[ CAS No. 430-99-9 ] {[proInfo.proName]}

Name: 430-99-9|2-Fluoroacrylic acid|98%
Brand: Ambeed
SKU: A101455
Price: 5.0 USD
Availability: InStock
Rating: 99 (30 reviews)

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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 430-99-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 430-99-9 ]

CAS No. :	430-99-9	MDL No. :	MFCD03424474
Formula :	C₃H₃FO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	TYCFGHUTYSLISP-UHFFFAOYSA-N
M.W :	90.05	Pubchem ID :	2782523
Synonyms :

Calculated chemistry of [ 430-99-9 ]

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	17.88
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) :	-6.36 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.85
Log Po/w (XLOGP3) :	0.69
Log Po/w (WLOGP) :	0.97
Log Po/w (MLOGP) :	0.16
Log Po/w (SILICOS-IT) :	0.1
Consensus Log Po/w :	0.55

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.77
Solubility :	15.4 mg/ml ; 0.171 mol/l
Class :	Very soluble
Log S (Ali) :	-1.05
Solubility :	8.02 mg/ml ; 0.089 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	0.12
Solubility :	118.0 mg/ml ; 1.31 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.12

Safety of [ 430-99-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501	UN#:	3261
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 430-99-9 ]

* 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 [ 430-99-9 ]
Downstream synthetic route of [ 430-99-9 ]

[ 430-99-9 ] Synthesis Path-Upstream 1~12

1
[ 13989-27-0 ]
[ 430-99-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 2 h;	In a 250 ml four-necked flask, 2-fluoropropenal (8.89 g, 0.12 mol)m-cpba 26 g (0.15 mol),Dichloromethane 30g, incubated at 20 stirring 2h, cooled to about 0 ,Filtration, the filtrate was concentrated to dryness to give crude 2-fluoroacrylic acid,Crystallization with 10g n-heptane to obtain 2-fluoro acrylic acid products.Yield 92percent.

Reference： [1] Patent: CN107417524, 2017, A, . Location in patent: Paragraph 0068; 0069; 0070; 0071; 0072; 0073; 0074-0077

2
[ 67-56-1 ]
[ 420-25-7 ]
[ 201230-82-2 ]
[ 430-99-9 ]
[ 2343-89-7 ]

Yield	Reaction Conditions	Operation in experiment
70.9%	at 100℃; for 13 h; Autoclave	8.98 g (71.87 mmol) of 1-bromo-1-fluoroethene, 8.01 g (79.2 mmol) of triethylamine, 51.5 mg (0.072 mmol) of dichloro[bis(diphenylphosphinophenyl)ether]palladium (II), and 36 mE of non-dried methanol were placed in a 1 50-mE stainless autoclave, and 1.0 MPaG carbon monoxide was introduced thereto, followed by stirring at 100° C. for 13 hours. After completion of the reaction, the autoclave was cooled, and the unreacted gas was purged. The autoclave was opened, and 186 mg (1.0 mmol) of hexafluorobenzenewas added as an internal standard substance, followed by stirring. The mixture was then allowed to stand for a short period of time to precipitate the salt. The supernatant was diluted with deuterated chloroform, and subjected to quantification based on 19F-NMR integral values. The diluted supernatant was found to contain 50.93 mmol (yield: 70.9percent) of 2-fluoroacrylic acid methyl ester, 10.13 mmol (yield:14.1percent) of 2-fluoroacrylic acid, and 8.12 mmol (recovery:11.3percent) of unreacted 1 -bromo-1 -fluoroethene. The conversion was 87.5percent, and the selectivity was 81.0percent.

Reference： [1] Patent: US2016/318842, 2016, A1, . Location in patent: Paragraph 0149; 0150

3
[ 332061-81-1 ]
[ 430-99-9 ]

Reference： [1] Patent: US2004/24243, 2004, A1,

4
[ 57965-29-4 ]
[ 430-99-9 ]

Reference： [1] Journal of Fluorine Chemistry, 2001, vol. 107, # 1, p. 113 - 116

5
[ 79-10-7 ]
[ 430-99-9 ]
[ 159331-07-4 ]
[ 33420-54-1 ]

Reference： [1] Patent: WO2013/3495, 2013, A2, . Location in patent: Paragraph 0041

6
[ 2343-89-7 ]
[ 430-99-9 ]

Reference： [1] Organic and Biomolecular Chemistry, 2015, vol. 13, # 3, p. 717 - 728

7
[ 760-80-5 ]
[ 430-99-9 ]

Reference： [1] Collection of Czechoslovak Chemical Communications, 1983, vol. 48, # 1, p. 319 - 326
[2] Journal of Fluorine Chemistry, 2002, vol. 113, # 2, p. 211 - 218

8
[ 425-83-2 ]
[ 430-99-9 ]

Reference： [1] Journal of the American Chemical Society, 1954, vol. 76, p. 479

9
[ 50-00-0 ]
[ 758-93-0 ]
[ 430-99-9 ]

Reference： [1] Journal of Organic Chemistry, 1968, vol. 33, # 1, p. 286 - 291
[2] , Gmelin Handbook: F: PerFHalOrg.4, 2.2.4, page 68 - 115,

10
[ 815-49-6 ]
[ 430-99-9 ]

Reference： [1] , 1969, vol. 5, p. 1879 - 1883[2] Zhurnal Organicheskoi Khimii, 1969, vol. 5, p. 1932 - 1937

11
[ 433-63-6 ]
[ 430-99-9 ]

Reference： [1] Journal of Fluorine Chemistry, 1991, vol. 54, # 1-3, p. 74

12
[ 50-00-0 ]
[ 598-73-2 ]
[ 430-99-9 ]

Reference： [1] Journal of Organic Chemistry, 1968, vol. 33, # 1, p. 286 - 291

[ 430-99-9 ] Synthesis Path-Downstream 1~88

1
[ 425-83-2 ]
[ 430-99-9 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 479

2
[ 50-00-0 ]
[ 598-73-2 ]
[ 430-99-9 ]

Reference： [1]Journal of Organic Chemistry,1968,vol. 33,p. 286 - 291

3
[ 815-49-6 ]
[ 430-99-9 ]

Reference： [1]Journal of Organic Chemistry USSR (English Translation),1969,vol. 5,p. 1879 - 1883
Zhurnal Organicheskoi Khimii,1969,vol. 5,p. 1932 - 1937

4
[ 430-99-9 ]
[ 100-01-6 ]
[ 21133-78-8 ]

Reference： [1]Journal of general chemistry of the USSR,1968,vol. 38,p. 1697 - 1700
Zhurnal Obshchei Khimii,1968,vol. 38,p. 1741 - 1744

5
[ 433-63-6 ]
[ 430-99-9 ]

Reference： [1]Journal of Fluorine Chemistry,1991,vol. 54,p. 74

6
[ 760-80-5 ]
[ 430-99-9 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1983,vol. 48,p. 319 - 326
[2]Journal of Fluorine Chemistry,2002,vol. 113,p. 211 - 218

9
[ 57965-29-4 ]
[ 430-99-9 ]

Reference： [1]Journal of Fluorine Chemistry,2001,vol. 107,p. 113 - 116

10
[ 430-99-9 ]
[ 425-83-2 ]

Reference： [1]Journal of Fluorine Chemistry,2002,vol. 113,p. 211 - 218

11
[ 4383-22-6 ]
[ 430-99-9 ]
[ 664342-20-5 ]

Reference： [1]Organic Process Research and Development,2019
[2]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[3]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

12
[ 430-99-9 ]
[ 17150-62-8 ]
[ 664342-21-6 ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

13
[ 430-99-9 ]
[ 52853-55-1 ]
N-benzyl-N-(2-methallyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

14
[ 430-99-9 ]
[ 54436-58-7 ]
N-benzyl-N-(pent-4-enyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

15
[ 430-99-9 ]
[ 145126-90-5 ]
N-benzyl-N-(hex-5-enyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

16
[ 430-99-9 ]
[ 664342-19-2 ]
N-(but-3-enyl)-N-(4-fluorobenzyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

17
[ 430-99-9 ]
[ 664342-18-1 ]
N-(but-3-enyl)-N-(4-methoxybenzyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 57 - 60
[2]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

18
[ 430-99-9 ]
[ 16522-55-7 ]

Yield	Reaction Conditions	Operation in experiment
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 3h;Inert atmosphere;	General procedure: Oxalyl dichloride (1.56 mmol, 0.14 mL) was added to the solution of the tested acid (1.72 mmol) in CH2Cl2 (5 mL) and DMF (a drop, about 0.05 mL) at 0 C under Ar atmosphere within 10 min. After the solution was stirred for 3 h at the room temperature, a solution of 3a-i (1.32 mmol) in dichloromethane (8.0 mL) was added at 0 C. The reaction solution was then warmed to room temperature and stirred for overnight. After quenched with saturated NaHCO3 aqueous solution, the mixture was extracted with EtOAc (2×15 mL), and the combined organic layers were washed with brine (20 mL) and dried over NaSO4. After filtration and concentration, the residue was purified by column chromatography to give the acylated product with two rotamers, and the isolated yields were shown in Table 2.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2.5h;Cooling with ice;	<strong>[430-99-9]2-fluoroacrylic acid</strong> (2.Oeq.) (54 mg) was dissolved in DCM (10 ml)3 drops of DMF were added,Under ice-cooling conditions,Oxalyl chloride (1.7 eq.) (44 [mu] v)In the ice bath conditions for 30min,Remove the ice bath,Natural recovery to room temperature,The reaction was carried out for 2 hours,(4-fluorophenylamino) -6-amino-7- (tetrahydrofuran-3-oxy) quinazoline(1 eq.) (112 mg) was dissolved in DCM (20 ml)Stir at 0 C for 5 min,Was added to the above acid chloride solution,Et3N (4 Oeq.) (169yL) was added,In the ice bath conditions for 30min,Remove the ice bath,After natural recovery to room temperature,The reaction was stirred overnight.After completion of the reaction,Concentrated to dry under reduced pressure crude,Purification by column chromatography (mobile phase 10: lDCM / MeOH) afforded N- (4- (3-chloro-4-fluorophenylamino) -7- (tetrahydrofuran-3-oxy) quinazoline- Yl) -2-fluorobut-2-enamide 80mg
	With trichlorophosphate; at 80℃;	General procedure: We used indole 7 as starting material to synthesize interediates15a-c by the method reported in the literature [32]. Different substituted acrylic acids were chlorinated by POCl3 to obtain the corresponding acyl chloride at 80 C. Under an ice bath, differently substituted acryl chloride was dissolved in dichloromethane and stirred at 0 C for 10-30 min. Another intermediates 15a-c were added to the above acryl chloride solution, and then added NaHCO3 solid powder, stirred at 0 C for 0.5-3 h. After the reaction was completed, the reaction mixture was filtered and solvent was distilled off under reduced pressure. The crude product was purified using flash chromatography with dichloromethane/methanol(v/v, from 50:1 to 20:1) as eluents

With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;Inert atmosphere;

Add in a 50mL eggplant bottle<strong>[430-99-9]2-fluoroacrylic acid</strong> 113.07 mg (1.26 mmol).10 mL of dry dichloromethane was added to suspend it.Add oxalyl chloride 115 muL (1.36 mmol) and a drop of DMF,After argon gas was fully replaced, it was allowed to react at room temperature for 2 h.2-Fluoroacryloyl chloride was prepared, and after completion of the reaction, it was charged into a constant pressure dropping funnel.In another 50 mL eggplant bottle, compound 41 300 mg (1.05 mmol) was added.Dissolved in 10 mL of dry dichloromethane,Add 913 muL (5.23 mmol) of DIPEA,After the replacement with argon gas, the acid chloride solution was slowly added dropwise under ice bath.After the completion of the dropwise addition, the reaction was carried out for 1 h. After the reaction was completed by TLC, the reaction mixture was washed with water and brine, dried over anhydrous sodium sulfate andDichloromethane: methanol = 100:1).The product (42) was obtained in 247.00 mg.It was a white solid, yield: 65.80%.

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 2611 - 2623
[2]Tetrahedron,2016,vol. 72,p. 4845 - 4853
[3]Patent: CN103965120,2016,B .Location in patent: Paragraph 0407; 0409; 0415; 0416
[4]European Journal of Medicinal Chemistry,2019,vol. 163,p. 367 - 380
[5]Patent: CN109305967,2019,A .Location in patent: Paragraph 0180; 0182; 0183; 0184

19
[ 332061-81-1 ]
[ 430-99-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In sodium hydroxide;	EXAMPLE 4 Synthesis of 2-fluoroacrylic Acid 31 g of 2-chloro-2-fluoropropionic acid were dissolved in 320 ml of a 2N NaOH solution and heated at 100° C. for 24 h. The medium was subsequently acidified with 140 ml of 2N HCl. The 2-fluoroacrylic acid was extracted with two times 200 ml of diethyl ether. 20 g of 2-fluoroacrylic acid were recovered after evaporation of the ether. The yield of 2-fluoroacrylic acid, based on the amount of 2-chloro-2-fluoropropionic acid employed, was 90percent.

Reference： [1]Patent: US2004/24243,2004,A1

20
[ 50-00-0 ]
[ 758-93-0 ]
[ 430-99-9 ]

Reference： [1]Journal of Organic Chemistry,1968,vol. 33,p. 286 - 291
[2]Gmelin Handbuch der Anorganischen Chemie,Gmelin Handbook: F: PerFHalOrg.4, 2.2.4, page 68 - 115

21
[ 430-99-9 ]
[ 20698-91-3 ]
[ 1095714-01-4 ]

Yield	Reaction Conditions	Operation in experiment
55%		Example 149; Compound of Formula (Iaa) wherein M=tert-butoxy, Q=4-tert-butyl-3-methoxybenzoyl, Z=1,3-thiazol-2-yl, X=fluoro, Y=hydroxymethyl, J=1H-pyrazol-1-ylmethylStep 149a. A solution of <strong>[430-99-9]2-fluoroacrylic acid</strong> (2 g, 22 mmol) in dichloromethane (80 mL) was added DCC (4.58 g, 22 mmol). at 0° C. The resulting mixture was stirred at 0° C. for 15 min before addition of a solution of methyl (R)-(-)-mandelate (4.06 g, 24 mmol) and DMAP (136 mg, 0.11 mmol) in 20 mL of dichloromethane. The mixture was stirred at rt for 16 h before being filtered and the organic solution was washed with brine, dried (Na2SO4) and evaporated. The residue was chromatographed (silica, hexane-EtOAc) to give the desired compound (2.9 g, 55percent) as white crystals.1H NMR (CDCl3) 7.50 (m, 2H), 7.43 (m, 3H), 6.09 (s, 1H), 5.83 (dd, 1H), 5.45 (dd, 1H), 3.77 (s, 3H).13C NMR (CDCl3): 168.7, 159.7 (d), 152.9 (d), 133.3, 129.8, 129.2, 127.9, 104.3, 75.6, 53.0.

Reference： [1]Patent: US2009/4140,2009,A1 .Location in patent: Page/Page column 36

22
[ 79-10-7 ]
[ 430-99-9 ]
[ 159331-07-4 ]
[ 33420-54-1 ]

Yield	Reaction Conditions	Operation in experiment
	With fluorine; sodium fluoride; at -78℃;Inert atmosphere;	Example 2: Synthesis of 2,3-difluoropropionic acid (G) [0041] To a solution of acrylic acid in 2H,3H-decafluoropentane was added sodium fluoride as scavenger for HF. The suspension was cooled to -78C under vigorous stirring. Fluorine was introduced to the mixture under the same conditions as example 1. After the reaction, the mixture was filtered and analyzed by GC/MS.

Reference： [1]Patent: WO2013/3495,2013,A2 .Location in patent: Paragraph 0041

23
[ 430-99-9 ]
[ 1430422-35-7 ]
[ 1430422-36-8 ]

Yield	Reaction Conditions	Operation in experiment
77%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; for 60h;Inert atmosphere;	To a suspension of 6-bromo-2,2-dimethyl-1-vinyl-2,3-dihydro-1H-inden-1-amine (1.12 g, 4.21 mmol) and 2-fluoropropenoic acid (0.568 g, 6.31 mmol) in dry EtOAc (20 mL)were added 1-propanephosphonic acid cyclic anhydride (T3P) (3.76 mL, 6.31 mmol) and triethylamine (1.47 mL, 10.52 mmol) under nitrogen. After 1.5 h, more 2-fluoropropenoic acid (0.189 g, 2.10 mmol) and 1-propanephosphonic acid cyclic anhydride (T3P) (1.25 mL, 2.10 mmol) was added and stirring continued. After a total of 2.5 days, water was added and the phases were separated. The aq layer was extracted twice with EtOAc and the combined organics were dried over MgSO4, filtered and concentrated. Purification by column chromatography using a gradient of 0-10percent EtOAc in heptane as eluent afforded 1.097 g(77percent) of the title compound. 1H NMR (500 MHz, CHLOROFORM-d) delta 1.10 (s, 3 H), 1.22 (s,3 H), 2.67 -2.77 (m, 2 H), 4.71 (d, 1 H), 5.13 (dd, 1 H), 5.23 (d, 1 H), 5.62-5.75 (m, 1 H), 6.36 (dd, 1 H), 6.62 (br. s., 1 H), 7.08 (d, 1 H), 7.38 (dd, 1 H), 7.53 (d, 1 H). MS (ES-) m/z336,338 [M-H]-

Reference： [1]Patent: WO2013/54108,2013,A1 .Location in patent: Page/Page column 55

24
[ 430-99-9 ]
[ 1430422-41-5 ]
[ 1430422-42-6 ]

Yield	Reaction Conditions	Operation in experiment
27%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In ethyl acetate; at 0 - 20℃; for 75h;Inert atmosphere;	To a suspension of 1?-ethenyl-6?-(3 -fluoropropoxy)-4-[(2H3)methyloxy]-1?,3dihydrospiro[cyclohexane-1,2?-inden]-1?-amine (1.376 g, 4.09 mmol) and in dry ethyl acetate (30 mL) were 1-propanephosphonic acid cyclic anhydride (3.67 mL, 6.14 mmol) and triethylamine (0.570 ml, 4.09 mmol) added at 0 °C under an nitrogen atmosphere. The reaction mixture was then allowed to reach r.t. The mixture was stirred 3 days, then more 1-propanephosphonic acid cyclic anhydride (1.223 mL, 2.05 mmol) and triethylamine (0.285 mL, 2.05 mmol) was added, stirred for another 3h. Water was then added and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organics were dried over Na2SO4 and evaporated. Purification of the residue by silica gel chromatographyusing heptane/ethylacetate 5:1-4:1-3:1 as eluant gave the title compound (0.45 g, 27 percent yield).The product was used as such in the next step.

Reference： [1]Patent: WO2013/54108,2013,A1 .Location in patent: Page/Page column 60; 61

25
[ 430-99-9 ]
[ 1430422-08-4 ]
[ 1430422-09-5 ]

Yield	Reaction Conditions	Operation in experiment
43%		2-Fluoroacrylic acid (1.45 g, 16.06 mmol) and HBTU (7.31 g, 19.27 mmol) were dissolved in dichloromethane (30 mL). Triethylamine (3.36 mL, 24.09 mmol) was added and the reaction was stuffed for 6 min. 6?-Bromo-1?-ethenyl-4-methoxy-1?,3?-dihydrospiro[cyclohexane-1,2?-inden]-1?-amine (mixture of isomers) (2.7 g, 8.03 mmol) was added as a solution in dichloromethane (20 mL). The reaction was stuffed for 16 h. The reaction mixture was poured in water. The phases were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Column chromatography (silica gel) usingdichloromethane yielded 1.4 g (43 percent) of the title compound. MS (ES-) mlz 406, 408 [M-H]-.

Reference： [1]Patent: WO2013/54108,2013,A1 .Location in patent: Page/Page column 39

26
[ 430-99-9 ]
[ 1430422-17-5 ]
[ 1430422-18-6 ]

Yield	Reaction Conditions	Operation in experiment
14.46%		2-Fluoroacrylic acid (3.04 g, 33.70 mmol) and 0-(lH-Benzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (25.6 g, 67.41 mmol) were dissolved in DCM (60 mL). Triethylamine (11.74 mL, 84.26 mmol) was added and the reaction was stirred for 6 min. ( s,4's)-5-Bromo-4'-methoxy-3-vinyl-3H-spiro[benzofuran-2,r-cyclohexan]-3-amine (5.7 g, 16.85 mmol) was added as a solution in DCM (40 mL). The reaction was stirred for 16 h. The reaction mixture was poured in water. The phases were separated and the aqueous phase extracted with DCM. The combined organic phases were dried over MgSO4., filtered and the solvent evaporated. The product was purified by column chromatography using MeOH 0percent to 10percent in DCM to yield 1 g (14.46 percent). 1H NMR (500 MHz, CDC13) delta ppm 1.53 - 1.60 (m, 1 H) 1.60 - 1.72 (m, 2 H) 1.89 - 2.10 (m, 5 H) 3.23 (tt, 3.98 Hz, 1 H) 3.37 (s, 3 H) 4.81 (d, 1 H) 5.18 (dd, 1 H) 5.29 (d, 1 H) 5.64 - 5.77 (m, 1 H) 6.49 - 6.59 (m, 2 H) 6.74 (d, 1 H) 7.32 (d, 1 H) 7.37 (dd, 1 H). MS (ES-) m/z 408, 410 [M-H]~

Reference： [1]Patent: WO2013/54108,2013,A1 .Location in patent: Page/Page column 46; 47

27
[ 430-99-9 ]
[ 1430422-25-5 ]
[ 1430422-26-6 ]

Yield	Reaction Conditions	Operation in experiment
37%		2-Fluoroacrylic acid (2.042 g, 22.68 mmol) and O-( 1 H-benzotriazol- 1 -yl)-N,N,N?,N?15 tetramethyluronium hexafluorophosphate (10.32 g, 27.22 mmol) were taken up in DCM (30mL) and TEA (4.74 mL, 34.02 mmol) was added. The reaction was stirred for 6 min 6-bromo-3,3-dimethyl-4-vinylchroman-4-amine (3.2 g, 11.34 mmol) was added as a solution in DCM (20 mL) and the reaction was stirred for 16 h. The reaction mixture was poured into brine and the phases were separated. The aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and the solvent evaporated. Theproduct was purified by column chromatography using EtOAc 0percent to 100percent in heptane to yield1.5 g (37 percent) of the title compound. 1H NMR (500 MHz, DMSO-d6) delta ppm 0.92 (s, 3 H) 0.99(s, 3 H) 3.80 - 3.99 (m, 2 H) 4.72 (d, 1 H) 5.28 (dd, 1 H) 5.36 (d, 1 H) 5.43 - 5.59 (m, 1 H)6.45 (dd, 1 H) 6.77 (d, 1 H) 7.27 (s, 1 H) 7.31 (d, 1 H) 7.55 (br. s., 1 H). MS (ES+) m/z 354,356 [M+H]+

Reference： [1]Patent: WO2013/54108,2013,A1 .Location in patent: Page/Page column 50

28
[ 430-99-9 ]
[ 1443234-84-1 ]
[ 1443236-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; 3-[(diethoxyphosphinyl)oxy]-1,2,3-benzotriazin-4(3H)-one; In N,N-dimethyl acetamide; at 50℃; for 12h;Inert atmosphere; Sealed tube;	Ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3- 0.10 mmol), <strong>[430-99-9]2-fluoroacrylic acid</strong> (0.013 g, 0.15 mmol), 3-[(diethoxyphosphoryl)oxy]- l,2,3-benzotriazin-4(3H)-one (0.060 g, 0.20 mmol), and DIPEA (0.070 mL, 0.40 mmol) were suspended in DMA (1.0 mL) in a sealed tube. The reaction mixture was purged with argon and the reaction flask was capped and heated to 50 °C for 12 hours. The completed reaction was passed through a syringe filter, and was directly purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1percent NH4OH modifier to afford ethyl 4-{3-[(2-fluoroacryloyl)amino]phenyl}-7H-pyrrolo[2,3-<i]pyrimidine-5- carboxylate. LRMS (ESI) calc'd for C18H] 6FN403 [M+H]+: 355, found 355. 1H NMR (600 MHz, DMSO-D6) delta 12.99 (s, 1H), 10.44 (s, 1H), 8.91 (s, 1H), 8.32 (s, 1H), 8.09 (t, J= 1.8 Hz, 1H), 7.87 (ddd, J= 1.1, 2.1, 8.0 Hz, 1H), 7.45 (t, J= 7.8 Hz, 1H), 7.40 (dt, J = 1.3, 7.7 Hz, 1H), 5.72 (dd, J = 3.6, 47.6 Hz, 1H), 5.44 (dd, J = 3.7, 15.6 Hz, 1H), 3.85 (q, J = 7.1 Hz, 2H), 0.84 (t, J = 7.1 Hz, 3H).

Reference： [1]Patent: WO2013/85802,2013,A1 .Location in patent: Page/Page column 93

29
[ 430-99-9 ]
(S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine [ No CAS ]
(S)-1-(3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidin-1-yl)-2-fluoroprop-2-en-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	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;	The crude product (5.6 mg) of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 2 as an intermediate, 4-(dimethylamino)but-2-enoic acid hydrochloride (6.3 mg), and HATU (15 mg) were dissolved in DMF (1.0 ml). DIPEA (50 mul) was added thereto, followed by stirring overnight. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by preparative reversed-phase HPLC purification (water/acetonitrile (0.1percent formic acid)) to obtain the title compound as a colorless, amorphous substance (2.3 mg)
	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;	[0293]The crude product (5.6 mg) of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 2 as an intermediate, 4-(dimethylamino)but-2-enoic acid hydrochloride (6.3 mg), and HATU (15 mg) were dissolved in DMF (1.0 ml). DIPEA (50 mul) was added thereto, followed by stirring overnight. Chloroform and water were added to the reaction mixture to separate the organic layer. After being washed with a saturated sodium chloride solution, the organic layer was dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by preparative reversed-phase HPLC purification (water/acetonitrile (0.1percent formic acid)) to obtain the title compound as a colorless, amorphous substance (2.3 mg). Table 1 shows the physical properties thereof. [0295] In accordance with Example 4, except that <strong>[430-99-9]2-fluoro-acrylic acid</strong> was used in place of 4-(dimethylamino)but-2-enoic acid hydrochloride, the title compound was obtained as a colorless, amorphous substance. Table 2 shows the physical properties thereof.

Reference： [1]Patent: EP2657233,2013,A1 .Location in patent: Paragraph 0200; 0202
[2]Patent: US2016/193210,2016,A1 .Location in patent: Paragraph 0293; 0295

30
[ 430-99-9 ]
[ 1609468-24-7 ]
[ 1609467-09-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.25h;	Example 1345-amino-3-[4-(4-chlorophenoxy)phenyl]-1 -[(3R)-1 -(2-fluoroacryloyl)piperidin-3-yl]-I H-pyrazole-4-carboxamide To a solution of (R)-5-amino-3-(4-(4-chlorophenoxy)phenyl)-1 -(piperidin-3-yl)-1 Hpyrazole-4-carboxamide (prepared as described in Example 13, step 7) (79.1 mg, 0.192 mmol) in N,N-dimethylformamide (2.00 mL)was cooled to 0°C. 2-(1H- Benzotriazol-1-yl)tris(dimethylamino)phosphonium hexafluorophosphate (106 mg, 0.24 mmol), N,N-diisopropylethylamine (65.3 mg, 0.48 mmol) and <strong>[430-99-9]2-fluoroacrylic acid</strong> (21.69mg, 0.24 mmol) were added at 0°C. The reaction mixture was stirred for 15 mm at 0°C and then quenched by pouring over ice water. The solid was filtered and purified by reverse phase HPLC to afford the title compound. MS (M+H) m/z 484.1.

Reference： [1]Patent: WO2014/68527,2014,A1 .Location in patent: Page/Page column 167

31
[ 430-99-9 ]
[ 1609468-26-9 ]
[ 1609467-25-5 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.5h;	Example 1505-amino-3-[4-(2,4-difluorophenoxy)phenyl]-1 -[(3R)-1 -(2-fluoroacryloyl)piperidin-3- yl]-l H-pyrazole-4-carboxamide To a solution of (R)-5-amino-3-(4-(2,4-difluorophenoxy)phenyl)-1 -(piperidin-3-yl)-H-pyrazole-4-carboxamide (prepared as described in Example 26, step 1) (200 mg,0.48 mmol) in N,N-dimethylformanide (3 mL) at 0 °C was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (235 mg, 0.53 mmol), N, N-diisopropylethylamine (0.22 mL, 1.21 mmol) and <strong>[430-99-9]2-fluoroacrylic acid</strong> (43.6 mg, 0.48 mmol). After 30 mm, the mixture was poured into water/ethyl acetate and the layers seperated. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by reverse-phase HPLC to afford the title compound. 1H NMR (600 MHz,DMSO-d6) 6 ppm 1.57 (m, 1 H), 1.89 - 2.09 (m, 3 H), 2.97 (m, 0.5 H), 3.22 (m, 1 H),3.61 (m, 0.5 H), 3.97 (m, 1 H), 4.13 - 4.42 (m, 2 H), 5.11 - 5.38 (m, 2 H), 6.45 (br. s., 2H), 7.00 - 7.09 (m, 2 H), 7.15 - 7.24 (m, 1 H), 7.42-7.38 (m, 1 H), 7.51 - 7.59 (m, 3 H).MS (M+H) m/z486.1.

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 80 - 85
[2]Patent: WO2014/68527,2014,A1 .Location in patent: Page/Page column 181; 182

32
[ 430-99-9 ]
[ 1609468-35-0 ]
[ 1609467-40-4 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0℃; for 0.5h;	Example 1655-amino-I -[(3R)-I -(2-fluoroacryloyl)piperidin-3-yl]-3-(4-[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-I H-pyrazole-4-carboxamide (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (218 mg, 0.49 mmol), diisopropylamine (0.2 mL, 1.12 mmol) and <strong>[430-99-9]2-fluoroacrylic acid</strong>(40.3 mg, 0.45 mmol) were added to a solution of (R)-5-amino-1-(piperidin-3-yl)-3-(4- ((6-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)- 1 H-pyrazole-4-carboxam ide (prepared as described in Example, step 2) (200 mg, 0.45 mmol) in N,N-dimethylformamide (3 mL) at 0 °C. After 30 mm, the mixture was poured into water/ethyl acetate and the layers separated. The organic layer was dried (Na2504) and concentrated. The crude productwas purified by reverse phase HPLC to afford the title compound. 1H NMR (600 MHz,DMSO-d6) 6 ppm 8.18 (t, J=7.69 Hz, 1 H), 7.70 (d, J=7.47 Hz, 1 H), 7.62 (d, J=8.35 Hz,2 H), 7.41 (d, J=8.35 Hz, 1 H), 7.27 - 7.34 (m, 2 H), 6.45 (s, 2 H), 5.31 (br. s., 1 H), 5.11-5.26 (m, 2 H), 4.10-4.44 (m, 3 H), 3.79-4.06 (m, 1 H), 3.66 (m, 1 H), 3.26 (m, 1 H),2.96 (m., 1 H), 2.07 (m, 1 H), 1.95 (d, J=12.30 Hz, 1 H), 1.58 (m, 1 H). MS (M+H) m/z519.1.

Reference： [1]Patent: WO2014/68527,2014,A1 .Location in patent: Page/Page column 195

33
[ 430-99-9 ]
[ 132959-53-6 ]
(S)-1-(2-allylpyrrolidin-1-yl)-2-fluoroprop-2-en-1-one [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

34
[ 430-99-9 ]
[ 1208242-58-3 ]
N-allyl-N-(2,4-dimethoxybenzyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

35
[ 798542-73-1 ]
[ 430-99-9 ]
N-allyl-N-(2,4-dimethoxybenzyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

36
[ 430-99-9 ]
allyl(3,4-dimethoxybenzyl)amine [ No CAS ]
N-allyl-N-(3,4-dimethoxybenzyl)-α-fluoroacrylamide [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 5777 - 5785

37
[ 430-99-9 ]
[ 267243-68-5 ]
[ 1420403-40-2 ]