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[ CAS No. 2062-26-2 ] {[proInfo.proName]}

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2D 3D

Chemical Structure| 2062-26-2

Chemical Structure| 2062-26-2

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Quality Control of [ 2062-26-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 2062-26-2 ]

Product Details of [ 2062-26-2 ]

CAS No. :	2062-26-2	MDL No. :	MFCD00002696
Formula :	C₁₀H₇F₃O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ANRMAUMHJREENI-ZZXKWVIFSA-N
M.W :	216.16	Pubchem ID :	688070
Synonyms :

Calculated chemistry of [ 2062-26-2 ]

Physicochemical Properties

Num. heavy atoms :	15
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.1
Num. rotatable bonds :	3
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	48.11
TPSA :	37.3 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) :	-5.48 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.68
Log Po/w (XLOGP3) :	3.01
Log Po/w (WLOGP) :	3.85
Log Po/w (MLOGP) :	2.9
Log Po/w (SILICOS-IT) :	2.77
Consensus Log Po/w :	2.84

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.17
Solubility :	0.145 mg/ml ; 0.000669 mol/l
Class :	Soluble
Log S (Ali) :	-3.46
Solubility :	0.0753 mg/ml ; 0.000348 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.75
Solubility :	0.381 mg/ml ; 0.00176 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.94

Safety of [ 2062-26-2 ]

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

Application In Synthesis of [ 2062-26-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 2062-26-2 ]
Downstream synthetic route of [ 2062-26-2 ]

[ 2062-26-2 ] Synthesis Path-Upstream 1~1

1
[ 2062-26-2 ]
[ 53473-36-2 ]

Reference： [1] Tetrahedron Letters, 2008, vol. 49, # 42, p. 6137 - 6140
[2] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 14, p. 1519 - 1522
[3] Patent: WO2009/83899, 2009, A2, . Location in patent: Page/Page column 6; 17
[4] Patent: WO2009/83903, 2009, A1, . Location in patent: Page/Page column 6; 17
[5] Patent: EP2168944, 2010, A1, . Location in patent: Page/Page column 47-48
[6] Organic Process Research and Development, 2013, vol. 17, # 12, p. 1531 - 1539

[ 2062-26-2 ] Synthesis Path-Downstream 1~39

1
[ 2062-26-2 ]
[ 105919-36-6 ]

Yield	Reaction Conditions	Operation in experiment
> 100%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3 - 18h;Product distribution / selectivity;	A solution of Compound 10a (20.6 g, 95.4 mmol) in anhydrous methylene chloride (200 mL) was treated with oxalyl chloride (16.6 mL, 190 mmol) and ?3 drops? of anhydrous dimethylformamide. The resulting solution was stirred at room temperature under an argon atmosphere for 18 h. The solvent was concentrated to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride Compound 10b as a solid, which was used without further purification in the next step. Step B. (E)-5-bromo-2-[2-(4-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazoleTo a 5-L 4-neck round bottom flask equipped with a magnetic stirrer, argon inlet-argon outlet to a carbonate scrub, two stoppers, and a room temperature water bath was charged with 4-(trifluoromethyl)cinnamic acid (315 g, 1.46 mol) and dichloromethane (3.15 L) to give a slurry. To the slurry was added oxalyl chloride (151.71 mL, 1.75 mol) and DMF (1.13 mL, 14.57 mmol). Upon addition of DMF, gas evolution commenced, and the reaction was continued for about 3 h during which time a solution developed. When the reaction was complete (LC-MS), it was concentrated to dryness to give 342.4 g of 3-(4-trifluoromethyl-phenyl)-acrylol chloride Compound 10b (>100%) as a yellow oily solid.
100%	With thionyl chloride; In N,N-dimethyl-formamide; for 4h;Reflux;	General procedure: To a solution of 1.2 equiv of substituted cinnamic acid 1a-l (5 mmol) in 5 equiv of thionyl chloride(3.6 mL), a catalytic amount of DMF was added. The reaction mixture was refluxed for 4 h, andthen, solvent was evaporated under vacuum to get the product 2a-l in the form of a solid residue inquantitative yield. The solid residue was directly added partially to an ice-cold stirred solution of1.0 equiv of tert-butyl (2-aminoethyl)carbamate or tert-butyl (3-aminopropyl)carbamate and 2.0 equivtriethylamine in DCM (20 mL). After the addition, the mixture was warmed to room temperature andstirred for 2 h. Then, DCM (20 mL) was added and washed with 0.2 M HCl (40 mL), H2O (40 mL),5% saturated. NaHCO3 (40 mL) and brine (40 mL), then dried over anhydrous magnesium sulfate.The solvent was removed in vacuo to give the corresponding cinnamamide derivatives 3a-l (65%-75%,from 1a-l) and 4a-g (59%-70%, from 1a-g) as a white solid. 3a-l, 4a-g (4 mmol) in DCM/TFA(9:1, 40 mL) were stirred at room temperature for 1 h. Solvents were removed in vacuo to yield 5a-l(100%) and 6a-g (100%) as a colorless oil.
100%	With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide;Reflux; Inert atmosphere;	General procedure: To a solution of appropriate substituted trans-cinnamic acid 2a-p (1 mmol) in dry dichloromethane the thionyl chloride (2 mmol)and a catalytic amount of DMF was added. The reaction mixturewas refluxed for 2-4 h under anhydrous conditions, the solventwas evaporated under vacuum to obtain corresponding substitutedcinnamoyl chlorides 3a-p which was further used for the next stepwithout further purification.

99%	With thionyl chloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 3h;	To a cold (0 C.) solution of trans-4-trifluoromethylcinnamic acid (6 g) in a mixture of DCM (20 mL) and DMF (few drops) was added dropwise oxalyl chloride (2.6 mL, 1.1 equivalents). The reaction mixture was stirred at 0 C. for 3 h and concentrated in vacuo to yield the crude title compound as a beige solid (6.5 g, 99%).
91%	With oxalyl dichloride; at 20℃; for 5h;	General procedure: To a stirred solution of the appropriate acid 3a-d (6 mmol) in DCM (50 mL) was added oxalyl chloride (1 mL, 12 mmol), and the mixture was stirred at r.t. for 5h. The resulting solution was concentrated under reduced pressure to give the desired product, which was used for the next step without further purification.
	With thionyl chloride; In dichloromethane; for 1.5h;	To a 500 mL round-bottomed flask was added 4-(trifluoromethyl)cinnamic acid (231 mL, 116 mmol), DCM (7.44 mL, 116 mmol), thionyl chloride (17.7 mL, 243 mmol), and a few drops of DMF. The resulting mixture was stirred at reflux for about 1.5 hours and followed by LCMS (MeOH quench). Once no starting material was present, the solvents were reduced and the oil was used immediately in the next step.
	With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 0 - 20℃; for 2h;	Oxalyl chloride (11.7mL) was added dropwise to a suspension of 4-trifluoromethylcinnamic acid (19.4g) and DMF (6 drops) in THF (100mL) at 0§C, and the mixture was stirred at room temperature for 2 hours. After the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (60mL), and poured into 25% aqueous ammonia-ethyl acetate (5:1, 120mL). The aqueous layer was salted out, extracted with a mixed solution (650mL) of ethyl acetate-THF (12:1), followed by ethyl acetate (100mL x 2), and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain the title compound (18.0g) as colorless plate-like crystals. 1H-NMR (CDCl3) delta: 5.58 (2H, br s), 6.53 (1H, d, J = 15.8 Hz), 7.63-7.72 (5H, m). IR (KBr): 3326, 3167, 1686, 1636, 1617, 1404, 1190 cm-1.
	With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; at 0 - 20℃; for 2h;	(i) (E)-3-(4-Trifluoromethylphenyl)-2-propenamide To a THF (100 mL) suspension of 4-trifluoromethylcinnamic acid (19.4 g) and DMF (6 droplets), oxalyl chloride (11.7 mL) was added dropwise at 0§C, followed by stirring at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (60 mL) and the solution was poured into 25% ammonia water-ethyl acetate (5:1., 120 mL). After the aqueous layer was salted out, the organic layer was extracted with a mixture (650 mL) of ethyl acetate and THF (12:1), and ethyl acetate (100 mL x 2), and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was recrystallized from ethyl acetate-hexane to obtain the title compound (18.0 g) as colorless plates. 1H-NMR (CDCl3) delta: 5.58 (2H, br s), 6.53 (1H, d, J = 15.8 Hz), 7.63-7.72 (5H, m). IR (KBr): 3326, 3167, 1686, 1636, 1617, 1404, 1190 cm-1.
	With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 20℃; for 0.5h;Inert atmosphere;	^-(S-Acetyl-benzylJ-oxazol^-yll-^^-trifluoromethyl-phenylJ-vinyll-carbamic acid tert-butyl ester:; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of trans-4-(trifluoromethyl)cinnamic acid (20 mg, 0.10 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.02 mL, 0.23 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 3- (4-trifluoromethyl-phenyl)-acryloyl chloride.; In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(3-acetyl-benzyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (15 mg, 0.05 mmol) in THF (1.0 mL) was added to a suspension of NaH (5 mg, 0. 12 mmol) in THF (0.5 mL) at 0 0C. The resulting suspension was stirred at 0 0C for 5 min and at rt for 30 min. It was cooled to 0 0C and treated dropwise with a solution of the above prepared 3-(4-trifluoromethyl-phenyl)-acryloyl chloride in THF (1.0 mL). The resulting suspension was stirred for 5 min at 0 0C followed by 30 min at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to give the title compound as a yellow oil. TLC: rf (6:4 hept-EA) = 0.20. LC-MS-conditions 02: tR = 1.17 min, [M+H]+ = 515.82
	With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 20℃; for 0.5h;Inert atmosphere;	[2-(3-Acetyl-benzyl)-oxazol-4-yl]-[2-(4-trifluoromethyl-phenyl)-vinyl]-carbamic acid tert-butyl esterIn a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of trans-4-(trifluoromethyl)cinnamic acid (20 mg, 0.10 mmol) in toluene (1.0 mL) was treated with a drop of DMF followed by oxalyl chloride (0.02 mL, 0.23 mmol) and the resulting yellow solution was stirred at rt for 30 min. The solvent was then removed under reduced pressure (coevaporation with toluene) to give 3-(4-trifluoromethyl-phenyl)-acryloyl chloride.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 4h;Inert atmosphere;	General procedure: Oxalyl chloride (0.63 mmol) was added to a well stirred solution of cinnamic acid (19a-l) in DCM (15 mL) kept at 0 C under nitrogen atmosphere. To this one or two drops (catalytic amount) of DMF was added and leave it to room temparature for 4 h. Triethylamine (2 eq) was added to a well stirred solution of benzophenone amine (2a &16, 200 mg, 0.63 and 0.57 mmol respectively) dissolved in THF (10 mL) kept at 0 oC under nitrogen atmosphere. To this cinnamoyl chloride dissolved in dry THF (30 mL) was added via syringe and leave it at room temparature and the mixture was stirred for 6 h. After the solvent was removed under reduced pressure and redissolved in CHCl3 (20 mL x 2) followed by addition of water (15 mL). The organic layer was separated and evaporated to dryness. The residue was washed with aq NaOH to remove any excess acid and extracted with CHCl3. The organic extract was dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography using ethyl acetate/hexane to afford the pure product.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;	General procedure: To the solution of substituted cinnamic acids (14a-o, 1.1 mmol) in dry dichloromethane was added the oxalyl chloride (3mmol) and a catalytic amount of N,N-dimethyl formamide(1 mol%) at 0 C and stirred for 3 h at room temperature. After completion of reaction excess of solvent and oxalyl chloride were removed under reduced pressure to get respected acid chlorides (15a-o). Acid chlorides (15a-o)were dissolved in dry tetrahydrofuran and added to the stock solutions of 2? amino Z- combretastatin A4 (13, 1.0 mmol) and triethylamine (3 mmol) in dry tetrahydrofuran at 0 C and stirred at room temperature for 12 h. After completion of reaction, the reaction mixturewas diluted with ethyl acetate and washed with water, brine solution, dried over sodium sulphate,filtered and filtrate was concentrated under reduced pressure to get crude compounds.Crude compounds weredissolved in dry THF and added the TBAF (1.0 M in THF, 2.5 mmol) at 0 C and stirred at room temperature for 1h. After completion of reaction monitored by TLC the reaction mixture was diluted with ethyl acetate and washed with water ,brine solution, dried over sodium sulphate,filtered and filtrate was concentrated under reduced pressure to get crude compound.Crude compound waspurified by column chromatography using ethyl acetate and hexane as elutents to afford respectedZ-2?-(cinnamamide)combretastatin A4 derivatives.
	With thionyl chloride; for 1.5h;Reflux;	General procedure: Cinnamic acid (10.0g, 0.067mol) solution in thionyl chloride (100ml, 20equiv) was refluxed for 1.5h, and then evaporated under reduced pressure. The crude product was used in the next step without further purification.
	With thionyl chloride; In dichloromethane; for 4h;Inert atmosphere; Reflux;	General procedure: To a solution of the corresponding acid (3 mmol) in dry CH2Cl2 (6 mL) was added thionyl chloride (0.65 mL, 9 mmol). The mixture was heated to reflux for 4 h under dry condition. The solvent was removed under reduced pressure to give the corresponding acyl chloride. The crude product was used to the next step without further purification.
	With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 20℃; for 3h;	General procedure: A solution of CA or CAD (1 equiv.), thionyl chloride (5 equiv.) and two drops of DMF in drytoluene was stirred at room temperature for 3 h. Solvent was evaporated. The residue
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 3h;Inert atmosphere; Reflux;	General procedure: Thionyl chloride (2 equiv) was added dropwise to the requisite carboxylicacid (1 equiv) in anhydrous CH2Cl2 (1.1 M) and DMF (fewdrops) at 0 C, and the resultant mixture was stirred and heated at refluxfor 3 h. The solution was cooled to r.t. and the solvent was concentratedin vacuo to afford the product(s), which was used directlywithout further purification.
	With thionyl chloride; at 20 - 85℃; for 3h;Inert atmosphere;	General procedure: Synthesis of amides from the carboxylic acid: A 100 mL round bottom flask was charged with carboxylic acid (11 mmol) to which thionyl chloride (10 mL) was added dropwise under flow of argon at room temperature. The reaction mixture was refluxed for 3 h at 85 C, then the excess SOCl2 was removed in vacuo to afford the crude acid chloride on one hand, whereas in another flask solution of 8-aminoquinoline (10 mmol) and NEt3 (11 mmol) in dichloromethane (20 mL) was stirred for 10-15 minutes. Deprotonated amine was added to a solution of acid chloride at 0 C. The reaction was allowed to warm to room temperature and stirred overnight for complete conversion. Upon completion, it was quenched with saturated NaHCO3 solution and extracted with CH2Cl2 three times. These extracts were combined and dried over NaSO4. After evaporation in vacuum, the crude amide product was purified by flash column chromatography (Hexane: ethyl acetate 10:1) through silica gel.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 3h;	Step 2: a) Trans-3-(4-trifluoromethyl-phenyl)-acryloyl chloride To a cold (O0C) solution of trans-4-trifluoromethylcinnamic acid (6 g) in a mixture of DCM (20 ml.) and DMF (few drops) was added dropwise oxalyl chloride (2.6 ml_, 1.1 equivalents). The reaction mixture was stirred at 00C for 3 h and concentrated in vacuo to yield the crude title compound as a beige solid (6.5 g, 99%).
	With thionyl chloride; at 20℃; for 1h;	General procedure: The different substituted cinnamic acid derivatives (1, 5 mmol) were dissolved in SOCl2 (10 mL) and stirred in room temperature for 1 h. The solution was concentrated under vacuum to obtain product 2 as yellow oil. The corresponding cinnamic acid chloride was dissolved in dry dichloromethane (5 mL). The solution was added dropwise to a solution of piperazine prepared from piperazine (10 mmol) dissolved in glacial acetic acid (20 mL). The reaction solution was adjusted to pH 7-9 by 40% NaOH, and then extracted with dichloromethane (3 ). The organic phase was washed with saturated sodium chloride (3 ). The organic layer was separated and dried over anhydrous magnesium sulphate,filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with dichloromethane methanol(50:1) to give the desired product 3a-3h.

Reference： [1]Patent: US2007/259936,2007,A1 .Location in patent: Page/Page column 167; 171
[2]Organic Process Research and Development,2015,vol. 19,p. 1774 - 1783
[3]Molecules,2016,vol. 21
[4]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5726 - 5732
[5]Patent: US2011/281869,2011,A1 .Location in patent: Page/Page column 36
[6]Journal of Medicinal Chemistry,2004,vol. 47,p. 3282 - 3294
[7]European Journal of Medicinal Chemistry,2018,vol. 149,p. 56 - 68
[8]Journal of Materials Chemistry,2004,vol. 14,p. 3468 - 3473
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[11]Helvetica Chimica Acta,2002,vol. 85,p. 3616 - 3623
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[16]Patent: US2007/173506,2007,A1 .Location in patent: Page/Page column 77
[17]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1918 - 1927
[18]Patent: EP1350792,2003,A1 .Location in patent: Page/Page column 29
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2
[ 2062-26-2 ]
[ 53473-36-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen;5%-palladium/activated carbon; In methanol; under 1500.15 Torr;	A solution of 4-thfluoromethylcinnamic acid (commercial available) in methanol is hydrogenated with Pd/C (5 wt%) at 2 bar until 4-trifluoromethylcinnamic acid has reacted completely. After removal of the catalyst by filtration the 4-thfluoromethylhydrocinnamic acid is further reacted in step 2 to compound 2.
	With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; methanol; at 20℃; for 10h;	(11-1) Synthesis of 3-(4-trifluoromethylphenyl)-1-propanol (compound 11-1) 4-Trifluoromethylcinnamic acid (10.0 g) was dissolved in methanol (20 ml) and tetrahydrofuran (50 ml), 10% palladium carbon (5.00 g) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hr. The reaction container was purged with nitrogen, the solution was filtered, and the filtrate was concentrated to give a colorless powder (10.5 g). The colorless powder was dissolved in tetrahydrofuran (100 ml), and a tetrahydrofuran-borane tetrahydrofuran solution (1 mol/l, 59.5 ml) was added dropwise to the mixture under ice-cooling, and the mixture was stirred under ice-cooling for 30 min, and further at room temperature for 16 hr. To the reaction mixture was added water, 1 mol/l aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (9.53 g) as a colorless oil. 1H-NMR(CDCl3) delta (ppm): 1.54(1H, brs), 1.87-1.94(2H, m), 2.78(2H, t, J=7.7Hz), 3.68(2H, t, J=6.3Hz), 7.31(2H, d, J=8.0Hz), 7.54(2H, d, J=8.0Hz).

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 6137 - 6140
[2]Bioorganic and Medicinal Chemistry Letters,2000,vol. 10,p. 1519 - 1522
[3]Patent: WO2009/83899,2009,A2 .Location in patent: Page/Page column 6; 17
[4]Patent: EP2168944,2010,A1 .Location in patent: Page/Page column 47-48
[5]Organic Process Research and Development,2013,vol. 17,p. 1531 - 1539

3
[ 64-17-5 ]
[ 2062-26-2 ]
[ 101466-85-7 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuric acid; for 19h;Reflux;	In a 100 mL round-bottomed flask were added (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (2 g, 9.25 mmol) and sulfuric acid (0.200 ml, 3.75 mmol) in anhydrous ethanol (20.00 ml) to give a white suspension. Heated to reflux and stirred 19 hours. Concentrated the reaction mixture to dryness. The residue was neutralized with sat. NaHCC>3 (15 mL). Extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (15 mL). The organic layer was dried over MgSC , filtered and concentrated to give (E)-ethyl 3-(4-(trifl uoromethy I) phen yi)acry late (2.20 g, 9.01 mmol, 97 % yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 7.95 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 16.0 Hz, 1 H), 6.79 (d, J = 16.0 Hz, 1 H), 4.21 (q, J = 7.0 Hz, 2H), 1.27 (t, J = 7.0 Hz, 3H).

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Angew. Chem.,2016,vol. 128,p. 15603 - 15607,5

4
[ 455-19-6 ]
[ 141-82-2 ]
[ 2062-26-2 ]

Yield	Reaction Conditions	Operation in experiment
92%	With piperidine; pyridine;	General procedure: A mixture of malonic acid (1.61g, 11.5 mmol), the desired aldehyde 2a-d (5.7 mmol) and a catalytic amount of piperidine (0.1 mL) was heated in a solution of pyridine (5 mL) at reflux for 2 h. The resultant mixture was poured into ice and a solution of 2 M HCl aq. was added dropwise. The formed solid was collected by filtration, washed with water and purified by flash column chromatography eluting with n-hexane:EtOAc 100:0 v/v, increasing to 80:20 v/v to give the title compound.
90 - 96%		Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acid A solution of 4-trifluoromethylbenzaldehyde (7.7 mL, 57.7 mmol), malonic acid (12.0 g, 115.4 mmol), 0.567 muL piperidine (5.75 mmol) in 30 mL of pyridine was stirred at 70 C. for 18 h. The reaction solution was cooled to room temperature. Water (300 mL) was added and the resulting mixture was acidified to pH 4 (litmus) using concentrated hydrochloric acid to give a precipitate. The solid was filtered, and washed with water until the filtrate was neutral. The solid product was dried in vacuo to give the title Compound 10a as a white powder (11.2 g, 90%). 1HNMR (400 MHz, DMSO-d6) delta (ppm): 12.60 (bs, 1H), 7.92 (d, 2H, J=8.2 Hz), 7.77 (d, 2H, J=8.2 Hz), 7.66 (d,1 H, J=16.0 Hz), 6.70 (d,1H, J=16.0 Hz). Step A. 3-(4-trifluoromethyl-phenyl)-acrylic acidA 2-L 4-neck round bottom flask equipped with an air condenser/argon inlet, mechanical stirrer, thermocouple and a stopper was charged with 4-(trifluoromethyl)benzaldehyde (250 g, 196.2 mL, 1.44 mol), malonic acid (302.6 g, 2.87 mol), and pyridine (750 mL). An exotherm developed (about 38-40 C.), which was maintained for 30 min. Piperidine (14.202 mL, 143.58 mmol) was then added to the reaction and a second exotherm developed (Tmax about 42 C. after about 10 min.). The reaction was stirred for 30 min and then heated to 60 C. for 18 h (overnight). The reaction appeared to be complete by TLC, and was cooled to about 40 C., diluted into water (2 L; done to prevent reaction freezing), cooled to room temperature, and further diluted with water (4 L, 6 L total). The slurry was acidified to pH=2.0-3.0 with concentrated hydrochloric acid (about 675-700 mL). The material was stirred for 30 min., and a white solid was collected by filtration. The filter cake was washed with water until the filtrate was neutral (pH about 5.5-6, 2.5 L), air-dried in a Buchner funnel for 2 h, and then further dried in a vacuum oven at 60 C. overnight to provide 300.5 g (96%) of the title Compound 10a as a white solid.
		General procedure: To a solution of malonic acid (200 mmol) in pyridine (60 mL) was added aldehyde (150 mmol), the heterogeneous mixture was stirred at room temperature for several minutes. Piperidine (2.0 mL) was then added, and the mixture was heated to 80 C slowly (about 30 min should be allowed for this period). After the reaction mixture was refluxed at 80 deg;C for 4-5 h, it was finally heated under reflux (110-115 C) for additional 8 h. The reaction mixture was allowed to cool to room temperature, and then it was acidified by slowly pouring into hydrochloric acid (1.5 N, 90 mL) with stirring. The solid was separated by suction filtration and washed with cold water (3 times). The solid was then dried at 60 C. It could be purified by recrystallization from methyl ethyl ketone (12 mL/1 g). The hot solution was then filtered rapidly through a steam-heated Buechner funnel and chilled for several hours. The pure product could be obtained after filtration and drying.

	With piperidine; pyridine; for 3h;	General procedure: To a mixture of the corresponding aldehyde (10 mmol), pyridine (6 mL) and piperidine (0.6 mL) was added malonic acid (1.25 g, 12 mmol). The mixture was stirred for 3 h at 90-100 C, then cooling to room temperature. The reaction mixture was neutralized with hydrochloric acid solution (10 mol/L, 80 mL) at 0 C. The white solid was filtered, washed with cold water, and dried to afford the corresponding acid.
	With piperidine; pyridine; at 90℃;Inert atmosphere;	General procedure: To a stirred solution of malonic acid (10 mmol) in pyridine(5 mL) and piperidine (3-5 drops) the corresponding aldehydes1a-p (8 mmol) were added. The resulting mixture was stirred at 90C for 8-12 h. The progress of the reaction was monitored byTLC analyses which indicated the disappearance of the starting material. After the completion of the reactions the reaction mixture were cooled to ambient temperature and the reaction mixture was neutralized with 1N HCl in ice bath resulting a white solid.This soled was filtered and washed three times with cold water.The recrystallization were done from aqueous ethanol (1:1)afforded the product 2a-p.
	With pyridine; at 90℃;	General procedure: 7a-u were prepared by Knoevenagel condensation [45]. Briefly, 5mmol of different aldehydes (6a-u) and 10mmol malonic acid (1.04g) were stirred at 90C in 2mL pyridine solvent overnight. When the reaction was finished as monitored by TLC, 3M HCl was slowly dropped into the mixture until precipitation was complete. The formed precipitate was collected by filtration, washed with cold water and dried in vacuum, yielding compounds 7a-u. Intermediates 7c and 7d (1mmol) was further reacted with different substituted benzyl bromides (2.5mmol) in CH3CN with the presence of K2CO3 (2.0 equiv), followed by hydrolysis in 1M NaOH for 1h to give intermediates 7v-z, which were used in the next step without further purification.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 149,p. 56 - 68
[2]Patent: US2007/259936,2007,A1 .Location in patent: Page/Page column 166-167; 171
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 3859 - 3874
[4]Journal of Medicinal Chemistry,2019,vol. 62,p. 7264 - 7288
[5]Molecular Crystals and Liquid Crystals,2010,vol. 528,p. 138 - 146
[6]Tetrahedron Letters,2011,vol. 52,p. 4906 - 4910
[7]Chemical Biology and Drug Design,2013,vol. 81,p. 275 - 283
[8]MedChemComm,2015,vol. 6,p. 1036 - 1042
[9]Journal of Medicinal Chemistry,2015,vol. 58,p. 5242 - 5255
[10]PLoS ONE,2015,vol. 10
[11]European Journal of Medicinal Chemistry,2017,vol. 126,p. 517 - 525
[12]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 5726 - 5732
[13]European Journal of Medicinal Chemistry,2018,vol. 143,p. 361 - 375

5
[ 2062-26-2 ]
[ 125617-18-7 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 4593 - 4607
[2]Canadian Journal of Chemistry,2006,vol. 84,p. 1146 - 1154
[3]Journal of the American Chemical Society,2005,vol. 127,p. 17192 - 17193
[4]Journal of Medicinal Chemistry,2004,vol. 47,p. 3282 - 3294
[5]Journal of Organic Chemistry,2001,vol. 66,p. 4619 - 4624
[6]Organic and Biomolecular Chemistry,2015,vol. 13,p. 4255 - 4259
[7]Chemistry - A European Journal,2015,vol. 21,p. 7030 - 7034
[8]Advanced Synthesis and Catalysis,2015,vol. 357,p. 2442 - 2446
[9]Angewandte Chemie - International Edition,2016,vol. 55,p. 15377 - 15381
Angew. Chem.,2016,vol. 128,p. 15603 - 15607,5

6
[ 2062-26-2 ]
[ 115093-99-7 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ammonium hydroxide; thionyl chloride; In N-methyl-acetamide; toluene;	Reference Example 5 Production of 4-(trifluoromethyl)cinnamamide 4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added to toluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3 ml, 361 mmol) was added dropwise at room temperature. The mixture was heated at 45 C. for 2 hours. The obtained reaction mixture was added dropwise to 25% aqueous ammonia (325 ml) while keeping the mixture at 5-20 C. The mixture was stirred at room temperature for 1 hour. The crystals were filtered, washed with water and isopropyl ether and dried under reduced pressure to give 4-(trifluoromethyl)-cinnamamide (60.76 g, yield 94%). H-NMR (CDCl3-DMSO-d6, delta, 300 MHz) 5.93(1H,s), 6.53(1H,d,J=15.8 Hz), 6.75(1H,s), 7.48-7.53(5H,m).
94%	With ammonium hydroxide; thionyl chloride; In N-methyl-acetamide; toluene;	Reference Example 14 Production of 4-(trifluoromethyl)cinnamamide 4-(Trifluoromethyl)cinnamic acid (64.85 g, 300 mmol) was added in toluene (325 ml) and dimethylformamide (2.2 ml). Thionyl chloride (26.3 ml, 361 mmol) was added dropwise at room temperature, and the mixture was heated at 45 C. for 2 hours. The obtained reaction mixture was added dropwise to 25% aqueous ammonia (325 ml) while keeping the mixture at 5-20 C. The mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with 20 water and isopropyl ether and dried under reduced pressure to give 4-(trifluoromethyl)cinnamamide (60.76 g, yield 94%). 1H-NMR (CDCl3-DMSO-d6, delta, 300 MHz) 5.93(1H,s), 6.53(1H,d,J=15.8 Hz), 6.75(1H,s), 7.48-7.53(5H,m).
	With ammonium hydroxide; thionyl chloride; In N,N-dimethyl-formamide; toluene;	Reference Example 17 (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenamide (E)-3-(4-(Trifluoromethyl)phenyl)-2-propenoic acid (2400 g, 11.1 mol) and DMF (N,N-dimethylforrnamide)(82 ml) were added to toluene (12 L). SOCl2 (52.6 mL, 721 mmol) was added dropwise at room temperature and the mixture was stirred at 45-50 C. for 1 hour. The toluene solution cooled to room temperature was added dropwise to 25% aqueous ammonia (12L) at 5-25 C. The mixture was stirred at 45-55 C. for 1 hour. After allowing to cool to room temperature and stirring, the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water (12 L) and dried under reduced pressure to give (E)-3-(4-(trifluoromethyl)phenyl)-2-propenamide (2293 g, 10.7 mol, yield 96%). 1H-NMR (DMSO-d6, delta, 300 MHz) 6.72(1H,d,J=16.1 Hz), 7.20(1H,s), 7.46(1H,d,J=15.9 Hz), 7.62(1H,s), 7.67-7.83(4H,m).

Reference Example 14-chloromethyl-2-[(E)-2-(4-trifluoromethylphenyl)ethenyl]-1,3-oxazole [59.1] (i) (E)-3-(4-trifluoromethylphenyl)-2-propenamide To a suspension of 4-trifluoromethylcinnamic acid (19.4 g), and DMF (6 drops) in THF (100 ml), oxalyl chloride (11.7 ml) was added at 0 C, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (60 ml) and poured into a mixture of 25% aqueous ammonia-ethyl acetate (5:1, 120 ml). The water layer was salted out; the organic layer was extracted with ethyl acetate-THF (12:1, 650 ml) and ethyl acetate (100 ml x 2). The extract was dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the titled compound (18.0 g) as colorless plate crystals.1H-NMR (CDCl3) delta: 5.58 (2H, br s), 6.53 (1H, d, J = 15.8 Hz), 7.63-7.72 (5H, m). IR (KBr): 3326, 3167, 1686, 1636, 1617, 1404, 1190 cm-1.

Reference： [1]Patent: US2003/69419,2003,A1
[2]Patent: US2003/69419,2003,A1
[3]Patent: US2003/69419,2003,A1
[4]Patent: EP1439178,2004,A1 .Location in patent: Page 24

7
[ 2062-26-2 ]
[ 101466-85-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuric acid; In ethanol;	(a) Ethyl 4-trifluoromethylcinnamate 4-Trifluoromethylcinnamic acid (10.2 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (10.9 g, 95%) as a colorless oil.
	With sulfuric acid; In ethanol;	EXAMPLE 5 Preparation of 4-nitro-3-(4-trifluoromethylphenyl)heptanedioic acid ethyl, methyl ester A suspension of 300 g of 4-trifluoromethylcinnamic acid (J. Org. Chem. 43:980 (1978)) and 25 ml of concentrated sulfuric acid in 1.7 liters of ethanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-trifluoromethylcinnamic acid ethyl ester, mp 40-41 C. NMR (CDCl3) delta=7.83 (m, 4H); 7.68 (d, J=15 Hz, 1H); 6.75 (d, J=15 Hz, 1H); 4.19 (q, J=6 Hz, 2H); 1.20 (t, J=6 Hz, 3H). IR (cm-1) 2980, 1715, 1644, 1479, 1442, 1368, 1336.
	With sulfuric acid; In ethanol;	EXAMPLE 6 Preparation of 4-nitro-3-(4-trifluoromethylphenyl)heptanedioic acid ethyl, methyl ester A suspension of 300 g of 4-trifluoromethylcinnamic acid (J. Org. Chem. 43:980 (1980) and 25 ml of concentrated sulfuric acid in 1.7 liters of ethanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-trifluoromethylcinnamic acid ethyl ester, mp 40-41 C. NMR (CDCl3) delta=7.83 (m, 4H); 7.68 (d, J=15 Hz, 1H); 6.75 (d, J=15 Hz, 1H); 4.19 (q, J=6 Hz, 2H); 1.20 (t, J=6 Hz, 3H). IR (cm-1) 2980, 1715, 1644, 1479, 1442, 1368, 1336.

Reference： [1]Patent: US6005116,1999,A
[2]Patent: US4584313,1986,A
[3]Patent: US4548947,1985,A

8
[ 103-82-2 ]
[ 917351-49-6 ]
[ 104-01-8 ]
[ 140-10-3 ]
[ 1929-29-9 ]
[ 943-89-5 ]
[ 32857-62-8 ]
[ 2062-26-2 ]
[ 53473-36-2 ]
[ 637-44-5 ]
[ 501-52-0 ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]cinnamic amide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-3-phenylpropiolic amide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-2-phenylacetamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-2-(4-trifluoromethylphenyl)acetamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-2-(4-methoxyphenyl)acetamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-3-phenylpropionamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-3-(4-trifluoromethylphenyl)propionamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-3-(4-methoxyphenyl)propionamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-4-(trifluoromethyl)cinnamamide [ No CAS ]
N-[3-dimethylamino-1-(4-methylphenyl)propyl]-4-methoxycinnamamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%; 100%; 93%; 98%; 93%; 96%; 78%; 98%; 56%; 87%	With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h;	Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction.

Reference： [1]Patent: WO2006/135694,2006,A2 .Location in patent: Page/Page column 71-73

9
[ 103-82-2 ]
[ 917351-50-9 ]
[ 104-01-8 ]
[ 140-10-3 ]
[ 1929-29-9 ]
[ 943-89-5 ]
[ 32857-62-8 ]
[ 2062-26-2 ]
[ 53473-36-2 ]
[ 637-44-5 ]
[ 501-52-0 ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-2-(4-trifluoromethylphenyl)acetamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-2-(4-methoxyphenyl)acetamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-2-phenylacetamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-3-phenylpropionamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-3-(4-trifluoromethylphenyl)propionamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-3-(4-methoxyphenyl)propionamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]cinnamamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-4-(trifluoromethyl)cinnamamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-4-methoxycinnamamide [ No CAS ]
N-[3-dimethylamino-1-(2-naphthyl)propyl]-3-phenylpropiolamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%; 79%; 67%; 66%; 84%; 94%; 76%; 100%; 100%; 100%	With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h;	Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction.

Reference： [1]Patent: WO2006/135694,2006,A2 .Location in patent: Page/Page column 71-73

10
[ 885672-69-5 ]
[ 103-82-2 ]
[ 104-01-8 ]
[ 140-10-3 ]
[ 1929-29-9 ]
[ 943-89-5 ]
[ 32857-62-8 ]
[ 2062-26-2 ]
[ 53473-36-2 ]
[ 637-44-5 ]
[ 501-52-0 ]
[ 885673-16-5 ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-2-(4-trifluoromethylphenyl)acetamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-2-(4-methoxyphenyl)acetamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-3-phenylpropionamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-3-(4-trifluoromethylphenyl)propionamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-3-(4-methoxyphenyl)propionamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]cinnamamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-4-(trifluoromethyl)cinnamamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-4-methoxycinnamamide [ No CAS ]
N-[1-(4-chlorophenyl)-3-dimethylaminopropyl]-3-phenylpropiolamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92 - 94%; 96%; 96%; 92%; 83%; 81%; 83 - 97%; 97%; 83%; 100%	With polyvinylpyridine polymer-supported dimethylaminopyridine; PS-carbodiimide; In dichloromethane; at 20℃; for 96h;	Example 4: Alternative Synthesis of Amides[0237] The appropriate amine (1 eqv, 50 mg), PS-DCC (2 eqv), PS-DMAP (0.2 eqv), carboxylic acid (5 eqv) and DCM (15 ml) were added to a vial and shaken at room temperature for four days. The mixture was then filtered and the solute was concentrated. 1H- NMR spectra were run to control that the reactions were complete. The crude product was then dissolved in CH2Cl2 (20 ml) and washed with IM NaOH (2 x 15 ml). The CH2Cl2-phase was then concentrated. 1H-NMR spectra were run to control the purity. If the product was not pure (>98% purity) ion exchange chromatography (SCX-2) was used for the final purification. The pure product was then converted to the corresponding HCl salt using HCl saturated ether.AU reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1H NMR spectroscopy. AU yields >100% are mainly due to remaining carboxylic acid in the sample. EPO <DP n="75"/>Example 5: Miniaturization of the Alternative Synthesis of Amides[0270] To check the robustness of the alternative method and to enable the production of larger libraries, the reaction was scaled down linearly from 50 mg to 25 and 5 mg of the starting amine, respectively. Table 2 is a summary of the miniaturization experiments. As seen in Table 2, this was accomplished without problems as both the yields and purities were in the same range as for the 50 mg reactions.TABLE 2 MINIATURIZATION EXPERIMENTS[0271] All reactions were run to 100% conversion according to 1H NMR spectroscopy. Purities were determined by 1HNMR spectroscopy after basic extraction.

Reference： [1]Patent: WO2006/135694,2006,A2 .Location in patent: Page/Page column 71-73

11
[ 2062-26-2 ]
[ 18107-18-1 ]
[ 20754-22-7 ]

Yield	Reaction Conditions	Operation in experiment
99%	In methanol; hexane; benzene; at 0 - 20℃; for 0.5h;	A solution of TMSCHN2 (2.0 M in hexanes, 1.6 eq) was added dropwise with stirring to a 0 C. solution of the (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (0.25 M) in benzene:methanol (2:1). The reaction was allowed to warm to rt over the course of 0.5 h. Concentration of the reaction mixture afforded the desired (E)-methyl 3-(4-trifluoromethyl)phenyl)acrylate as a white solid in 99% yield (0.898 g). 1H NMR (300 MHz, CDCl3): delta7.69 (1H, d, J=15.9 Hz), 7.62 (4H, m), 6.50 (1H, d, J=15.9 Hz), 3.87 (3H, s). 13C NMR (75 MHz, CDCl3): delta167.0, 143.2, 138.0, 128.4, 126.1, 126.0, 120.6, 52.1.
99%	In methanol; hexane; benzene; at 0 - 20℃; for 0.5h;	A solution of TMSCHN2 (2.0 M in hexanes, 1.6 eq) was added dropwise with stirring to a 0 C. solution of the (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (0.25 M) in benzene:methanol (2:1). The reaction was allowed to warm to rt over the course of 0.5 h. Concentration of the reaction mixture afforded the desired (E)-methyl 3-(4-trifluoromethyl)phenyl)acrylate as a white solid in 99% yield (0.898 g). 1H NMR (300 MHz, CDCl3): delta7.69 (1H, d, J=15.9 Hz), 7.62 (4H, m), 6.50 (1H, d, J=15.9 Hz), 3.87 (3H, s). 13C NMR (75 MHz, CDCl3): delta167.0, 143.2, 138.0, 128.4, 126.1, 126.0, 120.6, 52.1.

Reference： [1]Patent: US2013/178520,2013,A1 .Location in patent: Paragraph 0215; 0216; 0217
[2]Patent: US2014/343118,2014,A1 .Location in patent: Paragraph 0298-0299
[3]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 3047 - 3051

12
[ 2062-26-2 ]
[ 37073-15-7 ]
[ 1334172-20-1 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4906 - 4910

13
[ 2062-26-2 ]
[ 37073-15-7 ]
[ 1334172-12-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In tetrahydrofuran; at 70℃;	General procedure: A mixture of alpha,beta-unsaturated aromatic or aliphatic acid (10 mmol), CH3SO2Bt (10 mmol) and Et3N (15 mmol) were refluxed in dry THF (50 mL) overnight. The solvent was evaporated and the residue was dissolved in CH2Cl2 (100 mL). The organic phase was washed with brine (3 times) and dried over anhydrous Na2SO4. The organic phase was concentrated under vacuum to give a crude product, which could be further purified by recrystallization from a proper solvent.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 4906 - 4910

14
[ 2062-26-2 ]
anti-2,3-dibromo-3-(4-trifluoromethyl)propanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With copper(II) nitrate trihydrate; trimethylsilyl bromide; In acetonitrile; at 50℃; for 2h;	General procedure: In a pressure tube, to a solution of alpha,beta-unsaturated carboxylic acid (0.5 mmol, 1 equiv) and copper(II) nitrate trihydrate (60.4 mg, 0.25 mmol, 0.5 equiv) in 3 mL dry acetonitrile, bromotrimethylsilane (306.18 mg, 2 mmol, 4 equiv) was added. The reaction mixture was stirred vigorously at 50C for 2 h (in case of ortho substituted compounds, the reaction mixture was stirred for 3 h). After neutral aqueous work-up, organics were extracted by dichloromethane. Organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure. Upon recrystallization from hexane, the corresponding products were obtained in pure form in good yields.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2842 - 2845
[2]Chinese Journal of Chemistry,2011,vol. 29,p. 2350 - 2354

15
[ 2062-26-2 ]
[ 155252-35-0 ]
[ 1357099-18-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;	General procedure: To a solution of compound 12 (1.0 mmol) in dichloromethane (20 ml) was added EDCI.HCl (1.1 mmol) and HOBt (0.1 mmol). Then added corresponding chalcone acids (11a-h) (1.0 mmol) and the reaction mixture was stirred at room temperature for 24 h. The reaction was monitored by TLC. After completion of reaction, water was added to reaction mixture and extracted with dichloromethane (2 × 30 ml). The solvent was evaporated under reduced pressure to afford the crude product which was further purified by column chromatography on silica gel using ethyl acetate and hexane as solvent system to obtain the pure products as solids.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 47,p. 530 - 545

16
[ 1322088-10-7 ]
[ 2062-26-2 ]
[ 1403877-24-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 24h;	General procedure: To a 50 mL round bottom flask equipped with a magnetic stir bar was added N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (EDCI) (0.13 mmol), 4-dimethylaminopyridine (DMAP) (0.01 mmol), acid (8a-k, 8m-q, 0.11 mmol), alcohol (7a or 7b, 0.1 mmol) and CH2Cl2 (15 mL), and the reaction mixture was stirred at room temperature for 24 h. Acetic acid (0.5 mL) was added and the reaction mixture was stirred for 10 min to convert excess alcohol 7 to a more easily separable acetate. The mixture was washed with saturated aqueous NH4Cl solution, diluted with Et2O (15 mL), and the layers were separated. The aqueous layer was extracted with Et2O (2×10 mL), and the combined organic layers were dried, filtered and concentrated under reduced pressure. The crude material was chromatographed on SiO2 (petroleum ether and ethyl acetate (7:1) as eluent).

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 62,p. 148 - 157

17
[ 2062-26-2 ]
[ 68-12-2 ]
[ 21469-76-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With tert.-butylhydroperoxide; copper diacetate; In 1,1,2-trichloroethane; at 90℃; for 12h;	General procedure: To a solution of carboxylic acids 1 (0.1 mmol) in TCE (1.0 mL) was added Cu(OAc)2 (5 mol%) and N, N-disubstituted formamides 2 (0.5 mmol), followed by adding a solution of TBHP (2.0 equiv.). The resulting mixture was stirred at 90 oC until it completed. When the reaction was finished, the reaction mixture was cooled to room temperature and poured into saturated Na2S2O3 solution (3.0 mL), extracted with EtOAc (3×8.0 mL), then washed with saturated brine. The combined organic layers were dried over anhydrous Na2SO4. After removing the solvents in vacuo, the residue was purified by flash column chromatography on silica gel or preparative TLC on GF 254 to afford the desired products 3.
77%	With di-tert-butyl peroxide; copper(II) sulfate; at 140℃; for 12h;Schlenk technique; Inert atmosphere;	General procedure: CuSO4 (0.06 mmol) and cinnamic acid (0.3 mmol) were added to a Schlenk tube equipped with a magnetic stir bar under argon atmosphere. Then N-substituted formamide (2.0 mL) and DTBP (di-tert-butyl peroxide, 0.6 mmol) were added under Ar. The resulting reaction mixture was kept stirring until TLC monitoring indicated the complete disappearance of the starting material. At the end of the reaction, the reaction mixture was cooled to room temperature and was diluted with ethyl acetate and water was added. The combined organic phase was dried over anhydrous Na2SO4. After removal of the solvent, the residue was subjected to column chromatography on silica gel using ethyl acetate and petroleum ether mixtures to afford the corresponding product.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 6679 - 6681
[2]Tetrahedron,2013,vol. 69,p. 7258 - 7263

18
[ 2062-26-2 ]
[ 99696-01-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With chloro-trimethyl-silane; copper(II) nitrate trihydrate; In acetonitrile; at 100℃; for 2h;	General procedure: In a pressure tube, to a solution of alpha,beta-unsaturated carboxylic acid (0.5 mmol, 1 equiv) and copper(II) nitrate trihydrate (423 mg, 1.75 mmol, 3.5 equiv) in dry acetonitrile (3 mL), chlorotrimethylsilane (65 mg, 0.6 mmol, 1.2 equiv) was added. The reaction mixture was stirred vigorously at 100 C for 2 h. The reaction was quenched with saturated sodium bicarbonate solution and organics were extracted using dichloromethane. Organic layer was dried over sodium sulfate and the solvent was removed under reduced pressure, giving the corresponding products in pure form in excellent yields.
89%	With copper(II) nitrate; In acetonitrile; at 110℃; for 8h;Sealed tube; Green chemistry;	General procedure: A 25-mL Schlenk tube was charged with alpha,beta-unsaturated acid (0.4 mmol), Cu(NO3)2 (0.48 mmol), and CH3CN (2 mL). The tube was sealed, then the mixture was stirred under air at 110 C for 8 h. After completion of the reaction as monitored by thin-layer chromatography (TLC), H2O (5 mL) was added. The mixture was extracted with dichloromethane (3 X 4 mL). The combined organic layers were washed with saturated sodium bicarbonate solution (10 mL) and water (10 mL), dried over anhydrous Na2SO4, then concentrated by rotary evaporator. Finally, the residue was purified by column chromatography on silica gel (mobile phase: petroleum ether/ethyl acetate 6:1) to provide the desired products (3). (E)-(2-Nitrovinyl)benzene (3a) [18, 19, 21]

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 2842 - 2845
[2]Research on Chemical Intermediates,2016,vol. 42,p. 6079 - 6087
[3]Organic and Biomolecular Chemistry,2013,vol. 11,p. 6713 - 6716

19
[ 2062-26-2 ]
1-acetoxy-6α-hydroxy-4αH-1,10-secoeudesma-5(10),11(13)-dien-12,8β-olide [ No CAS ]
[ 1613152-43-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; triethylamine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;	General procedure: To a suspension of a corresponding acid (pelargonic acid for 12, capric acid for 13, lauric acid for 14, myristic acid for 15, stearic acid for 16, p-bromocinnamic acid for 17, p-trifluoromethylcinnamic acid for 18) (0.2 mmol), DMAP and DCC in anhydrous CH2Cl2 (1 mL) was added ABL (0.1 mmol) in anhydrous CH2Cl2 (1 mL) solution. After completion of the reaction from 5 to 20 h at room temperature, water (2 mL) was added to the mixture and stirred for 20 min, then extracted with CH2Cl2, dried and filtered. After removal of the solvent, the crude product was purified by silica gel chromatography (EtOAc/PE) to afford analogues 12-18 in the yield from 65% to 83%.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 80,p. 71 - 82

20
[ 1188382-13-9 ]
[ 2062-26-2 ]
(3S,6R,8S)-6-hydroxy-3,6,9-trimethyl-2-oxo-2,3,3α,4,5,6,6α,7,8,9β-decahydroazuleno[4,5-β]furan-8-yl (E)-3-(4-(trifluoromethyl)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%		General procedure: To a solution of compound 5 (20 mg, 0.075 mmol) and acid (0.075 mmol) in DCM (10 mL) at room temperature was added DMAP (18.3 mg, 0.15 mmol). After stirring for 10 min, EDCI (71.9 mg, 0.34 mmol) was added in one portion. The reaction was allowed to stir overnight. Then, water (15mL) was added. The reaction mixture was extracted with DCM (3·10mL). The organic layer was then washed with brine, dried over Na2SO4, and concentrated in vacuum. Purification by flash column chromatography (PE: EtOAc=4:1) provided the derivatives of interest.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 83,p. 307 - 316

21
[ 2062-26-2 ]
[ 3832-75-5 ]

Reference： [1]Angewandte Chemie - International Edition,2014,vol. 53,p. 4652 - 4656
Angew. Chem.,2014,vol. 126,p. 4740 - 4744,5

22
[ 2062-26-2 ]
[ 873-55-2 ]
[ 855298-16-7 ]

Yield	Reaction Conditions	Operation in experiment
51%	With tert.-butylhydroperoxide; iodine; In water; toluene; at 90℃; for 12h;	General procedure: A 25 mL tube was charged with cinnamic acid (0.3 mmol), sodiumbenzene sulfinate (1.2 mmol), iodine (2 equiv), TBHP in H2O(0.6 mmol) and toluene (2 mL). The resulting reaction mixture waskept stirring at 90 C for 12 h. Upon completion of the reaction, thereaction mixturewas cooled to room temperature. After removal ofthe solvent, the residue was subjected to column chromatographyon silica gel using ethyl acetate and petroleum ether mixtures toafford the desired product in high purity.

Reference： [1]Organic and Biomolecular Chemistry,2019,vol. 17,p. 5578 - 5585
[2]Tetrahedron,2015,vol. 71,p. 5059 - 5063

23
[ 372-19-0 ]
[ 2062-26-2 ]
(E)-3-(4-(trifluoromethyl)phenyl)-N-(3-fluorophenyl)-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: To an anhydrous THF solution at 78 C in dry ice and acetonebath) of the acids was added N-methylmorpholine (NMM)(1.5 equiv), stirred for 2 min, isobutylchloroformate (IBCF)(1.27 equiv), stirred for 5 min. The reaction mixture was treatedwith the desired anilines (1.2 equiv), allowed to warm to roomtemperature and further stirred for 2-4 h. The salts were filteredand rinsed with THF and the filtrate was concentrated in vacuo.The mixture was diluted with EtOAc (200 mL) and washed withwater (100 mL). The combined organic layers were dried withanhydrous Na2SO4, and concentrated in vacuo. The residue waspurified by column chromatography on SiO2

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6486 - 6496

24
[ 2062-26-2 ]
[ 371-40-4 ]
(E)-3-(4-(trifluoromethyl)phenyl)-N-(4-fluorophenyl)-2-propenamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: To an anhydrous THF solution at 78 C in dry ice and acetonebath) of the acids was added N-methylmorpholine (NMM)(1.5 equiv), stirred for 2 min, isobutylchloroformate (IBCF)(1.27 equiv), stirred for 5 min. The reaction mixture was treatedwith the desired anilines (1.2 equiv), allowed to warm to roomtemperature and further stirred for 2-4 h. The salts were filteredand rinsed with THF and the filtrate was concentrated in vacuo.The mixture was diluted with EtOAc (200 mL) and washed withwater (100 mL). The combined organic layers were dried withanhydrous Na2SO4, and concentrated in vacuo. The residue waspurified by column chromatography on SiO2

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 6486 - 6496

25
[ 2062-26-2 ]
[ 112734-22-2 ]
(E)-N-(4-bromo-2-fluorobenzyl)-3-(4-(trifluoromethyl)phenyl)acrylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	To a solution of (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (67) (500 mg, 2.31 mmol) <strong>[112734-22-2](4-bromo-2-fluorophenyl)methanamine</strong> (66) (519 mg, 2.54 mmol) in DMF (5 ml) was added HATU (924 mg, 2.43 mmol) and DIEA (0.81 ml, 4.63 mmol) at 0° C. under nitrogen. After being stirred overnight at room temperature, the reaction mixture was quenched with 10percent citric acid and diluted with ethyl acetate. The resulting organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was chromatographed on silica gel eluting with a gradient of hexane/ethyl acetate (20-40percent) to afford 460 mg of the desired product (68) in 91percent yield as a white solid. 1H-NMR (DMSO-d6) delta: 8.74 (1H, t, J=5.05 Hz), 7.79 (4H, s), 7.56-7.52 (2H, m), 7.42 (1H, d, J=8.34 Hz), 7.33 (1H, d, J=8.34 Hz), 6.81 (1H, d, J=15.66 Hz), 4.41 (2H, d, J=5.05 Hz). LC/MS (M+1): 404.

Reference： [1]Patent: US9156830,2015,B2 .Location in patent: Page/Page column 145

26
[ 2062-26-2 ]
[ 108-59-8 ]
[ 20754-22-7 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium bromide; In N,N-dimethyl-formamide; at 130℃; for 12h;Schlenk technique;	General procedure: To a Schlenk tube equipped with a magnetic stir bar were added under air, carboxylic acid (0.3 mmol), dimethyl malonate (1.8 mmol) and KBr (0.09 mmol) in DMF (2 mL). The resultant reaction mixture was kept stirring at the required temperature for 12 h. After indicated reaction time, the mixture was cooled down to room temperature. It was poured into ethyl acetate, then washed with water, extracted with ethyl acetate, dried by anhydrous Na2SO4, then filtered and evaporated under vacuum, the residue was purified by flash column chromatography (petroleum ether or petroleum ether/ethyl acetate) to afford the corresponding coupling products with high purity.
68%	With potassium bromide; In N,N-dimethyl-formamide; at 130℃; for 12h;Schlenk technique;	In a Schlenk tube charged sequentially 4-trifluoromethyl cinnamic acid (0.3mmol), potassium bromide (0.09mol), and N, N- dimethylformamide (2mL), with micro-injector added malonate acid dimethyl ester (1.8mmol), the system was sealed in a 130 C oil bath was heated with stirring for about 12 hours, after the completion of the reaction, 4mL of water was added to quench the reaction, and then extracted with ethyl acetate (10mL × 3), the combined organic phase was dried over anhydrous sodium sulfate, and concentrated by a simple column chromatography (eluent petroleum ether (60-90 C)), to give the product 4-trifluoromethyl cinnamate, yield rate of 68%.

Reference： [1]Tetrahedron,2015,vol. 71,p. 9067 - 9072
[2]Patent: CN104311415,2016,B .Location in patent: Paragraph 0062; 0063

27
[ 16642-92-5 ]
[ 537-42-8 ]
(E)-4-(3,5-dimethoxystyryl)phenyl 3-(4-(trifluoromethyl)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;	General procedure: The caffic acid derivitives (1mmol), HATU (1.2mmol) and N,N-diisopropylethylamine (2mmol) were dissolved in dichloromethane and stirred at room temperature for 30min. Compound 11 (1mmol) was then added to the solution, and stirred overnight. The reaction mixture was extracted with dichloromethane. The organic layer was washed with diluted hydrochloric acid, saturated sodium bicarbonate solution and brine. Then it was dried with anhydrous magnesium sulfate, and the solvent was evaporated in vacuum to give the crude product, which was purified by chromatography on silica gel.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 124,p. 1006 - 1018

28
[ 2062-26-2 ]
[ 186393-31-7 ]
(E)-1-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: DIPEA (3 mol), HATU (1.5 mol) were added sequentially to a stirred solution of acid (1.1 mol) in DMF (10 v), after 5 minutes, corresponding amine (1.0 mol) was added, stirred at room temperature under argon atmosphere for 16 h. Then the reaction mixture was diluted with water (50 v), extracted with EtOAc (50 v X 2), evaporated the solvent in vacuo, the crude product was purified by column chromatography to afford 5/6(a-h), 5/6(m-s), 7(a-b), 10/11(a-c) and 10/11g (38-87%) as solids.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2818 - 2823

29
[ 2062-26-2 ]
[ 131565-87-2 ]
(E)-1-((3S,4R)-3,4-dihydroxypyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: DIPEA (3 mol), HATU (1.5 mol) were added sequentially to a stirred solution of acid (1.1 mol) in DMF (10 v), after 5 minutes, corresponding amine (1.0 mol) was added, stirred at room temperature under argon atmosphere for 16 h. Then the reaction mixture was diluted with water (50 v), extracted with EtOAc (50 v X 2), evaporated the solvent in vacuo, the crude product was purified by column chromatography to afford 5/6(a-h), 5/6(m-s), 7(a-b), 10/11(a-c) and 10/11g (38-87%) as solids.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2818 - 2823

30
[ 2062-26-2 ]
[ 90481-32-6 ]
(E)-1-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		General procedure: DIPEA (3 mol), HATU (1.5 mol) were added sequentially to a stirred solution of acid (1.1 mol) in DMF (10 v), after 5 minutes, corresponding amine (1.0 mol) was added, stirred at room temperature under argon atmosphere for 16 h. Then the reaction mixture was diluted with water (50 v), extracted with EtOAc (50 v X 2), evaporated the solvent in vacuo, the crude product was purified by column chromatography to afford 5/6(a-h), 5/6(m-s), 7(a-b), 10/11(a-c) and 10/11g (38-87%) as solids.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 2818 - 2823

31
[ 284462-37-9 ]
[ 2062-26-2 ]
(E)-N-methyl-4-(4-(3-(4-(trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 0 - 25℃; for 12h;	Example 9 (E)-N-methyl-4-(4-(3-(4- (0133) (trifluoromethyl)phenyl)acrylamido)phenoxy)picolinamide (6t) (0134) To a solution of (E)-3-(4-(trifluoromethyl)phenyl)acrylic acid (94.5 mg, 0.5 mmol) in dry dimethylformamide, EDCI (115 mg, 0.6 mmol) and HOBT (81 mg, 0.6 mmol) were added at 0 C and the reaction mixture was stirred for 20 min. To the reaction mixture 4-(4-aminophenoxy)-N-methylpicolinamide (121.5 mg, 0.5 mmol) was added and stirred at room temperature (25C) for 12 h. The contents of the reaction mixture were poured into ice-cold water (25 mL), extracted with ethyl acetate (3X15.0) and the combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained residue was purified by column chromatography using ethyl acetate-hexane (0-50%) as eluent to give 163 mg (74%) of analytically pure compound (6t). mp: 210-212 C ; 1H NMR (CDC13+DMSO): delta 10.06 (s, 1H), 8.40 (d, = 5.47 Hz, 1H), 8.23 (d, = 4.72 Hz, 1H), 7.83 (d, = 8.87 Hz, 2H), 7.73 (d, = 9.25 Hz, 1H), 7.70-7.63 (m, 5H), 7.08 (d, J = 8.87 Hz, 2H), 6.98 (dd, J = 2.45, 5.47 Hz, 1H), 6.92 (d, J = 15.67 Hz, 1H), 2.99 (d, = 5.09 Hz, 3H) ; MS (ESI): m z 442 [M+H]+.

Reference： [1]Patent: WO2017/125946,2017,A1 .Location in patent: Page/Page column 24-25

32
[ 2062-26-2 ]
[ 1421-65-4 ]
methyl 3-(3,4-dihydroxyphenyl)-(2S)-2-((2E)-3-(4-(trifluoromethyl)phenyl)acrylamido)propanoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48.4%		General procedure: To a solution of the corresponding substitutedacid (1 eq, 2.02 mmol) in dichloromethane-N,N-dimethylformamide(DMF) (3 : 1, 20 mL) was added 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) (1 eq, 2.02 mmol),N,N-diisopropylethylamine (DIEA) (1 eq, 2.02 mmol) andN-hydroxybenzotriazole (HOBt) (1 eq, 2.02 mmol). After themixture was stirred at room temperature for 30 min, correspondingamine (1 eq, 2.02 mmol) and triethylammoniumacetate (TEA) (3 eq, 6.06 mmol) was added. The solution wasstirred at room temperature for 4 h and then extracted withdichloromethane. The organic layer was washed with 1 N HClsolution, saturated NaHCO3 solution, water and brine, driedover Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (ethylacetate-hexane, 1 : 2) to obtain the title compound.

Reference： [1]Biological and Pharmaceutical Bulletin,2017,vol. 40,p. 1475 - 1482

33
[ 2062-26-2 ]
(+/-)-3,4-cis-3,4-dihydroxypiperidine hydrochloride [ No CAS ]
(E)-1-(cis-3,4-dihydroxypiperidin-1-yl)-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;Inert atmosphere;	General procedure: DIPEA (3 mol), HATU (1.5 mol) were added sequentially to astirred solution of acid (1.1 mol) in DMF (10 v). After 5 min, correspondingamine (1.0 mol) was added and stirred at RT under argonatmosphere for 16 h. After completion of the reaction, the reactionmixturewas diluted withwater (50 v), extracted with EtOAc (50 v X2) and evaporated the solvent in vacuo to get the crude product. Thecrude product was purified by column chromatography using silicagel to afford 5a-e, 5k, 5m, 7a-d, 7h, 7j, 12a-d, 12i, 13a-b and 13e asliquids/solids in 55e87% yield.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 150,p. 39 - 52

34
[ 2062-26-2 ]
(3αS,6R,8S,9βS)-8-hydroxy-6,9-dimethyl-3-methylene-2-oxo-2,3,3α,4,5,6,6α,7,8,9β-decahydroazuleno[4,5-b]furan-6-yl acetate [ No CAS ]
(3αS,6R,8S,9βS)-6-acetoxy-6,9-dimethyl-3-methylene-2-oxo-2,3,3α,4,5,6,6α,7,8,9β-decahydroazuleno[4,5-β]furan-8-yl (E)-3-(4-(trifluoromethyl)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%		General procedure: To a solution of compound 4 (20 mg, 0.065 mmol) and acid(0.065 mmol) in DCM (10 mL) at room temperature was addedDMAP (15.9 mg, 0.13 mmol). After stirring for 10 min, EDCI(25.0 mg, 0.13 mmol) was added in one portion. The reaction wasallowed to stir overnight. Then, water (10 mL) was added. The reactionmixture was extracted with DCM (310 mL). The organiclayer was then washed with brine, dried over Na2SO4, andconcentrated in vacuum. Purification by flash column chromatography(PE: EtOAc 4:1) provided the derivatives of interest.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 149,p. 90 - 97

35
[ 2062-26-2 ]
[ 56222-08-3 ]
(E)-N-methyl-N-(2-nitrobenzyl)-3-(4-(trifluoromethyl)phenyl)acrylamide [ No CAS ]

Reference： [1]MedChemComm,2018,vol. 9,p. 2008 - 2016

36
[ 1392497-89-0 ]
[ 2062-26-2 ]
(E)-3-(2,4,5-trimethoxyphenyl)allyl (E)-3-(4-(trifluoromethyl)phenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.8%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;Inert atmosphere;	General procedure: A mixture of the compound 3 or 4 (5mmol), cinnamic acid derivatives (6mmol), and DMAP (1mmol) in DCM (15mL) was stirred for 10minat room temperature. Successively, EDCI (6-10mmol) were added quickly in one portion. The reaction mixture was continually stirred at room temperature for 10-18h under nitrogen and monitored by TLC. Then the clear solution treated with an aqueous saturated NaHCO3 solution containing ice (60mL) for 5min. The aqueous reaction mixture was extracted with DCM (3×20mL). The combined extracts were dried with dry Na2SO4 and concentrated in vacuo. The crude compound was purified by flash chromatography (SiO2; 100:0-50:50-0:100 hexanes/DCM, v/v). The final esters were obtained as solid substances after concentration of organic solvents under reduced pressure.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 183

37
[ 97-77-8 ]
[ 2062-26-2 ]
[ 1184304-16-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	In 1,2-dichloro-ethane; at 90 - 100℃;Schlenk technique;	Add 0.5 mmol of 4-trifluoromethylcinnamic acid and 0.55 mmol of tetraethylthiuram disulfide to 0.5 to 1 ml of dichloroethane to make a mixture,Place the mixture in a 5ml Schlenk tube,Put it in an oil bath at 90 100 , after 36 48h reaction,Cool to room temperature to obtain the reaction solution;(2) The reaction solution obtained in step (1) is directly concentrated to obtain a concentrate,The concentrate was made with ethyl acetate / petroleum ether = 2/1 (v / v) as the developing agent,Perform TLC separation,74.6 mg of target product was obtained.

Reference： [1]European Journal of Organic Chemistry,2020,vol. 2020,p. 198 - 208
[2]Patent: CN111018735,2020,A .Location in patent: Paragraph 0211-0217

38
[ 2062-26-2 ]
[ 20350-15-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
26%	With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39.
26%	With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39.

Reference： [1]Jiang, Yao-Yao; Wu, Shaochun; Wu, Yan-Wei; Gao, Yang; Chong, Daochen; Sun, Changning; Wei, Mei-Yan; Gu, Yu-Cheng; Shao, Chang-Lun; Gu, Yuchao [European Journal of Medicinal Chemistry, 2022, vol. 240]
[2]Jiang, Yao-Yao; Wu, Shaochun; Wu, Yan-Wei; Gao, Yang; Chong, Daochen; Sun, Changning; Wei, Mei-Yan; Gu, Yu-Cheng; Shao, Chang-Lun; Gu, Yuchao [European Journal of Medicinal Chemistry, 2022, vol. 240]

39
[ 2062-26-2 ]
[ 20350-15-6 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
37%	With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39.
37%	With N,N-dimethyl-4-aminopyridine; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In dichloromethane at 45℃;	4.1.2. General synthetic methods for compounds 2-39 General procedure: To a stirred solution of 1 (50.0mg, 0.18mmol), DMAP (21.8mg, 0.18mmol) and EDCl (110.7mg, 0.71mmol) in 15 mL dry DCM were added the corresponding cinnamic acid reagent (1-2 equiv). The reaction mixture was stirred at 45°C and the progress of the reaction was monitored by silica gel TLC and UPLC-MS. After 1-2h, the reaction mixture was quenched with water and diluted with ethyl acetate. The organic layer was separated and evaporated under a vacuum. The residue was purified by repeated silica gel CC followed by semi-preparative HPLC to yield compounds 2-39.

Reference： [1]Jiang, Yao-Yao; Wu, Shaochun; Wu, Yan-Wei; Gao, Yang; Chong, Daochen; Sun, Changning; Wei, Mei-Yan; Gu, Yu-Cheng; Shao, Chang-Lun; Gu, Yuchao [European Journal of Medicinal Chemistry, 2022, vol. 240]
[2]Jiang, Yao-Yao; Wu, Shaochun; Wu, Yan-Wei; Gao, Yang; Chong, Daochen; Sun, Changning; Wei, Mei-Yan; Gu, Yu-Cheng; Shao, Chang-Lun; Gu, Yuchao [European Journal of Medicinal Chemistry, 2022, vol. 240]

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
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