 1 H); MS (DCI/NH3) m/z 297 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2010/36998, 2010, A2 Location in patent: Page/Page column 178

8
[ 532-24-1 ]
4-(trifluoromethoxy)phenylhydrazine hydrochloride [ No CAS ]
[ 1220278-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: tropinone; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With sulfuric acid In 1,4-dioxane at 80℃; for 16h; Stage #2: With sodium hydroxide In water	97A A solution of 4-(trifluoromethoxy)phenylhydrazine hydrochloride (1062 mg, 5.0 mmol; Maybridge), tropinone (696 mg, 5.0 mmol; Aldrich), and concentrated sulfuric acid (2.0 mL; J.T Baker) in dioxane (30 mL) was heated to 80 0C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, basified with 5 NNaOH (aqueous), and then extracted with ethyl acetate (3x50 mL). The combined organic phase was concentrated and the residue was purified by reverse-phase HPLC [Waters XBridge RP 18 column, 5 μm, 30x100 mm, flow rate 40 mLZminute, 20-95% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (300 MHz, methanol-^) δ ppm 1.58 - 1.73 (m, 1 H), 1.90 (t, J=9 Hz, 1 H), 2.25 - 2.34 (m, 2 H), 2.37 (s, 3 H), 2.48 (dd, J=Il, 1 Hz, 1 H), 3.21 - 3.28 (m, 1 H), 3.53 - 3.60 (m, 1 H), 4.20 (d, J=5 Hz, 1 H), 6.91 (dt, J=9, 1 Hz, 1 H), 7.24 - 7.31 (m, 2 H); MS (DCI/NH3) m/z 297 (M+H)+.

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2010/36998, 2010, A2 Location in patent: Page/Page column 149-150

9
[ 42466-67-1 ]
4-(trifluoromethoxy)phenylhydrazine hydrochloride [ No CAS ]
[ 400073-87-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium acetate; acetic acid; In water; at 100℃; for 15h;Inert atmosphere;	A mixture of ethyl (2£T)-2-cyano-3-ethoxy-2-propenoate (113) (1.87 g, 11.1 mmol), 4-(trifluoromethoxy)phenylhydrazine hydrochloride (114) (2.286 g, 10.00 mmol) and NaOAc (0.90 g, 1 1.0 mmol) in AcOH (7.5 mL) and water (2.5 mL) was heated to 100 0C under N2 for 15 h. The mixture was poured onto ice, and the resulting precipitate was filtered and recrystallised (MeOH/water) to give ethyl 5-amino-l-[4-(trifluoromethoxy)phenyl]-lH-pyrazole- 4-carboxylate (115) (2.965 g, 94%) as white flakes: mp 102-103 0C; 1H NMR [(CD3)2SO] delta 7.73 (s, 1 H), 7.68 (d, J = 9.1 Hz, 2 H), 7.53 (d, J = 9.1 Hz, 2 H), 6.41 (br s, 2 H), 4.22 (q, J = 7.1 Hz, 2 H), 1.27 (t, J = 7.1 Hz, 3 H). APCI MS m/z 316 [M + H]+.

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 855 - 866
[2]Patent: WO2011/14774,2011,A1 .Location in patent: Page/Page column 53

10
[ 85302-07-4 ]
[ 133115-72-7 ]
[ 1203661-43-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: 2-(dimethylaminomethylene)cyclohexane-1,3-dione; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With sodium hydroxide In methanol; water Reflux; Stage #2: With acetic acid In water at 110℃;
	Stage #1: 2-(dimethylaminomethylene)cyclohexane-1,3-dione; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With sodium hydroxide In methanol; water for 2h; Reflux; Stage #2: With acetic acid In methanol; water at 110℃; for 2h;	To a solution of Gl (8.98 mmol) in methanol (20 mL) and water (3 mL) was added (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (8.98 mmol) and sodium hydroxide (8.98 mmol). The reaction mixture heated at reflux for 2 h and concentrated in vacuo. Then to the residue were added AcOH (20 mL) and water (10 mL), and the reaction mixture was heated to 1 10 °C for 2 h. On completion of the reaction, the solution was concentrated in vacuo, the residue was diluted with EtOAc (20 mL) and saturated NaHC03 solution (20 mL), then washed with brine (20 mL). The organic layer was dried over anhydrous MgS04j filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give G2.
	Stage #1: 2-(dimethylaminomethylene)cyclohexane-1,3-dione; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With sodium hydroxide In methanol; water for 2h; Reflux; Stage #2: With acetic acid In water at 110℃; for 2h;	4 General Procedure for the Synthesis of G2 To a solution of G1 (8.98 mmol) in methanol (20 mL) and water (3 mL) was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (8.98 mmol) and sodium hydroxide (8.98 mmol). The reaction mixture was heated at reflux for 2 h and concentrated in vacuo. Then to the residue were added AcOH (20 mL) and water (10 mL), and the reaction mixture was heated to 110° C. for 2 h. On completion of the reaction, the solution was concentrated in vacuo, the residue was diluted with EtOAc (20 mL) and saturated NaHCO3 solution (20 mL), then washed with brine (20 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to give G2.

Reference： [1]Location in patent: experimental part Guo, Songpo; Song, Yang; Huang, Qingqing; Yuan, Hai; Wan, Baojie; Wang, Yuehong; He, Rong; Beconi, Maria G.; Franzblau, Scott G.; Kozikowski, Alan P. [Journal of Medicinal Chemistry, 2010, vol. 53, # 2, p. 649 - 659]
[2]Current Patent Assignee: INSTITUT PASTEUR; NATIONAL INSTITUTE OF HEALTH AND MEDICAL RESEARCH - WO2011/113606, 2011, A1 Location in patent: Page/Page column 26
[3]Current Patent Assignee: QURIENT CO LTD; INSTITUT PASTEUR - US2014/155387, 2014, A1 Location in patent: Paragraph 0158; 0162

11
[ 59997-51-2 ]
[ 133115-72-7 ]
[ 1208234-80-3 ]

Yield	Reaction Conditions	Operation in experiment
91%	Stage #1: trimethylacetylacetonitrile; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With hydrogenchloride In ethanol; water monomer for 18h; Reflux; Stage #2: With sodium hydroxide In ethanol; water monomer	A27 Intermediate A27: 3-fert-Butyl-1 -(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-amine.Intermediate A27 A solution of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.83 g, 8.01 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.10 g, 8.81 mmol) in a mixture of cone hydrochloric acid (12 M, 2.0 mL) and EtOH (20 mL) was heated at reflux for 18 hr. The mixture was cooled to RT and was partitioned between aq. NaOH (2.0 M, 50 mL) and ether (100 mL). The organic layer was separated and was washed with brine (100 mL) and then dried and evaporated in vacuo to afford the title cmpound, Intermediate A27, as a yellow solid (2.22 g, 91%); R' 2.29 min (Method 2); m/z 300 (M+H)+, (ES+).
90%	In toluene for 16h; Reflux;
	With hydrogenchloride In ethanol for 18h; Reflux;	General procedure C for synthesis of 5-aminopyrazoles under conductive heating. General procedure: A stirred solution of the hydrazine hydrochloride (1 eq), β-ketonitrile (1 eq) and a drop of HCl (conc.) in EtOH (10 mL) was heated at reflux for 18 h. After cooling to rtrt, the mixture was basified to pH 12 by the addition of an aqueous NaOH solution (10%) (compound 6) or a sat. NaHCO3 solution (compounds 10-17) and extracted with EtOAc (3 x30 mL). The organic extracts were combined, washed with brine (40 mL), dried over Na2SO4 and the solvent was evaporated in vacuo. Purification by flash column chromatography on SiO2 or recrystallization from a hexane/EtOAc mixture gave the desired product.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2011/124930, 2011, A1 Location in patent: Page/Page column 53
[2]Pan, Shulei; Zhang, Liting; Luo, Xinling; Nan, Jinshan; Yang, Wei; Bin, Huachao; Li, Yang; Huang, Qiao; Wang, Tianqi; Pan, Zhiling; Mu, Bo; Wang, Falu; Tian, Chenyu; Liu, Yang; Li, Linli; Yang, Shengyong [Journal of Medicinal Chemistry, 2022, vol. 65, # 3, p. 2035 - 2058]
[3]Röhm, Sandra; Schröder, Martin; Dwyer, Jessica E.; Widdowson, Caroline S.; Chaikuad, Apirat; Berger, Benedict-Tilman; Joerger, Andreas C.; Krämer, Andreas; Harbig, Jule; Dauch, Daniel; Kudolo, Mark; Laufer, Stefan; Bagley, Mark C.; Knapp, Stefan [European Journal of Medicinal Chemistry, 2020, vol. 208]

12
[ 461-82-5 ]
[ 133115-72-7 ]

Yield	Reaction Conditions	Operation in experiment
57%	Stage #1: 4-(trifluoromethoxy)aniline With hydrogenchloride; NaNO₂ In water monomer at 0℃; for 1h; Stage #2: With hydrogenchloride; tin(II) chloride dihydrochloride In water monomer at 0℃; for 2h;	79.1 Step 1: To a solution of 4-(trifluoromethoxy)aniline (1.77 g, 10.0 mmol) in concentrated HCl (10 mL) was added an aqueous solution (2.5 mL) of NaNO2 (690 mg, 10.0 mmol) at 0 °C, and the reaction mixture was stirred for 1 h. A solution of SnCl2.2H2O (4.52 g, 20 mmol) in concentrated HCl (1 mL) was then added at 0 °C. The reaction solution was stirred for 2 h at room temperature. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate hydrogen chloride (1.3 g, yield 57%) as a white solid, which was used for the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 3H), 7.30 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H) ppm. MS: (M+H)+: m/z = 193.1.
57%	Stage #1: 4-(trifluoromethoxy)aniline With hydrogenchloride; NaNO₂ In water monomer at 0℃; for 1h; Stage #2: With hydrogenchloride; tin(II) chloride dihydrochloride In water monomer at 0℃; for 2h;	79.1 Step 1: To a solution of 4-(trifluoromethoxy)aniline (1.77 g, 10.0 mmol) in concentrated HCl (10 mL) was added an aqueous solution (2.5 mL) of NaNO2 (690 mg, 10.0 mmol) at 0 °C, and the reaction mixture was stirred for 1 h. A solution of SnCl2.2H2O (4.52 g, 20 mmol) in concentrated HCl (1 mL) was then added at 0 °C. The reaction solution was stirred for 2 h at room temperature. The precipitate was filtered and washed with ethanol and ether to yield ethyl 3-hydrazinobenzoate hydrogen chloride (1.3 g, yield 57%) as a white solid, which was used for the next reaction without further purification. 1H NMR (400 MHz, DMSO-d6): δ 10.39 (s, 3H), 7.30 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.9 Hz, 2H) ppm. MS: (M+H)+: m/z = 193.1.
	Stage #1: 4-(trifluoromethoxy)aniline With hydrogenchloride; NaNO₂ In water monomer for 0.333333h; Cooling with ice; Stage #2: With hydrogenchloride; tin(II) chloride dihydrochloride In water monomer at -10 - -5℃; for 2h;

	With hydrogenchloride; stannous chloride; NaNO₂ In water monomer at 0 - 5℃; for 0.75h; Inert atmosphere;
	With stannous chloride; NaNO₂

Reference： [1]Current Patent Assignee: 5 METIS - WO2022/40157, 2022, A1 Location in patent: Paragraph 00562-00565
[2]Current Patent Assignee: 5 METIS - WO2022/40157, 2022, A1 Location in patent: Paragraph 00562-00565
[3]Location in patent: experimental part Li, Yuhao; Liu, Rui; Yan, Zhangwei; Zhang, Xiangning; Zhu, Hongjun [Bulletin of the Korean Chemical Society, 2010, vol. 31, # 11, p. 3341 - 3347]
[4]Zhao, Dongbing; Shi, Zhuangzhi; Glorius, Frank [Angewandte Chemie - International Edition, 2013, vol. 52, # 47, p. 12426 - 12429][Angew. Chem., 2013, vol. 125, # 47, p. 12652 - 12656,4]
[5]Lv, Kunzhi; Liu, Yuanyuan; Li, Yi; Xu, Guanghui; Pan, Xuechun; Li, Fangshi; Chen, Kai; Huang, Bin; Yang, Yaping [Journal of Chemical Research, 2015, vol. 39, # 10, p. 594 - 600]

13
[ 625-36-5 ]
[ 133115-72-7 ]
[ 1181214-07-2 ]

Yield	Reaction Conditions	Operation in experiment
37%	With PS-DIEA In tetrahydrofuran at 20℃; for 12h;	2.1 The compound was prepared according to Rees and Tsoi Chem. Commun. 2000, 415. A suspension of (4- trifluoromethoxyphenyl)-hydrazine hydrochloride (300 mg, 1.32 mmol, 1.00 eq), 3- chloropropionyl chloride (167 mg, 1.32 mmol, 1.00 eq), and PS-DIEA (1.30 grams (g), 5.28 mmol, 4.00 eq) in TΗF (20 mL) was stirred at ambient temperature for 12 h. The solution was then filtered, concentrated to dryness, and purified via chromatography (2:2:1, hexane: EtOAc: acetone) to afford the desired intermediate (120 mg, 37%).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2011/17504, 2011, A1 Location in patent: Page/Page column 18-19

14
[ 623-27-8 ]
[ 133115-72-7 ]
[ 1181214-16-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	In isopropyl alcohol at 20℃; for 1.08333h;	6.1 The compound was prepared according to Paulvannan et al. Tetrahedron2000, 56, 8071. To a stirred solution of benzene- 1 ,4-dicarbaldehyde (1.50 g, 11.2 mmol, 1.0 eq) in z-PrOΗ (250 mL) was added 4-trifluoromethoxyphenylhydrazine hydrochloride (2.55 g, 11.2 mmol, 1.0 eq) portionwise over 5 min. The solution was stirred at ambient temperature for 1 h before concentration to dryness and purification via chromatography (2:2: 1 hexane: EtOAc: acetone) to afford the intermediate (2.48 g, 72%).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2011/17504, 2011, A1 Location in patent: Page/Page column 22

15
[ 90994-06-2 ]
[ 133115-72-7 ]
[ 1549708-76-0 ]

Yield	Reaction Conditions	Operation in experiment
4.327 g	With hydrogenchloride In water at 85 - 100℃; for 16.5h;	4.1.6 4-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)benzonitrile (46) (Scheme 1C) General procedure: A suspension of 4-hydrazinylbenzonitrile hydrochloride (42) (9.360g, 55.19mmol, 1.25 equiv) in 6M HCl (220mL) was added to a solution/suspension of mucobromic acid (45) (11.430g, 44.32mmol, 1.00 equiv) in 6M HCl (300mL), and the resulting suspension was stirred at 65-95°C for 18h, when TLC analysis indicated the reaction was complete.28 The viscous canary yellow suspension was cooled to 20°C and the solid was collected by filtration and washed sequentially with water and hexanes. The dried crude product was triturated with MeOH to furnish 46 (10.047g, 64%) as an amorphous off-white solid.

Reference： [1]Brooke, Darby G.; Van Dam, Ellen M.; Watts, Colin K.W.; Khoury, Amanda; Dziadek, Marie A.; Brooks, Hilary; Graham, Lisa-Jane K.; Flanagan, Jack U.; Denny, William A. [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 3, p. 1029 - 1039]

16
[ 39739-52-1 ]
[ 133115-72-7 ]
[ 1628176-86-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With pyridine at 0 - 20℃; for 18h;	5 Methyl 4-nitrobenzimidate hydrochloride (0.53 g, 2.4 mmol) was dissolved in pyridine (2.5 mL) and cooled to 0° C. To this stirred solution was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (0.559 g, 2.45 mmol) in three portions, and the dark red solution was warmed to RT for 18 h. The reaction mixture was then diluted with water and CH2Cl2. The aqueous layer was washed with CH2Cl2, and the combined organic layers were washed with a saturated solution of NH4Cl and dried over MgSO4. Concentration followed by purification by flash column chromatography using 0-70% EtOAc/hexanes as eluent gave 4-nitro-N′-(4-(trifluoromethoxy)phenyl)benzimidohydrazide as a red solid (0.47 g, 57%): 1H NMR (400 MHz, CDCl3) δ 8.31-8.23 (m, 2H), 7.99-7.90 (m, 2H), 7.20-7.06 (m, 4H), 6.47 (s, 1H), 4.71 (s, 2H); 13C NMR (101 MHz, CDCl3) δ 148.24, 145.70, 145.55, 142.84, 139.89, 126.26, 123.85, 122.24, 121.92, 119.37, 114.82; ESIMS m/z 340 ([M+H]+).

Reference： [1]Current Patent Assignee: CORTEVA INC - US2014/275559, 2014, A1 Location in patent: Paragraph 0033; 0034

17
[ 1571-08-0 ]
[ 133115-72-7 ]
[ 1627747-88-9 ]

Yield	Reaction Conditions	Operation in experiment
87%	In ethanol at 20℃;	1 Preparation of (E)-Methyl 4-((2-(4-(trifluoromethoxy)phenyl) hydrazono)methyl)benzoate [0086] To a magnetically stirred solution of methyl 4-formylbenzoate (1.71 g, 10.41 mmoL) dissolved in EtOH (mL) was added (4-(trifluoromethoxy)phenyl)-hydrazine hydrochloride (2 g, 10.41 mmoL) and the reaction was stirred at room temperature overnight. The solvent was concentrated under reduced pressure and dried under high vacuum to give (E)-methyl 4-((2-(4-(trifluoromethoxy)phenyl)-hydrazono)methyl)benzoate (3.08 g, 87%): mp 142-145° C.; 1H NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.04 (d, J=8.0 Hz, 2H), 7.72-7.65 (m, 3H), 7.13 (q, J=8.9 Hz, 4H), 3.93 (s, 3H); 19F NMR (376 MHz, CDCl3) δ -58.36; ESIMS m/z 338 ([M+H])+.

Reference： [1]Current Patent Assignee: CORTEVA INC - US2014/275557, 2014, A1 Location in patent: Paragraph 0085; 0086

18
[ 63617-98-1 ]
[ 133115-72-7 ]
[ 1628176-88-4 ]

Yield	Reaction Conditions	Operation in experiment
1.6 g	With pyridine at 20℃; for 18h;	9 Preparation of methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate To a magnetically stirred solution of methyl 4-(imino(methoxy)methyl)benzoate hydrochloride (1.15 g, 5.00 mmol) in anhydrous pyridine (5 mL) cooled by an ice bath was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.14 g, 5.00 mmol) in several portions. After warming to room temperature overnight (18 h), the yellow reaction mixture was diluted with water (25 mL) and washed with CH2Cl2 (250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give an orange-yellow solid (1.60 g). The solid was dissolved in formic acid (15 mL), warmed to reflux, and stirred at reflux for 8 h. The reaction mixture was cooled to room temperature, diluted with water, and washed with diethyl ether (250 mL). The combined diethyl ether washes were washed with water (3*50 mL), washed with brine (50 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator to give the title compound (1.42 g, 78%) as a tan solid.
1.60 g	With pyridine at 24℃; for 18h; Cooling with ice;	6 Example 6 Preparation of methyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate To a magnetically stirred solution of methyl 4-(imino(methoxy)methyl)benzoate hydrochloride (1.15 g, 5.00 mmol) in anhydrous pyridine (5 mL) cooled by an ice bath was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.14 g, 5.00 mmol) in several portions. After warming to room temperature overnight (18 h), the yellow reaction mixture was diluted with water (25 mL) and washed with CH2Cl2 (250 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated to give an orange-yellow solid (1.60 g). The solid was dissolved in formic acid (15 mL), warmed to reflux, and stirred at reflux for 8 h. The reaction mixture was cooled to room temperature, diluted with water, and washed with diethyl ether (250 mL). The combined diethyl ether washes were washed with water (3*50 mL), washed with brine (50 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator to give the title compound as a tan solid (1.42 g, 78%).
1.6 g	With pyridine at 20℃; for 18h; Cooling with ice;	2 To a magnetically stirred solution of methyl 4-(imino(methoxy)methyl)benzoate hydrochloride (1.15 g, 5.00 mmol) in anhydrous pyridine (5 mL) cooled by an ice bath was added (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (1.14 g, 5.00 mmol) in several portions. After warming to room temperature (RT) and stirring overnight (18 hours (h)), the yellow reaction mixture was diluted with water (25 mL) and washed with CH2Cl2 (2×50 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give an orange yellow solid (1.60 g). The orange yellow solid was dissolved in formic acid (15 mL) and heated at reflux for 8 h. The reaction mixture was cooled to RT, diluted with water and washed with ether (2×50 mL). The ether layers were washed with water (3×50 mL), brine (50 mL) and dried over MgSO4. Concentration furnished the title compound as a tan solid (1.42 g, 78%). A small sample was purified by flash column chromatography using 0-100% EtOAc/hexanes as eluent to give an off-white solid

Reference： [1]Current Patent Assignee: CORTEVA INC - US2014/275558, 2014, A1 Location in patent: Paragraph 0050; 0051
[2]Current Patent Assignee: CORTEVA INC - US2014/275561, 2014, A1 Location in patent: Paragraph 0033; 0034
[3]Current Patent Assignee: CORTEVA INC - US2014/275559, 2014, A1 Location in patent: Paragraph 0025; 0026

19
[ 122-51-0 ]
[ 57-13-6 ]
[ 133115-72-7 ]
[ 2088417-40-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: urea; 4-(trifluoromethoxy)phenylhydrazine hydrochloride With toluene-4-sulfonic acid In chlorobenzene at 140℃; for 2h; Stage #2: orthoformic acid triethyl ester With chlorosulfonic acid In chlorobenzene at 80℃; for 4h;	1 Example 1 Preparation of 1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-ol (C1) Example 1 Preparation of 1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-ol (C1) (0276) (0277) A mixture of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (2.00 g, 8.75 mmol), urea (0.709 g, 11.81 mmol), and para-toluenesulfonic acid monohydrate (0.0170 g, 0.0870 mmol) in chlorobenzene (7.95 mL) was heated at 140° C. for 2 hours. The mixture was cooled to 80° C., and triethoxymethane (1.56 mL, 9.36 mmol) was added followed by chlorosulfonic acid (0.0120 mL, 0.175 mmol). The reaction mixture was heated at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and filtered. The residue was dried under high vacuum overnight to provide the title compound (2.14 g, 99%): mp>300° C.; 1H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 7.91-7.79 (m, 2H), 7.54 (dq, J=7.7, 1.0 Hz, 2H), 5.40 (s, 1H); ESIMS m/z 246 ([M+H]+)

Reference： [1]Current Patent Assignee: CORTEVA INC - US2017/66757, 2017, A1 Location in patent: Paragraph 0276; 0277

20
[ 2125724-46-9 ]
[ 133115-72-7 ]
[ 2125724-41-4 ]

Yield	Reaction Conditions	Operation in experiment
82%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 12h;	5 Preparation of compound Q23 To a 100 mL single-necked flask was added compound Q6 (100 mg, 0.29 mmol), EDCI (113.1 mg, 0.59 mmol), HOBt (79.7 mg, 0.59 mmol), DMAP (144.2 mg, 1.18 mmol) and p-trifluoromethoxyphenylhydrazine Hydrochloric acid salt (137.2mg, 0.59mmol), add anhydrous DCM (10mL), stirring at room temperature for 12h, TLC detection reaction is complete, add 20mL water, with DCM (20mL × 3) extraction of water phase, combined organic phase, respectively Washed with water (30 mL), saturated NaCl solution (30 mL), dried over anhydrous NaSO4, concentrated under reduced pressure and subjected to silica gel column chromatography (PE: EA = 2: 1) to give compound Q23 (124 mg pale yellow solid, 82%).

Reference： [1]Current Patent Assignee: EAST CHINA NORMAL UNIVERSITY - CN106928095, 2017, A Location in patent: Paragraph 0162

21
[ 765-87-7 ]
[ 133115-72-7 ]
[ 893410-19-0 ]

Yield	Reaction Conditions	Operation in experiment
6%	With hydrogenchloride; acetic acid In methanol; water at 60℃; for 3h;	15.1 6-(Trifluoromethoxy)-2, 3,4, 9-tetrahydro- 1H-carbazol- 1-one A solution of 4-trifluoromethoxyphenylhydrazine hydrochloride (2.04 g, 8.92 mmol) in methanol (20 mL) was added slowly at 60 °C to a mixture of 1,2-cyclohexanedione (2.0 g, 17.84 mmol) in acetic acid (44 mL) and concentrated hydrochloric acid (16 mL). The reaction mixturewas stirred for 3 hours at 60 °C. The reaction mixture was diluted with ethyl acetate, and it was washed with water followed by brine. The organic layer was dried over sodium sulfate, and it was concentrated under reduced pressure. The residue was purified on an ISCO chromatograph (0-20% ethyl acetate/hexane) to give the product as a white solid (135 mg, 6%); ‘H NIVIR (300 MHz) (CDC13) 8.80 (bs, 1H), 7.51 (s, 1H), 7.40 (d, J= 9 Hz, 1H), 7.26-7.23 (m, 1H), 3.00 (t, J= 6 Hz, 2H), 2.67 (t, J= 6 Hz, 2H), 2.30-2.26 (m, 2H).

Reference： [1]Current Patent Assignee: RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY - WO2019/5841, 2019, A1 Location in patent: Page/Page column 86; 87

22
[ 461-58-5 ]
[ 133115-72-7 ]
[ 2344679-11-2 ]

Yield	Reaction Conditions	Operation in experiment
63.7%	In isopropyl alcohol at 135℃; for 3h; Microwave irradiation;	9.1 Step 1. Synthesis of Intermediate c The mixture of compound a (4.00 g, 17.5 mmol, 1.00 eq, HC1) and compound b (1.54 g, 18.4 mmol, 1.05 eq) in i-PrOH (13 mL) was stirred for 3 hours at 135 °C under microwave. The mixture was worked up without monitoring. The mixture was cooled and diluted with Ethyl acetate (100 mL), then washed with water (30 mL x 3), brine (30 mL), dried with NaiSOr. concentrated in vacuo to give compound c (16.0 g, 55.8 mmol, 63.7% yield, 90.3% purity) as yellow solid, which was confirmed by LCMS (EW14597-1-P1B, RT=0.625min, m/z+l=260.5). LC-MS (ESI): m/z (M+H) 260.5.

Reference： [1]Current Patent Assignee: NYSNOBIO IRELAND DAC; AN2H DISCOVERY LTD - WO2019/204815, 2019, A1 Location in patent: Paragraph 651-653

23
[ 2404706-93-8 ]
[ 133115-72-7 ]
[ 2404708-45-6 ]
[ 2404708-62-7 ]

Yield	Reaction Conditions	Operation in experiment
1: 78% 2: 11%	Stage #1: C₂₀H₂₁NO₃; 4-(trifluoromethoxy)phenylhydrazine hydrochloride In ethanol at 120℃; for 1h; Microwave irradiation; Inert atmosphere; Stage #2: With methanol; potassium carbonate at 20℃; for 16h; Inert atmosphere;	1.ii Compound 23b and 24b: General procedure: Compound 23b and 24b (131 mg, 67% yield) was synthesized from compound 4 (129 mg, 0.40 mmol) and 4-(trifluoromethoxy)phenylhydrazme hydrochloride (100 mg, 0.44 mmol) using the same procedure as described for the synthesis of compound 23a and 24a. Tire crude product was purified by column chromatography (silica gel, eluting with 50% EtOAc in hexanes) to give a mixture of compound 23b and 24b. m/z:::480 (M+l ).Compound 2Sb and 26b: A mixture of compound 23b and 24b (129 mg, 0.27 mmol) and K2CQ3 (111 mg, 0.80 mmol) in MeOH (2.8 mL) was stirred at room temperature for 16 h. 10% aq. NaHrPOr was added. The mixture was extracted with EtOAc. The organic extracts were dried over Na SOr, filtered, and concentrated. The residue was purified by column chromatography (silica gel, eluting with 0% to 30% acetone in hexanes) to give compound 25b (100 mg, 78% yield) and 26b (14 mg, 1 1% yield). Compound 25b: white solid; m/z = 480 (M + 1); Compound 26b: white solid; m/z::= 480 (M + 1 ).

Reference： [1]Current Patent Assignee: AAPHARMASYN LLC; REATA PHARMACEUTICALS, INC. - WO2019/241796, 2019, A1 Location in patent: Page/Page column 72; 75; 147; 159; 160

24
[ 13669-42-6 ]
[ 133115-72-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium acetate In ethanol; water for 2h;	2.1.1. General procedure for the synthesis of compounds 3q1-3q21 General procedure: The quinoline-3-carbaldehyde (0.1 mmol) was dissolved in EtOH and reacted with 0.13 mmol of phenyl hydrazine hydrochloride or derivative compounds in the presence of a solution of 0.4 g of sodium acetate in water for about 2 h. The precipitate formed at the end of the reaction was filtered off. The crystals obtained were purified by recrystallization from ethanol. The final compounds were obtained as amixture of E/Z stereoisomers.

Reference： [1]Celik, Ismail; Erol, Meryem; Fatullayev, Hanifa; Kuyucuklu, Gulcan; Puskullu, Mustafa Orhan; Uzunhisarcikli, Ebru [Bioorganic Chemistry, 2020, vol. 101]

25
[ 2470163-97-2 ]
[ 133115-72-7 ]
[ 2470162-70-8 ]

Yield	Reaction Conditions	Operation in experiment
53%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 1h;	2.2 Step 2- Preparation of (Z)-1-(3-(5-methyl-2-(2,2,2-trifluoroethoxy)phenyl)-4- oxothiazolidin-2-ylidene)-3-(4-(2-(4-(trifluoromethoxy)phenyl)hydrazine-1- carbonyl)phenyl)urea (A3): (Z)-4-(3-(3-(5-Methyl-2-(2,2,2-trifluoroethoxy)phenyl)-4- oxothiazolidin-2-ylidene)ureido)benzoic acid (prepared as in Step 1; 0.220 g, 0.471 mmol) was combined in a vial with (benzotriazol-1-yloxy)tripyrrolidinophosphonium (0312) hexafluorophosphate (PyBOP; 0.490 g, 0.941 mmol) and (4- (trifluoromethoxy)phenyl)hydrazine hydrochloride (0.129 g, 0.490 mmol). To the solids were added dichloromethane (1.88 mL) followed by N,N-diisopropylethylamine (0.329 mL, 1.88 mmol). The reaction mixture became homogeneous and was stirred for 1 h. The mixture was concentrated. Purification by silica gel chromatography (eluting with 0- 40% acetone in hexanes) afforded the title compound as a yellow foam (0.160 g, 53%).

Reference： [1]Current Patent Assignee: CORTEVA INC - WO2020/163146, 2020, A1 Location in patent: Page/Page column 67

26
[ 17990-42-0 ]
[ 133115-72-7 ]
[ 2593308-47-3 ]

Yield	Reaction Conditions	Operation in experiment
40.05%	With acetic acid; trifluoroacetic acid In ethyl acetate Heating;	3.2 The synthesis for the preparation of compound 2a-2o General procedure: The indole ring substituted analogs 2a-2o were synthesized by employing the appropriate substituted phenylhydrazine in the Fischer indolization [19]. Compound 1 (100mg) and substituted phenylhydrazines were dissolved in ethyl acetate with refluxing at 110 overnight. The reaction was monitored by thin-layer chromatography (TLC). After the reaction completed, acetic acid in the reaction mixture was removed under reduced pressure. Then, the remainder was dissolved in ethyl acetate. The organic layer was washed with deionizedwater, and dried over MgSO4 and evaporated. The crude product was separated by preparative silica gel chromatography in petroleum ether: ethyl acetate=10:1 to 8:1 or dichloromethane: ethyl acetate=100:1 ratio, respectively.

Reference： [1]Wu, Panpan; He, Hao; Ma, Hang; Tu, Borong; Li, Jiahao; Guo, Shengzhu; Chen, Silin; Cao, Nana; Zheng, Wende; Tang, Xiaowen; Li, Dongli; Xu, Xuetao; Zheng, Xi; Sheng, Zhaojun; David Hong, Weiqian; Zhang, Kun [Bioorganic Chemistry, 2021, vol. 107]

27
[ 118431-88-2 ]
4-(trifluoromethoxy)phenylhydrazine hydrochloride [ No CAS ]
3-cyclopropyl-1-(4-(trifluoromethoxy)phenyl)-1H-pyrazol-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With hydrogenchloride; In ethanol; for 20h;Reflux;	General procedure: A stirred solution of the hydrazine hydrochloride (1 eq), β-ketonitrile (1 eq) and a drop of HCl (conc.) in EtOH (10 mL) was heated at reflux for 18 h. After cooling to rtrt, the mixture was basified to pH 12 by the addition of an aqueous NaOH solution (10%) (compound 6) or a sat. NaHCO3 solution (compounds 10-17) and extracted with EtOAc (3 x30 mL). The organic extracts were combined, washed with brine (40 mL), dried over Na2SO4 and the solvent was evaporated in vacuo. Purification by flash column chromatography on SiO2 or recrystallization from a hexane/EtOAc mixture gave the desired product.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 208

28
[ 13720-16-6 ]
[ 133115-72-7 ]
[ 2644623-91-4 ]

Yield	Reaction Conditions	Operation in experiment
30.7%	With acetic acid at 115℃; for 2h; Inert atmosphere;	General procedure: The indole ring substituted analogs 6-11 were synthesized by employing the appropriate substituted phenylhydrazine in the Fischer indolization as the previously reported methods [53]. A mixture of compound 5 (482mg, 1.0mmol), phenylhydrazine (2.0mmol), and glacial acetic acid (10mL) was refluxed under N2 for 2h. The reaction mixture was pipetted into distilled water and extracted with ethyl acetate and then dried over MgSO4 and evaporated. The crude product was chromatographed to obtain the target 11-oxooleanolic acid derivatives. The purities of all TESTED compounds were confirmed by analytical HPLC with a dual pump Shimadzu LC 20A system equipped with a C18 column (250mm×4.6mm, 5μM YMC). Analytical method conditions: flow rate=0.5mL/min, injection volume=10μL, isocratic elution system=80% solvent A (70% water, 20% acetonitrile, 5% glacial acetic acid, 228 5% tetrahydrofuran) and 20% solvent B (acetonitrile) at room temperature and run time=15min. The purities of all compounds are over 95% and Rt are between 7.0 and 10min.

Reference： [1]Jin, Jingwei; He, Hao; Zhang, Xinyue; Wu, Rihui; Gan, Lishe; Li, Dongli; Lu, Yujing; Wu, Panpan; Wong, Wing-Leung; Zhang, Kun [Bioorganic Chemistry, 2021, vol. 113]

29
[ 1196-69-6 ]
[ 133115-72-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium acetate In ethanol for 3h;	2.1.1. General procedure for synthesis of 5i1-5i19 General procedure: Indole-5-carbaldehyde (0.1 mmol) was dissolved in EtOH andreacted with phenylhydrazine hydrochloride or its derivativesin the presence of an aqueous sodium acetate solution forapproximately 3 h. The precipitate formed at the end of thereaction was filtered, and the crystals obtained were purifiedby recrystallization from ethanol.

Reference： [1]Erol, Meryem; Celik, Ismail; Ince, Ufuk; Fatullayev, Hanifa; Uzunhisarcikli, Ebru; Puskullu, Mustafa Orhan [Journal of Biomolecular Structure and Dynamics, 2022, vol. 40, # 17, p. 8112 - 8126]

30
[ 133115-72-7 ]
[ 762294-76-8 ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine; copper (II) carbonate hydroxide; 1,4-diazabicyclo [2.2.2] octane-1,4-diium-1,4-disulfinate; N-fluorobis(benzenesulfon)imide In acetonitrile at 40℃; for 2h; Sealed tube; Inert atmosphere;
49%	With pyridine; copper (II) carbonate hydroxide; 1,4-diazabicyclo[2.2.2]octane-triethylenediamine-bis(sulfur dioxide); N-fluorobis(benzenesulfon)imide In acetonitrile at 40℃; for 2h; Inert atmosphere; Sealed tube;	10 Synthesis of 4-trifluoromethoxybenzenesulfonyl fluoride: Add 91.4mg (0.4mmol) 4-trifluoromethoxyphenylhydrazine hydrochloride, 8.8mg (0.04mmol) basic copper carbonate, and 277.5mg (0.88mmol) N-fluorobisbenzenesulfonate into a 10mL sealed tube. Amide (NFSI), 120.2mg (0.5mmol) 4-diazabicyclo[2.2.2]octane-bis(sulfur dioxide) adduct (DABSO), replace the air in the sealed tube with argon to ensure that the system is in In an inert gas environment, and under the protection of argon, 63.3 mg (0.8 mmol) of pyridine and 4.0 mL of acetonitrile were added, the lid was tightly closed, and the sealed tube was placed in an oil bath at 40° C. and stirred for 2 hours.After the reaction, it was cooled to room temperature, solid impurities were filtered off, the filtrate was concentrated and spin-dried to obtain the target compound 4-trifluoromethoxybenzenesulfonyl fluoride, a yellow liquid product, with an isolated yield of 49%.This product has a low boiling point and is easy to vacuum. Instead of pumping with a vacuum pump, it is mixed with n-pentane and spin-dried several times to basically ensure that the product is not lost.

Reference： [1]Chen, Qing-Yun; Guo, Yong; Hu, Xiaojun; Liu, Chao; Liu, Yongan; Ma, Xiaoyu; Pan, Qijun; Pang, Wan; Wu, Jingjing [Organic and Biomolecular Chemistry, 2021, vol. 19, # 41, p. 8999 - 9003]
[2]Current Patent Assignee: SHANGHAI INSTITUE OF TECHNOLOGY - CN113603619, 2021, A Location in patent: Paragraph 0093-0097

31
[ 40138-16-7 ]
[ 133115-72-7 ]
[ 2761537-80-6 ]

Yield	Reaction Conditions	Operation in experiment
24%	In water monomer; dimethyl sulfoxide at 20℃; for 2h;	79.2 Step 2: A solution of 2-formylphenylboronic acid (330 mg, 2.2 mmol) and (4- (trifluoromethoxy)phenyl)hydrazine hydrogen chloride (500 mg, 2.2 mmol) in DMSO/H2O (10 mL, v/v = 1/4) was stirred at room temperature for 2 h. LCMS analysis showed no starting materials left. The reaction mixture was diluted with water (25 mL), extracted with EtOAc (2 × 25 mL), washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. Further purification by crystallization with MeOH/H2O (10 mL, v/v = 1/1) afforded the desired product 2-(p-trifluoromethoxyphenyl)-1,2-dihydro-2,3,1- benzodiazaborinin-1-ol (164 mg, yield 24%) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 8.23 (s, 2H), 7.90-7.70 (m, 1H), 7.87-7.76 (m, 5H), 7.41(d, J = 8.4 Hz, 1H) ppm. HPLC purity: 98.99% at 210 nm and 97.83% at 254 nm. MS: (M+H)+: m/z = 307.0.
24%	In water monomer; dimethyl sulfoxide at 20℃; for 2h;	79.2 Step 2: A solution of 2-formylphenylboronic acid (330 mg, 2.2 mmol) and (4- (trifluoromethoxy)phenyl)hydrazine hydrogen chloride (500 mg, 2.2 mmol) in DMSO/H2O (10 mL, v/v = 1/4) was stirred at room temperature for 2 h. LCMS analysis showed no starting materials left. The reaction mixture was diluted with water (25 mL), extracted with EtOAc (2 × 25 mL), washed with brine (2 × 10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. Further purification by crystallization with MeOH/H2O (10 mL, v/v = 1/1) afforded the desired product 2-(p-trifluoromethoxyphenyl)-1,2-dihydro-2,3,1- benzodiazaborinin-1-ol (164 mg, yield 24%) as a white solid. 1HNMR (400 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.41 (d, J = 7.5 Hz, 1H), 8.23 (s, 2H), 7.90-7.70 (m, 1H), 7.87-7.76 (m, 5H), 7.41(d, J = 8.4 Hz, 1H) ppm. HPLC purity: 98.99% at 210 nm and 97.83% at 254 nm. MS: (M+H)+: m/z = 307.0.

Reference： [1]Current Patent Assignee: 5 METIS - WO2022/40157, 2022, A1 Location in patent: Paragraph 00562-00564; 00566
[2]Current Patent Assignee: 5 METIS - WO2022/40157, 2022, A1 Location in patent: Paragraph 00562-00564; 00566

32
[ CAS Unavailable ]
[ 133115-72-7 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
30%	With N,N-dimethyl-4-aminopyridine; triethylamine In dichloromethane at 0 - 25℃; for 6.5h;	9 Example 9 4-Trifluoromethoxyphenylhydrazine hydrochloride (1.0 mmol), 4-dimethylaminopyridine (0.1 mmol), and triethylamine (1.1 mmol) were dissolved in anhydrous dichloromethane, cooled to 0 °C, and separated. L-10-camphorsulfonyl chloride (1.1 mol) was added in batches, and the reaction was raised to 25°C for 6.5 h. TLC monitored the reaction of the raw materials. The organic layer was washed with water 3 times (8 ml3) and saturated brine 3 times (8 mL3). 3), dried, suction filtered, concentrated to remove dichloromethane, the crude product was subjected to column chromatography (CH2Cl2:MeOH=20:1) to obtain the target compound I-9. Beige solid, m.p.95-97, yield 30%.

Reference： [1]Current Patent Assignee: NANJING FORESTRY UNIVERSITY - CN114621121, 2022, A Location in patent: Paragraph 0064-0066

33
[ 360-53-2 ]
[ 133115-72-7 ]
[ 2852734-73-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine In acetonitrile at 20℃;	18 Manufacture of 1-[4-(trifluoromethoxy)phenyl]-5-fluoro-3-methoxy-4-trifluoromethylpyrazole 0.5 g (2.2 mmol) of 4-(trifluoromethoxy)phenylhydrazine hydrochloride was dissolved in 22 ml of acetonitrile, and 1,3,3,3-tetrafluoro-1-methoxy-2-(trifluoromethyl)-1 - Propene0.6 g (2.8 mmol) and 1.5 g (11.3 mmol) of N,N-diisopropylethylamine were added and stirred at room temperature for 43.2 hours.Column purification of the reaction solution,0.05 g of crudely purified 1-[4-(trifluoromethoxy)phenyl]-5-fluoro-3-methoxy-4-trifluoromethylpyrazole represented by the following formula (R) was obtained.

Reference： [1]Current Patent Assignee: NOK CORPORATION - WO2022/230599, 2022, A1 Location in patent: Paragraph 0085-0087

34
[ 104-88-1 ]
[ 96-33-3 ]
[ 133115-72-7 ]
[ 2811645-69-7 ]

Yield	Reaction Conditions	Operation in experiment
86 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	1 Example 1 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3a (54μL, 0.6mmol), KBr (43mg , 0.36mmol), K2CO3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro -1H-Pyrazole-5-carboxylic acid methyl ester 4aaa (yield 86%). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0045-0048

35
[ 104-88-1 ]
[ 96-33-3 ]
[ 133115-72-7 ]
[ 2811646-14-5 ]

Yield	Reaction Conditions	Operation in experiment
65 %	With oxone; potassium carbonate; potassium bromide In acetonitrile at 20℃; Cooling with ice;	2 Example 2 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3a (54μL, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (323mg, 1.05mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 6 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-5 - Methyl carboxylate 4aaa' (65% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0049-0052

36
[ 104-88-1 ]
[ 140-88-5 ]
[ 133115-72-7 ]
[ 2811645-96-0 ]

Yield	Reaction Conditions	Operation in experiment
73 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	22 Example 22 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3b (60mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro -1H-Pyrazole-5-carboxylic acid ethyl ester 4aab (73% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0110-0112

37
[ 1663-39-4 ]
[ 104-88-1 ]
[ 133115-72-7 ]
[ 2811645-97-1 ]

Yield	Reaction Conditions	Operation in experiment
82 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	23 Example 23 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3c (77mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro - tert-butyl 1H-pyrazole-5-carboxylate 4aac (yield 82%). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0113-0115

38
[ 25662-28-6 ]
[ 104-88-1 ]
[ 133115-72-7 ]
[ 2811645-98-2 ]

Yield	Reaction Conditions	Operation in experiment
75 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	24 Example 24 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3d (76mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product (3aR,6aS)-3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)- 3a,4,5,6-Tetrahydrocyclopenta[c]pyrazole-6a(1H)-carboxylate methyl ester 4aad (75% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0115-0118

39
[ CAS Unavailable ]
[ 104-88-1 ]
[ 133115-72-7 ]
[ 2811645-99-3 ]

Yield	Reaction Conditions	Operation in experiment
83 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	25 Example 25 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3e (84mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product (3aR,7aS)-3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)- 1,3a,4,5,6,7-Tetrahydro-7aH-indazole-7a-carboxylate methyl ester 4aae (83% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0119-0121

40
[ 104-88-1 ]
[ 9011-14-7 ]
[ 133115-72-7 ]
[ 2811646-00-9 ]

Yield	Reaction Conditions	Operation in experiment
81 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	26 Example 26 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3f (60mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-5-methyl-1-(4-trifluoromethoxyphenyl)-4 , 5-Dihydro-1H-pyrazole-5-carboxylic acid methyl ester 4aaf (81% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0122-0124

41
[ 104-88-1 ]
[ CAS Unavailable ]
[ 133115-72-7 ]
[ 2811646-03-2 ]

Yield	Reaction Conditions	Operation in experiment
76 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	27 Example 27 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3g (32mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro -1H-pyrazole-5-carbonitrile 4aag (76% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0125-0127

42
[ 104-88-1 ]
[ 78-94-4 ]
[ 133115-72-7 ]
[ 2811646-05-4 ]

Yield	Reaction Conditions	Operation in experiment
58 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	28 Example 28 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3h (42mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro -1H-pyrazole-5-ethanone 4aah (58% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0128-0130

43
[ 100-69-6 ]
[ 104-88-1 ]
[ 133115-72-7 ]
[ 2811646-08-7 ]

Yield	Reaction Conditions	Operation in experiment
56 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	29 Example 29 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3i (63mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro -1H-pyrazole-5-pyridine 4aai (56% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0131-0133

44
[ CAS Unavailable ]
[ 104-88-1 ]
[ 133115-72-7 ]
[ 2811646-09-8 ]

Yield	Reaction Conditions	Operation in experiment
52 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	30 Example 30 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3j (63mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-5-phenyl-1-(4-trifluoromethoxyphenyl)-4 , 5-Dihydro-1H-pyrazole 4aaj (52% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0134-0136

45
[ 402-50-6 ]
[ 104-88-1 ]
[ 133115-72-7 ]
[ 2811646-10-1 ]

Yield	Reaction Conditions	Operation in experiment
43 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	31 Example 31 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3k (103mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-5-(4-trifluorophenyl) Fluoromethylphenyl)-4,5-dihydro-1H-pyrazole 4aak (43% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0137-0139

46
[ 104-88-1 ]
[ 762-42-5 ]
[ 133115-72-7 ]
[ 2811646-16-7 ]

Yield	Reaction Conditions	Operation in experiment
68 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	32 Example 32 Take a 5mL round bottom flask, weigh 2a (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg 0.3mmol), 3l (86mg, 0.6mmol), KBr (43mg , 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-1H-pyrazole-4 , Methyl 5-dicarboxylate 4aal (68% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0140-0142

47
[ CAS Unavailable ]
[ 96-33-3 ]
[ 133115-72-7 ]
[ 2811645-79-9 ]

Yield	Reaction Conditions	Operation in experiment
74 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	12 Example 12 Take a 5mL round bottom flask, weigh 2b (35mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg, 0.3mmol), 3a (54μL, 0.6mmol), KBr ( 43mg, 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-phenyl-1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazole - Methyl 5-carboxylate 4aba (74% yield). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0080-0082

48
[ 89-98-5 ]
[ 96-33-3 ]
[ 133115-72-7 ]
[ 2811645-80-2 ]

Yield	Reaction Conditions	Operation in experiment
83 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	13 Example 13 Take a 5mL round bottom flask, weigh 2c (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg, 0.3mmol), 3a (54μL, 0.6mmol), KBr ( 43mg, 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(2-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro - 1H-Pyrazole-5-carboxylic acid methyl ester 4aca (yield 83%). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0083-0085

49
[ 587-04-2 ]
[ 96-33-3 ]
[ 133115-72-7 ]
[ 2811645-81-3 ]

Yield	Reaction Conditions	Operation in experiment
82 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	14 Example 14 Take a 5mL round bottom flask, weigh 2c (46mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg, 0.3mmol), 3a (54μL, 0.6mmol), KBr ( 43mg, 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(3-chlorophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro - 1H-pyrazole-5-carboxylic acid methyl ester 4ada (yield 82%). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%. T

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0086-0088

50
[ 1122-91-4 ]
[ 96-33-3 ]
[ 133115-72-7 ]
[ 2811645-82-4 ]

Yield	Reaction Conditions	Operation in experiment
83 %	With oxone; potassium carbonate; potassium bromide In water; acetonitrile at 20℃; Cooling with ice;	15 Example 15 Take a 5mL round bottom flask, weigh 2e (61mg, 0.33mmol) into the bottle, add 1mL MeCN, 0.1mL water, cool in an ice-water bath, add 1a (69mg, 0.3mmol), 3a (54μL, 0.6mmol), KBr ( 43mg, 0.36mmol), K 2 CO 3 (145mg, 1.05mmol), Oxone (276mg, 0.9mmol) was added and kept for 10 minutes, then the ice bath was removed, and the reaction was stirred at room temperature for 3 hours. After the reaction was completed, it was quenched with saturated sodium sulfite, extracted with ethyl acetate, and the combined organic phases were washed once with saturated sodium chloride. Dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and column chromatography to obtain the target product 3-(4-bromophenyl)-1-(4-trifluoromethoxyphenyl)-4,5-dihydro - 1H-Pyrazole-5-carboxylic acid methyl ester 4aea (yield 83%). The purity is confirmed by the hydrogen nuclear magnetic resonance spectrum, the hydrogen spectrum is clean, there are few miscellaneous peaks, and the purity is greater than 95%.

Reference： [1]Current Patent Assignee: UNIV FUJIAN AGRICULTURE and FORESTRY - CN115260099, 2022, A Location in patent: Paragraph 0089-0091

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