[ CAS No. 135355-96-3 ] {[proInfo.proName]}

Name: 135355-96-3|(E)-4-(tert-Butoxy)-4-oxobut-2-enoic acid|95%
Brand: Ambeed
SKU: A419369
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Quality Control of [ 135355-96-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 135355-96-3 ]

Product Details of [ 135355-96-3 ]

CAS No. :	135355-96-3	MDL No. :	MFCD08669525
Formula :	C₈H₁₂O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BAXKSCVINAKVNE-SNAWJCMRSA-N
M.W :	172.18	Pubchem ID :	5797551
Synonyms :

Calculated chemistry of [ 135355-96-3 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.5
Num. rotatable bonds :	4
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.19
TPSA :	63.6 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) :	-6.73 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.79
Log Po/w (XLOGP3) :	0.87
Log Po/w (WLOGP) :	0.97
Log Po/w (MLOGP) :	0.84
Log Po/w (SILICOS-IT) :	0.52
Consensus Log Po/w :	1.0

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-1.19
Solubility :	11.1 mg/ml ; 0.0643 mol/l
Class :	Very soluble
Log S (Ali) :	-1.79
Solubility :	2.79 mg/ml ; 0.0162 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.24
Solubility :	99.3 mg/ml ; 0.577 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.26

Safety of [ 135355-96-3 ]

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

Application In Synthesis of [ 135355-96-3 ]

* 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 [ 135355-96-3 ]

[ 135355-96-3 ] Synthesis Path-Downstream 1~21

1
[ 135355-96-3 ]
[ 111024-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h;
	With oxalyl dichloride
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;

	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; Inert atmosphere;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.666667h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.666667h;	tert-Butyl (S)-E-4-((3-(benzyloxy)-1-ethoxy-1-oxopropan-2-yl)(4-methoxybenzyl)amino)-4-oxobut-2-enoate (1). To a solution of O-benzyl-L-serine ethyl ester hydrochloride (6.7 g, 25.6 mmol) in DMF (51mL) were added i-Pr2NEt (12.7 mL, 76.8 mmol) and p-methoxybenzyl chloride (3.49 mL, 25.6 mmol)successively at rt. After being stirred for 24 h at 50 °C, the resulting mixture was quenched by addition ofwater and extracted with AcOEt. The extracts were washed with water, dried over Na2SO4, filtered, andconcentrated. The residual oil was purified through silica gel column chromatography (MeOH/CHCl3 =1/99) to give O-benzyl-N-p-methoxybenzyl-L-serine ethyl ester (6.5 g, 73%) as a colorless oil. To asolution of fumaric acid mono-t-butyl ester (0.78 g, 4.5 mmol) in CH2Cl2 (24 mL) were added oxalylchloride (1.2 mL, 11.3 mmol) and DMF (35 μL, 0.45 mmol) successively at rt. After being stirred for 40min, the reaction mixture was concentrated to give a crude t-butyl (E)-4-chloro-4-oxo-2-butenoate, whichwas dissolved in CH2Cl2 (31 mL) and the resulting mixture was added to a solution ofO-benzyl-N-p-methoxybenzyl-L-serine ethyl ester (1.3 g, 3.8 mmol) and i-Pr2NEt (1.6 mL, 9.4 mmol) inCH2Cl2 (6 mL) at rt. After being stirred for 30 min at the same temperature, the reaction was quenched byaddition of sat. aq. NaHCO3 and extracted with CHCl3. The extracts were washed with brine, dried overMgSO4, filtered and concentrated. The residual brown oil was purified through silica gel columnchromatography (Et2O/n-hexane = 1/1) to give 1 (0.96 g, 51%) as a pale yellow oil. A 89 : 11 mixture ofrotamers of 1: colorless oil; [α]D19 -74 (c 1.07, CHCl3); 1H-NMR (400 MHz, CHCl3): δ 7.37-7.16 (m,8H), 6.85 (d, J = 6.8 Hz, 1.78H), 6.78-6.74 (m, 1.11H), 6.68 (d, J = 15.6 Hz, 0.11H) , 4.82 (d, J = 17 Hz,0.89H), 4.76-4.73 (m, 0.22H), 4.69-4.64 (m, 1.78H), 4.48-4.27 (m, 2.33H), 4.20-3.88 (m, 3.77H),3.83-3.66 (m, 3.22H), 1.49 (s, 0.99H), 1.46 (s, 8.01H), 1.23 (t, J = 7.3 Hz, 2.67H), 1.16 (t, J = 7.3 Hz,0.33H); 13C-NMR (100 MHz, CDCl3): δ 168.5, 168.3, 167.0, 165.8, 164.5, 159.0, 158.6, 137.6, 137.2,134.2, 134.0, 132.7, 132.6, 129.3, 129.0, 128.5, 128.2 (2 peaks), 128.0, 127.7, 127.5, 127.4, 127.37, 113.9,113.4, 81.4, 73.0, 68.3, 66.9, 61.7, 61.2, 60.2, 59.2, 55.1, 51.6, 27.8, 14.0, 13.8; MS (FAB) m/z 498(M+H)+, 520 (M+Na)+, 121 (base peak); HRMS (FAB) m/z calcd for C28H36NO7 (M+H)+: 498.2492 found498.2491.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃;	tert-Butyl-(2E)-4-chloro-4-oxobut-2-enoate (2E)-4-tert-Butoxy-4-oxobut-2-enic acid (172 mg, 1.00 mmol) and DMF (5 jiL) were dissolved in DCM (2.0 mL) and cooled to 0 °C. Oxalic chloride (1.0 ml, 2.0 M, 2.0 mmol) was added dropwise under stirring. Stirring was continued until the evolution of gas ceased. Then, the solvent was distilled and the residue was used without purification in the next step. Yield: 191 mg (quant.).

Reference： [1]Koerber-Ple; Massiot [Journal of Heterocyclic Chemistry, 1995, vol. 32, # 4, p. 1309 - 1315]
[2]Denmark, Scott E.; Thorarensen, Atli; Middleton, Donald S. [Journal of the American Chemical Society, 1996, vol. 118, # 35, p. 8266 - 8277]
[3]Sibi, Mukund P.; Stanley, Levi M.; Jasperse, Craig P. [Journal of the American Chemical Society, 2005, vol. 127, # 23, p. 8276 - 8277]
[4]Sibi, Mukund P.; Stanley, Levi M.; Soeta, Takahiro [Organic Letters, 2007, vol. 9, # 8, p. 1553 - 1556]
[5]Mukund P, Sibi; Soeta, Takahlro; Jasperse, Craig P. [Organic Letters, 2009, vol. 11, # 23, p. 5366 - 5369]
[6]Yoshimura, Tomoyuki; Takuwa, Masatoshi; Tomohara, Keisuke; Uyama, Makoto; Hayashi, Kazuhiro; Yang, Pan; Hyakutake, Ryuichi; Sasamori, Takahiro; Tokitoh, Norihiro; Kawabata, Takeo [Chemistry - A European Journal, 2012, vol. 18, # 48, p. 15330 - 15336]
[7]Hyakutake, Ryuichi; Yoshimura, Tomoyuki; Ueda, Yoshihiro; Hayashi, Kazuhiro; Furuta, Takumi; Kawabata, Takeo [Heterocycles, 2018, vol. 97, # 2, p. 1128 - 1147]
[8]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - WO2020/7704, 2020, A1 Location in patent: Page/Page column 40

2
[ 100922-16-5 ]
[ 135355-96-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	With lithium hydroxide In tetrahydrofuran at 0℃; for 1h;
93%	With lithium hydroxide In tetrahydrofuran
86%	With lithium hydroxyde monohydrate In tetrahydrofuran; lithium hydroxide monohydrate at 20 - 25℃; for 6h;

698 mg

With lithium hydroxide monohydrate In tetrahydrofuran for 0.5h; Inert atmosphere;

3
[ 576-26-1 ]
[ 135355-96-3 ]
[ 1378314-79-4 ]

Yield	Reaction Conditions	Operation in experiment
72%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere;

Reference： [1]Chung, Yu-Chiang; Janmanchi, Damodar; Wu, Hsyueh-Liang [Organic Letters, 2012, vol. 14, # 11, p. 2766 - 2769]

4
[ 135355-96-3 ]
[ 1256918-39-4 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
80%	With dmap; N,N'-ditert-butylcarbodiimide hydrochloride In dichloromethane at 20℃;	6.1 Step 1: Synthesis of tert-butyl (4'-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-4-(2- hydroxypropan-2-yl)- lH-imidazol- 1 -yl)-3 ,3 '-difluoro-5 -(methylsulfonyl)biphenyl- yl)methyl fumarate[00106] To a stirred solution of 2-(2-(2-(2,6-dichlorophenyl)propan-2-yl)-l-(3,3'- difluoro-4'-(hydroxymethyl)-5'-(methylsulfonyl)biphenyl-4-yl)-lH-imidazol-4-yl)propan- 2-ol (prepared in the manner described in PCT Publication No. WO 2010/138598, 100 mg, 0.16 mmol) in (¾(¾ (2 mL) was added N,N'-di-/er/-butylcarbodiimidehydrochloride (47 mg, 0.24 mmol), 4-(dimethylamino)pyridine (10 mg, 0.08 mmol) and mono-/er/-butylfumerate ester (42 mg, 0.24 mmol) at rt. The reaction mixture was stirred at rt overnight. The mixture was diluted with CH2CI2 (10 mL) and was washed with water (3 x 3 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to afford 150 mg of the crude product with 77% LCMS purity. The crude product was purified by silica gel column chromatography, and the product eluted off the column at 40% EtOAc in Hexanes to afford 100 mg (80%, 0.13 mmol) of tert-butyl (4'-(2-(2-(2,6- dichlorophenyl)propan-2-yl)-4-(2-hydroxypropan-2-yl)- IH-imidazol- 1 -yl)-3 ,3 '-difluoro- 5-(methylsulfonyl)biphenyl-4-yl)methyl fumarate with 96% LCMS purity. LCMS:(Ascentis Express CI 8 (50 X 2.1 mm- 2.7 μιη); Solvent A = 10 mM NH4COOH in 98% H20 and 2% acetonitrile; Solvent B = 98% acetonitrile and 2% 10 mM NH4COOH in H20; gradient 0-100% (1.5 min) then 100% (1.5-3.2 min), 100-0% (3.2-3.6 min), 0% (3.6-4 min) B over 4 min.) retention time: 2.345 min; LCMS (MM-ES+APCI), flow 1 ml/min, m/z: 763.

Reference： [1]Current Patent Assignee: EXELIXIS INC - WO2012/135082, 2012, A1 Location in patent: Page/Page column 33

5
[ 135355-96-3 ]
[ 1429383-33-4 ]
[ 1429383-34-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (E)-3-t-butoxycarbonyl-2-butenoic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h; Stage #2: (1R,2R)-2-(tert-butyldimethylsilyloxy)-2-(3-chlorophenyl)-N-(cyclopropylmethyl)-1-(1-(phenylsulfonyl)-1H-indol-2-yl)ethanamine With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h;	1.I Step I. (E)-tert-butyl 4-(((tR,2R)-2-(tert-butyldimethylsilyloxy)-2-(3-chlorophenyl)-t- (1 -(phenylsulfonyl)- 1H-indol-2-yl)ethyl)(cyclopropylmethyl)amino)-4-oxobut-2-enoate Step I. (E)-teri-butyl 4-(((lR,2R)-2-(ieri-butyldimethylsilyloxy)-2-(3-chlorophenyl)-l- (1 -(phenylsulfonyl)- lH-indol-2-yl)ethyl)(cyclopropylmethyl)amino)-4-oxobut-2-enoate One drop of DMF was added to a solution of (E)-4-ieri-butoxy-4-oxobut-2-enoic acid (1.952 g, 1 1.34 mmol) and oxalyl chloride (1.588 mL, 18.14 mmol) in DCM (23 mL) at rt. After 2 hours the reaction mixture was concentrated in vacuo, diluted with DCM and concentrated in vacuo again (this was repeated twice) to provide a brown oil. This oil was dissolved in DCM (20 mL) and added to a solution of (lR,2R)-2-(ieri- butyldimethylsilyloxy)-2-(3-chlorophenyl)-N-(cyclopropylmethyl)-l -(l- (phenylsulfonyl)-lH-indol-2-yl)ethanamine (2.70 g, 4.54 mmol, Step H) in DCM (20 mL) at rt. DIPEA (2.97 mL, 17.01 mmol) was then added to the reaction mixture. After 2 hours the reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with DCM (2x) and the organics were pooled, washed with brine, dried over MgSC>4, filtered and the filtrate was concentrated in vacuo to provide a dark brown oil. Purification by chromatography on silica gel (330 g silica gel column, RediSep Rf, Teledyne Isco, Lincoln, NE; eluent: ethyl acetate in hexane 10% to 35%, gradient elution) provided the title compound as an off-white foam. Mass spectrum (ESI) m/z 749.2 [M + H]+.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2013/49250, 2013, A1 Location in patent: Page/Page column 134; 135

6
[ 135355-96-3 ]
[ 1429382-56-8 ]
[ 1429384-64-4 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (E)-3-t-butoxycarbonyl-2-butenoic acid With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: (1R,2R)-2-amino-2-(4-chloro-2-fluorophenyl)-1-(3-chlorophenyl)ethanol In N,N-dimethyl-formamide at 20℃; for 22h;	62.A Step A. (E)-tert-Butyl 4-(((lR,2R)-l-(4-chloro-2-fiuorophenyl)-2-(3-chlorophenyl)-2- hydroxyethyl)amino)-4-oxobut-2-enoate Step A. (E)-tert-Butyl 4-(((lR,2R)-l-(4-chloro-2-fiuorophenyl)-2-(3-chlorophenyl)-2- hydroxyethyl)amino)-4-oxobut-2-enoate To (E)-4-tert-butoxy-4-oxobut-2-enoic acid (0.90g, 0.525 mmol; AMRI, Albany, NY) and HBTU (0.2g, 0.525 mmol) was added dry DMF (858uL) followed by DIEA (0.12 g, 0.913 mmol). The reaction mixture was stirred at rt for about 20 min. after which (lR,2R)-2-amino-2-(4-chloro-2-fluorophenyl)-l-(3-chlorophenyl)ethanol (0.137g, 0.456 mmol, Intermediate Bl) was added. The reaction mixture was stirred at rt for 22h. The mixture was diluted with EtOAc, washed with water, then saturated aq. NaHC03 solution. The organic layers were extracted with EtOAc, combined, dried over MgSC , filtered and the filtrate was concentrated under reduced pressure. The crude residue was purified by chromatography on silica gel (eluent: 5 to 95% EtOAc : hexanes, gradient elution). 'H NMR (400 MHz, CDC13) δ ppm 1.13 - 1.21 (m, 6 H) 1.13 - 1.21 (m, 2 H) 1.34 - 1.46 (m, 12 H) 1.95 (s, 1 H) 4.03 (d, J=7.34 Hz, 1 H) 4.89 (d, J=4.40 Hz, 1 H) 5.35 (dd, J=8.31, 4.40 Hz, 1 H) 6.47 - 6.57 (m, 1 H) 6.71 - 6.80 (m, 1 H) 6.92 (s, 1 H) 6.93 - 6.96 (m, 1 H) 6.97 (s, 1 H) 6.98 - 7.04 (m, 2 H) 7.04 - 7.09 (m, 2 H) 7.13 (d, J=6.36 Hz, 2 H) 7.25 (s, 1 H). Mass Spectrum (CI+) m/z = 454.1 (M+l), 909.2 (2M+1).

Reference： [1]Current Patent Assignee: AMGEN INC - WO2013/49250, 2013, A1 Location in patent: Page/Page column 206; 207

7
[ 5835-79-0 ]
[ 45022-27-3 ]
[ 1448896-84-1 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: General Procedure C Preparation of Mono-Esters of Fumaric Acid Coupling Reaction of Morpholin-4-ylalkyl-1-ol with Fumaric Acid [0429] [0430] Fumaric acid (1.0 eq.) is dissolved in an inert solvent such as dichloromethane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), or N,N-dimethylacetamide (DMA, DMAc) (ca. 3 mL/mmol) and the solution is treated with 1.0-1.5 eq. of a carbodiimide dehydration agent such as 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDAC, EDC), N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl-carbodiimide (DCC) at a temperature from ca. 0 C. (ice bath) to room temperature. The mixture is then reacted with a solution of an appropriately functionalized of morpholin-4-ylalkyl-1-ol (1.0-1.5 eq.) in the same solvent. Optionally, a catalytic or stoichiometric amount of 4-(N,N-dimethylaminopyridine (DMAP) is added to the mixture at a temperature from ca. 0° C. to room temperature. When the amine is in a salt form, an equimolar amount of an organic tertiary base, such as triethylamine (TEA), or diisopropylethylamine (DIEA) may be added to free the amine base prior to the coupling step. The reaction mixture is stirred for 4 to 12 hours at room temperature. Optionally the organic solvents are removed under reduced pressure using a rotary evaporator and the residue diluted with an appropriate extraction solvent such as diethyl ether (Et2O), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), or others. Water is added to the reaction mixture, the aqueous phase was acidified using 1N hydrochloric acid until aqueous pH reaches to pH 2. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the organic solvents are removed under reduced pressure using a rotary evaporator. If required, the crude reaction products are further purified by well-known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass-guided reversed-phase preparative HPLC/lyophilization, precipitation, or crystallization to yield the pure desired product. Example 15 (4-Morpholinobutyl)fumarate (39) [0471] t-butyl hydrogen fumarate (MHF) (0.2 mol) is activated with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (47.75 g, 0.25 mol) in 200 mL of dichloromethane (DCM) at ca. 0 C. 4-Morpholin-4ylbutyl-1-ol (31.8 g, 0.2 mol) and 4-N,N-dimethylaminopyridine (DMAP) (1 g, 0.008 mol) were added to the activated carboxylic acid. After work-up and isolation, the crude material is reacted with 50% vol-% trifluoroacetic acid in DCM. The free acid is purified by mass-guided preparative HPLC to afford the title compound (40).

Reference： [1]Patent: US2013/203753,2013,A1 .Location in patent: Paragraph 0428-0430; 0470-0472

8
[ 135355-96-3 ]
[ 1624984-87-7 ]
[ 1624984-88-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (E)-3-t-butoxycarbonyl-2-butenoic acid; (1S,2R)-2-amino-1-(3-chlorophenyl)-2-(4-chlorophenyl)-ethanol 2,2,2-trifluoroacetate With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 8h; Stage #2: With sodium hydride In tetrahydrofuran; mineral oil at 20℃; for 2h;	78.C Step C. tert-Butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3- oxomorpholin-2-yl)acetate and tert-butyl 2-((25',5i?,65)-6-(3-chlorophenyl)-5 chlorophenyl)-3-oxomorpholin-2-yl)acetate Step C. tert-Butyl 2-((2i?,5i?,65)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3- oxomorpholin-2-yl)acetate and tert-butyl 2-((25',5i?,65)-6-(3-chlorophenyl)-5 chlorophenyl)-3-oxomorpholin-2-yl)acetate (E)-4-(tert-Butoxy)-4-oxobut-2-enoic acid (148 mg, 0.859 mmol; AMRI, Albany, NY), N-ethyl-N-isopropylpropan-2-amine (390 μ, 2.241 mmol) and HATU (327 mg, 0.859 mmol) were added to a solution of (15',2i?)-2-amino-l-(3-chlorophenyl)-2-(4- chlorophenyl)ethanol 2,2,2-trifluoroacetate (296 mg, 0.747 mmol, Example 78, Step B) in DMF (7.5 mL) at room temperature. After 8 hours, the mixture was diluted with ethyl acetate and washed with 1 M LiCl, 1 M HCl, saturated NaHC03, and brine. The organic layer was dried over Na2S04, filtered and the filtrate was concentrated under a vacuum. The residue was dissolved in THF (7.5 mL) and sodium hydride (44.8 mg, 1.121 mmol, 60% dispersion in mineral oil) was added. The mixture turned yellowish orange and gas evolution was observed. The mixture was stirred at room temperature for 2 hours and became cloudy. The reaction was quenched with saturated NH4C1 and extracted with ethyl acetate. The organic layer was dried over Na2S04, filtered and the filtrate was concentrated under a vacuum to give the title compounds as a mixture of diastereomers.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2014/130470, 2014, A1 Location in patent: Page/Page column 254

9
[ 135355-96-3 ]
[ 1801276-20-9 ]
[ 1801284-36-5 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	45.1 Step 1: Synthesis of INT-36 Step 1: Synthesis of INT-36 INT-36 To a solution of compound 9 (1 .0 mmol), mono-ferf-butylfumerate ester (1 .0 mmol), and DMAP (0.5 mmol) in DCM (5 mL) is added Λ/,/V-dicyclohexylcarbodiimide (1 .2 mmol) in DCM (5 mL). The mixture is stirred at RT overnight, diluted with DCM (10 mL), washed with water (3 x 3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to afford 1 -ieri-butyl 4-{4-[(3R)-3-([2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2- diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methyl (2£)-but-2-enedioate (INT-36).
	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	45.1 Step 1: Synthesis of INT-36 Step 1: Synthesis of INT-36 To a solution of compound 9 (1.0 mmol), mono-tert-butylfumerate ester (1.0 mmol), and DMAP (0.5 mmol) in DCM (5 mL) is added N,N'-dicyclohexylcarbodiimide (1.2 mmol) in DCM (5 mL). The mixture is stirred at RT overnight, diluted with DCM (10 mL), washed with water (3*3 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to afford 1-tert-butyl 4-{4-[(3R)-3-([2-chloro-3-(trifluoromethyl)phenyl]methyl}-(2,2-diphenylethyl)amino)butoxy]-2-fluoro-6-methanesulfonylphenyl}methyl (2E)-but-2-enedioate (INT-36).

Reference： [1]Current Patent Assignee: INSPIRNA INC - WO2015/106164, 2015, A1 Location in patent: Page/Page column 96
[2]Current Patent Assignee: INSPIRNA INC - US2017/66791, 2017, A1 Location in patent: Paragraph 0498; 0499

10
[ 61644-18-6 ]
[ 45022-27-3 ]
C₁₃H₂₀O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 50 - 70℃;	A mixture of <strong>[61644-18-6]chloromethyl 2-methylpropanoate</strong> (1.5 eq), tert-butyl hydrogen fumarate (0.5 g, 1.0 eq), and Cs2CO3 (2.0 eq) in N-methylpyrrolidone (10 mL) was stirred between 50 to 70 C. overnight. The reaction was concentrated in vacuo to a residue, diluted with ethyl acetate, and washed with water, saturated bicarbonate solution and brine. The organic phase was separated, dried over Na2SO4, filtered and concentrated in vacuo to yield the crude product. The crude material was then purified by silica gel column chromatography using ethyl acetate and hexanes to yield compound (6a).

Reference： [1]Patent: US2016/229819,2016,A1 .Location in patent: Paragraph 0290

11
[ 135355-96-3 ]
[ 2145062-47-9 ]
[ 2313240-41-2 ]

Yield	Reaction Conditions	Operation in experiment
45%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	14A tert-Butyl (25)-3-[ 1- { [5-carbamoyl- 1 -(3-chloropyridin-2-yl)- 1H- 1 ,2,4-triazol-3-yl]methyl }-3-(4- chlorophenyl)-5-oxo- 1 ,5-dihydro-4H- 1 ,2,4-triazol-4-yl] - 1,1,1 -trifluoropropan-2-yl (2E)-but-2-enedioate A solution of 3-( { 3-(4-chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro-1 H-i ,2,4-triazol- i-yl } methyl)- 1 -(3-chloropyridin-2-yl)- 1 H-i ,2,4-triazole-5-carboxamide (Example8A, 100 mg, 184 pmol) in dichloromethane (1 ml) was treated with EDCI (42.3 mg, 221 pmol)followed by 4-N,N-dimethylaminopyridine (2.2 mg, 17.4 pmol) and (2E)-4-tert-butoxy-4-oxobut-2-enoic acid (38.0 mg, 221 pmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 58.3 mg (45% of th.) of the title compound.LC-MS (Method 2): R = 2.14 mm; MS (ESIpos): m/z = 697.1 [M+H]‘H-NMR (400 MHz, DMSO-d6): ö [ppm] = 8.54 (dd, iH), 8.33 (s, iH), 8.23 (dd, iH), 8.00 (s, iH),7.73-7.52 (m, 5H), 6.47-6.39 (m, 1H), 6.34-6.26 (m, 1H), 5.71-5.62 (m, 1H), 5.23-5.11 (m, 2H),4.46-4.31 (m, 2H), 1.48 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2019/81291, 2019, A1 Location in patent: Page/Page column 54; 55

12
[ 135355-96-3 ]
[ 2145062-48-0 ]
[ 2313240-36-5 ]

Yield	Reaction Conditions	Operation in experiment
35%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	12A tert-Butyl (25)-3- [1 -( { 5-carbamoyl- 1- [3-(trifluoromethyl)pyridin-2-yl] - 1H- 1 ,2,4-triazol-3-yl } methyl)-3-(4-chlorophenyl)-5-oxo- 1 ,5-dihydro-4H- 1 ,2,4-triazol-4-yl] - 1,1,1 -trifluoropropan-2-yl (2E)-but-2-enedioate A solution of 3-( { 3-(4-chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro-1 H-i ,2,4-triazol- i-yl } methyl)- 1- [3-(trifluoromethyl)pyridin-2-yl] - 1-i ,2,4-triazole-5-carboxamide(Example 4A, 100 mg, 173 pmol) in dichloromethane (940 p1) was treated with EDCI (39.9 mg,208 pmol) followed by 4-N,N-dimethylaminopyridine (2.12 mg, 17.4 pmol) and (2E)-4-tert-butoxy-4-oxobut-2-enoic acid (35.8 mg, 208 pmol). The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 44.9 mg (35% of th.) of the title compound.LC-MS (Method 2): R = 2.19 mm; MS (ESIpos): mlz = 731.2 [M+H]‘H-NMR (400 MHz, DMSO-d6): ö [ppm] = 8.86 (dd, 1H), 8.49 (dd, 1H), 8.33 (s, 1H), 7.99 (s, 1H),7.90 (dd, 1H), 7.73-7.52 (m, 4H), 6.45-6.37 (m, 1H), 6.32-6.22 (m, 1H), 5.71-5.58 (m, 1H), 5.24-5.11 (m, 2H), 4.47-4.30 (m, 2H), 1.48 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2019/81291, 2019, A1 Location in patent: Page/Page column 52; 53

13
[ 135355-96-3 ]
[ 2143936-54-1 ]
[ 2313240-39-8 ]

Yield	Reaction Conditions	Operation in experiment
24%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	13A tert-Butyl (25)-3- [1 -( { 5-carbamoyl- 1- [2-(trifluoromethyl)phenyl] -1 H-i ,2,4-triazol-3-yl } methyl)-3-(4-chlorophenyl)-5-oxo- 1 ,5-dihydro-4H- 1 ,2,4-triazol-4-yl] - 1,1,1 -trifluoropropan-2-yl (2E)-but-2-enedioate A solution of 3-( { 3-(4-chlorophenyl)-5-oxo-4- [(2S)-3,3,3-trifluoro-2-hydroxypropyl] -4,5-dihydro-1 H-i ,2,4-triazol- i-yl } methyl)- 1- [2-(trifluoromethyl)phenyl] - 1-i ,2,4-triazole-5-carboxamide(Example 6A, 100 mg, 174 pmol) in dichloromethane (940 p1) was treated with EDCI (39.9 mg,208 pmol) followed by 4-N,N-dimethylaminopyridine (2.12 mg, 17.4 pmol) and (2E)-4-tert-butoxy-4-oxobut-2-enoic acid (35.9 mg, 208 pmol),. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by preparative HPLC (Method 4) affording 30.0 mg (24% of th.) of the title compound.LC-MS (Method 2): R = 2.27 mm; MS (ESIpos): m/z = 730.2 [M+H]‘H-NMR (400 MHz, DMSO-d6): ö [ppm] = 8.17 (s, 1H), 7.94-7.51 (m, 9H), 6.47-6.33 (m, 1H),6.3 1-6.21 (m, 1H), 5.75-5.55 (m, 1H), 5.13 (s, 2H), 4.48-4.29 (m, 2H), 1.48 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - WO2019/81291, 2019, A1 Location in patent: Page/Page column 53; 54

14
[ 135355-96-3 ]
[ 2433828-52-3 ]
[ 2433836-50-9 ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: (E)-3-t-butoxycarbonyl-2-butenoic acid; (R)-3-hydroxy-4-((3-((2-mercaptoethyl)amino)-3-oxopropyl)amino)-2,2-dimethyl-4-oxobutyl acetate With dmap In dichloromethane at 0 - 25℃; for 0.166667h; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 2h;	111 Example 111: Synthesis of Compound 1269: Synthesis of tert-butyl (2E)-4-[(2-[3-[(2R)-4- (acetyloxy)-2-hydroxy-3,3-dimethylbutanamido] propanamidoJethyI)suIfanyij-4-oxobut-2- enoate To a stirred mixture of (2E)-4-(tert-butoxy)-4-oxobut-2-enoic acid (500 mg, 2.91 mmol, 1.00 equiv) and (3i?)-3-hydroxy-2,2-dimethyl-3-([2-[(2- sulfanylethyl)carbamoyl]ethyi]carbamoyl)propyl acetate from Example 96 (Compound 1261) (930 mg, 2.91 mmol, 1.00 equiv) in DCM (10 mL) was added DMAP (35 mg, 0.29 mmol, 0.10 equiv) at 0 degrees C. The resulting mixture was stirred for 10 min at 25 degrees C. To the above mixture was added DCC (599 mg, 2.91 mmol, 1.00 equiv) at 25 degrees C, then the resulting mixture was stirred for 2 h at 25 degrees C. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH=10: 1) to afford the title compound as tert- butyl (2)-4- [(2- [3-[(2i?)-4-(acetyloxy)-2-hydroxy-3,3 - dimethylbutanamido]propanamido]ethyl)sulfanyl]-4-oxobut-2-enoate (Compound 1269) (450 mg, 30%) as a colorless oil. MS: (ES, m/s): 475 [M+H]+

Reference： [1]Current Patent Assignee: VECTIVBIO COMET - WO2020/113209, 2020, A1 Location in patent: Paragraph 2121

15
[ 49715-04-0 ]
[ 135355-96-3 ]
[ 2593177-92-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	Stage #1: (E)-3-t-butoxycarbonyl-2-butenoic acid With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane; water at 0℃; for 0.166667h; Stage #2: chlorosulfuric acid chloromethyl ester In dichloromethane; water for 16h;	tert- Butyl chloromethyl (2£)-but-2-enedioate (2£)-4-/ert-butoxy-4-oxobut-2-enoic acid (CAS RN 135355-96-3, 1.72 g, 10.0 mmol) and sodium hydrogen carbonate (3.36 g, 40.0 mmol) were dissolved in a mixture of dichloromethane (62 mL) and water (62 mL). Tetrabutylammonium hydrogen sulfate (340 mg, 1000 pmol) was added and the mixture was stirred at 0 °C for 10 min. Then, a solution of chloromethyl sulfurochloridate (1.4 ml, 13 mmol) in dichloromethane (7.0 mL) was added dropwise. The ice bath was removed and stirring was maintained for 16 h. Dichloromethane was added and the phases were separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvent was distilled. The crude product was purified by chromatography on silica gel with a gradient of cyclohexane - ethyl acetate to give 2.05 g (100 % purity, 93 % yield) of the title compound. LC-MS Method 1): Rt= 1.34 min; MS (ESIpos): m/z = 165 [M+H-C4H8]+-NMR (600 MHz, DMSO-d6) d [ppm]: 1.469 (16.00), 5.970 (4.04), 6.723 (0.51), 6.750 (1.50), 6.775 (1.54), 6.801 (0.50).

Reference： [1]Current Patent Assignee: ELANCO ANIMAL HEALTH INC - WO2021/18849, 2021, A1 Location in patent: Page/Page column 56-57

16
[ 135355-96-3 ]
[ 85081-18-1 ]
[ 2633639-09-3 ]

Yield	Reaction Conditions	Operation in experiment
49.91%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	3 (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl 1-tert-butyl (2E)-but-2-enedioate To a mixture of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-ol (500 mg, 1.565 mmol, 1 equiv) in DCM (20 mL) were added (2E)-4-(tert-butoxy)-4-oxobut-2-enoic acid (404 mg, 2.348 mmol, 1.5 equiv), EDCl (900 mg, 4.696 mmol, 3 equiv) and DMAP (191 mg, 1.565 mmol, 1 equiv). The resulting solution was stirred at room temperature overnight. The reaction was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 370 mg (49.91%) of (2R,3R,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl 1-tert-butyl (2E)-but-2-enedioate as a yellow solid.LCMS (ESI): [M+H]+: 474.5

Reference： [1]Current Patent Assignee: DISPERSOL TECHNOLOGIES LLC - US2021/87191, 2021, A1 Location in patent: Paragraph 0119-0121

17
[ 135355-96-3 ]
[ CAS Unavailable ]
[ 105659-66-3 ]

Yield	Reaction Conditions	Operation in experiment
920 mg	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h;	2.1 Step 1 EDCI (2.12 g, 11 mmol) was added to a mixutre of (E)-4-(tert-butoxy)-4-oxobut-2-enoic acid (1.00 g, 5.52 mmol), DIPEA (1.9 mL, 11 mmol), DMAP (0.067 g, 0.55 mmol) and cyclohexanol (0.58 mL, 5.52 mmol) in DCM (30 mL). The mixture was stirred at RT for 16 h, then concentrated onto silica and purified by chromatography on silica gel (0-20% EtOAc/DCM) to afford tert-butyl cyclohexyl fumarate (920 mg, 3.55 mmol) as a clear colourless oil. LCMS m/z 254.7 (M+H)+(ES+).1H NMR (400 MHz, DMSO) δ 6.64 (d, J = 1.3 Hz, 2H), 4.89 - 4.66 (m, 1H), 1.84 - 1.77 (m, 2H), 1.71 - 1.60 (m, 2H), 1.54 - 1.19 (m, 15H).

Reference： [1]Current Patent Assignee: SITRYX THERAPEUTICS LTD - WO2022/38365, 2022, A2 Location in patent: Page/Page column 63-64

18
[ 696-71-9 ]
[ 135355-96-3 ]
[ 2762670-59-5 ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In ethyl acetate at 20℃; for 12h; Inert atmosphere;	3.1 Step 1 A mixture of cyclooctanol (177 g, 1.38 mol), (E)-4-(tert-butoxy)-4-oxobut-2-enoic acid (238 g, 1.38 mol), DMAP (16.9 g, 138 mmol) and DIPEA (357 g, 2.76 mol) in EtOAc (1.43 L) was degassed and purged with N2 three times. EDC.HCl (530 g, 2.76 mol) was added into the mixture, and the mixture was stirred at 20 °C for 12 h under a N2 atmosphere. The mixture was then added into water (1.50 L), and the mixture was extracted with EtOAc (2 x 1.00 L). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 2-20% EtOAc/petroleum ether) to give tert-butyl cyclooctyl fumarate (245 g, 868 mmol, 63 %) as a yellow oil.1H NMR (400 MHz, DMSO) δ: 6.72-6.58 (m, 2H), 4.97-4.91 (m, 1H), 1.79-1.38 (m, 23H).

Reference： [1]Current Patent Assignee: SITRYX THERAPEUTICS LTD - WO2022/38365, 2022, A2 Location in patent: Page/Page column 65

19
(2E)-4-(tert-butoxy)-4-oxobut-2-enoic acid [ No CAS ]
[ 1080-06-4 ]
tert-butyl (S,E)-4-((3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-yl)amino)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With pyridine; 1-propanephosphonic acid cyclic anhydride In ethyl acetate; acetonitrile at -5 - 0℃; for 3h;

Reference： [1]Ashbrook, Chloe; Carnell, Andrew J.; Goulding, Ellie; Hatton, Harry; Johnson, James R.; Kershaw, Neil M.; McCue, Hannah V.; Rigden, Daniel J.; Ward, Lucy C. [Angewandte Chemie - International Edition, 2022, vol. 61, # 14][Angew. Chem., 2022, vol. 134, # 14]

20
[ 135355-96-3 ]
[ CAS Unavailable ]
[ 105659-67-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With 4-dimethylaminopyridine; dicyclohexyl-carbodiimide In dichloromethane at 0 - 25℃;

Reference： [1]Bitai, Jacqueline; Nimmo, Alastair J.; Slawin, Alexandra M. Z.; Smith, Andrew D. [Angewandte Chemie - International Edition, 2022, vol. 61, # 25][Angew. Chem., 2022, vol. 134, # 25]

21
[ 100-02-7 ]
[ 135355-96-3 ]
[ 1013386-37-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: (2E)-4-(tert-butoxy)-4-oxobut-2-enoic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20 - 25℃; for 1h; Inert atmosphere; Stage #2: 4-nitro-phenol With N-ethyl-N,N-diisopropylamine In dichloromethane Inert atmosphere;

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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

[ CAS No. 135355-96-3 ] {[proInfo.proName]}

Quality Control of [ 135355-96-3 ]

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[ 135355-96-3 ] Synthesis Path-Downstream 1~21

Related Functional Groups of [ 135355-96-3 ]

Alkenes

Aliphatic Chain Hydrocarbons

Esters

Carboxylic Acids

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[ 135355-96-3 ]