[ CAS No. 2032-34-0 ] {[proInfo.proName]}

Name: 2032-34-0|3,3-Diethoxypropanenitrile|98%
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2D 3D

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Quality Control of [ 2032-34-0 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 2032-34-0 ]

SDS Specification

Alternatived Products of [ 2032-34-0 ]

Product Details of [ 2032-34-0 ]

CAS No. :	2032-34-0	MDL No. :	MFCD00040558
Formula :	C₇H₁₃NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WBOXEOCWOCJQNK-UHFFFAOYSA-N
M.W :	143.18	Pubchem ID :	74851
Synonyms :

Calculated chemistry of [ 2032-34-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.86
Num. rotatable bonds :	5
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	37.68
TPSA :	42.25 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) :	-6.8 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.12
Log Po/w (XLOGP3) :	0.52
Log Po/w (WLOGP) :	1.3
Log Po/w (MLOGP) :	0.34
Log Po/w (SILICOS-IT) :	0.93
Consensus Log Po/w :	1.04

Druglikeness

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

Water Solubility

Log S (ESOL) :	-0.73
Solubility :	26.9 mg/ml ; 0.188 mol/l
Class :	Very soluble
Log S (Ali) :	-0.98
Solubility :	15.1 mg/ml ; 0.105 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.46
Solubility :	4.96 mg/ml ; 0.0347 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.44

Safety of [ 2032-34-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P501-P261-P270-P210-P271-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330-P302+P352+P312-P304+P340+P312-P403+P235	UN#:	N/A
Hazard Statements:	H302+H312+H332-H315-H319-H227	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 2032-34-0 ]

* 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 [ 2032-34-0 ]
Downstream synthetic route of [ 2032-34-0 ]

[ 2032-34-0 ] Synthesis Path-Upstream 1~3

1
[ 2032-34-0 ]
[ 50-01-1 ]
[ 156-81-0 ]

Reference： [1] Journal of the American Chemical Society, 1950, vol. 72, p. 2587,2593
[2] Journal of Medicinal Chemistry, 2004, vol. 47, # 1, p. 240 - 253

2
[ 2032-34-0 ]
[ 41365-75-7 ]

Reference： [1] Archiv der Pharmazie, 1995, vol. 328, # 6, p. 487 - 495
[2] Tetrahedron Asymmetry, 1993, vol. 4, # 11, p. 2307 - 2310

3
[ 2032-34-0 ]
[ 59278-65-8 ]
[ 1375108-40-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With p-toluenesulfonic acid monohydrate In toluene for 3 h; Reflux	A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3percent methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75percent). 1H NMR (400 MHz, DMSO-de) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H).
75%	With toluene-4-sulfonic acid In toluene for 3 h; Dean-Stark; Reflux	A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4-bromobenzaldehyde (2g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatusfor 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of N,N-dimethylformamide, diluted with chloroform, and washed with aq sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification of the residue by flash chromatography (0-3percentmethanol in dichloromethane) followed by trituration in diethyl ether provided the titlecompound (1.75 g, 75percent). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (dd, J=8.72, 1.89Hz, 1H) 8.08 (d, J=8.84 Hz, 1H) 8.38 (d, J=2.02 Hz, 1H) 9.13 (d, J=1.52 Hz, 1H) 9.21(d, 1H).
75%	With toluene-4-sulfonic acid In toluene for 3 h; Reflux	a) 7-bromoquinoline-3 -carbonitrileA mixture of 3,3-diethoxypropanenitrile (1.801 mL, 12.00 mmol),2-amino-4-bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Starkapparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. NaHCO3 solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification by flash chromatography (0-3percent methanol in dichloromethane) followed by trituration in diethylether provided the title compound (1.75 g, 75percent). ‘H NMR (400 MHz, DMSO-d6) ö ppm7.95 (dd, J8.72, 1.89 Hz, 1 H) 8.08 (d, J8.84 Hz, 1 H) 8.38 (d, J2.02 Hz, 1 H) 9.13 (d, J1.52 Hz, 1 H) 9.21 (d, 1 H).

75%

With toluene-4-sulfonic acid In toluene for 3 h; Reflux; Dean-Stark

A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na₂S0₄), and concentrated in vacuo. Purification by flash chromatography (0-3percent methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75percent). 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H)

Reference： [1] Patent: WO2013/28447, 2013, A1, . Location in patent: Page/Page column 119-120
[2] Patent: WO2013/52716, 2013, A1, . Location in patent: Page/Page column 50; 65
[3] Patent: WO2013/177253, 2013, A2, . Location in patent: Page/Page column 61
[4] Patent: WO2014/8223, 2014, A2, . Location in patent: Page/Page column 73

[ 2032-34-0 ] Synthesis Path-Downstream 1~88

1
[ 288-14-2 ]
[ 64-67-5 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 192

2
[ 67522-42-3 ]
[ 2032-34-0 ]
[ 109-94-4 ]
2-formyl-3-(2-oxo-1,2-dihydro-benz[cd]indol-4-ylamino)-acrylonitrile [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1945,vol. 10,p. 76,85

3
[ 52-67-5 ]
[ 2032-34-0 ]
(2Ξ,4S)-2-cyanomethyl-5,5-dimethyl-thiazolidine-4-carboxylic acid ; hydrochloride [ No CAS ]

Reference： [1]Chemistry of Penicillin,

4
[ 1070-71-9 ]
[ 141-52-6 ]
[ 2032-34-0 ]

Reference： [1]Nippon Kagaku Zasshi,1956,vol. 77,p. 1689,1691
Chem.Abstr.,1959,p. 5163

5
[ 61310-53-0 ]
[ 141-52-6 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

6
[ 2032-34-0 ]
[ 18456-87-6 ]
3-(3,6-diisopropyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydro-xanthen-9-yl)-propionitrile [ No CAS ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1940,vol. <2> 155,p. 65,73

7
[ 2032-34-0 ]
[ 50-01-1 ]
[ 156-81-0 ]

Reference： [1]Journal of the American Chemical Society,1950,vol. 72,p. 2587,2593
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 240 - 253

8
[ 2032-34-0 ]
[ 34297-27-3 ]
(2Ξ,4S)-2-cyanomethyl-5,5-dimethyl-thiazolidine-4-carboxylic acid methyl ester [ No CAS ]

Reference： [1]Chemistry of Penicillin,

9
[ 41365-74-6 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

10
[ 2032-34-0 ]
[ 17356-08-0 ]
[ 333-49-3 ]

Yield	Reaction Conditions	Operation in experiment
48%	With sodium; In butan-1-ol; at 40 - 50℃; for 5h;Inert atmosphere;	Under the protection of nitrogen, at 40 ~ 50 ,To n-butanol (88 mL) was added sodium metal (4.8 g)After stirring, the reaction solution was added with thiourea (16 g)<strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> (28 g),Heated to reflux for 5 hours, cooled to room temperature,With acetic acid to adjust the pH to 7 ~ 8, filtered to give a yellow solid,Recrystallization from water gave pale yellow 2-thiocytosine (12 g) in 48% yield.

Reference： [1]Patent: CN106336443,2017,A .Location in patent: Paragraph 0040; 0057-0060
[2]Journal of the American Chemical Society,1950,vol. 72,p. 2587,2593

11
[ 2032-34-0 ]
[ 119-26-6 ]
[ 90323-50-5 ]

Reference： [1]Nippon Kagaku Zasshi,1956,vol. 77,p. 1689,1691
Chem.Abstr.,1959,p. 5163

12
[ 2032-34-0 ]
[ 57-13-6 ]
[ 71-30-7 ]

Reference： [1]Journal of Biological Chemistry,1949,vol. 177,p. 567

13
[ 151-50-8 ]
[ 2032-35-1 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1945,vol. 10,p. 76,85

14
[ 2032-34-0 ]
[ 109-94-4 ]
3-(1-acetyl-1,2-dihydro-benz[cd]indol-4-ylamino)-2-formyl-acrylonitrile [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1953,vol. 36,p. 1137,1141

15
[ 2032-34-0 ]
[ 109-94-4 ]
3-anilino-2-formyl-acrylonitrile [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1945,vol. 10,p. 76,85

16
[ 2032-34-0 ]
[ 109-94-4 ]
3-acenaphthen-4-ylamino-2-formyl-acrylonitrile [ No CAS ]

Reference： [1]Journal of the Chemical Society,1954,p. 2853,2859

17
[ 2032-34-0 ]
[ 2372-45-4 ]
[ 64861-67-2 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1978,p. 107 - 117

18
[ 2032-34-0 ]
[ 141-97-9 ]
[ 40065-21-2 ]

Reference： [1]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1972,vol. 21,p. 2279 - 2280
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1972,vol. 21,p. 2341 - 2342

19
[ 141-52-6 ]
[ 871-29-4 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1964,vol. 29,p. 1800 - 1808

20
[ 13435-20-6 ]
[ 2032-35-1 ]
[ 2032-34-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1978,p. 1946 - 1962

21
[ 143-33-9 ]
[ 2032-35-1 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1975,vol. 97,p. 7152 - 7157

22
[ 2032-34-0 ]
[ 41365-75-7 ]

Reference： [1]Archiv der Pharmazie,1995,vol. 328,p. 487 - 495
[2]Tetrahedron Asymmetry,1993,vol. 4,p. 2307 - 2310

23
[ 2032-34-0 ]
[ 160429-01-6 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,1994,vol. 58,p. 1939 - 1941

24
[ 2032-34-0 ]
[ 51089-83-9 ]
Dibenzyl 5-cyanomethyl-3,7-diethyl-2,8-dimethyldihydrodipyrrin-1,9-dicarboxylate [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1997,p. 1215 - 1227

25
[ 2032-34-0 ]
[ 181046-74-2 ]
(2E,4E)-6-(4,5-Dimethyl-[1,3]dithiol-2-ylidene)-2-formyl-hexa-2,4-dienenitrile [ No CAS ]

Reference： [1]Journal of Materials Chemistry,1998,vol. 8,p. 1185 - 1192

26
[ 2032-34-0 ]
[ 181296-27-5 ]
(2E,4E)-6-Benzo[1,3]dithiol-2-ylidene-2-formyl-hexa-2,4-dienenitrile [ No CAS ]

Reference： [1]Journal of Materials Chemistry,1998,vol. 8,p. 1185 - 1192

27
[ 288-14-2 ]
[ 64-67-5 ]
aq.-ethanolic NaOH [ No CAS ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,1957,vol. 22,p. 192

29
[ 2032-34-0 ]
[ 7664-93-9 ]
[ 64-17-5 ]
[ 61310-53-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 40 The reaction was carried out in a manner as described in Example 25, except that, from the top of the reaction tube, a starting gas mixture comprising 15% by volume of acrylonitrile, 15% by volume of ethyl nitrite, 18% by volume of ethanol, 11% by volume of oxygen, 16% by volume of nitrogen monoxide and 25% by volume of nitrogen was fed at a rate of 48 l/hr (space velocity=3200/hr) and the reaction temperature was changed to 75 C. As a result, cyanoacetoaldehyde diethylacetal was obtained, as an acetal, at a space time yield of 33 g/l.Cat.hr.

31
[ 2032-34-0 ]
[ 57-13-6 ]
sodium butylate solution [ No CAS ]
[ 71-30-7 ]

Reference： [1]Journal of Biological Chemistry,1949,vol. 177,p. 567

32
[ 2032-34-0 ]
[ 427878-69-1 ]
1-amino-5-(2-cyano-3-oxo-propionyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 628 - 632

33
[ 2032-34-0 ]
sodium butylate solution [ No CAS ]
[ 153309-68-3 ]

Reference： [1]Archiv der Pharmazie,1995,vol. 328,p. 487 - 495

34
[ 2032-34-0 ]
sodium butylate solution [ No CAS ]
[ 170801-80-6 ]

Reference： [1]Archiv der Pharmazie,1995,vol. 328,p. 487 - 495

35
[ 2032-34-0 ]
[ 153309-68-3 ]

Reference： [1]Tetrahedron Asymmetry,1993,vol. 4,p. 2307 - 2310

36
[ 41365-74-6 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660

37
[ 10601-80-6 ]
[ 2032-34-0 ]

Reference： [1]Journal of the American Chemical Society,1947,vol. 69,p. 2660
[2]Journal of the American Chemical Society,1947,vol. 69,p. 2660

38
[ 107-31-3 ]
[ 2032-34-0 ]
3,3-diethoxy-2-formylpropionitrile potassium salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium tert-butylate; In tetrahydrofuran; hexane; at 10 - 20℃; for 3.08h;	To a stirred solution of 3, 3-diethoxypropane-nitrile (283.80 g, 1.98 moles) and methyl formate (148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at [10C] was added 1.0 M potassium [TERT-BUTOXIDE] in THF (2.2 L, 2.2 moles). The temperature was maintained in the range of [10C] to [15 C] throughout the 45 minute addition. Following the addition, the resulting slurry was stirred for 2 hours at ambient temperature. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with [1/1] hexanes/THF and dried overnight at [60C] in a vacuum oven to yield 302.5 grams (73.0%) of the above compound P-5A as a pale tan [POWDER.'H-NMR] (CD30D) was consistent with the desired structure.
	With potassium tert-butylate; In tetrahydrofuran; hexane;	Preparation of 3,3-Diethoxy-2-formylpropionitrile Potassium Salt (II) To a stirred solution of <strong>[2032-34-0]3,3-diethoxypropane-nitrile</strong> (1,283.80 g, 1.98 moles) and methyl formate (148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C. was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 moles). Temperature was maintained in the range of 10 C. to 15 C. throughout the 45 minute addition. Following the addition, the resulting slurry was stirred 2 hours at ambient room temperature. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 C. in a vacuum oven. The yield of pale tan powder was 302.5 grams (73.0%).
	With potassium tert-butylate; In tetrahydrofuran; hexane;	Preparation of 3,3-Diethoxy-2-formylpropionitrile Potassium Salt (II) To a stirred solution of <strong>[2032-34-0]3,3-diethoxypropane-nitrile</strong> (I, 283.80 g, 1.98 moles) and methyl formate (148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C. was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 moles). Temperature was maintained in the range of 10 C. to 15 C. throughout the 45 minute addition. Following the addition, the resulting slurry was stirred 2 hours at ambient room temperature. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 C. in a vacuum oven. The yield of pale tan powder was 302.5 grams (73.0%).

Reference： [1]Patent: WO2004/14907,2004,A1 .Location in patent: Page 33-34
[2]Patent: US2003/171584,2003,A1
[3]Patent: US2002/55513,2002,A1

39
bisbenzyltoluene [ No CAS ]
[ 2032-34-0 ]
[ 58243-08-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example A glass apparatus was used which consisted of a 500 ml three-necked flask fitted with stirrer, a thermometer and a 20 cm-long distillation column with reflux divider and receivers. 308.2 g (2.04 mol) of <strong>[2032-34-0]3,3-diethoxypropionitrile</strong> (94.9% pure) 30.0 g of dibenzyltoluene (Marlotherm) 8.0 g of C10-C13-n-alkyl benzenesulfonic acid (Marlon AS 3 acid) were used. The three components were combined, a pressure of 600 hPa was produced and the mixture was heated. The elimination and distillation of the ethanol started from 120 C. The temperature was increased to 180 C. and ethanol was distilled off without residue. The temperature was then reduced to 90 C. and the pressure lowered to 20 hPa. At a reflux: take-off ratio of 2:1 and head temperatures of 83-92 C., 198.3 g of pale yellow 3-ethoxyacrylonitrile with a purity of 98.7% were produced. The residue which remained was 46.7 g. It was liquid at room temperature, homogeneous and readily soluble in methanol.

Reference： [1]Patent: US2002/28962,2002,A1

40
[ 2032-34-0 ]
[ 109-94-4 ]
[ 69791-38-4 ]

Yield	Reaction Conditions	Operation in experiment
	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; mineral oil;	Preparation of cyanomalondialdehyde. To a dried flask was added sodium hydride (0.82 g, 50% suspended in mineral oil, 17 mmol). The sodium hydride was washed three times with 15 mL of ether, and then 15 mL of ether was added to the flask. After cooling the slurry to 0 C., ethyl formate (10.4 g, 140 mmol) was added. To this mixture was added <strong>[2032-34-0]3,3-diethoxypropionitrile</strong> (2 g, 14 mmol) in 10 ml of ether over 2 hours (syringe pump). The mixture was stirred at room temperature for 20 hours, and then poured into 100 mL of ice water. This solution was extracted three times with ether, and then the ether extracts were discarded. The aqueous phase was acidified to pH 3 with concentrated HCl and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered, and concentrated to yield 0.3 g of cyanomalondialdehyde as a yellow solid. Additional product was recovered from the pH 3 aqueous phase: the aqueous phase was concentrated to dryness, and then dissolved in 5 mL of methanol. The inorganic salt was removed by filtration, and the filtrate was concentrated to yield 1 g of cyanomalondialdehyde as a yellow solid. 1H NMR (300 MHz, DMSO-d6) delta8.94 (s, 2H), 4.95 (br s, 1H).

Reference： [1]Patent: US6420349,2002,B1

41
[ 2032-34-0 ]
[ 71-30-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium ethanolate; acetic acid; urea; In 5,5-dimethyl-1,3-cyclohexadiene; water;	EXAMPLE 1 78.1 g (1.3 mols) of urea and 81.7 g (1.2 mols) of sodium ethylate were suspended in 240 g of xylene, and the suspension was heated to reflux temperature. Over a period of 60 minutes 143.2 g (1 mol) of cyanoacetaldehyde-diethylacetal were added. The resulting mixture was heated at the boiling point for an additional 3 hours, and then the alcohol which had formed during the reaction was distilled off. The residual suspension was admixed with 500 g of water, and the aqueous product phase which formed was separated from the xylene phase. By neutralization of the aqueous phase with 72 g (1.2 mols) of acetic acid, the cytosine was precipitated. Subsequent recrystallization from water in the presence of activated charcoal yielded 82.3 g (74.1% of theory) of pure cytosine.
	With sodium ethanolate; urea; In water; toluene;	EXAMPLE 5 39 g (0.65 mol) of urea, 39.1 g (0.575 mol) of sodium ethylate and 71.6 g (0.5 mol) of cyanoacetaldehyde-diethylacetal were combined in 100 g of toluene, and the mixture was heated at its boiling point for 5 hours. Thereafter, the ethanol which had formed was removed by azeotropic distillation with toluene, and the residue was taken up in 250 g of water. After separation of the aqueous phase, cytosine was precipitated by addition of 34.5 g (0.575 mol) of acetic acid, filtered off and purified in analogy to Example 1. 34.1 g (61.3% of theory) of cytosine were obtained.
	With sodium ethanolate; urea; In 5,5-dimethyl-1,3-cyclohexadiene; ethanol; water;	EXAMPLE 3 78.1 g (1.3 mols) of urea and 81.7 g (1.2 mols) of sodium ethylate were suspended in 240 g of xylene and the suspension was admixed with 23 g (0.5 mol) of ethanol. The mixture was heated to the reflux temperature, and over the course of 1 hour 143.2 g (1 mol) of cyanoacetaldehyde-diethylacetal were added, and the mixture was heated for 3 additional hours at the boiling point. The alcohol present in the reaction mixture was distilled off, and the residue was admixed with 500 g of water. Cytosine was precipitated from the aqueous phase by the addition of 72 g (1.2 mols) of acetic acid, filtered off and recrystallized from water in the presence of activated charcoal. 81.6 g (73.5% of theory) of cytosine were obtained.

Reference： [1]Patent: US5026852,1991,A
[2]Patent: US5026852,1991,A
[3]Patent: US5026852,1991,A

42
[ 110-62-3 ]
[ 2032-34-0 ]
[ 64935-37-1 ]
[ 1198476-02-6 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 9558 - 9561

43
[ 64-17-5 ]
[ 107-13-1 ]
[ 2032-34-0 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 9558 - 9561

44
[ 2032-34-0 ]
[ 100-52-7 ]
[ 56069-64-8 ]

Reference： [1]Journal of Organic Chemistry,2009,vol. 74,p. 9558 - 9561

45
[ 2032-34-0 ]
[ 214470-59-4 ]
[ 1248588-02-4 ]

Reference： [1]Molecules,2010,vol. 15,p. 4261 - 4266

46
[ 2032-34-0 ]
[ 100-52-7 ]
[ 1247933-44-3 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7180 - 7191

47
[ 628733-99-3 ]
[ 2032-34-0 ]
[ 1263419-99-3 ]

Yield	Reaction Conditions	Operation in experiment
47%		To a solution of ethyl 1 -amino- lH-pyrrole-2-carboxylate (15d) (3.0 g, 19.46 mmol) in EtOH (100 mL) was added <strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> (25 mL, 95%, 158.23 mmol), IN HCl (aq. 5 mL) and heated at reflux for 18 h. The reaction mixture was cooled to room temperature, treated with DBU (32.5 niL, 213.18 mmol), and stirred with heating at 80 0C for Ih. The reaction mixture was concentrated in vacuo to remove most of EtOH. The residue obtained was diluted with EtOAc (300 mL), washed with water (200 mL, 150 mL). The combined aqueous solution was acidified with 4N HCl to pH = 1 and extracted with chloroform (2 x 300 mL), chloroform/methanol (3:1, 200 mL). The combined extracts were dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue obtained was purified by columnchromatography (silica gel 120 g, eluting with hexanes/ethyl acetate/MeOH, 1 :1 :0 to 2:2:1, product Rf = 0.35 with hexanes/ethyl acetate/MeOH 2:2:1) to give 4-hydroxypyrrolo[l,2- b]pyridazine-3-carbonitrile (15f) (1.44 g, 47%) as a brown solid. 1H NMR (300 MHz, DMSO- d6): delta 8.16 (s, IH), 7.90 (dd, J= 1.6, 2.6 Hz, IH), 7.08 (dd, J= 1.6, 4.5 Hz, IH), 6.80 (dd, J= 2.6, 4.5 Hz, IH); MS (ES"): 157.8 (M - H)1.
47%		To a solution of ethyl 1 -amino- 1 H-pyrrole-2-carboxylate lib (3.0 g, 19.46 mmol) in EtOH (100 mL) was added <strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> (25 mL, 95%, 158.23 mmol), IN HC1 (aq. 5 mL) and heated at reflux for 18 h. The reaction mixture was cooled to RT, treated with DBU (32.5 mL, 213.18 mmol), and heated at reflux for 1 h. The reaction mixture was concentrated in vacuo and the residue obtained was diluted with ethyl acetate (300 mL), extracted with water (200 mL, 150 mL). The aqueous layers were combined acidified with 4 N HC1 to pH = 1 and extracted with chloroform/methanol (3:1, 4 x 200 mL). The combined chloroform layers were dried over MgS04 filtered and concentrated in vacuum. The residue obtained was purified by flash column chromatography [silica gel 120 g, eluting with hexanes/ethyl acetate/MeOH, 1 : 1 :0 to 2:2: 1 (Rf = 0.35 with hexanes/ethyl acetate/MeOH = 2:2:1)] to furnish 4-hydroxy-[l,2-b]pyridazine-3-carbonitrile 11c (1.44 g, 47%) as a brown solid; NMR (300 MHz, DMSO- 6): delta 8.16 (s, 1H), 7.90 (dd, J= 1.6, 2.6 Hz, 1H), 7.08 (dd, J = 1.6, 4.5 Hz, 1H), 6.80 (dd, J= 2.6, 4.5 Hz, 1H); MS (ES"): 157.8 (M - H).

Reference： [1]Patent: WO2011/14817,2011,A1 .Location in patent: Page/Page column 87; 88
[2]Patent: WO2011/150356,2011,A1 .Location in patent: Page/Page column 89

48
[ 2032-34-0 ]
1-amino-pyrrole-2,5-dicarboxylic acid diethyl ester [ No CAS ]
[ 779345-31-2 ]

Yield	Reaction Conditions	Operation in experiment
45%		To a solution of diethyl l-amino-lH-pyrrole-2,5-dicarboxylate 21b (3.0 g, 13.26 mmol) in EtOH (90 mL) was added <strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> (18 mL, 95%, 113.93 mmol), HCl (aqueous 1 N, 3.5 mL) and heated at reflux for 15 h. The reaction mixture was cooled to room temperature added DBU (24 mL, 157.43 mmol) and stirred at 80 0C for Ih. The reaction mixture was concentrated in vacuum to remove ethanol. The residue obtained was diluted with EtOAc (200 mL) and extracted with water (200 mL, 150 mL). The aqueous layer was combined and acidified with 4N aqueous HCl to pH = 1. The aqueous layer was with chloroform/methanol (3:1, 300 mL, 2 x 200 mL). The organic layers were combined dried over MgSO4, filtered and concentrated in vacuum. The residue obtained was purified by column chromatography (silica gel, 120 g eluting with hexanes/ethyl acetate/MeOH, 1:1 :0 to 2:2:1, Rf = 0.39 with hexanes/ethyl acetate/MeOH = 2:2:1) to give ethyl 3-cyano-4-hydroxypyrrolo[l,2-b]pyridazine-7-carboxylate 21c (1.379 g, 45%) as a yellow solid); 1H NMR (300 MHz, DMSOd6): delta 7.95 (s, IH), 7.07 (d, J = 4.5 Hz, IH), 6.60 (d, J= 4.5 Hz, IH), 4.24 (q, J= 7.1 Hz, 2H), 1.28 (t, J= 7.1 Hz, 3H); MS (ES"): 230.4 (M - H)".

Reference： [1]Patent: WO2011/14817,2011,A1 .Location in patent: Page/Page column 91; 92

49
[ 2032-34-0 ]
[ 1263420-13-8 ]
[ 1263420-14-9 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of methyl l-amino-4-nitro-lH-pyrrole-2-carboxylate (47b) (417 mg, 2.25 mmol) in EtOH (12 mL) was added <strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> (2.9 mL, 95%, 18.36 mmol), IN HCl (aq. 0.6 mL) and heated at reflux for 15 h. The reaction mixture was cooled to room temperature, treated with DBU (3.8 mL, 24.90 mmol), and stirred at 80 0C for Ih. The reaction mixture was concentrated in vacuo to remove most of EtOH. The residue obtained was diluted with EtOAc (75 mL), washed with water (50 mL, 30 mL). The combined aqueous solution was acidified with 4N HCl to pH = 1 and extracted with chloroform/methanol (3:1, 4 x 100 mL). The combined extracts were dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue obtained was purified by column chromatography [silica gel 120 g, eluting with chloroform/methanol, 1 :0 to 4:1,( Rf = 0.46 with chloroform/methanol = 4:1)] to give 4- hydroxy-6-nitropyrrolo[l,2-b]pyridazine-3-carbonitrile (47c) (343 mg) as a brown-purple gum; 1U NMR (300 MHz, DMSO-J6): delta 9.58 (s, IH), 8.21 (d, J= 2.2 Hz, IH), 7.87 (s, IH), 6.93 (d, J = 2.2 Hz, IH); MS (ES'): 203.0 (M-I).
		To a solution of methyl l-amino-4-nitro-lH-pyrrole-2-carboxylate 18c (417 mg, 2.25 mmol) in EtOH (12 mL) was added <strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> 18d (2.9 mL, 95%, 18.36 mmol), IN HC1 (aq. 0.6 mL) and heated at reflux for 15 h. The reaction mixture was cooled to room temperature, treated with DBU (3.8 mL, 24.90 mmol), and stirred at 80 C for lh. The reaction mixture was concentrated in vacuo to remove most of EtOH. The residue obtained was diluted with EtOAc (75 mL), washed with water (50 mL, 30 mL). The combined aqueous solution was acidified with 4N HC1 to pH = 1 and extracted with chloroform/methanol (3:1, 4 x 100 mL). The combined extracts were dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue obtained was purified by column chromatography [silica gel 120 g, eluting with chloroform/methanol, 1 :0 to 4:1,( Rf = 0.46 with chloroform/methanol = 4:1)] to give 4- hydroxy-6-nitropyrrolo[l,2-b]pyridazine-3-carbonitrile 18e (343 mg) as a brown-purple gum; 1H NMR (300 MHz, DMSO-<¾: delta 9.58 (s, 1H), 8.21 (d, J= 2.2 Hz, 1H), 7.87 (s, 1H), 6.93 (d, J = 2.2 Hz, 1H); MS (ES"): 203.0 (M-l).

Reference： [1]Patent: WO2011/14817,2011,A1 .Location in patent: Page/Page column 105
[2]Patent: WO2011/150356,2011,A1 .Location in patent: Page/Page column 93-94

50
[ 107-31-3 ]
[ 2032-34-0 ]
[ 449811-60-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In tetrahydrofuran; at 10 - 20℃; for 2.75h;	To a stirred solution of <strong>[2032-34-0]3,3-diethoxypropane-nitrile</strong> (I-1A, 283.80 g, 1.98 moles) and methyl formate (I-1B, 148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C. was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 moles). The temperature was maintained in the range of 10 C. to 15 C. throughout the 45 minute addition. Following the addition, the resulting slurry was stirred for 2 hours at ambient temperature. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 C. in a vacuum oven to provide I-1C. 1H-NMR (CD3OD) was consistent with the desired structure.
	With potassium tert-butylate; In tetrahydrofuran; at 10 - 20℃; for 2.075h;	To a stirred solution of <strong>[2032-34-0]3,3-diethoxypropane-nitrile</strong> (I-1A, 283.80 g, 1.98 moles) and methyl formate (I-1B, 148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C. was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 moles). The temperature was maintained in the range of 10 C. to 15 C. throughout the 4.5 minute addition. Following the addition, the resulting slurry was stirred for 2 hours at ambient temperature. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 C. in a vacuum oven to provide I-1C, 1H-NMR (CD3OD) was consistent with the desired structure.
	With potassium tert-butylate; In hexane; at 10 - 20℃; for 2.33333h;	To a stirred solution of 3,3-dietiioxypropane-nitrile (1-8.4, 283.80 g, 1.98 moles) and methyl formate (I-8B, 148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 moles). The temperature was maintained in the range of 10 C to 15 C throughout the 45 minute addition. Following the addition, the resulting slurry was stirred for 2 hours at ambient temperature. Hexane (400 mL) was then added and stirring was continued for another 20 mm. The slimy' was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 C in a vacuum oven to provide I-8C. -NMR (CD3OD) was consistent with the desired structure.

	With potassium tert-butylate; In tetrahydrofuran; at 10 - 20℃; for 2.75h;	To a stirred solution of <strong>[2032-34-0]3,3-diethoxypropane-nitrile</strong> (1-iA, 283.80 g, 1.98 moles) and methyl formate (I- IB, 148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C was added 1.0 M potassium tert-butoxide in THF (2.2 L. 2.2 moles). The temperature was maintained in the range of 10 C to 15 C throughout the 45 minute addition. Following the addition, the resulting slurry was stirred for 2 hours at ambient temperature. Hexane (400 niL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 CC in a vacuum oven to provide I-1C.?H-NMR (CD3OD) was consistent with the desired structure.
	With potassium tert-butylate; In tetrahydrofuran; at 10 - 20℃; for 2.75h;	To a stirred solution of <strong>[2032-34-0]3,3-diethoxypropane-nitrile</strong> (I-1A, 283.80 g, 1.98 moles) and methyl formate (I-1B, 148.80 g, 2.48 moles) in anhydrous THF (1.1 L) at 10 C. was added 1.0 M potassium tert-butoxide in THF (2.2 L, 2.2 moles). The temperature was maintained in the range of 10 C. to 15 C. throughout the 45 minute addition. Following the addition, the resulting slurry was stirred for 2 hours at ambient temperature. Hexane (400 mL) was then added and stirring was continued for another 20 min. The slurry was filtered and the cake washed with 1/1 hexanes/THF and dried overnight at 60 C. in a vacuum oven to provide I-1C. 1H-NMR (CD3OD) was consistent with the desired structure.

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 2255 - 2265
[2]Patent: US2018/230157,2018,A1 .Location in patent: Paragraph 0265-0266
[3]Patent: US2020/17510,2020,A1 .Location in patent: Paragraph 0096-0097
[4]Patent: WO2020/36986,2020,A1 .Location in patent: Page/Page column 62
[5]Patent: WO2020/36979,2020,A1 .Location in patent: Page/Page column 51
[6]Patent: US2020/48261,2020,A1 .Location in patent: Paragraph 0141; 0142

51
[ 2032-34-0 ]
[ 57597-64-5 ]
[ 1312992-76-9 ]

Reference： [1]Organic Letters,2011,vol. 13,p. 3730 - 3733

52
[ 2032-34-0 ]
[ 1222172-49-7 ]
[ 1222172-50-0 ]

Yield	Reaction Conditions	Operation in experiment
96%		Example 4 Methyl 2-[(2-cyanovinyl)amino]-4-ethoxy-5-acetylamidobenzoate (a compound of formula I, R=methyl) Trifluoroacetic acid (70 mL) was mixed with water (11 mL, 0.6 mol) at room temperature, and 2-cyanoacetaldehyde diethylacetal (23 mL, 0.15 mol, commercially available) was added thereto. The mixture was reacted for 12 h at room temperature to obtain a solution 1. In addition, the title compound of example 3 (a compound of formula II, i.e. methyl 4-ethoxy-5-acetylamido-2-aminobenzoate) (30 g, 0.12 mol) was suspended in ethyl acetate (400 mL), and the above obtained solution 1 was added thereto. The reaction mixture first turned to clear and then changed to cloudy. After reacted for 3-5 h at room temperature, the reaction was finished. The reaction mixture was filtered, washed with ethyl acetate and dried to give 35 g of the title compound as an offwhite powder with a yield of 96%. 1HNMR (300 MHz, DMSO) delta 1.39 (t, 3H), 2.06 (s, 3H), 3.82 (s, 3H), 4.25 (q, 2H), 5.14 (d, 1H), 7.05 (s, 1H), 8.21 (t, 1H), 8.41 (s, 1H), 9.02 (s, 1H), 10.41 (d, 1H). MS/ESI: 303.9 (M+H), 326.0 (M+Na), 302.0 (M-H).

Reference： [1]Patent: US2011/263860,2011,A1 .Location in patent: Page/Page column 5

53
[ 2032-34-0 ]
[ 1222172-51-1 ]
[ 1222172-52-2 ]

Yield	Reaction Conditions	Operation in experiment
90.6%		Example 16 Ethyl 2-[(2-cyanovinyl)amino]-4-ethoxy-5-acetylamidobenzoate (a compound of formula I, R=ethyl) To a mixture of trifluoroacetic acid (60 mL) and water (10 mL) at room temperature, 2-cyanoacetaldehyde diethylacetal (20 mL, 0.133 mol, commercially available) was added, and reacted for 9 h at room temperature to obtain a solution 1. In addition, the title compound of example 15 (26 g, 0.1 mol) was suspended in ethyl acetate (400 mL) at room temperature, followed by addition of the above obtained solution 1. The reaction mixture first became clear and then changed to cloudy. After stirring for 12 h at room temperature, the reaction mixture was filtered and washed with ethyl acetate and dried to give 28 g of the title compound as a gray white powder with a yield of 90.6%. 1HNMR (300 MHz, DMSO) delta 1.30 (t, 3H), 1.39 (t, 3H), 2.06 (s, 3H), 4.22 (q, 2H), 4.29 (q, 2H), 5.13 (d, 1H), 7.04 (s, 1H), 8.20 (t, 1H), 8.36 (s, 1H), 9.01 (s, 1H), 10.45 (d, 1H). MS/ESI: 316.0 (M-H).

Reference： [1]Patent: US2011/263860,2011,A1 .Location in patent: Page/Page column 6-7

54
[ 2032-34-0 ]
[ 93109-27-4 ]
C₂₅H₃₂N₂O₃ [ No CAS ]

Reference： [1]CrystEngComm,2011,vol. 13,p. 4617 - 4624

55
[ 869066-99-9 ]
[ 2032-34-0 ]
[ 779345-24-3 ]

Yield	Reaction Conditions	Operation in experiment
50%		Step 5: Ethy -cyano-4-hydroxypyrrolo[l,2-Z?]pyridazine-6-carboxylate[00170] To a round bottom flask was added diethyl 1 -amino- lH-pyrrole-2,4- dicarboxylate (40 g, 177 mmol), diethoxypropionitrile (53 mL) and p-TSA (10 g, 0.052 mmol). The reaction was heated at 125 C for 3 hours and the EtOH was removed. The reaction was cooled to room temperature before DBU (30 g, 340 mmol) was added. The reaction was then heated at 80 C for 2 hours. The reaction was cooled to room temperature and diluted with CH2CI2. The mixture was washed with 5% citric acid solution (2 x), water and brine solution. The organic layer was concentrated and the residue was purified by flash silica gel column chromatography (10% MeOH in CHC13) to yield 20 g (50%) of the title compound as a brown oil. LCMS (condition A): m/z = 230.2 -ve. XH NMR (400MHz, CDC13) delta ppm: 9.53 (1H, br s), 8.32 (1H, s), 7.75 (1H, s), 6.75 (1H, s), 4.25 (2H, q), 1.28 (3H, t).
50%	With 1,8-diazabicyclo[5.4.0]undec-7-ene;toluene-4-sulfonic acid; In ethanol; at 80 - 125℃; for 5h;	To a round bottom flask was added diethyl 1 -amino- lH-pyrrole-2,4- dicarboxylate (40 g, 177 mmol), diethoxypropionitrile (53 mL) and pTSA (10 g, 0.052 mmol). The reaction was heated at 125 C for 3 hours and the EtOH was removed. The reaction was cooled to room temperature before DBU (30 g, 340 mmol) was added. The reaction was then heated at 80 C for 2 hours. The reaction was cooled to room temperature and diluted with CH2CI2. The mixture was washed with 5% citric acid solution (2 x), water and brine solution. The organic layer was concentrated and the residue was purified by flash silica gel column chromatography (10% MeOH in CHC13) to yield 20 g (50%) of the title compound as a brown oil. LCMS (condition A): m/z = 230.2 -ve. XH NMR (400MHz, CDC13) delta ppm: 9.53 (1H, br s), 8.32 (1Eta, s), 7.75 (1Eta, s), 6.75 (1Eta, s), 4.25 (2Eta, q), 1.28 (3Eta, t).

Reference： [1]Patent: WO2012/125887,2012,A1 .Location in patent: Page/Page column 70
[2]Patent: WO2012/125886,2012,A1 .Location in patent: Page/Page column 80

56
[ 2032-34-0 ]
[ 1400580-12-2 ]
[ 1400580-13-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 4: 6-Brom -4-hydroxypyrrolo[l,2-/?]pyridazine-3-carbonitrile[00176] To a round bottom flask was added the methane sulfonic acid salt of methyl l-amino-4-bromo-lH-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3- diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85 C over 1 hour and then stirred at 85 C for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in (¾(¾ and washed with water and brine solution. The organic layer was separated, dried over Na2S04, filtered and concentrated. The resulting residue was transferred into a 2L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85 C for 5 hours then cooled to rt and diluted with CH2CI2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2S04, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z = 236.0 -ve. XH NMR (400MHz, DMSO-i¾) delta ppm: 9.76 (IH, br.s), 7.62 (IH, s), 7.39 (IH, d, 2.0Hz), 6.43 (lH,d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step.
		To a round bottom flask was added the methane sulfonic acid salt of methyl l-amino-4-bromo-lH-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3- diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85 C over 1 hour and then stirred at 85 C for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in CH2CI2 and washed with water and brine solution. The organic layer was separated, dried over Na2S04, filtered and concentrated. The resulting residue was transferred into a 2L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85 C for 5 hours then cooled to rt and diluted with CH2CI2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2S04, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z = 236.0 -ve. XH NMR (400MHz, DMSO-d6) delta ppm: 9.76 (1H, br.s), 7.62 (1H, s), 7.39 (1H, d, 2.0Hz), 6.43 (lH,d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step.

Reference： [1]Patent: WO2012/125887,2012,A1 .Location in patent: Page/Page column 73-74
[2]Patent: WO2012/125886,2012,A1 .Location in patent: Page/Page column 83; 84
[3]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 306 - 311

57
[ 932-95-6 ]
[ 2032-34-0 ]
(Z,Z)-3,3'-(thiophen-2,5-diyl)bis(2-formylacrylonitrile) [ No CAS ]

Reference： [1]New Journal of Chemistry,2013,vol. 37,p. 409 - 415

58
[ 823-82-5 ]
[ 2032-34-0 ]
(Z,Z)-3,3'-(furan-2,5-diyl)bis(2-formylacrylonitrile) [ No CAS ]

Reference： [1]New Journal of Chemistry,2013,vol. 37,p. 409 - 415

59
[ 2032-34-0 ]
[ 59278-65-8 ]
[ 1375108-40-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With p-toluenesulfonic acid monohydrate; In toluene; for 3h;Reflux;	A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-de) delta ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H).
75%	With toluene-4-sulfonic acid; In toluene; for 3h;Dean-Stark; Reflux;	A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (2g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatusfor 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of N,N-dimethylformamide, diluted with chloroform, and washed with aq sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification of the residue by flash chromatography (0-3%methanol in dichloromethane) followed by trituration in diethyl ether provided the titlecompound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.95 (dd, J=8.72, 1.89Hz, 1H) 8.08 (d, J=8.84 Hz, 1H) 8.38 (d, J=2.02 Hz, 1H) 9.13 (d, J=1.52 Hz, 1H) 9.21(d, 1H).
75%	With toluene-4-sulfonic acid; In toluene; for 3h;Reflux;	a) 7-bromoquinoline-3 -carbonitrileA mixture of 3,3-diethoxypropanenitrile (1.801 mL, 12.00 mmol),<strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Starkapparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. NaHCO3 solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2504), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethylether provided the title compound (1.75 g, 75%). ?H NMR (400 MHz, DMSO-d6) oe ppm7.95 (dd, J8.72, 1.89 Hz, 1 H) 8.08 (d, J8.84 Hz, 1 H) 8.38 (d, J2.02 Hz, 1 H) 9.13 (d, J1.52 Hz, 1 H) 9.21 (d, 1 H).

75%

With toluene-4-sulfonic acid; In toluene; for 3h;Reflux; Dean-Stark;

A mixture of 3,3-diethoxypropanenitrile (1.80 mL, 12.00 mmol), 2-amino-4- bromobenzaldehyde (2 g, 10.00 mmol) and p-toluenesulfonic acid monohydrate (0.380 g, 2.000 mmol) in toluene (30 mL) was heated under reflux using Dean-Stark apparatus for 3 h. The reaction was cooled, evaporated under reduced pressure, and the residue was dissolved in a small amount of DMF, diluted with chloroform, and washed with aq. sodium bicarbonate solution. The aqueous layer was extracted with chloroform, and the combined extracts were washed with brine, dried (Na2S04), and concentrated in vacuo. Purification by flash chromatography (0-3% methanol in dichloromethane) followed by trituration in diethyl ether provided the title compound (1.75 g, 75%). 1H NMR (400 MHz, DMSO-d6) delta ppm 7.95 (dd, J=8.72, 1.89 Hz, 1 H) 8.08 (d, J=8.84 Hz, 1 H) 8.38 (d, J=2.02 Hz, 1 H) 9.13 (d, J=1.52 Hz, 1 H) 9.21 (d, 1 H)

Reference： [1]Patent: WO2013/28447,2013,A1 .Location in patent: Page/Page column 119-120
[2]Patent: WO2013/52716,2013,A1 .Location in patent: Page/Page column 50; 65
[3]Patent: WO2013/177253,2013,A2 .Location in patent: Page/Page column 61
[4]Patent: WO2014/8223,2014,A2 .Location in patent: Page/Page column 73

60
[ 878001-20-8 ]
[ 2032-34-0 ]
[ 1420468-43-4 ]

Yield	Reaction Conditions	Operation in experiment
64%	With sodium methylate; In methanol; at 20℃;	To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (3.0 g, 16 mmol) and 3,3- bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) in methanol (10 mL) was added a 25% sodium methoxide in methanol over 20 minutes. The mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). Two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and solvent was evaporated in vacuo. The residue was then purified to give product. (3.66 g, 64%); 1 H NMR (400 MHz, DMSO-cf6) delta ppm 2.40 (s, 3 H) 2.94 (m, J=1 1 .37 Hz, 1 H) 3.08 (m, J=4.80 Hz, 1 H) 3.20 (s, 1 H) 3.43 (d, J=10.36 Hz, 1 H) 3.42 (d, J=1 1 .12 Hz, 6 H) 3.45 - 3.52 (m, 1 H) 4.60 (d, J=4.80 Hz, 1 H) 7.39 (t, J=7.71 Hz, 1 H) 7.59 (dd, J=17.18, 7.83 Hz, 2 H).
	With sodium methylate; In methanol; water; ethyl acetate;	a) (2E)-2-[bis(methyloxy)methyl]-3-[2-methyl-3-(trifluoromethyl)phenyl]-2-propenenitrile To a solution of 2-methyl-3-(trifluoromethyl)benzaldehyde (3.0 g, 16 mmol) and <strong>[2032-34-0]3,3-bis(ethyloxy)propanenitrile</strong> (2.3 g, 20 mmol) in methanol (10 mL) was added a 25% sodium methoxide in methanol over 20 minutes. The mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). Two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and solvent was evaporated in vacuo. The residue was then purified to give product. (3.66 g, 64%); 1H NMR (400 MHz, DMSO-d6) delta ppm 2.40 (s, 3H) 2.94 (m, J=11.37 Hz, 1H) 3.08 (m, J=4.80 Hz, 1H) 3.20 (s, 1H) 3.43 (d, J=10.36 Hz, 1H) 3.42 (d, J=11.12 Hz, 6H) 3.45-3.52 (m, 1H) 4.60 (d, J=4.80 Hz, 1H) 7.39 (t, J=7.71 Hz, 1H) 7.59 (dd, J=17.18, 7.83 Hz, 2H).

Reference： [1]Patent: WO2013/28263,2013,A1 .Location in patent: Page/Page column 43
[2]Patent: US9096605,2015,B2

61
[ 878001-20-8 ]
[ 2032-34-0 ]
[ 1420468-44-5 ]

Reference： [1]Patent: WO2013/28263,2013,A1

62
[ 2032-34-0 ]
2-[(2,3-dimethylphenyl)methyl]-3,3-bis(methyloxy)propanenitrile [ No CAS ]

Reference： [1]Patent: WO2013/28263,2013,A1

63
[ 2032-34-0 ]
[ 5779-93-1 ]
(2E)-2-[bis(methyloxy)methyl]-3-(2,3-dimethylphenyl)-2-propenenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium methylate; In methanol; at 20℃; for 0.333333h;	To a solution of 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20mmol) and 2,3- dimethylbenzaldehyde (2.1 g, 16 mmol) in methanol (10 mL) was added a 25-30percent of sodium methoxide in methanol over 20 minutes. The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). The two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and concentrated in vacuo. The residue was then purified to give product. It was used in next step. (1 .55 g, 33percent); 1 H NMR (600 MHz, DMSO-c/6) delta ppm 2.20 (s, 3 H) 2.28 (s, 3 H) 3.37 (s, 6 H) 5.13 (s, 1 H) 7.17 - 7.22 (m, 1 H) 7.27 (d, J=7.55 Hz, 1 H) 7.39 - 7.45 (m, 1 H) 7.79 (s, 1 H).

Reference： [1]Patent: WO2013/28263,2013,A1 .Location in patent: Page/Page column 48; 49

64
[ 2032-34-0 ]
cyclopropylhydrazine dihydrochloride [ No CAS ]
1-cyclopropyl-1H-pyrazol-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	In ethanol; at 80℃; for 18h;	Step 1. l-cyclopropyl-lH-pyrazol-5-amine [0634] A 100-mL round-bottom flask was charged with <strong>[2032-34-0]3,3-diethoxypropanenitrile</strong> (0.600 g, 4.19 mmol), cyclopropylhydrazine di-hydrochloride (0.610 g, 4.21 mmol) and ethanol (20 mL), and the resulting solution stirred for 18 h at 80 C. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10: 1, dichloromethane/methanol) to afford l-cyclopropyl-lH-pyrazol-5-amine (0.206 g, 36% ) as light yellow oil. MS (ESI, pos. ion) m/z 124[M+H]+.

Reference： [1]Patent: WO2015/74064,2015,A2 .Location in patent: Paragraph 0634

65
[ 2032-34-0 ]
[ 214470-59-4 ]
C₁₅H₁₇ClN₂O₄ [ No CAS ]

Reference： [1]Organic Preparations and Procedures International,2015,vol. 47,p. 207 - 213

66
[ 2032-34-0 ]
[ 5779-93-1 ]
(2E)-2-[bis(methyloxy)methyl]-3-(2,3-dimethylphenyl)-2-propenenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; water; ethyl acetate;	a) (2E)-2-[bis(methyloxy)methyl]-3-(2,3-dimethylphenyl)-2-propenenitrile To a solution of 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) and <strong>[5779-93-1]2,3-dimethylbenzaldehyde</strong> (2.1 g, 16 mmol) in methanol (10 mL) was added a 25-30percent of sodium methoxide in methanol over 20 minutes. The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). The two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and concentrated in vacuo. The residue was then purified to give product. It was used in next step. (1.55 g, 33percent); 1H NMR (600 MHz, DMSO-d6) delta ppm 2.20 (s, 3H) 2.28 (s, 3H) 3.37 (s, 6H) 5.13 (s, 1H) 7.17-7.22 (m, 1H) 7.27 (d, J=7.55 Hz, 1H) 7.39-7.45 (m, 1H) 7.79 (s, 1H).

Reference： [1]Patent: US9096605,2015,B2

67
[ 2032-34-0 ]
[ 109-94-4 ]
C₈H₁₃NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In diethyl ether; at 20℃; for 48h;	7-(benzyloxy)quinoline-3-carbonitrile (113): 113 was prepared according to the procedure of Cai T.B., et ad journal of Medicinal Chemistry, 51:1849-1860, 2008. Characterization data for 113: < (500MHz, CDC13) 5.28 (s, 2H), 7.39-7.51 (m, 5H), 7.65 (dd, 1H, J 2.5 Hz and 9.0 Hz), 8.05 (d, 1H, J 9.0 Hz), 8.14 (d, 1H, / 2.5 Hz), 8.63 (d, 1H, J 2.0 Hz), 9.15 (d, 1H, J 2.0 Hz) <5C (500MHz, CDC13) 70.6, 116.3, 121.7, 122.3, 122.8, 123.1, 123.3125.4, 127.7, 128.5, 129.5, 130.8, 141.2, 149.1, 151.4.

Reference： [1]Patent: WO2015/188015,2015,A1 .Location in patent: Page/Page column 33; 34

68
[ 2032-34-0 ]
methyl 2-amino-5-methoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzoate [ No CAS ]
(E)-methyl 2-((2-cyanovinyl)amino)-5-methoxy-4-(3-(4-methylpiperazin-1-yl)propoxy)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19.40 g		Charged <strong>[2032-34-0]3,3-diethoxypropionitrile</strong> (20 ml, 19.08 g, 0.1332 mol, 2.25 eq), trifmoroacetic acid (40 ml, 59.56 g, 0.5223 mol, 8.82 eq) and water (10 ml) to the reaction flask at 25-30C under nitrogen atmosphere. Stirred for 6 h at 5-10 C under nitrogen atmosphere. Added dropwise a solution of methyl 2-amino-5-methoxy-4-(3-(4-methyl piperazin-1- yl)propoxy)benzoate in 80 ml ethylacetate within 30-45 min. Stirred the mixture for 10 min. Check the reaction by TLC. Filtered the solid and air dried to afford the title product as light yellow solid. Yield: 19.40 g

Reference： [1]Patent: WO2015/198249,2015,A1 .Location in patent: Page/Page column 11; 17-18

69
[ 2032-34-0 ]
[ 1208361-39-0 ]
[ 1400580-13-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 3101 - 3106

70
[ 2032-34-0 ]
[ 41365-74-6 ]

Yield	Reaction Conditions	Operation in experiment
	With [2,2]bipyridinyl; water; palladium diacetate; at 70℃; for 24h;Schlenk technique; Sealed tube;	General procedure: Some less successful substrates are tabulated below. To an oven dried Schlenk carousel tube containing the appropriate nitrile (1 mmol) was added palladium acetate (11 mg, 5 mol%), 2,2'-bipyridine, (7.8 mg, 5 mol%) and either water (2 mL, 0.5 M) or water/dioxane (1.4 mL/0.6 mL) as stated. The tube was then sealed and the reaction mixture heated at 70 C for 24 hours. After being allowed to cool to room temperature, the reaction mixture was diluted with methanol (5 mL) and the solvent removed in vacuo on a rotary evaporator. 1,4-Dimethoxybenzene (46 mg, 1/3 mmol)) was used as an NMR standard and the crude reaction mixture was analysed by 1H NMR spectroscopy.

Reference： [1]Tetrahedron Letters,2017,vol. 58,p. 4090 - 4093

71
[ 2032-34-0 ]
[ 50709-36-9 ]
1-(2,6-dichlorophenyl)-1H-pyrazol-5-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	In ethanol; for 18h;Reflux;	<strong>[50709-36-9](2,6-dichlorophenyl)hydrazine hydrochloride</strong> (600 mg, 2.81 mmol) and 3,3-diethoxypropanenitrile (400 mg, 2.79 mmol) were dissolved in 20 mL ethanol and refluxed for 18 h. The solvent was evaporated and residue was purified by silica gel chromatography using DCM/MeOH, to obtain final compound as off-white compound (430 mg, 68%). 1H NMR (dmso-d6, 600 MHz) delta 7.77 (br s, 1H), 7.69 (d, 2H, J=8.2 Hz), 7.61 (t, 1H, J=8.2 Hz), 5.60 (s, 1H). 13C NMR (150 MHz, dmso-d6) delta 151.30, 141.51, 139.01, 135.47, 134.02, 129.80, 89.77. ESI-HRMS Calc m/z for C9H9Cl2N3 228.0090 (M+H)+, found 228.0095.

Reference： [1]Patent: US2018/230105,2018,A1 .Location in patent: Paragraph 0613; 0614

72
[ 2032-34-0 ]
[ 120-21-8 ]
(E)-3-(4-(diethylamino) phenyl)-2-formylacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With potassium tert-butylate; In tetrahydrofuran; at 60℃;	General procedure: Add (0.5 g, 2.8 mmol) aldehyde in a stirred mixture of potassium tertiary-butoxide (0.60 g, 4.23 mmol) and 3, 3,-diethoxypropionitrile(0.63 g, 5.64 mmol) in 5 ml THF. Reflux the reaction mixture for overnight at 60 C, add 20 ml water to the solution and the mixture after cooling. It was extracted with diethyl ether. The organic phase was washed with water, sodium bicarbonate and then brine solution androtary evaporated under vacuum to get reddish oil. Then 20 ml of hydrochloric acid solution (1 M) was added and the solution was refluxedffior 1 h, neutralized and extracted with diethyl ether. The combined organic phase was washed with saturated NaOH solution. The product obtained was puriffied by using hexane/ethyl acetate system by column chromatography.3.2. Synthesis of (E)-3-(4-(diethylamino) phenyl)-2-formylacrylonitrile Red crystalline solid. Yield-68%.Melting point-96-98 C1HNMR (500 MHz, CDCl3): delta = 9.47 (s, 1 H), 7.95 (d, J=8.5 Hz,2 H), 7.65 (s, 1 H), 6.71 (d, J=8.5 Hz, 2 H), 3.49 (q, J=7.0 Hz, 4 H),1.26 (t, J=7.0 Hz, 6 H).13CNMR (126 MHz, CDCl3): delta =187.70, 157.64, 152.43, 135.04,118.91, 116.51, 111.47, 103.65, 44.97, 12.53.CHN analysis: Expected: C, 73.66; H, 7.06; N, 12.27; Results: C,73.62, H, 7.05 N, 12.29. Molecular formula: C14H16N2OFT-IR: 1668(C=O stretch), 2218 (C?N stretch), 1474(Ar-C=Cstretch), 1607(C=C stretch)Mass: Calculated 228.1263 for C14H16N2O found 229.1327 (M+1)

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2019,vol. 371,p. 223 - 237

73
[ 2032-34-0 ]
[ 4181-05-9 ]
(E)-3-(4-(diphenylamino) phenyl)-2-formylacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium tert-butylate; In tetrahydrofuran; at 60℃;	General procedure: Add (0.5 g, 2.8 mmol) aldehyde in a stirred mixture of potassium tertiary-butoxide (0.60 g, 4.23 mmol) and 3, 3,-diethoxypropionitrile(0.63 g, 5.64 mmol) in 5 ml THF. Reflux the reaction mixture for overnight at 60 C, add 20 ml water to the solution and the mixture after cooling. It was extracted with diethyl ether. The organic phase was washed with water, sodium bicarbonate and then brine solution androtary evaporated under vacuum to get reddish oil. Then 20 ml of hydrochloric acid solution (1 M) was added and the solution was refluxedffior 1 h, neutralized and extracted with diethyl ether. The combined organic phase was washed with saturated NaOH solution. The product obtained was puriffied by using hexane/ethyl acetate system by column chromatography.

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2019,vol. 371,p. 223 - 237

74
[ 2032-34-0 ]
[ 7570-45-8 ]
(E)-3-(9-ethyl-9H-carbazol-3-yl)-2-formylacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium tert-butylate; In tetrahydrofuran; at 60℃;	General procedure: Add (0.5 g, 2.8 mmol) aldehyde in a stirred mixture of potassium tertiary-butoxide (0.60 g, 4.23 mmol) and 3, 3,-diethoxypropionitrile(0.63 g, 5.64 mmol) in 5 ml THF. Reflux the reaction mixture for overnight at 60 C, add 20 ml water to the solution and the mixture after cooling. It was extracted with diethyl ether. The organic phase was washed with water, sodium bicarbonate and then brine solution androtary evaporated under vacuum to get reddish oil. Then 20 ml of hydrochloric acid solution (1 M) was added and the solution was refluxedffior 1 h, neutralized and extracted with diethyl ether. The combined organic phase was washed with saturated NaOH solution. The product obtained was puriffied by using hexane/ethyl acetate system by column chromatography.

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2019,vol. 371,p. 223 - 237

75
[ 2032-34-0 ]
[ 18413-61-1 ]
(E)-3-(10-ethyl-10H-phenothiazine-3-yl) 2formylacrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium tert-butylate; In tetrahydrofuran; at 60℃;	General procedure: Add (0.5 g, 2.8 mmol) aldehyde in a stirred mixture of potassium tertiary-butoxide (0.60 g, 4.23 mmol) and 3, 3,-diethoxypropionitrile(0.63 g, 5.64 mmol) in 5 ml THF. Reflux the reaction mixture for overnight at 60 C, add 20 ml water to the solution and the mixture after cooling. It was extracted with diethyl ether. The organic phase was washed with water, sodium bicarbonate and then brine solution androtary evaporated under vacuum to get reddish oil. Then 20 ml of hydrochloric acid solution (1 M) was added and the solution was refluxedffior 1 h, neutralized and extracted with diethyl ether. The combined organic phase was washed with saturated NaOH solution. The product obtained was puriffied by using hexane/ethyl acetate system by column chromatography.

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2019,vol. 371,p. 223 - 237

76
[ 64-67-5 ]
[ 76064-23-8 ]
[ 61310-53-0 ]
[ 2032-34-0 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; triethylamine; In acetonitrile; at 40℃; for 10h;	Inject 600.50 grams of sodium methoxide into a 600 ml autoclave.300 grams of acetonitrile, sealed autoclave, ice salt bath for 20 minutes,Inhaled ethyl formate 33.6 g. A nitrogen gas of 1.50 MPa was introduced.The temperature was raised to 110 C with stirring, and the reaction was kept for 15 hours, and the temperature was lowered to room temperature.A white syrupy compound II was obtained which was diluted with 200 g of acetonitrile (CAN).And added to a 1L three-neck bottle, mechanically stirred. Further, 1.50 g of tetrabutylammonium bromide and 63 g of diethyl sulfate were added. Add 6.5 g of triethylamine and warm to 40 C.Stir at this temperature for 10 hours and cool to room temperature. filter,The solid was beaten with 100 g of acetonitrile, filtered, and the mother liquor was spun at 50 C.The mixture I was distilled to give a yield of 98.6% and a purity of 96.3%

Reference： [1]Patent: CN109912454,2019,A .Location in patent: Paragraph 0037; 0038-0048

77
[ 2032-34-0 ]
[ 4922-99-0 ]
2-(thiophen-2-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7-amine [ No CAS ]