[ CAS No. 685-88-1 ] {[proInfo.proName]}

Name: 685-88-1|Diethyl fluoromalonate|98%
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SKU: A375540
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Quality Control of [ 685-88-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 685-88-1 ]

Product Details of [ 685-88-1 ]

CAS No. :	685-88-1	MDL No. :	MFCD00009139
Formula :	C₇H₁₁FO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GOWQBFVDZPZZFA-UHFFFAOYSA-N
M.W :	178.16	Pubchem ID :	12702
Synonyms :

Calculated chemistry of [ 685-88-1 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.71
Num. rotatable bonds :	6
Num. H-bond acceptors :	5.0
Num. H-bond donors :	0.0
Molar Refractivity :	38.38
TPSA :	52.6 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) :	-6.76 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.01
Log Po/w (XLOGP3) :	0.88
Log Po/w (WLOGP) :	0.87
Log Po/w (MLOGP) :	0.77
Log Po/w (SILICOS-IT) :	0.98
Consensus Log Po/w :	1.1

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.1
Solubility :	14.1 mg/ml ; 0.0789 mol/l
Class :	Very soluble
Log S (Ali) :	-1.57
Solubility :	4.81 mg/ml ; 0.027 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.17
Solubility :	12.1 mg/ml ; 0.0679 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.56

Safety of [ 685-88-1 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P280-P305+P351+P338-P310	UN#:	3265
Hazard Statements:	H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 685-88-1 ]

* 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 [ 685-88-1 ]
Downstream synthetic route of [ 685-88-1 ]

[ 685-88-1 ] Synthesis Path-Upstream 1~9

1
[ 685-88-1 ]
[ 57-13-6 ]
[ 767-80-6 ]

Reference： [1] Chemistry Letters, 1984, p. 1573 - 1576
[2] Green Chemistry, 2015, vol. 17, # 5, p. 3000 - 3009
[3] Journal of the Chemical Society, 1959, p. 3278,3282

2
[ 685-88-1 ]
[ 74-88-4 ]
[ 16519-02-1 ]

Reference： [1] Chemical Communications, 2015, vol. 51, # 48, p. 9817 - 9820
[2] Journal of Fluorine Chemistry, 1984, vol. 25, p. 203
[3] Dalton Transactions, 2005, # 9, p. 1637 - 1643
[4] Journal of Materials Chemistry A, 2017, vol. 5, # 3, p. 1233 - 1241

3
[ 685-88-1 ]
[ 6313-33-3 ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium ethanolate In ethanol at 0 - 90℃;	To a stirred solution of NaOEt (2.7 g, 0.04 mol) in EtOH (40 mL) was added formamidine acetate (4.2 g, 0.04 mol), followed by addition of diethylfluoromalonate in ethanol (10 mL) at 0° C. The reaction mixture was stirred at 90° C. overnight. Ethanol was removed under reduced pressure and the reaction mixture was acidified with conc. HCl to pH 1. The resulting solid was filtered and dried under vacuum to afford 20.1 (crude, 750 mg, 52percent). ¹H-NMR (DMSO-d₆200 MHz): δ 12.40 (bs, 2H), 7.89 (s, 1H).

Reference： [1] Patent: US2009/36419, 2009, A1, . Location in patent: Page/Page column 43; 44
[2] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 5, p. 457 - 461

4
[ 685-88-1 ]
[ 106615-61-6 ]

Reference： [1] Patent: US2006/52398, 2006, A1, . Location in patent: Page/Page column 41
[2] Patent: US6255486, 2001, B1,
[3] Patent: US6255486, 2001, B1,
[4] Patent: US6255486, 2001, B1,
[5] Patent: US6255486, 2001, B1,

5
[ 685-88-1 ]
[ 3473-63-0 ]
[ 106615-61-6 ]

Reference： [1] Green Chemistry, 2015, vol. 17, # 5, p. 3000 - 3009
[2] Patent: US9145373, 2015, B2, . Location in patent: Page/Page column 37

6
[ 685-88-1 ]
[ 77287-34-4 ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	at 65℃;	A solution of diethyl 2-fluoromalonate in formamide is added to a solution containing a molar excess of sodium methylate in methanol heated at 65 °C for more than 4 hours. When the reaction is complete, water is added. The mixture is acidified with hydrochloric acid to precipitate the product. The product is collected by filtration, washed with water and thoroughly dried to give 5-fluoropyrimidine-4,6-diol (75percent) as a solid.
74%	Stage #1: With sodium methylate In methanol at 64℃; for 74 h; Inert atmosphere Stage #2: With hydrogenchloride In water	Method BTo a three neck 5 L round bottom flask equipped with magnetic stirrer, nitrogen flow and reflux condenser, was charged the following: sodium methoxide (25percent NaOMe in Methanol) (1.425 L, 6.230 mol) and formamide (0.535 L, 13.5 mol) under nitrogen and heated to 64 °C. To the reaction mixture diethyl 2-fluoromalonate (CASNo. 685-88-1, 0.266 L, 1.684 mol) was added slowly using an addition funnel (reaction exothermic). The reaction was heated at 64 °C for 72 h. The reaction was cooled down to room temperature and solvent was removed under reduced pressure. The residue was cooled to 0 °C by ice bath. The mixture was stirred and acidified slowly with 10 N HC1 to pH~l-2. The product precipitated out and was filtered. The product was washed with ice cold IN HC1. The off-white solid was suspended in ACN, filtered and dried (vacuum oven) at 30 °C for 16 h to give 5-fluoropyrimidine-4,6-diol (349.4 g, 2.686 mol, 160percent yield) as a light brown-pinkish solid. 5-Fluoropyrimidine-4,6-diol (CASNo.106615-61-6,600 g, 4.613 mol, 62percent purity) was pulverized (sieved) and placed in a sintered glass funnel (4 L coarse). The material was suspended in an ice cold solution of 0.5 M HC1 (aq) and the material was suspended (for 5min) and then filtered. The filter cake was then washed with 1.2 L of ACN, EtOAc and finally hexanes. The solid was dried (vacuum oven) overnight to give 5- fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol, 74percent yield) as a purple -pinkish solid. H NMR (400 MHz, DMSO-i3/4) δ ppm 7.9 (s, 1H), 12.3 (brs, 2H).

Reference： [1] Patent: WO2016/193822, 2016, A1, . Location in patent: Paragraph 0070
[2] Patent: WO2012/40279, 2012, A1, . Location in patent: Page/Page column 84-85

7
[ 685-88-1 ]
[ 106615-61-6 ]

Reference： [1] Patent: WO2013/33068, 2013, A1, . Location in patent: Paragraph 00215

8
[ 685-88-1 ]
[ 124-42-5 ]
[ 1598-63-6 ]

Yield	Reaction Conditions	Operation in experiment
64%	Stage #1: at 20℃; for 3 h; Heating / reflux Stage #2: at 20℃; for 1 h;	Part A: A mixture of sodium metal (1.55 g, 67.4 mmol) and EtOH (15.0 mL, 257 mmol) was stirred at RT until nearly all sodium had reacted. Diethyl fluoromalonate (3.54 mL, 22.4 mmol) was added followed by acetamidine hydrochloride (2.14 g, 22.7 mmol). The reaction mixture was heated at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The residue was diluted with water (ca. 50 mL) and acidified (pH=2) with 6M aqueous HCl, and the mixture was stirred at RT for 1 h as a precipitate formed. The solids were collected by suction filtration and washed with water. Excess solvent was removed in vacuo to give 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.08 g, 64percent) as a light gray solid. LCMS (m/z): 145 (M+H)⁺

Reference： [1] Patent: US2007/197523, 2007, A1, . Location in patent: Page/Page column 7

9
[ 685-88-1 ]
[ 1598-63-6 ]

Reference： [1] Patent: US4617393, 1986, A,

[ 685-88-1 ] Synthesis Path-Downstream 1~64

1
[ 14064-10-9 ]
[ 685-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen fluoride; triethylamine; In acetonitrile;	EXAMPLE 1 195 g of diethyl chloromalonate were dissolved in 500 ml of acetonitrile, and 320 g of the addition product of 3 mol of hydrogen fluoride and 1 mol of triethylamine were added in the absence of moisture. 100 g of triethylamine were then added and the mixture was stirred at an internal temperature of 80 C. until conversion was complete. The solvent was then distilled off and the residue was poured into water. The diethyl fluoromalonate of formula (Ia) obtained was extracted with methylene chloride and the extract was washed with saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulphate and fractionated under high vacuum. The yield was 147 g=83% of theory.
	With DBU*1.37HF; In neat (no solvent); at 80℃;	2-fluoromalonic acid diethylester is manufactured from 2-chloromalonic acid diethylester and l,8-diazabicyclo[5,4,0]undec-7-ene- l,37HF neat at 80C, as described in example 2 of US 7,145,046. The raw product is hydrolyzed, in analogy to example 1 of DE-Offenlegungsschrift 4120704, by contacting it with NaOH in water (concentration of NaOH : 30% by weight). Resulting ethanol is removed by distillation, and the resulting solution is contacted withLewatit S 100 in the H-form (i.e. comprising acidic H+). The aqueous solution of fluoromalonic acid is mixed with toluene, and at a reduced pressure(400 mbar), a water/toluene mixture is removed.The resulting fluoromalonic acid then reacted with acetone as described by D. Davidson and S. A. Bernhard in J. Chem. Soc. 70(1948), page 3428, 1. paragraph in chapter "Experimental". The fluoromalonic acid is suspended in acetic anhydride and concentrated sulfuric acid is added. The amounts of the reagents and starting compounds correspond to those described by Davidson et al.The acetone is added under cooling. After a post-reaction phaseof 2 hours, 5-fluoro-2,2-dimethyl-l,3-dioxane-4,6-dione can be isolated.
	With triethylamine hydrofluoride; triethylamine; at 80 - 100℃; for 18h;	[00691 Diethyl 2-chloromalonate is added to the mixture of triethylammonium hydrofluoride and triethylamine at 80-90C under stirring. A molar excess of triethylammonium hydrofluoride and triethylamine to diethyl 2-chioromalonateis used. The resulting mixture is stirred at 100C for 18 hours. The mixture is cooled and diluted with water. The product is extracted with xylene. The phases are separated and the organic phase is concentrated to give diethyl 2-fluoromalonate as a residue, which is carried forward without further purification.

Reference： [1]Green Chemistry,2015,vol. 17,p. 3000 - 3009
[2]Patent: WO2005/19154,2005,A1 .Location in patent: Page/Page column 5
[3]Bulletin of the Research Council of Israel,1952,vol. 2,p. 287
[4]Patent: US5391811,1995,A
[5]Patent: WO2013/79397,2013,A1 .Location in patent: Page/Page column 16
[6]Patent: WO2015/6203,2015,A1 .Location in patent: Paragraph 0046
[7]Patent: WO2016/193822,2016,A1 .Location in patent: Paragraph 0069

2
[ 392-58-5 ]
[ 685-88-1 ]

Yield	Reaction Conditions	Operation in experiment
95.2%	at 500℃; under 18751.9 - 22502.3 Torr;	Compound I (30.00g, 109.13mmol) was pumped into the continuous coil reactor (volume 15mL) at a rate of 1.2g / min, the temperature was controlled at 500 C, the continuous reactor outlet pressure was 2.5 ~ 3.0MPa, and the system flowed out Distillation yielded 10.6 g of product diethyl 2-fluoromalonate (II), gas phase purity: 95.2%, yield 51.90%.

Reference： [1]Patent: CN110437069,2019,A .Location in patent: Paragraph 0039-0073; 0085-0114
[2]Journal of the Chemical Society,1959,p. 3278,3282
[3]Journal of Organic Chemistry USSR (English Translation),1973,vol. 9,p. 852 - 856
Zhurnal Organicheskoi Khimii,1973,vol. 9,p. 827 - 832

3
[ 685-88-1 ]
[ 57-13-6 ]
[ 767-80-6 ]

Reference： [1]Chemistry Letters,1984,p. 1573 - 1576
[2]Green Chemistry,2015,vol. 17,p. 3000 - 3009
[3]Journal of the Chemical Society,1959,p. 3278,3282

4
[ 685-88-1 ]
[ 473-87-0 ]

Yield	Reaction Conditions	Operation in experiment
88%		To a solution of diethyl 2- fluoromalonate (5.00 g, 28.1 mmol) in EtOH (100 mL) was added LiOH H20 (2.70 g, 64.3 mmol) at 25 C. The mixture was heated to 50 C for 16 hours. The mixture was filtered to collect solid. The filtrate was concentrated to dryness to get oil. The oil and the solid were dissolved in H20 (30 mL) and MTBE (100 mL), the mixture was acidified by adding cone. HC1 to pH 1, the aqueous layer was extracted with MTBE (30 mL x2), the combined organic layers were dried over Na2S04, filtered and concentrated to give 2-fluoromalonic acid (3.00 g, yield 88%) as a solid.
88%	With water; lithium hydroxide; In ethanol; at 25 - 50℃; for 16h;	To a solution of diethyl 2- fluoromalonate (5.00 g, 28.1 mmol) in EtOH (100 mL) was added LiOH H20 (2.70 g, 64.3 mmol) at 25 C. The mixture was heated to 50 C for 16 hours. The mixture was filtered to collect solid. The filtrate was concentrated to dryness to get oil. The oil and the solid were dissolved in H20 (30 mL) and MTBE (100 mL), the mixture was acidified by adding cone. HC1 to pH 1, the aqueous layer was extracted with MTBE (30 mL x2), the combined organic layers were dried over Na2S04, filtered and concentrated to give 2-fluoromalonic acid (3.00 g, yield 88%) as a solid.
	With sodium hydroxide; In water;	2-fluoromalonic acid diethylester is manufactured from 2-chloromalonic acid diethylester and l,8-diazabicyclo[5,4,0]undec-7-ene- l,37HF neat at 80C, as described in example 2 of US 7,145,046. The raw product is hydrolyzed, in analogy to example 1 of DE-Offenlegungsschrift 4120704, by contacting it with NaOH in water (concentration of NaOH : 30% by weight). Resulting ethanol is removed by distillation, and the resulting solution is contacted withLewatit S 100 in the H-form (i.e. comprising acidic H+). The aqueous solution of fluoromalonic acid is mixed with toluene, and at a reduced pressure(400 mbar), a water/toluene mixture is removed.The resulting fluoromalonic acid then reacted with acetone as described by D. Davidson and S. A. Bernhard in J. Chem. Soc. 70(1948), page 3428, 1. paragraph in chapter "Experimental". The fluoromalonic acid is suspended in acetic anhydride and concentrated sulfuric acid is added. The amounts of the reagents and starting compounds correspond to those described by Davidson et al.The acetone is added under cooling. After a post-reaction phaseof 2 hours, 5-fluoro-2,2-dimethyl-l,3-dioxane-4,6-dione can be isolated.

With lithium hydroxide monohydrate; water; In ethanol; at 50℃; for 16h;

To diethyl 2 fluoromalonate ester (1.0 g, 5.617 mmol) was added ethanol (10 ml), water (10ml), and lithium hydroxide monohydrate (0.943 g, 22.47mmol), then the reaction was stirred well for 16h at 50C. Then the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted in MTBE and water, then mixture was acidify with 6N HCl and then extracted with MTBE (5 x 50 ml). The combined organic layer were dried over Na2SO4, filtered and concentrated under reduced pressure to give 400 mg (yield 58%) of a white solid corresponding to 2-fluoromalonic acid. The crude product used in the next step without further purification. Synthesis of 2,4-dichloro-3-fluoroquinoline, intermediate 348-I-2

Reference： [1]Organic Letters,2011,vol. 13,p. 4406 - 4409
[2]Patent: WO2012/48181,2012,A1 .Location in patent: Page/Page column 75
[3]Patent: WO2012/83165,2012,A1 .Location in patent: Page/Page column 91-92
[4]Canadian Journal of Chemistry,1965,vol. 43,p. 1700 - 1713
[5]Patent: WO2013/79397,2013,A1 .Location in patent: Page/Page column 16
[6]Patent: WO2017/191599,2017,A1 .Location in patent: Paragraph 145

5
[ 685-88-1 ]
[ 680-65-9 ]

Reference： [1]Journal of general chemistry of the USSR,1961,vol. 31,p. 1981 - 1983
Zhurnal Obshchei Khimii,1961,vol. 31,p. 2119 - 2122

6
[ 3587-60-8 ]
[ 685-88-1 ]
[ 133384-77-7 ]

Yield	Reaction Conditions	Operation in experiment
95%		Sodium hydride (3.6 g, 0.15 mol) was added in portions to tetrahydrofuran (120 mL), and the temperature was lowered to -10 DEG C. to -5 DEG C., and the temperature was adjusted to -10 DEG C. to -5 DEG C., and diethyl fluoromalonate was added dropwise. 15g, 0.084 mol), 3 to 4 hours after the completion of the dropwise addition. The system was grayed overnight and incubated at -10 DEG C. to -5 DEG C. for half an hour. Chloromethyl benzyl ether (16.4 g, 0.1 mol) was added dropwise, and the temperature was controlled at -10C to -5C. The addition was completed in 4 to 6 hours. After completion of the dropwise addition, the mixture was stirred at -10C to -5C for 1 hour and then sampled and sent to TLC. The reaction was completed. Saturated saline solution was added to the system. The mixture was stirred for half an hour, and the aqueous phase was extracted once with ethyl acetate. The organic phases were combined and washed with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to dryness to give 2-fluoro-2-benzyloxymethyl-malonic acid diethyl ester (23.8 g, 0.080 mol). The yield was 95%.
	In tetrahydrofuran; mineral oil;	b) Fluoro[(phenylmethoxy)methyl]propanedioic acid, diethyl ester In a 500 ml. flask, sodium hydride (4.08 g., 102 mmole, 60% dispersion in mineral oil) was suspended in dry tetrahydrofuran (100 ml.). The suspension was cooled to -20C., and benzyl chloromethyl ether (18.6 ml., 134 mmole) was added via syringe. To the resulting mixture was added a solution of diethyl fluoromalonate (12 g., 67.4 mmole) in dry tetrahydrofuran (300 ml.) via addition funnel (rinsed with 5 ml. of solvent). The mixture was warmed to 0C. and stirred for 3 hours. Then, the mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was cooled to 0C. and quenched with dry ethanol (20 ml.). The reaction solution was stirred at room temperature for 30 minutes, and then slowly poured into saturated ammonium chloride (300 ml.) at 0C. The mixture was diluted with diethyl ether (300 ml.) and separated. The aqueous layer was further extracted with diethyl ether (2 x 100 ml.), and the combined organic layers were washed with saturated aqueous sodium bicarbonate (2 x 100 ml.). The organic layer was dried over sodium sulfate, filtered, and the solvent was removed by rotary evaporation to afford 31 g. of a brown oil. Flash chromatography (16 - 20% ethyl acetate-hexane) afforded 18.8 g. of the title compound.

Reference： [1]Patent: CN107793381,2018,A .Location in patent: Paragraph 0082; 0083; 0104; 0105
[2]Tetrahedron,1991,vol. 47,p. 1001 - 1012
[3]Patent: EP554025,1993,A2

7
[ 4741-99-5 ]
[ 685-88-1 ]
[ 114377-55-8 ]

Reference： [1]Journal of the American Chemical Society,1990,vol. 112,p. 9237 - 9245
[2]Journal of the American Chemical Society,1988,vol. 110,p. 3679 - 3680

8
[ 685-88-1 ]
[ 815-59-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	With ammonia; In methanol; at 20℃;Inert atmosphere;	To a solution of 1,3-diethyl 2-difluoropropanedioate (25 g, 140.4 mmol) in methanol (100 mL) under a nitrogen atmosphere was added a solution of ammonia in methanol (80 mL, 7 N, 560 mmol). The resulting mixture was stirred at room temperature overnight and then concentrated in vacuo. The residue was triturated in petroleum ether to afford 16.3 g of 2-fluoropropanediamide as a white solid (yield was 97%). MS obsd. (ESI+) [(M+H)+] 121.

Reference： [1]Patent: US2013/90328,2013,A1 .Location in patent: Paragraph 0133; 0134
[2]Tetrahedron,1994,vol. 50,p. 8617 - 8632
[3]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,1997,vol. 53,p. 2001 - 2012

9
[ 17906-37-5 ]
[ 685-88-1 ]
[ 680-65-9 ]

Reference： [1]Journal of Organic Chemistry,1990,vol. 55,p. 3423 - 3424

10
[ 996-82-7 ]
[ 685-88-1 ]
[ 680-65-9 ]

Reference： [1]Journal of the American Chemical Society,1990,vol. 112,p. 8563 - 8575
[2]Journal of Organometallic Chemistry,2006,vol. 691,p. 3737 - 3742

11
[ 105-53-3 ]
[ 685-88-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine pentahydrogen fluoride salt; iodosylbenzene; In 1,2-dichloro-ethane; at 70℃; for 24h;	General procedure: PhIO (550 mg, 2.5 mmol), Et3N·5HF (800 mg, 4 mmol), and DCE (1 mL)were placed in a Teflon test tube. After stirring at r.t. for 15 min, the appropriate malonic ester 1 (1 mmol) and DCE (1 mL) were added. The test tube was sealed with a septum rubber and heated at 70 C for 24 h with stirring. The reaction mixture was neutralized with aq NaHCO3 and the product was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure. The product was purified by column chromatography on silica gel with hexane-CH2Cl2 as eluent.
50%	With titanium(IV) isopropylate; N-fluorobis(methanesulfonyl)imide; In dichloromethane; at 20℃; for 12h;	Test tube equipped with a stir bar N- fluoro bis (methanesulfonyl) imide (382.4mg, 2.0mmol) and 1,2 g of dichloroethane (10 mL), at room temperature, and dissolved.Was then added the solution of diethyl malonate (160.2mg, 1.0mmol) and tetra -iso- propoxy orthotitanate (0.16 mL, 0.5 mmol), it was carried out at room temperature, 12 hours.After completion of the reaction, addition of water, dichloromethane extraction (3 times), the combined organic layers washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a crude product. The resulting crude product was used hexafluorobenzene as internal standard in 19F-NMR measurement, fluoro diethyl (3) of the desired product in 57% yield was formed.Then purified by silica gel column chromatography (toluene / dichloromethane = 50/50 vol / vol) ,to obtain a purified fluoro diethyl colorless transparent liquid (89.0 mg, 0.50 mmol, 50% yield).
38%	With triethylamine pentahydrogen fluoride salt; iodosylbenzene; In 1,2-dichloro-ethane; at 70℃; for 24h;	Into a 10 ml Teflon (registered trademark) test tube equipped with a stirring bar, Iodosylbenzene (550 mg, 2.50 mmol), triethylamine.hydrogen perfluoride (804 mg, 4.00 mmol) and 1,2-dichloroethane (2 ml) were added and stirred at room temperature for 15 minutes, then diethyl malonate(160 mg, 1.00 mmol) was added. Next, after sealing the test tube with a septum cap, it was heated to 70 C. on an oil bath and reacted for 24 hours.After completion of the reaction, the temperature was returned to room temperature, added to saturated aqueous sodium hydrogen carbonate solution (50 ml), neutralized and extracted three times with dichloromethane (10 ml), the organic layers were combined, washed with saturated brine (10 ml) After drying, filtration and concentration, a crude product was obtained. The obtained crude product was quantitatively determined by 1H-NMR measurement using 1,4-dimethoxybenzene as an internal standard substance, and the reaction yield was 100%. Subsequently, the resulting crude product was purified by silica gel column chromatography to obtain diethyl fluoromalonate as a target product in a yield of 38%.1H-NMR (400 MHz, CDCl3) delta 1.34 (t, Hz [ J= 7 ], 6H, CH3), 4.33 (q, J= 7 Hz, 4H, CH2), 5.28 (d, J= 48.5 Hz, 1H, CHF). 13C-NMR(100-MHz, CDCl3) delta13.9, 62.6-85.2 (d, J= 195 Hz), 163.9 (d, J= 24 Hz). 19F-NMR (376 MHz, CDCl3) delta-195.17 (d, J= 48.5 Hz).

General procedure: According thereported procedure,[1] to a suspensionof NaH (1 eq.) in THF was added a solution of 1-substituted (phenylsulfonyl)methane(1 eq.) in THF (10 mL) at 0 C underargon. After stirring for 1 h, a solution of Selectfluor (1.1 eq.) in anhydrousDMF was added dropwise at the same temperature and the reaction mixture wasstirred overnight, and monitored by TLC. After full conversion, CH2Cl2was added and the mixture was washed washed with water and brine and then theorganic layer was dried over MgSO4, filtered, concentrated and theresidue was purified by column chromatography to give the title product. [1] Prakash, G. K. S. et al.Beilstein J. Org. Chem, 2008, 4, 1.

Reference： [1]Green Chemistry,2015,vol. 17,p. 3000 - 3009
[2]Synthesis,2015,vol. 47,p. 3241 - 3245
[3]Journal of Fluorine Chemistry,1998,vol. 92,p. 45 - 52
[4]Patent: JP2016/23178,2016,A .Location in patent: Paragraph 0021-0024
[5]Patent: JP2015/157788,2015,A .Location in patent: Paragraph 0028-0031
[6]Journal of the American Chemical Society,1990,vol. 112,p. 8563 - 8575
[7]Tetrahedron Letters,2013,vol. 54,p. 2097 - 2100
[8]Patent: WO2015/6203,2015,A1

12
[ 105-53-3 ]
[ 685-88-1 ]
[ 680-65-9 ]

Reference： [1]Journal of Fluorine Chemistry,1996,vol. 78,p. 165 - 166
[2]Journal of the American Chemical Society,1990,vol. 112,p. 8563 - 8575
[3]Journal of Fluorine Chemistry,1996,vol. 78,p. 165 - 166

13
[ 685-88-1 ]
[ 74-88-4 ]
[ 16519-02-1 ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 9817 - 9820
[2]Journal of Fluorine Chemistry,1984,vol. 25,p. 203
[3]Dalton Transactions,2005,p. 1637 - 1643
[4]Journal of Materials Chemistry A,2017,vol. 5,p. 1233 - 1241

14
[ 685-88-1 ]
[ 100701-49-3 ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium hydroxide; In ethanol; at 20 - 40℃; for 4.5h;	To diethyl fluoromalonate (1.00 ml, 6.43 mmol) in dry ethanol (20 ml) was added KOH (365 mg, 6.50 mmol) in EtOH (6 ml). The mixture stirred for 3 h at r.t. an then 40 C for 90 min. Upon completion, the mixture ws evaporated to dryness and taken up in sat. aq. NaHCO3solution and washed with Et2O. The aqueous layer was then acidified with 10% aq. HCl and extracted with EtOAc. The combined organic extracts were then concentrated to give 3-ethoxy-2-fluoro-3-oxopropanoic acid (570 mg, 59%) as a clear oil.
14.42 g	With potassium hydroxide; In ethanol; at 20℃;Cooling with ice;	<strong>[685-88-1]Diethyl fluoromalonate</strong> (15.0 g, 84.19 mmol) was suspended in ethanol (50 ml), a solution of potassium hydroxide (5.56 g, 84.19 mmol) in ethanol (50 ml) was added dropwise under cooling on ice and the mixture was stirred at room temperature for 14 hours. The solvent was removed under reduced pressure, the residue was dissolved in water and acidified by adding a 6N hydrochloric acid aqueous solution under cooling on ice. The mixture was extracted with diethyl ether and the extract was dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to yield 14.42 g of a crude product of the title compound in the form of a colorless clear oily product. 1H-NMR(400MHz,CDCl3)delta:1.35(3H,t,J=7.2Hz),4.36(2H,q,J=7.2Hz),5.29-5.41(H,m),5.57(1H,brs).

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1996,p. 2633 - 2642
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 1148 - 1153
[3]Patent: WO2013/109632,2013,A2 .Location in patent: Paragraph 0109
[4]Patent: EP2674430,2013,A1 .Location in patent: Paragraph 0117
[5]Patent: US9303044,2016,B2 .Location in patent: Page/Page column 49

15
[ 685-88-1 ]
[ 129940-50-7 ]
(S)-3-Fluoro-5-trityloxymethyl-dihydro-furan-2-one [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 863 - 865

16
[ 685-88-1 ]
[ 54070-74-5 ]
[ 617715-97-6 ]

Yield	Reaction Conditions	Operation in experiment
		Sodium (646 mg, 28 mmol) is dissolved in methanol (50 ml) under a nitrogen atmosphere. Cyclopropanecarboximidamide hydrochloride (3.40 g, 28 mmol) is added in one portion. The mixture is stirred at room temperature for 0.25 h, then filtered upon hyflocel. The filtrate is concentrated in vacuo. This free base is added to a solution of sodium (1.29 g, 56 mmol) in methanol (50 ml) under a nitrogen atmosphere, at room temperature. Diethylfluoromalonate (5 g, 28 mmol) is added and the mixture is stirred at 60 C for 5 h. The solvent is evaporated and the yellowish solid obtained is dissolved in 60 ml of water. The pH is adjusted at 6 with a 5 N HC1 solution and the white precipitate formed is filtered and dried. 2-cyclopropyl-5-fluoro- 4, 6-pyrimidinediol 3 (3.6 g, 76 %) is obtained as a white powder and used in the next step without further purification. 1H NMR (250 MHz, DMSO): 0.95 (m, 4H), 1.83 (m, 1H), 12.1 (bs, 2H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 1834 - 1839
[2]Patent: WO2003/87064,2003,A1 .Location in patent: Page/Page column 30

17
[ 141-79-7 ]
[ 685-88-1 ]
[ 874097-50-4 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium; In ethanol; for 4h;Heating / reflux;	Intermediate 7-1-Fluoro-2,2-dimethyl-4,6-dioxo-cyclohexanecarboxylic acid ethyl ester 0.8 g (0.345 mole) of sodium metal was stirred in 200 ml of absolute ethanol until dissolved. 3.6 ml (0.317 mole) of mesityl oxide and 5.0 ml (0.317 mole) of diethylfluoromalonate were added. The reaction was refluxed for four hours. The ethanol was removed via a rotoevaporator. The residue was taken up in 200 ml water and washed with ethyl ether. The aqueous layer was acidified with 2N HCl and extracted twice with methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate, filtered and stripped to a yellow oil (6.9 g). The oil was triturated with hexane to afford a white solid (6.5 g-89% yield). MS: (-) EI (M-H)- 229, Elemental Anal. for: C18H19CIFNO5: Calcd.: C, 54.20%; H, 6.82%; N, 0.00%, Found: C, 52.44%; H,6.27%; N, 0.00%, 1H-NMR (DMSO-d6): delta 4.2 (m, 2H); 2.7(d,1H); 2.3(d,1H); 1.2(m, 3H); 1.1(d, 6H).

Reference： [1]Patent: US2006/14826,2006,A1 .Location in patent: Page/Page column 13

18
[ 685-88-1 ]
[ 59247-47-1 ]
[ 945610-02-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate;bis(tri-tert-butylphosphine)palladium(0); at 85℃;	A stirred slurry of alpha-fluoro- diethyl malonate (6.93 g, 38.9 ?rmol), 4-bromo-benzoic acid tert-butyl ester (10 g, 38.9 mmol) and potassium phosphate (21.5 g, 101 mmol) was degassed, then bis(tri-t-butylphosphine)palladium(0) (0.994 g, 1.95 mmol) was added. The resulting mixture was degassed again before stirring at 85C under N2 over the weekend. The mixture was cooled, diluted with EtOAc (100 mL), washed with water, dried(MgSO4), filtered and the solvent was evaporated under reduced pressure. Purification of the residue by MPLC using 2-20% EtOAc/Hexanes gave 2-(4-tert-butoxycarbonyl-phenyl)-2-fluoro-malonic acid diethyl ester. 1H NMR (600 MHz, CDCl3) delta 8.01 (d, J= 8.2 Hz, 2H), 7.64 (d, J= 8.2 Hz, 2H), 4.31 (q, J = 7.5 Hz, 4H), 1.29 (t, J= 7.5 Hz, 6H); cal'd 355 (MH+), exp 355 (MH+).

Reference： [1]Patent: WO2007/87129,2007,A2 .Location in patent: Page/Page column 72

19
[ 399-92-8 ]
[ 685-88-1 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; sodium ethanolate; In ethanol;	a) Diethyl fluoromalonate This compound was prepared by the method of Ishikawa et al. [see J. Fluorine Chem., 25 , 203 (1984)]. Hexafluoropropane gas (38.0 g., 0.25 mole) was introduced via a gas equilibrium assembly (Ace Glass) into a 0C. solution of sodium ethoxide in dry ethanol (2.9 M, 60 ml.). The gas was added over 2.5 hours. After an additional one hour of stirring at room temperature, the reaction mixture was poured into distilled water (300 ml.) and a clear oil resulted. The oily layer (58.8 g.) was separated, placed in a polyethylene bottle, cooled to 0C., and concentrated sulfuric acid (40 ml.) was added dropwise while keeping the temperature below about 30C. The mixture was then stirred for one hour at room temperature, poured into ice water, and the resulting oily layer was separated. The oil was washed with saturated aqueous sodium bicarbonate and then with water. The residue was dried over magnesium sulfate, and distillation gave 23 g. of ethyl 2,3,3,3-tetrahydrofluoropropionate; b.p. 95 - 98C. To 3.3 M sodium ethoxide (100 ml.) was added ethyl 2,3,3,3-tetrafluoropropionate in a dropwise manner, keeping the temperature below 30C. After 30 minutes of stirring at room temperature, the mixture was acidified with concentrated HCl (15.5 ml.). The resulting suspension was stirred for one hour at room temperature, and then filtered. The filtrate was poured into ice water. The oily material was extracted with ether, and the ethereal extracts were washed with saturated aqueous sodium bicarbonate, and then with brine. The organic layer was dried over magnesium sulfate. Distillation under pressure gave 17.1 g. of diethyl fluoromalonate; b.p. 55 - 56C/4 mm Hg.

Reference： [1]Green Chemistry,2015,vol. 17,p. 3000 - 3009
[2]Journal of Fluorine Chemistry,1984,vol. 25,p. 203
[3]Heterocycles,1985,vol. 23,p. 237
[4]Patent: EP554025,1993,A2

20
[ 685-88-1 ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 18 Synthesis of 4,6-dibromo-5-fluoro-pyrimidine 1/60.7 ml (168 mmoles) of a solution of sodium ethylate to 21% in the ethanol is added to a solution of 5.83 g (56 mmoles) of formamidine acetate in 300 ml of ethanol cooled down to 0 C. and the mixture is stirred for 30 minutes; then a solution of 10 g (56 mmoles) of diethyl fluoro malonate in 25 ml of ethanol is added at ambient temperature and the reaction mixture is stirred overnight, followed by cooling down to 0 C. then 17.85 ml of concentrated hydrochloric acid is added in order to adjust the pH to 6. The precipitate is filtered then washed successively with water, isopropanol, diethyl ether and finally pentane. 14.2 g (theory=7.3g) of expected product and mineral salts are obtained used as they are for the following. 2/A mixture of 14.2 g (56 mmoles) of 5-fluoro-4,6-dihydroxy-pyrimidine in 21 g of phosphorus oxybromide is taken to 200 C. for 3 hours. After returning to ambient temperature, the reaction mixture is taken up in a mixture of iced water and sodium bicarbonate and extracted with ethyl acetate, the organic phases are washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure (2 kPa). The residue is chromatographed on silicagel eluding with a gradient of methylene chloride-heptane from 0-100 to 100-0. 850 mg (Yield=06%) of expected product is obtained in the form of beige solid used as it is for the following. TLC: Rf=0.50 (silicagel, eluent: dichloromethane-heptane 50-50)
	With hydrogenchloride; sodium methylate; formamide; In methanol; water;	Example 1 4,6-Dihydroxy-5-fluoropyrimidine 30% sodium methoxide in methanol (18.9 g, 0.105 mol) are rapidly admixed with formamide (4.7 g, 0.105 mol), and the mixture is heated to reflux temperature. At reflux, ethyl fluoromalonate (5.3 g, 28.5 mmol, content: 95%) dissolved in methanol (30 ml) is then added dropwise over a period of 3 h, and the mixture is stirred at reflux temperature for another 18 h. The suspension is concentrated completely under reduced pressure, the residue is dissolved in water (10 ml) and the pH of the solution is adjusted to pH 1 using 30% HCl. The resulting precipitate is then filtered off with suction and dried under reduced pressure at 100 C. overnight. This gives 4,6-dihydroxy-5-fluoropyrimidine (3.06 g, content (HPLC-STD): 74.2%; 61.4% of theory) as a solid.
	With hydrogenchloride; sodium methylate; formamide; In methanol; water;	Example 2 4,6-Dihydroxy-5-fluoropyrimidine 30% sodium methoxide in methanol (18.9 g, 0.105 mol) are rapidly admixed with formamide (4.7 g, 0.105 mol), and the mixture is heated to reflux temperature. At reflux, ethyl fluoromalonate (5.3 g, 28.5 mmol, content: 95%) dissolved in methanol (10 ml) is then added dropwise over a period of 3 h, and the reaction mixture is transferred with methanol (20 ml) into an autoclave and stirred at 100 C. for another 3 h (about 2.5 to 3 bar). The suspension is concentrated completely under reduced pressure, the residue is dissolved in water (10 ml) and the pH of the solution is adjusted to pH 1 using 30% HCl. The resulting precipitate is then filtered off with suction and dried under reduced pressure at 100 C. overnight. This gives 4,6-dihydroxy-5-fluoropyrimidine (3.01 g, content (HPLC-STD): 79.3%; 64.4% of theory) as a solid.

	With hydrogenchloride; sodium methylate; formamide; In methanol; water;	Example 3 4,6-Dihydroxy-5-fluoropyrimidine 30% sodium methoxide in methanol (63.0 g, 0.35 mol) are rapidly admixed with formamide (22.5 g, 0.5 mol) and the mixture is heated to reflux temperature. At reflux, ethyl fluoromalonate (17.8 g, 95.0 mmol, content: about 95%) is then added over a period of 225 min, and the mixture is stirred at reflux temperature for a further 3 h. The suspension is concentrated completely under reduced pressure, the residue is dissolved in water (65 ml) and the pH of the solution is adjusted to pH 1 using 30% HCl. The resulting precipitate is then filtered off with suction and dried at 100 C. under reduced pressure overnight. This gives 4,6-dihydroxy-5-fluoropyrimidine (11.74 g, content (HPLC-STD): 82.5%; 78.4% of theory) as a solid.
	With hydrogenchloride; sodium methylate; formamide; In methanol; water;	Example 4 4,6-Dihydroxy-5-fluoropyrimidine 30% sodium methoxide in methanol (63.0 g, 0.35 mol) are rapidly admixed with formamide (33.75 g, 0.75 mol) and the mixture is heated to reflux temperature. At reflux, ethyl fluoromalonate (17.8 g, 95.0 mmol, content: about 95%) is then added over a period of 200 min, and the mixture is stirred at reflux temperature for a further 3 h. The suspension is concentrated completely under reduced pressure, the residue is dissolved in water (65 ml) and the pH of the solution is adjusted to pH 1 using 30% HCl. The resulting precipitate is then filtered off with suction and dried at 100 C. under reduced pressure overnight. This gives 4,6-dihydroxy-5-fluoropyrimidine (12.1 g, content (HPLC-STD): 90.2%; 88.3% of theory) as a solid.

Reference： [1]Patent: US2006/52398,2006,A1 .Location in patent: Page/Page column 41
[2]Patent: US6255486,2001,B1
[3]Patent: US6255486,2001,B1
[4]Patent: US6255486,2001,B1
[5]Patent: US6255486,2001,B1

21
[ 685-88-1 ]
[ 1598-63-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	In diethyl ether; water; acetamidine hydrochloride; ethyl acetate;	(Step b) Preparation of 2-Methyl-4,6 dihydroxy-5-fluoropyrimidine According to the procedure of J. Chem. Soc. 1959, 3286, a solution of 0.92 g (40 mmol) of sodium metal dissolved in 20 mL of methaol was treated with 2.08 g (22 mmol) of acetamidine hydrochloride. After 5 minutes, to this stirred mixture was added 3.6 g (20 mmol) of diethyl fluoromalonate. The reaction mixture was heated to reflux for 18 hours, cooled to 23 C., and then concentrated in vacuo. The residue was dissolved in water, neutralized with aqueous 3N HCl (6 mL), and chilled. A precipitate which formed was isolated by filtration and triturated with a 1:1 mixture of diethyl ether/ethyl acetate. The resulting crude product (1.36 g, 47%) was used without further purification. 1 H NMR (60 MHz, DMSO-D6) delta 6.3 (br s, 2H), 2.32 (s, 3H); IR (Nujol) 3400-3600, 1690, 1650 cm-1.

Reference： [1]Patent: US4617393,1986,A

22
[ 685-88-1 ]
[ 124-42-5 ]
[ 1598-63-6 ]

Yield	Reaction Conditions	Operation in experiment
64%		Part A: A mixture of sodium metal (1.55 g, 67.4 mmol) and EtOH (15.0 mL, 257 mmol) was stirred at RT until nearly all sodium had reacted. Diethyl fluoromalonate (3.54 mL, 22.4 mmol) was added followed by acetamidine hydrochloride (2.14 g, 22.7 mmol). The reaction mixture was heated at reflux for 3 h, cooled to RT and concentrated under reduced pressure. The residue was diluted with water (ca. 50 mL) and acidified (pH=2) with 6M aqueous HCl, and the mixture was stirred at RT for 1 h as a precipitate formed. The solids were collected by suction filtration and washed with water. Excess solvent was removed in vacuo to give 4,6-dihydroxy-5-fluoro-2-methylpyrimidine (2.08 g, 64%) as a light gray solid. LCMS (m/z): 145 (M+H)+

Reference： [1]Patent: US2007/197523,2007,A1 .Location in patent: Page/Page column 7

23
[ 685-88-1 ]
Morpholine-4-carboxamidine; hydrobromide [ No CAS ]
[ 944401-89-2 ]

Yield	Reaction Conditions	Operation in experiment
12%		[0347] Sodium hydride (60% in oil, 3.9 g, 96.5 mmol) was washed with hexanes in a round bottom flask under argon and cooled with an ice water bath. EtOH (100 mL) was slowly added. The resulting mixture was warmed to RT and stirred for 30 minutes. To the base mixture, diethyl 2-fluoromalonate (5.7 g, 32.2 mmol) was added, followed by morpholinoformarnidine hydrobromide (6.8 g, 32.2 mmol). The mixture was heated to 90-950C with stirring under argon. After 12 hours, the reaction was cooled to room temperature and the EtOH was removed in vacuo. The resulting white solid was dissolved in water (25 mL) and acidified with cone. HCl to pH = 3-4. A white precipitate formed which was collected on a Biichner filter, washed with water (2x50 mL), air dried on the filter, and dried in vacuo to give 5-fluoro-2-morpholinopyrimidine-4,6-diol (0.87 g, 12%). LC/MS (m/z): 216.0 (MH+), Rt 0.63 minutes.
12%		Synthesis of 5-fluoro-2-mo holinopyrimidine-4,6-diol[00123] Sodium hydride (60% in oil, 3.9 g, 96.5 mmol) was washed with hexanes in a round bottom flask under argon and cooled with an ice water bath. EtOH (100 mL) was slowly added. The resulting mixture was warmed to RT and stirred for 30 minutes. To the base mixture, diethyl 2-fluoromalonate (5.7 g, 32.2 mmol) was added, followed by mo holinoformamidine hydrobromide (6.8 g, 32.2 mmol). The mixture was heated to 90-95 C with stirring under argon. After 12 hours, the reaction was cooled to room temperature and the EtOH was removed in vacuo. The resulting white solid was dissolved in water (25 mL) and acidified with cone. HC1 to pH = 3-4. A white precipitate formed which was collected on a Buchner filter, washed with water (2x50 mL), air dried on the filter, and dried in vacuo to give 5-fluoro-2-mo holino yrimidine-4,6-diol (0.87 g, 12%).

Reference： [1]Patent: WO2007/84786,2007,A1 .Location in patent: Page/Page column 121
[2]Patent: WO2012/109423,2012,A1 .Location in patent: Page/Page column 26-27

24
[ 685-88-1 ]
[ 6313-33-3 ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium ethanolate; In ethanol; at 0 - 90℃;	To a stirred solution of NaOEt (2.7 g, 0.04 mol) in EtOH (40 mL) was added formamidine acetate (4.2 g, 0.04 mol), followed by addition of diethylfluoromalonate in ethanol (10 mL) at 0 C. The reaction mixture was stirred at 90 C. overnight. Ethanol was removed under reduced pressure and the reaction mixture was acidified with conc. HCl to pH 1. The resulting solid was filtered and dried under vacuum to afford 20.1 (crude, 750 mg, 52%). 1H-NMR (DMSO-d6 200 MHz): delta 12.40 (bs, 2H), 7.89 (s, 1H).

Reference： [1]Patent: US2009/36419,2009,A1 .Location in patent: Page/Page column 43; 44
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 457 - 461

25
[ 685-88-1 ]
[ 139590-63-9 ]

Yield	Reaction Conditions	Operation in experiment
77%		Synthesis of 2-Fluoro-malonic acid monomethyl ester KOH (38 mg, 0.67 mmol) was added to a solution 2-fluoro-malonic acid diethyl ester (100 mg, 0.563 mmol) in methanol (0.7 mL). The reaction mixture was stirred for 4 hours at ambient temperature then concentrated. The residue was diluted with water, acidified with conc. HCl, and the product was extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 70 mg (77%) of 2-fluoro-malonic acid monomethyl ester

Reference： [1]Patent: US2009/239848,2009,A1 .Location in patent: Page/Page column 34

26
[ 685-88-1 ]
[ 138555-58-5 ]
[ 1182719-39-6 ]

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 5021 - 5024

27
[ 685-88-1 ]
[ 399-25-7 ]
[ 1201676-71-2 ]

Reference： [1]Journal of Fluorine Chemistry,2009,vol. 130,p. 759 - 761

28
[ 685-88-1 ]
[ 1204423-52-8 ]
[ 1204423-54-0 ]

Yield	Reaction Conditions	Operation in experiment
74%		(d) 3-[2-(4-Methoxyphenyl)thiazol-5-yl]-2-fluoropropionic acid; Potassium t-butoxide was added to a solution of <strong>[685-88-1]fluoromalonic acid diethyl ester</strong> (14.18 g, 79.57 mmol) in THF (250 mL) at room temperature, and the obtained mixture was then stirred for 10 minutes. The reaction solution was cooled to 0C. A solution of the compound (21.53 g, 75.78 mmol) obtained in Example 22(c) in THF (50 mL) was added thereto, and the reaction temperature was then raised to room temperature. The reaction mixture was stirred at room temperature for 2 hours, and acetic acid (0.87 mL, 15.16 mmol) was then added to the reaction solution. Thereafter, the solvent was distilled away, and water was then added to the residue, followed by extraction twice with ethyl acetate. The combined organic layer was washed with a saturated saline, and it was then dried over anhydrous sodium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a diester compound (21.50 g, yield: 74%) in the form of a yellow oily substance. 1 M-Sodium hydroxide aqueous solution (140 mL, 140 mmol) was added to a solution of the obtained diester compound (21.50 g, 56.37 mmol) in ethanol (400 mL), and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 5 M-hydrochloric acid was added to the reaction solution to make it acidic, and the solvent was then distilled away until the volume of the reaction solution became half of the original volume. The generated precipitate was collected by filtration. The filtrate was extracted with ethyl acetate twice. The combined organic layer was washed with a saturated saline, and it was then dried over anhydrous sodium sulfate, followed by concentration. The residue was combined with the precipitate collected by filtration, and the obtained product was then dissolved in a mixture of 1,4-dioxane (250 mL) and xylene (250 mL). The obtained mixture was stirred at 130C for 20 hours. Thereafter, the solvent was distilled away, and the residue was then washed with acetonitrile, so as to obtain the title compound (14.18 g, yield: 89%) in the form of a colorless powder. 1H NMR (400 MHz, CD3OD): delta (ppm) = 7.82 (2H, d, J = 9.0 Hz), 7.59 (1H, s), 7.01 (2H, d, J = 9.0 Hz), 5.23 (1H, ddd, 3.9, 6.3 and 48.1 Hz), 3.85 (3H, s), 3.60-3.40 (2H, m).

Reference： [1]Patent: EP2308838,2011,A1 .Location in patent: Page/Page column 69-70

29
[ 685-88-1 ]
[ 196877-76-6 ]
[ 1204423-81-3 ]

Yield	Reaction Conditions	Operation in experiment
97%		(c) 3-[3-(4-Methoxyphenyl)-4-bromoisoxazol-5-yl]-2-fluoropropionic acid; Potassium t-butoxide (3.62 g, 32.23 mmol) was added to a solution of <strong>[685-88-1]fluoromalonic acid diethyl ester</strong> (5.02 g, 28.20 mmol) in DMF (70 mL) at room temperature, and the obtained mixture was then stirred for 10 minutes. Thereafter, a solution of the compound obtained in Example 32(b) (7.20 g, 26.85 mmol) in DMF solution (10 mL) was added to the reaction solution, and the temperature of the obtained mixture was then raised to room temperature. The mixture was stirred at room temperature for 1 hour. Thereafter, ethyl acetate (80 mL), toluene (80 mL) and water (80 mL) were added to the reaction solution and the two layers were separated. The obtained organic layer was washed with water and a saturated saline, and it was then dried over anhydrous sodium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a diester compound (9.48 g, yield: 97%) in the form of a colorless oily substance. N-Bromosuccinimide (5.08 g, 28.54 mmol) was added to a solution of the obtained diester compound (9.48 g, 25.95 mmol) in DMF (80 mL), and the obtained mixture was then stirred at room temperature for 13 hours. Thereafter, ethyl acetate (80 mL), toluene (80 mL) and water (80 mL) were added to the reaction solution and the two layers were separated. The obtained organic layer was washed with water and a saturated saline, and it was then dried over anhydrous sodium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a bromo compound (11.53 g, yield: 100%) in the form of a colorless oily substance. A 1 M-sodium hydroxide aqueous solution (80 mL, 80 mmol) was added to a solution of the obtained bromo compound (11.53 g, 25.95 mmol) in ethanol (120 mL), and the obtained mixture was then stirred at room temperature for 1 hour. Thereafter, 5 M-hydrochloric acid was added to the reaction solution to make it acidic, and it was then extracted with ethyl acetate twice. The combined organic layer was washed with a saturated saline, and it was then dried over anhydrous sodium sulfate, followed by concentration. The obtained residue was dissolved in 1,4-dioxane (100 mL) and xylene (100 mL), and the obtained mixture was then stirred at 130C for 8 hours. Thereafter, the reaction solution was concentrated, so as to obtain the title compound (8.68 g, yield: 99%) in the form of a colorless powder. 1H NMR (400 MHz, CDCl3): delta (ppm) = 7.98 (2H, d, J = 9.0 Hz), 7.01 (2H, d, J = 9.0 Hz), 6.07 (1H, br.s), 5.45 (1H, ddd, J = 5.1, 7.8 and 48.1 Hz), 3.88 (3H, s), 3.50-3.33 (2H, m).

Reference： [1]Patent: EP2308838,2011,A1 .Location in patent: Page/Page column 78-79

30
[ 685-88-1 ]
[ 57-13-6 ]
[ 767-80-6 ]

Yield	Reaction Conditions	Operation in experiment
93%		To a heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1 .96 g, 10.67 mmol) in EtOH (1 1 ml_) was added 2.68 M NaOEt in EtOH (7.96 ml_, 21 .34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCI to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1 .45 g, 93%).
93%		Intermediate 69: 2-Chloro-5-fluoro-4,6-dimethylpyrimidine.Step A: 5-Fluoropyrimidine-2,4,6-triol. To a heterogeneous mixture of urea (641 mg, 10.67 mmol) and diethylfluoromalonate (1 .96 g, 10.67 mmol) in EtOH (1 1 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21 .34 mmol). The mixture was heated at reflux for 60 h and then allowed to cool to room temperature. The mixture was filtered and the cake was then dissolved in warm water and the resulting solution was acidified with concentrated HCI to pH 2. The mixture was allowed to cool to room temperature and then cooled in an ice bath before filtering. The cake was washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triol as a slightly off white solid (1 .45 g, 93%).
1.24 g	With sodium ethanolate; In ethanol; at 90℃;	To a solution of diethyl fluoromalonate (3.0 g) and urea (1.02 g) in ethanol (17 mL) was added 20% sodium ethoxide ethanol solution (11.5 g), and the mixture was stirred overnight at 90 C. To the reaction mixture was added hexane (20 mL) at room temperature, and the precipitate was collected by filtration, and washed with a mixed solvent of hexane/diisopropanol. To a solution of the obtained residue in water (60 mL) was added conc. hydrochloric acid at 0 C., and the precipitate was collected by filtration to give the title compound (1.24 g). 1H NMR (300 MHz, DMSO-d6) delta 9.00 (1H, brs).

Reference： [1]Patent: WO2011/50200,2011,A1 .Location in patent: Page/Page column 90
[2]Patent: WO2012/145581,2012,A1 .Location in patent: Page/Page column 83
[3]Patent: US2018/155333,2018,A1 .Location in patent: Paragraph 1839; 1840

31
[ 685-88-1 ]
[ 77287-34-4 ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	With methanol; sodium methylate; at 65℃;	A solution of diethyl 2-fluoromalonate in formamide is added to a solution containing a molar excess of sodium methylate in methanol heated at 65 C for more than 4 hours. When the reaction is complete, water is added. The mixture is acidified with hydrochloric acid to precipitate the product. The product is collected by filtration, washed with water and thoroughly dried to give 5-fluoropyrimidine-4,6-diol (75%) as a solid.
74%		Method BTo a three neck 5 L round bottom flask equipped with magnetic stirrer, nitrogen flow and reflux condenser, was charged the following: sodium methoxide (25% NaOMe in Methanol) (1.425 L, 6.230 mol) and formamide (0.535 L, 13.5 mol) under nitrogen and heated to 64 C. To the reaction mixture diethyl 2-fluoromalonate (CASNo. 685-88-1, 0.266 L, 1.684 mol) was added slowly using an addition funnel (reaction exothermic). The reaction was heated at 64 C for 72 h. The reaction was cooled down to room temperature and solvent was removed under reduced pressure. The residue was cooled to 0 C by ice bath. The mixture was stirred and acidified slowly with 10 N HC1 to pH~l-2. The product precipitated out and was filtered. The product was washed with ice cold IN HC1. The off-white solid was suspended in ACN, filtered and dried (vacuum oven) at 30 C for 16 h to give 5-fluoropyrimidine-4,6-diol (349.4 g, 2.686 mol, 160% yield) as a light brown-pinkish solid. 5-Fluoropyrimidine-4,6-diol (CASNo.106615-61-6,600 g, 4.613 mol, 62% purity) was pulverized (sieved) and placed in a sintered glass funnel (4 L coarse). The material was suspended in an ice cold solution of 0.5 M HC1 (aq) and the material was suspended (for 5min) and then filtered. The filter cake was then washed with 1.2 L of ACN, EtOAc and finally hexanes. The solid was dried (vacuum oven) overnight to give 5- fluoropyrimidine-4,6-diol (276.459 g, 2.125 mol, 74% yield) as a purple -pinkish solid. H NMR (400 MHz, DMSO-i¾) delta ppm 7.9 (s, 1H), 12.3 (brs, 2H).

Reference： [1]Patent: WO2016/193822,2016,A1 .Location in patent: Paragraph 0070
[2]Patent: WO2012/40279,2012,A1 .Location in patent: Page/Page column 84-85

32
[ 685-88-1 ]
(S<SUB>S</SUB>)-2-methyl-N-(2,2,2-trifluoroethylidene)-propane-2-sulfinamide [ No CAS ]
[ 1372420-76-2 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 4124 - 4126
[2]Organic and Biomolecular Chemistry,2014,vol. 12,p. 1454 - 1462

33
[ 956833-12-8 ]
[ 685-88-1 ]
[ 1391087-29-8 ]
[ 1391087-30-1 ]

Yield	Reaction Conditions	Operation in experiment
	With beta-isoquinidine; In 5,5-dimethyl-1,3-cyclohexadiene; at 20℃; for 96h;	General Procedure: In a small vial, MBH carbonate 1a-e (0.25 mmol, 1 equiv), 2-fluoromalonate 2, (67 mg, 0.375 mmol, 1.5 equiv), and catalyst I (8 mg, 0.025 mmol, 10 mol %) in 1 mL of toluene were stirred at room temperature overnight. The crude mixture was monitored by 1H NMR and after completion the crude was purified by column chromatography, affording compound 3. 1,1-diethyl 3-methyl 1-fluoro-2-phenylbut-3-ene-1,1,3-tricarboxylate (3a):1H NMR (400 MHz, CDCl3) delta 7.31-7.28(m, 2H), 7.24-7.20(m, 2H), 6.37-6.37(m, 1H), 6.17(m, 1H), 5.08 (d, JH-F = 35.2 Hz, 1H), 4.24-4.22 (m, 2H), 4.03-4.02(m, 2H), 3.63(s, 3H), 1.24-1.22(t, J = 7.1 Hz, 3H), 1.03-1.02(t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) delta 166.2, 165.2, 164.9, 164.8, 164.5, 138.1, 138.1, 134.9, 129.8, 129.8, 128.2, 127.8, 127.02, 126.9, 98.0, 95.9, 62.9, 62.7, 52.2, 49.0, 48.8, 13.8, 13.7; 19F NMR (376 MHz, CDCl3) delta -174.1 (d, J = 35.4 Hz). HRMS (ESI) calcd. for C18H25FNO6 (M+NH4)+, 370.1666 found 370.1665. Enantiomeric excess: 81%, -65.6 (CHCl3; c = 0.8 g/100 mL) determined by HPLC (Daicel Chiralpak IA, i-PrOH/Hexane = 5/95), UV 254 nm, flow rate 0.8 mL/min, major 9.7 min, minor 10.9 min.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 4124 - 4129
[2]Tetrahedron Letters,2012,vol. 53,p. 4124 - 4129

34
tert-butyl 2-(((tert-butoxycarbonyl)oxy)(phenyl)methyl)acrylate [ No CAS ]
[ 685-88-1 ]
[ 1391087-31-2 ]

Yield	Reaction Conditions	Operation in experiment
80%	With beta-isoquinidine; In toluene; at 20℃; for 96h;	General Procedure: In a small vial, MBH carbonate 1a-e (0.25 mmol, 1 equiv), 2-fluoromalonate 2, (67 mg, 0.375 mmol, 1.5 equiv), and catalyst I (8 mg, 0.025 mmol, 10 mol %) in 1 mL of toluene were stirred at room temperature overnight. The crude mixture was monitored by 1H NMR and after completion the crude was purified by column chromatography, affording compound 3.

Reference： [1]Tetrahedron Letters,2012,vol. 53,p. 4124 - 4129

35
[ 685-88-1 ]
formimidamide acetate [ No CAS ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
		[00215] Referring to Reaction Scheme 16, Stage 1, to a stirred solution of formamidine acetate (leq) in ethanol (50vol) was added a solution of sodium ethoxide in ethanol (2% w/w) (3eq) at 0C and the reaction mixture was stirred at that temperature for 30 minutes. To the resulting mixture was added a solution of diethyl fluoromalonate (leq) in ethanol (5 vol) and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was cooled to 0C and concentrated HC1 (3vol) was added to adjust the pH of the reaction mixture to pH6. The resulting precipitate was filtered, washed with z'sopropanol, diethylether and hexane to furnish the desired intermediate, which was used in the next stage without further purification

Reference： [1]Patent: WO2013/33068,2013,A1 .Location in patent: Paragraph 00215

36
[ 685-88-1 ]
[ 1354044-23-7 ]
[ 1446359-42-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In ethanol; at 70℃; for 24h;	A mixture of l-(2-fluorobenzyl)-5-(isoxazol-3-yl)-lH-pyrazole-3-carboximidamide (Intermediate-8C, 108 mg, 1.0 equiv.), diethyl 2-fluoromalonate (60 mu, 1.0 equiv.) and DBU (57 mu, 1.0 equiv.) in ethanol (1.9 ml) was heated to 70 C for 24 h. The mixture was concentrated under vacuum to give an oil. The oil was purified by column chromatography (0 to 20% dichloromethane in methanol) to give 5-fluoro-2-(l-(2-fluorobenzyl)-5-(isoxazol- 3-yl)-lH-pyrazol-3-yl)-6-hydroxypyrimidin-4(3H)-one (Compound 119, 145 mg, 100 % yield) as a white solid. 1H NMR (500 MHz, METHANOL-^) delta ppm 8.81 (d, 1 H) 7.42 (s, 1 H) 7.26 - 7.36 (m, 1 H) 7.05 - 7.18 (m, 2 H) 6.97 (t, 1 H) 6.92 (d, 1 H) 5.97 (s, 2 H).
100%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In ethanol; at 70℃; for 24h;	A mixture of 1 -(2-fluorobenzyl)-5 -(isoxazo 1-3 -yl)-l H-pyrazo le-3 -carboximidamide, diethyl 2-fluoromalonate (1 equiv.) and DBU (1 equiv.) in ethanol was heated to 70 C for 24 h. The mixture was concentrated under vacuum to give an oil. The oil was purified by column chromatography (0 to 20% dichloromethane in methanol) to give5 -fluoro-2-( 1 -(2-fluorobenzyl)-5 -(isoxazo 1-3 -yl)- 1 H-pyrazo 1-3 -yl)-6-hydroxypyrimidin-4(3H )-one (145 mg, 100 % yield) as a white solid.1H NMR (500 MHz, CD3OD) oe ppm 8.81 (d, 1 H), 7.42 (s, 1 H), 7.26 - 7.36 (m, 1 H) 7.05 -7.18 (m, 2 H), 6.97 (t, 1 H), 6.92 (d, 1 H), 5.97 (s, 2 H).

Reference： [1]Patent: WO2013/101830,2013,A1 .Location in patent: Page/Page column 168
[2]Patent: WO2014/144100,2014,A2 .Location in patent: Paragraph 00274

37
[ 685-88-1 ]
[ 1493-27-2 ]
[ 1643377-84-7 ]

Yield	Reaction Conditions	Operation in experiment
71%		NaH (0.88 g, 22 mmol 60% in mineral oil) was washed free from the oil with hexanes (3 × 10 mL) and was suspended in dry DMF (30 mL). <strong>[685-88-1]Diethyl fluoromalonate</strong> (2.85 g, 16 mmol) dissolved in dry DMF (10 mL) was added dropwise while cooled in ice. After stirring for 10 minutes, 1-fluoro-2-nitrobenzene (2.10 g, 15 mmol) in dry DMF (10 mL) was added and the mixture was heated to 90 C for 18 hours. After cooling to room temperature, the mixture was poured into water (300 mL), acidified with concentrated HCl (2 mL) and extracted with ether (3 × 70 mL). The combined extracts were washed with saturated NaHCO3 solution (2 × 50 mL) and brine (1 × 50 mL) and dried over Na2SO4. After evaporation of the solvent under reduced pressure an orange oil was obtained that was purified by Kugelrohr distillation (8 mbar, 200 C) to afford diethyl 2-fluoro-2-(2-nitrophenyl)malonate (3, 3.21 g, 71%) as an orange solid. M.p. 48-49 C; IR (neat, cm-1) 2996, 1755, 1530, 1276, 1103; deltaH (CDCl3, 400 MHz) 1.33 (6H, t, J 7.1, CH3), 4.31 - 4.43 (4H, m, CH2), 7.57 - 7.63 (2H, m, Ar-H), 7.66 - 7.71 (1H, m, Ar-H), 8.04 (1H, d, J 8.0, Ar-H); deltaF (CDCl3, 376 MHz) - 152.98 (s, C-F); deltaC (CDCl3, 100 MHz) 14.01 (s, CH3), 63.55 (s, CH2), 94.05 (d, 1JCF 198.7, C-F), 125.87 (s, Ar), 128.54 (s, Ar), 128.66 (s, Ar), 128.89 (s, Ar), 130.97 (s, Ar), 133.30 (s, Ar), 164.68 (d, 2JCF 25.1, COO); m/z (ASAP): 226.0 (85%, [M-CO2Et]+), 134.0 (100%).

Reference： [1]Beilstein Journal of Organic Chemistry,2014,vol. 10,p. 1213 - 1219

38
[ 1480-87-1 ]
[ 685-88-1 ]
[ 1643378-05-5 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: Diethyl 2-fluoromalonate (1, 1.07 g, 6.0 mmol) in DMF (5 mL) was added dropwise to a suspension of sodium hydride (0.32 g, 8.0 mmol, 60% in mineral oil) in DMF (10 mL) and the mixture was stirred at room temperature for 20 min. Fluoroarene 2 (5.0 mmol) in DMF (10 mL) was added and the mixture was heated to 80 C. The mixture was poured into crushed ice (150 mL), acidified with conc. HCl (5 mL) and extracted with diethyl ether (3 × 30 mL). The organic phase was washed with saturated aq. NaHCO3 solution (25 mL) and saturated brine (2 × 25 mL), dried (Na2SO4) and concentrated to give the crude diester. 1H and 19F NMR analysis confirmed the formation of the intermediate aryl-fluoromalonate 3 (deltaF ~ -150 ppm) which was used in the next step without any further purification.

Reference： [1]Beilstein Journal of Organic Chemistry,2014,vol. 10,p. 1213 - 1219

39
[ 685-88-1 ]
[ 1958-93-6 ]
[ 1632235-58-5 ]

Reference： [1]Chimia,2014,vol. 68,p. 425 - 429

40
[ 691-60-1 ]
[ 685-88-1 ]
5-fluoro-1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium methylate; In methanol; at 85℃; for 4h;	Compound 5.1. 5-Fluoro-l-isopropylpyrimidine-2,4,6(lH,3H,5H)-trione). To a 100 mL round bottom flask equipped with a reflux condenser and containing a solution of 1.1 (1.31 g, 0.013 mol, 1.00 equiv) in CH3OH (15 mL) were added diethyl fluoromalonate (2.41 g, 0.014 mol, 1.05 equiv) and NaOMe (1.74 g, 0.032 mol, 2.50 equiv). The reaction mixture was stirred for 4 h at 85C, and then was cooled to 0 C. The reaction mixture was quenched with careful addition of concentrated HCl, adjusting to pH=2 with the addition of excess concentrated HCl. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dried for 18 h under high vacuum to provide 2.65 g (98%) of a white solid. 1H-NMR (400 MHz, CDC13): delta ppm 5.56 - 5.50 (d, J = 24.0 Hz, 1H), 4.91 (m, 2H), 1.46 (m, 6H).
98%	With sodium methylate; In methanol; at 85℃; for 4h;	To a 100 mL round bottom flask containing a solution of 1.1 (1.31 g, 0.013 mol, 1.00 equiv) in CH3OH (15 mL) were added diethyl fluoromalonate (2.41 g, 0.014 mol, 1.05 equiv) and sodium methoxide (1.74 g, 0.032 mol, 2.50 equiv). The reaction flask was equipped with a reflux condenser and was stirred for 4 h in an oil bath heated at 85 C. The reaction was cooled to 0 C and was quenched with careful addition of concentrated HCl, adjusting to pH=2 with the addition of excess concentrated HCl. The reaction mixture was concentrated under reduced pressure and the resulting residue was dried for 18 h under high vacuum to provide 2.65 g of the title compound (98%). 1H-NMR (400 MHz, CDC13): delta ppm 5.53 (d, J = 24.0 Hz, 1H), 4.91 (m, 2H), 1.46 (m, 6H).

Reference： [1]Patent: WO2014/205234,2014,A1 .Location in patent: Paragraph 0089
[2]Patent: WO2014/205223,2014,A1 .Location in patent: Paragraph 0077-0078

41
[ 685-88-1 ]
[ 3473-63-0 ]
[ 106615-61-6 ]

Yield	Reaction Conditions	Operation in experiment
		Stage 1 (0506) To a stirred solution of formamidine acetate (1 eq) in ethanol (50 vol) was added a solution of sodium ethoxide in ethanol (2% w/w) (3 eq) at 0 C. and the reaction mixture was stirred at that temperature for 30 minutes. To the resulting mixture was added a solution of diethyl fluoromalonate (1 eq) in ethanol (5 vol) and the reaction mixture was stirred at ambient temperature for 72 hours. The reaction mixture was cooled to 0 C. and concentrated HCl (3 vol) was added to adjust the pH of the reaction mixture to pH6. The resulting precipitate was filtered, washed with isopropanol, diethylether and hexane to furnish the desired intermediate, which was used in the next stage without further purification.

Reference： [1]Green Chemistry,2015,vol. 17,p. 3000 - 3009
[2]Patent: US9145373,2015,B2 .Location in patent: Page/Page column 37

42
[ 685-88-1 ]
[ 1220039-94-0 ]
[ 1313280-33-9 ]

Yield	Reaction Conditions	Operation in experiment
43%	With sodium; In methanol; at 0 - 20℃;	6-Fluoroimidazo[1 ,2-a]pyridine-3-carboximidamide (Preparation 1 b, 2.0 g, 8.39 mmol,) was added portionwise to a stirred solution of sodium (0.46 g, 20.21 mmol) in methanol (35 mL) at 0 C. Diethyl 2-fluoromalonate (2.65 mL, 16.8 mmol) was then added and the reaction mixture was stirred from 0 C to room temperature overnight. The solvent was evaporated to dryness and the resulting crude was dissolved in water (90 mL). After stirring for 30 min, a 2N solution of hydrochloric acid was added until acid pH. The solid formed was filtered and dried to yield the title compound (0.95 g, 43%) as a brown solid that was used in the next synthetic step without further purification. LRMS (m/z): 265 (M+1 )+ 1H NMR delta (300 MHz, DMSO-d6): 7.6 (s, 1 H), 7.8 (s, 1 H), 8.7 (s, 1 H), 10.1 (s, 1 H), 12.6 (bs, 1 H).

Reference： [1]Patent: WO2015/91531,2015,A1 .Location in patent: Page/Page column 37; 38

43
[ 685-88-1 ]
1-(2,3-difluorobenzyl)-5-(difluoromethoxy)-1H-pyrazole-3-carboximidamide hydrochloride salt [ No CAS ]
2-(1-(2,3-difluorobenzyl)-5-(difluoromethoxy)-1H-pyrazol-3-yl)-5-fluoropyrimidine-4,6-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With sodium methylate; In methanol; at 23℃; for 1h;	Step 1: Synthesis of 2-( 1 -(2,3 -difluorobenzyl)-5 -(difluoromethoxy)- 1 H-pyrazol-3 -yl)-5- fluoropyrimidine-4,6-diol To a mixture containing diethyl 2-fluoromalonate (2 equiv.) and1 -(2,3 -difluorobenzyl)-5 -(difluoromethoxy)- 1 H-pyrazole-3 -carboximidamide hydrochloride (Described in step 3 towards the synthesis of Compound 1-52 (1 equiv.) in methanol was added a 25 wt% solution of sodium methoxide in methanol (5 equiv.). The mixture was stirred at 23 C for 1 h. To this mixture, was added HC1 (5 equiv.). The mixture was stirred vigorously for 15 mm. The precipitate formed was collected by filtration and dried under vacuum to deliver the desired intermediate, 2-( 1 -(2,3 -difluorobenzyl)-5-(difluoromethoxy)- 1 H-pyrazol-3 -yl)-5 -fluoropyrimidine-4,6-diol (475 mg, 44 % yield) as a cream colored solid.?H NMR (500 MHz, DMSO-d6) ppm 7.19 - 7.57 (m, 3 H), 7.11 - 7.16 (m, 1 H), 6.71 (s, 1 H), 5.41 (s, 2H).

Reference： [1]Patent: WO2015/89182,2015,A1 .Location in patent: Paragraph 00274

44
[ 685-88-1 ]
pyrazolo[1,5-a]pyridine-3-carboximidamide [ No CAS ]
5-fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4,6-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In methanol; at 0 - 20℃;	Pyrazolo[1,5-a]pyridine-3-carboximidamide (Preparation ib, 4.75 g, 29.47 mmol) was added portionwise to a stirred solution of sodium (1.63 g, 71.02 mmol) in methanol(120 mL) at 0 00 Diethyl 2-fluoromalonate (7.0 mL, 44.20 mmol) was then added and the reaction mixture was stirred from 0 C to room temperature overnight. The solvent was evaporated to dryness to yield the title compound (7.25 g, 99%) as a solid that was used in the next synthetic step without further purification.LRMS (mlz): 247 (M+1)1H-NMR (300 MHz, DMSO-d6): 7.2 (t, 1H), 7.5-7.7 (m, 1H), 8.7 (d, 1H), 8.8-8.9 (m, 2H), 11.8 (bs, 1H), 12.7 (bs, 1H).
	With methanol; sodium; at 0 - 20℃;	c) 5-Fluoro-2-pyrazolo[1,5-a]pyridin-3-ylpyrimidine-4,6-diol Pyrazolo[1 ,5-a]pyridine-3-carboximidamide (Preparation 1 b, 4.75 g, 29.47 mmol) was added portionwise to a stirred solution of sodium (1.63 g, 71.02 mmol) in methanol (120 ml.) at 0 C. Diethyl 2-fluoromalonate (7.0 ml_, 44.20 mmol) was then added and the reaction mixture was stirred from 0 C to room temperature overnight. The solvent was evaporated to dryness to yield the title compound (7.25 g, 99%) as a solid that was used in the next synthetic step without further purification. LRMS (m/z): 247 (M+1 ) +. 1H-NMR delta (300 MHz, DMSO-d6): 7.23 (t, 1 H), 7.50 - 7.73 (m, 1 H), 8.71 (d, 1 H), 8.85 - 8.94 (m, 2H), 11.83 (bs, 1 H), 12.70 (br.s., 1 H).

Reference： [1]Patent: WO2015/86693,2015,A1 .Location in patent: Page/Page column 53
[2]Patent: WO2016/198663,2016,A1 .Location in patent: Page/Page column 38

45
[ 685-88-1 ]
C₁₀H₁₅N₃O₂ [ No CAS ]
C₁₃H₁₄FN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%	In N,N-dimethyl-formamide; at 70℃; for 7h;Sealed tube; Inert atmosphere;	Compound 4 (20.9 g, 0.1 mol), compound 5 (18.7 g, 0.105 mol) and DMF (200 mL) were added into a reactor, then the reactor was sealed under nitrogen atmosphere, and the resulting mixture was kept at 70 C., stirred for 7 hours. After cooling to room temperature, the mixture was diluted with acetic ether (100 mL) and filtered. The filtrate was washed twice with water (2×100 mL), and the combined aqueous phases were extracted twice with acetic ether (2×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated to obtain compound 6 (26.7 g, yield 90.5%).

Reference： [1]Patent: US9278919,2016,B1 .Location in patent: Page/Page column 4; 5; 8

46
[ 50-00-0 ]
[ 685-88-1 ]
[ 756-31-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydrogencarbonate; In ethanol; water; at 20 - 25℃; for 4h;	(0076) Into a solution, prepared at room temperature, of 7 g of potassium hydrogencarbonate in 70 g of a 30% aqueous formaldehyde solution were metered, after addition of 7.0 g of ethanol, 100 g of diethyl 2-fluoromalonate at an internal temperature of 20 to 25 C. within 1 hour. After stirring at room temperature for a further 3 hours, 122 g of product were obtained in a purity of about 84% by extraction with ethyl acetate and concentration of the extract in the form of a pale beige oil. For further purification, the product was recrystallized from toluene.

Reference： [1]Chemical Biology and Drug Design,2016,vol. 87,p. 867 - 877
[2]Patent: US2017/197905,2017,A1 .Location in patent: Paragraph 0076

47
[ 5256-74-6 ]
[ 685-88-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogen fluoride; In neat (no solvent); at 0℃; for 5h;Inert atmosphere;	General procedure: Anhydrous liquid hydrogen fluoride (5 mL, 0.25 mmol) was placed into polypropylene flask at 0 C under nitrogen atmosphere. Diazomalonate (0.5 mmol) was added dropwise into the stirred reaction mixture at 0 C. The reaction mixture was stirred at 0 C for 5 h. Then, reaction mixture was poured into ice-water (100 mL). The obtained mixture was neutralized with solid NaHCO3, and extracted with dichloromethane (3x25 mL). The combined organic layers were washed with water (25 mL), dried over Na2SO4, and concentrated under reduced pressure. Crude material was purified by column chromatography (silica gel; hexane/EtOAc; linear gradient: 0-2% EtOAc).

Reference： [1]Tetrahedron,2016,vol. 72,p. 4835 - 4844

48
[ 685-88-1 ]
[ 88497-68-1 ]
[ 944401-89-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium; In ethanol; for 12h;Reflux;	Sodium metal (9.68 g, 421 mmol) was cut in small pieces and added to dry EtOH (300 mL) in portions. After all the sodium was dissolved, morpholine-4-carboxamidine sulfate (30 g, 168 mmol) and diethyl fluoromalonate (30 g, 168 mmol) were added to the mixture at 10 C. The resulting white suspension was stirred at 20 C. for 10 min and then heated under reflux for 12 h. The resulting purple suspension was concentrated under reduced pressure and water (150 mL) was added. The solution was treated with 6N HCl (60 mL) to obtain pH-4 at 10 C. The resulting yellow precipitate was collected by filtration, washed with water (40 mL*2) and the yellow filter cake was dried under an infrared lamp for 12 h to give 34 g (94%) of the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 3.65-3.57 (m, 4H) 3.53-3.46 (m, 4H); m/z (APCI-) for C8H10FN3O3 214.1 (M-H)-.

Reference： [1]Patent: US2017/15689,2017,A1 .Location in patent: Paragraph 0441; 0442

49
[ 685-88-1 ]
1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazole-3-carboximidamide hydrochloride [ No CAS ]
5-fluoro-2-(1-(2-fluorobenzyl)-5-(isoxazol-3-yl)-1H-pyrazol-3-yl)pyrimidine-4,6-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With sodium methylate; In methanol; at 20 - 35℃; for 0.5h;	Intermediate (5'B) (224.6 g, 698 mmols, 1.0 equiv.), methanol (2250 mL) and diethyl fluoromalonate (187 g, 1050 mmols, 1.5 equiv.) were charged to a suitable reaction vessel equipped with a mechanical stirrer and a digital thermometer. Then sodium methoxide in methanol solution (567 g, 30 wt. %, 3149 mmols, 4.5 equiv.) was charged via an addition funnel while maintaining the reaction temperature 20 to 35 C. The mixture was stirred at 20 to 35 C over 30 min. and a light suspension was obtained. The reaction was complete by HPLC. A solution of 1.5 N HC1 (2300 mL, 3450 mmols, 4.9 equiv.) was charged via an addition funnel over 1 h while maintaining the reaction temperature 20 to 30 C. A white suspension was obtained. The pH of the reaction mixture was to be ~1 by pH paper. The slurry was stirred at 20 to 30 C over 30 min. The resulting slurry was filtered, and the filter cake was washed with a pre-mixed solution of methanol and water (500 mL/500 mL), and then with water (1000 mL). The filter cake was dried under vacuum at 50 to 60 C over 16 h to furnish intermediate (6') as an off-white solid (264 g, 97% yield, >99% pure by HPLC). - MR (500 MHz, DMSO-d6) delta ppm 12.82 (br. s., 1 H); 12.31 (br. s., 1 H); 9.14 (d, J=1.53 Hz, 1 H); 7.55 (s, 1 H); 7.31 - 7.37 (m, 1 H); 7.18 - 7.25 (m, 1 H); 7.10 - 7.15 (m, 2 H); 6.97 - 7.02 (t, J=7.55 Hz, 1 H); 5.88 (s, 2 H).

Reference： [1]Patent: WO2017/95697,2017,A1 .Location in patent: Page/Page column 52-53

50
[ 685-88-1 ]
C₅H₉F₃N₂*ClH [ No CAS ]
C₈H₈F₄N₂O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium tert-butylate; In methanol; at 60℃; for 1h;Cooling with ice;	Step 2: Preparation of Compound a4 (0634) (0635) To a solution of Compound a2 hydrochloride (1.0 g, 5.25 mmol) in methanol (10 mL) was added potassium tert-butoxide (1.07 g, 9.54 mmol), the mixture was stirred 10 minutes under ice-cooling. After added Compound a3 (739 ul, 4.77 mmol), the solution was stirred at 60 C. for 1 hour. After added 2 mol/L hydrochloric acid aqueous solution, methanol was removed under reduced pressure. The precipitated solid was filtered, washed with water, and concentrated under reduced pressure to yield Compound a4 (648.8 mg, yield: 57%) as pale pink solid. (0636) LC-MS: m/z=241. [M+H]+ (0637) LC/MS method: Method A, retention time: 0.74 min

Reference： [1]Patent: US2017/158704,2017,A1 .Location in patent: Paragraph 0635; 0636; 0637

51
[ 685-88-1 ]
[ 1092546-75-2 ]
(S)-diethyl 2-(4-(4-chlorophenyl)-1,1,1-trifluoro-4-oxobutan-2-yl)-2-fluoromalonate [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 5102 - 5105

52
[ 685-88-1 ]
4,4,4-trifluoro-1-(4‘-nitrophenyl)but-2-en-1-one [ No CAS ]
(S)-diethyl 2-fluoro-2-(1,1,1-trifluoro-4-(4-nitrophenyl)-4-oxobutan-2-yl)malonate [ No CAS ]

Reference： [1]Organic Letters,2017,vol. 19,p. 5102 - 5105

53
[ 685-88-1 ]
[ 15567-09-6 ]
ethyl α-(N-butyl)carbamoylfluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With triethylamine; In 1,4-dioxane; at 20℃; for 12h;	In the reactor, 310 mg (2 mmol) of butylamine hydrobromide, 1.78 g (10 mmol) of diethyl fluoromalonate, 600 mg (6 mmol) of triethylamine and 10 ml of 1,4-dioxane ring. The reaction was stirred at room temperature for 12 hours. Filter, steamed awaySolvent and the residual mixture was directly subjected to column chromatography to obtain 405 mg of ethyl alpha- (N-butyl) carbamoyl fluoroacetateG, yield 99%.

Reference： [1]Patent: CN104496737,2017,B .Location in patent: Paragraph 0026; 0027

54
[ 685-88-1 ]
C₈H₉F₃NO₃S⁽¹⁺⁾*CF₃O₃S^(1-) [ No CAS ]
diethyl 2-(2,6-dimethylpyridin-4-yl)-2-fluoromalonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		General procedure: All flasks and stirrer bars were flame dried before use. To the N-oxide (0.2 mmol, 1.0 equiv.), dissolved in 2 cm3 dichloromethane was added Tf2O (0.3 mmol, 1.5 equiv.) at 0 C. In another flask, a suspension of NaH (0.7 mmol, 3.5equiv.) in 1 cm3 tetrahydrofuran was cooled to 0 C and the malonate (0.7 mmol, 3.5 equiv.) was added. After 15 min, the malonate solution was added to the activated N-oxide solution and the mixture was stirred at room temperature for 1 h. The reaction was quenched with NH4Cl solution and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine before being dried over MgSO4. The solvents were removed under reduced pressure and the crude product was purified by column chromatography.

Reference： [1]Monatshefte fur Chemie,2018,vol. 149,p. 715 - 719

55
[ 1073-23-0 ]
[ 685-88-1 ]
diethyl 2-(2,6-dimethylpyridin-4-yl)-2-fluoromalonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		General procedure: All flasks and stirrer bars were flame dried before use. Tothe N-oxide (0.2 mmol, 1.0 equiv.), dissolved in 2 cm3dichloromethane was added Tf2O (0.3 mmol, 1.5 equiv.) at0 C. In another flask, a suspension of NaH (0.7 mmol, 3.5equiv.) in 1 cm3 tetrahydrofuran was cooled to 0 C andthe malonate (0.7 mmol, 3.5 equiv.) was added. After15 min, the malonate solution was added to the activatedN-oxide solution and the mixture was stirred at roomtemperature for 1 h. The reaction was quenched withNH4Cl solution and the aqueous phase was extracted withdichloromethane. The combined organic layers werewashed with brine before being dried over MgSO4. Thesolvents were removed under reduced pressure and thecrude product was purified by column chromatography.

Reference： [1]Monatshefte fur Chemie,2018,vol. 149,p. 721 - 722

56
[ 685-88-1 ]
[ 2695-47-8 ]
diethyl 2-fluoro-2-(hex-5-en-1-yl)malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 0.75h;	Diethyl 2-fluoromalonate (5 g, 28.1 mmol) was added, over 10 min, to a stirred suspension of sodium hydride (1.347 g, 33.7 mmol) in tetrahydrofuran (50 mL) at 0C and the resulting colourless solution was stirred at 0 C for 15 min. and then at RT for 30 min. The solution was cooled to 0 C, a solution of 6-bromohex-l-ene (4.58 g, 28.1 mmol) in THF (20 mL) was then added over 5 min. and the resulting reaction mixture was heated to 60 C and stirred for 16 h. Then the reaction mixture was cooled to 0 C, quenched with ice cold water (100 mL) and extracted with ethyl acetate (2 x 200 mL). The combined organic layer was washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulphate, filtered and the filtrate concentrated under reduced pressure. The crude product was purified by combiflash chromatography (80 g Redisep S1O2 column, eluting with 10 % EtOAc in n- hexanes) to afford the title compound 162A (5 g, 68%) as a colourless oil. LC-MS retention time = 3.30 min; m/z = 261.2 [M+H]+ KINETIX XB-C18, (75 X 3) mm, 2.6 micron column; Flow rate: 1 mL/min; Mobile Phase A: 10 mM HCO2NH4 in 98% Water/ 2% ACN; Mobile Phase B: 10 mM HCO2NH4 in 2% Water/ 98% ACN; 20% B to 100% B over 4.6 min, then hold 0.4 min. at 20% B with flow rate 1.5 mL/min; Detection: UV at 220 nm. NMR (400MHz, CDCh) delta ppm 5.78 (ddt, J=17.1 , 10.3, 6.6 Hz, 1H), 5.01 (d, J=17.2 Hz, 1H), 4.95 (d, J=6.4 Hz, 1H), 4.34 (q, J=5.6 Hz, 4H), 2.18 - 2.05 (m, 4H), 1.43 - 1.40 (m, 4H), 1.30 (t, J=7.2 Hz, 6H).

Reference： [1]Patent: WO2018/89355,2018,A1 .Location in patent: Page/Page column 252-254

57
[ 685-88-1 ]
[ 141-05-9 ]
(−)-tetraethyl 1-fluoropropane-1,1,2,3-tetracarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With (R)-3,3?-dichloro-1,1?-binaphthalene-2,2?-diol; n-butyllithium; In hexane; tert-butyl methyl ether; at 20℃; for 2h;Inert atmosphere;	General procedure: Under argon atmosphere, n-butyllithium (0.10 mmol,20 mol%) in hexane (0.15 M, 0.67 mL) was added to a solutionof (R)-3,3-Cl2-BINOL (17.8 mg, 0.05 mmol, 10 mol%)in TBME (5.0 mL) at 0C. After stirring for 1 min, dibenzylmalonate (1a) (0.125 mL, 0.5 mmol, 1.0 eq) and diethyl maleate(2a) (0.096 mL, 0.6 mmol, 1.2 eq) was successively added tothe mixture at room temperature (r.t.). After 1 h, the reactionwas quenched with sat. NH4Cl aq. (2 mL) and stirred for 0.5 h.The aqueous layer was extracted with EtOAc (3 × 10 mL). Thecombined organic layers were washed with brine (20 mL),and dried over Na2SO4. After filtration and concentration, thecrude product was purified by column chromatography (hexane-EtOAc = 9 : 1, SiO2: 10 g) to give product 3aa as a colorless oil (214 mg, 94% yield, 90% ee)

Reference： [1]Chemical and Pharmaceutical Bulletin,2019,vol. 67,p. 452 - 460

58
[ 32889-11-5 ]
[ 685-88-1 ]
[ 536-74-3 ]
C₂₆H₂₅FN₂O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With copper(l) iodide; caesium carbonate; In tetrahydrofuran; at 80℃; for 1.5h;Inert atmosphere; Sealed tube;	First, put a stir bar in a 35 mL sealed tube, and then add phenylacetylene (38 muL, 0.33 mmol), 0.9 mL tetrahydrofuran (0.9 mL), 2-chloroacetamidoquinoline (66.2 mg, 0.3 mmol), 2 -<strong>[685-88-1]Diethyl fluoromalonate</strong> (82.7mg, 0.45mmol). To the mixed solution, add CuI (5.7mg, 0.03mmol) and Cs2CO3 (117.3mg, 0.36mmol), and fill it with a nitrogen tube N2 for 3 minutes, fully expel the air, seal the nozzle with a cock, and stir the reaction at 80 C for 1.5 hours. After the reaction, the system was cooled to room temperature, 2 ml of distilled water was added to the reaction system, extracted with ethyl acetate, and combined. For the organic phase, the solvent of the organic phase was distilled off under reduced pressure, and 133.8 mg of the product 4f was separated by silica gel column chromatography with a yield of 96%.

Reference： [1]Patent: CN110627718,2019,A .Location in patent: Paragraph 0046-0048

59
[ 1820-80-0 ]
[ 685-88-1 ]
6-fluoropyrazolo[1,5-a]pyrimidine-5,7-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55.7%	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In 1,4-dioxane; at 110℃; for 18h;Inert atmosphere;	Under nitrogen protection,Add 2.0 g (24.1 mmol) of raw material 1a,4.3 g (24.1 mmol) of the starting material 1b and 7.3 g (48.2 mmol) of DBU were dissolved in 40 mL of 1,4-dioxane and reacted at 110 C. for 18 hours.TLC detection. After the reaction, the solution was concentrated by rotary evaporation, 20 mL of ice water was added, and under the protection of nitrogen, about 14 mL of 5M HCl was added to adjust the pH of the solution to about 2, and a solid precipitated.Stir at low temperature, suction filter, and vacuum dry to obtain 2.27 g of the product as a gray solid with a yield of 55.7%.

Reference： [1]Patent: CN110857304,2020,A .Location in patent: Paragraph 0103-0107

60
[ 685-88-1 ]
[ 1123787-67-6 ]
C₁₂H₁₆FNO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
52.3%		Diethyl 2-fluoromalonate (93.7g, 0.53mol, 1.0eq.) Was dissolved in 1L of tetrahydrofuran, and the temperature was lower than 0 C and a 2.5M n-butyl lithium hexane solution (210.0mL, 0.53mol, 1.0eq.), Keep stirring for 0.5h after dropping, add 400mL of a compound of formula II (50.00g, 0.53mol, 1.0eq.) In tetrahydrofuran solution, and return to room temperature for 2h after the dropwise addition, add 400mL of saturation The ammonium chloride aqueous solution was separated, and the organic phase was washed with saturated brine, dried, and concentrated to obtain 75.7 g of the compound of formula III, with a yield of 52.3%. .

Reference： [1]Patent: CN110963955,2020,A .Location in patent: Paragraph 0087-0091

61
[ 685-88-1 ]
[ 1223573-30-5 ]
C₁₄H₂₁FO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.3%		Diethyl 2-fluoromalonate (89.1g, 0.5mol, 1.0eq.) Was dissolved in 1L of tetrahydrofuran, cooled to -40 , 1M KHMDS tetrahydrofuran solution (500ml, 0.5mol, 1.0eq. ), Keep stirring for 1h after dropping, add 400mL of tetrahydrofuran solution of the compound of formula II (79.00g, 0.50mol, 1.0eq.) Dropwise, and return to room temperature for 2h after the addition is completed, add 500mL of saturated ammonium chloride aqueous solution to separate, The organic phase was washed with saturated brine, dried, and concentrated to obtain 74.5 g of the compound of formula III, with a yield of 44.3%.

Reference： [1]Patent: CN110963955,2020,A .Location in patent: Paragraph 0100-0104

62
[ 685-88-1 ]
[ 1153949-11-1 ]
C₁₇H₂₅FN₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.5%		Diethyl 2-fluoromalonate (77.00g, 0.43mol, 1.05eq.) Was dissolved in 1L of tetrahydrofuran, cooled to -40 , 1M KHMDS tetrahydrofuran solution (425mL, 0.42mol, 1.03eq. ), After stirring for 1h, add 400mL of a tetrahydrofuran solution of the compound of formula II (80.00g, 0.41mol, 1.0eq.), Return to room temperature for 2h after the addition is completed, add 500mL of saturated ammonium chloride aqueous solution to separate, The organic phase was washed with saturated brine, dried, concentrated, column chromatography (petroleum ether / ethyl acetate), and concentrated to obtain 70.00 g of the compound of formula III, with a yield of 43.5%.

Reference： [1]Patent: CN110963955,2020,A .Location in patent: Paragraph 0062-0066

63
[ 685-88-1 ]
[ 83665-55-8 ]
C₁₂H₁₉FO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	Stage #1: fluoromalonic acid diethyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Inert atmosphere; Stage #2: 2-(2-iodoethyl)-1,3-dioxolane In N,N-dimethyl-formamide at 20℃; Inert atmosphere;

Reference： [1]Huang, Zhongxing; Low, Kam-Hung; Zhang, Suihan; Zheng, Yin; Zi, Weiwei [Journal of the American Chemical Society, 2022, vol. 144, # 4, p. 1951 - 1961]

64
[ 38771-21-0 ]
[ 685-88-1 ]
diethyl 2-but-3-ynyl-2-fluoropropanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With Cs₂CO₃ In acetone for 72h; Reflux; Inert atmosphere;	1 Step 1: Diethyl 2-but-3-ynyl-2-fluoro-propanedioate To a solution of diethyl 2-fluoropropanedioate (2.0 g, 11.23 mmol, 1.0 equiv; CAS RN 685-88- 1) in acetone (60 mL) were added 4-bromo-1-butyne (5.97 g, 44.9 mmol, 4.0 equiv; CAS RN 38771-21-0) and cesium carbonate (7.32 g, 22.5 mmol, 2.0 equiv) and the reaction mixture was heated to reflux for 72 h. The reaction mixture was quenched by addition of sat. aqueous NH4Cl (50 mL) and extracted with methyl tert-butyl ether (3 x 100 mL). The combined organic phases were dried over Na2SO4 and the solvent was removed under reduced pressure to obtain the title compound as light brown liquid (1.9 g, 65 %).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2022/49134, 2022, A1 Location in patent: Page/Page column 91; 186

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Technical Information

• Acyl Group Substitution • Alcohols Convert Acyl Chlorides into Esters • Alcoholysis of Anhydrides • Alkyl Halide Occurrence • Amines Convert Esters into Amides • An Alkane are Prepared from an Haloalkane • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Complex Metal Hydride Reductions • Convert Esters into Aldehydes Using a Milder Reducing Agent • Decarboxylation of 3-Ketoacids Yields Ketones • Deprotection of Cbz-Amino Acids • Ester Cleavage • Ester Hydrolysis • Friedel-Crafts Alkylation of Benzene with Haloalkanes • Grignard Reagents Transform Esters into Alcohols • Hantzsch Pyridine Synthesis • Heat of Combustion • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of an Ester to an Aldehyde • Specialized Acylation Reagents-Carbodiimides and Related Reagents • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • Transesterification

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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. 685-88-1 ] {[proInfo.proName]}

Quality Control of [ 685-88-1 ]

Related Doc. of [ 685-88-1 ]

Product Details of [ 685-88-1 ]

Calculated chemistry of [ 685-88-1 ] Expand+

Physicochemical Properties

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Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 685-88-1 ]

Application In Synthesis of [ 685-88-1 ]

[ 685-88-1 ] Synthesis Path-Upstream 1~9

[ 685-88-1 ] Synthesis Path-Downstream 1~64

Technical Information

Related Functional Groups of [ 685-88-1 ]

Fluorinated Building Blocks

Aliphatic Chain Hydrocarbons

Esters

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[ 685-88-1 ]