[ CAS No. 108-13-4 ] {[proInfo.proName]}

Name: 108-13-4|Malonamide|97%
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Quality Control of [ 108-13-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 108-13-4 ]

SDS Specification

Alternatived Products of [ 108-13-4 ]

Product Details of [ 108-13-4 ]

CAS No. :	108-13-4	MDL No. :	MFCD00008034
Formula :	C₃H₆N₂O₂	Boiling Point :	-
Linear Structure Formula :	H₂NCOCH₂CONH₂	InChI Key :	WRIRWRKPLXCTFD-UHFFFAOYSA-N
M.W :	102.09	Pubchem ID :	7911
Synonyms :

Calculated chemistry of [ 108-13-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.33
Num. rotatable bonds :	2
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	22.35
TPSA :	86.18 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-8.21 cm/s

Lipophilicity

Log Po/w (iLOGP) :	-0.33
Log Po/w (XLOGP3) :	-1.82
Log Po/w (WLOGP) :	-1.65
Log Po/w (MLOGP) :	-1.81
Log Po/w (SILICOS-IT) :	-1.37
Consensus Log Po/w :	-1.4

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	0.81
Solubility :	653.0 mg/ml ; 6.39 mol/l
Class :	Highly soluble
Log S (Ali) :	0.53
Solubility :	344.0 mg/ml ; 3.37 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	0.61
Solubility :	417.0 mg/ml ; 4.08 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 108-13-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 108-13-4 ]

* 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 [ 108-13-4 ]
Downstream synthetic route of [ 108-13-4 ]

[ 108-13-4 ] Synthesis Path-Upstream 1~8

1
[ 3377-20-6 ]
[ 7664-41-7 ]
[ 108-13-4 ]
[ 100-97-0 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1907, vol. <2>75, p. 498

2
[ 79-37-8 ]
[ 108-13-4 ]
[ 67-52-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 128

3
[ 108-13-4 ]
[ 105-58-8 ]
[ 67-52-7 ]

Reference： [1] Yuki Gosei Kagaku Kyokaishi, 1959, vol. 17, p. 232,234[2] Journal of Organic Chemistry, 1959, vol. 24, p. 19[3] Chem.Abstr., 1959, p. 18958

4
[ 79-37-8 ]
[ 108-13-4 ]
[ 71-43-2 ]
[ 67-52-7 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1916, vol. 35, p. 128

5
[ 108-13-4 ]
[ 645-36-3 ]
[ 84661-56-3 ]

Reference： [1] Patent: CN104496906, 2016, B, . Location in patent: Paragraph 0031-0035

6
[ 108-13-4 ]
[ 10177-08-9 ]

Reference： [1] Patent: US4242515, 1980, A,

7
[ 108-13-4 ]
[ 109-94-4 ]
[ 1193-24-4 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2011, vol. 2, # 2, p. 171 - 176

8
[ 897-38-1 ]
[ 7664-41-7 ]
[ 108-13-4 ]
[ 88-96-0 ]

Reference： [1] Justus Liebigs Annalen der Chemie, 1887, vol. 242, p. 46

[ 108-13-4 ] Synthesis Path-Downstream 1~81

1
[ 108-13-4 ]
[ 1186-67-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With bromine; In acetic acid; at 60℃; for 5h;	A solution of bromine in acetic acid (78 g, i.e. 25 ml in 200 ml) is added dropwise over 5 hours to 50 g of malonamide (0.49 mol) dissolved in 300 ml of acetic acid at 600C, with stirring and while maintaining the temperature at 6O0C. The medium decol- orises instantaneously. It turns yellow after 2 hours 30 minutes of addition. <n="47"/>After concentrating and drying, 90.94 g of a pale pink solid are obtained. This solid is triturated from 95% ethanol and then suction-filtered to give 79.24 g of 2-bromo- malonamide.YId = 89%. m.p. = 178C1H NMR (DMSO delta in ppm): 4.67 (s, 1H); 7.59 and 7.68 (s, 2H).Purity (HPLC) = 99%MS (APCI) m/z: 182 [M+H]+

Reference： [1]Patent: WO2008/6432,2008,A1 .Location in patent: Page/Page column 24; 45-46
[2]Journal of the Chemical Society. Perkin transactions II,1993,p. 1429 - 1432
[3]Journal of the Chemical Society,1921,vol. 119,p. 360
[4]Bulletin of the Chemical Society of Japan,1964,vol. 37,p. 547 - 549
[5]Journal of Physical Organic Chemistry,2010,vol. 23,p. 255 - 265

2
[ 108-13-4 ]
[ 30989-14-1 ]

Reference： [1]Synlett,2006,p. 194 - 200
[2]Chemische Berichte,1890,vol. 23,p. 241
[3]Chemische Berichte,1890,vol. 23,p. 241
[4]Journal of the Indian Chemical Society,1930,vol. 7,p. 633
[5]Journal of the Indian Chemical Society,1931,vol. 8,p. 206
Chemisches Zentralblatt,1931,vol. 102,p. 2594

3
[ 108-13-4 ]
[ 73003-80-2 ]

Reference： [1]Synlett,2006,p. 194 - 200
[2]Chemische Berichte,1884,vol. 17,p. 782
[3]Chemische Berichte,1884,vol. 17,p. 782

4
[ 108-13-4 ]
[ 69645-51-8 ]

Reference： [1]Magnetic Resonance in Chemistry,2005,vol. 43,p. 563 - 566
[2]Journal of the Chemical Society,1895,vol. 67,p. 1012
[3]Monatshefte fur Chemie,1904,vol. 25,p. 58
[4]Monatshefte fur Chemie,1904,vol. 25,p. 58
[5]Journal of the Chemical Society,1895,vol. 67,p. 1012
[6]Journal of the American Chemical Society,1914,vol. 36,p. 355
[7]Monatshefte fur Chemie,1904,vol. 25,p. 58
[8]Journal of Organic Chemistry,1968,vol. 33,p. 4296 - 4299
[9]Journal of Physical Organic Chemistry,2010,vol. 23,p. 255 - 265

5
[ 108-13-4 ]
[ 109-77-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With phosphorus pentoxide; under 15.0015 - 37.5038 Torr; for 1h;Heating;	General procedure: An example of the preparation of the amide intermediate was carried out. Closing the reaction kettle(When the boiling point of the amide intermediate at normal pressure is equal to or lower than the reaction temperature TB described below)Or keeping the reaction vessel open (when the boiling point of the amide intermediate at normal pressure is higher than the reaction temperature TB described below), stirring is continued (600 r/min), and the reaction temperature is changed to TB.After maintaining the reaction temperature TB for TD hours, the reaction vessel was closed and connected to a vacuum pump.The degree of vacuum in the autoclave was brought to 20-50 mbar (adjusted according to the type of nitrile product), and the distillate was used as a nitrile product. Calculating the yield of the nitrile product,A sample was taken for nuclear magnetic resonance spectroscopy and elemental analysis to characterize the obtained nitrile product.The specific reaction conditions and characterization results are shown in Tables A-6 and A-7 below.A-8, A-9 and A-10. These characterization results show thatThe nitrile product obtained has an extremely high purity (99% or more).In these nitrile product preparation examples, optionally at the beginning of the reaction,To the reaction vessel, 10 g of phosphorus pentoxide was added in one portion as a catalyst.
	With phosphorus pentoxide; at 250℃; under 15001.5 - 37503.8 Torr; for 1h;	General procedure: Following the amide intermediate preparation example. The reaction vessel is closed (when the amide intermediate has a boiling point at atmospheric pressure, etc.At or below the reaction temperature TB described below) or keeping the reactor open (when the amide intermediate has a boiling point higher than the reaction temperature TB described below at normal pressure), stirring is continued (600 r/min). The reaction temperature was changed to TB. After TD hours at the reaction temperature TB, the reaction vessel was closed and connected to a vacuum pump so that the degree of vacuum in the reaction vessel reached 20-50 mbar (according to the type of nitrile product and corresponding adjustment) to distill off the reaction vessel. The product is a nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic proteomics and elemental analysis to characterize the nitrile product obtained. Specific reaction conditions and characterization results are shown in Tables A-6, A-7, A-8, A-9 and A-10 below. These characterization results show that the nitrile product obtained has an extremely high purity (above 99%). In these nitrile product preparation examples, 10 g of phosphorous pentoxide may be added as a catalyst to the reaction vessel at a time, optionally at the beginning of the reaction.
	under 15.0015 - 37.5038 Torr; for 1h;Heating;	General procedure: An example of the preparation of the amide intermediate was carried out. Blocking the reaction vessel (when the amide intermediate is at a boiling point under normal pressure, etc.At or below the reaction temperature TB below) or to keep the reactor open (when the boiling point of the amide intermediate at normal pressure is higher than the reaction temperature TB described below), stirring is continued (600 r / min), The reaction temperature is changed to TB, and after maintaining the reaction temperature TB for TD hours, the reaction vessel is closed and connected to a vacuum pump, so that the degree of vacuum in the reaction vessel reaches 20-50 mbar (adjusted according to the type of nitrile product) to distill off As a nitrile product. The yield of the nitrile product was calculated and sampled for nuclear magnetic resonance spectroscopy and elemental analysis to characterize the obtained nitrile product. The specific reaction conditions and characterization results are shown in Tables A-6, A-7, A-8, A-9 and A-10 below. These characterization results indicate that the obtained nitrile product has an extremely high purity (99% or more).

Reference： [1]Patent: CN105001033,2018,B .Location in patent: Paragraph 0136; 0137; 0140
[2]Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences,1886,vol. 102,p. 1396
[3]Patent: CN105016945,2018,B .Location in patent: Paragraph 0136; 0137; 0140
[4]Patent: CN105016941,2018,B .Location in patent: Paragraph 0137; 0138; 0139; 0140; 0141

6
[ 7597-56-0 ]
[ 108-13-4 ]

Reference： [1]Journal of Organic Chemistry,1938,vol. 3,p. 313

7
[ 108-13-4 ]
[ 95-54-5 ]
[ 5999-14-4 ]

Reference： [1]RSC Advances,2015,vol. 5,p. 29447 - 29455
[2]Justus Liebigs Annalen der Chemie,1958,vol. 616,p. 87,91, 95
[3]Journal of the Chemical Society,1953,p. 2238

8
[ 95-82-9 ]
[ 108-13-4 ]
[ 69211-05-8 ]

Yield	Reaction Conditions	Operation in experiment
	(i) NaNO₂, aq. HCl, (ii) /BRN= 1751401/, NaOAc; Multistep reaction;

Reference： [1]Dubenko,R.G. et al. [Journal of Organic Chemistry USSR (English Translation), 1978, vol. 14, p. 1956 - 1961][Zhurnal Organicheskoi Khimii, 1978, vol. 14, p. 2112 - 2118]

9
[ 108-13-4 ]
[ 25603-67-2 ]
[ 94880-77-0 ]

Reference： [1]Journal of the Chemical Society,1962,p. 716 - 723

10
[ 108-13-4 ]
[ 106-40-1 ]
[ 69211-01-4 ]

Yield	Reaction Conditions	Operation in experiment
	(i) NaNO₂, aq. HCl, (ii) /BRN= 1751401/, NaOAc; Multistep reaction;

Reference： [1]Dubenko,R.G. et al. [Journal of Organic Chemistry USSR (English Translation), 1978, vol. 14, p. 1956 - 1961][Zhurnal Organicheskoi Khimii, 1978, vol. 14, p. 2112 - 2118]

11
[ 50743-32-3 ]
[ 108-13-4 ]
[ 86443-28-9 ]

Reference： [1]Heterocycles,1986,vol. 24,p. 1931 - 1941

12
[ 874-14-6 ]
[ 108-13-4 ]
[ 35441-11-3 ]

Yield	Reaction Conditions	Operation in experiment
65%		Intermediate 9 : 5-Cyclopropyl-2,6-dichloronicotinamide[0536] A mixture of compound l,3-dimethylpyrimidine-2,4(lH,3H)-dione (14 g, 0.1 mol), malonamide (45 g, 0.44 mol) and sodium ethoxide (34 g, 0.4 mol) in EtOH (500 mL) was refluxed for 20 mins. The mixture was cooled to r.t, quenched by water and acidified with 1 M HCl to pH = 1-2. The solid was filtered and the filter cake was concentrated in vacuo to afford compound 2,6-dihydroxynicotinamide. (10 g, yield: 65%). 1H-NMR (400MHz, DMSO-<¾) delta (ppm) 7.90-7.88 (d, 1H), 5.66-5.64 (d, 1H).

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 846 - 851
[2]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 157
[3]Journal of Organic Chemistry,1981,vol. 46,p. 846 - 851

13
[ 7033-39-8 ]
[ 108-13-4 ]
[ 75993-43-0 ]

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 846 - 851

14
[ 108-13-4 ]
[ 6552-63-2 ]
[ 128883-50-1 ]

Reference： [1]Journal of Heterocyclic Chemistry,1990,vol. 27,p. 523 - 525

15
[ 108-13-4 ]
[ 31217-00-2 ]
[ 75993-42-9 ]

Yield	Reaction Conditions	Operation in experiment
		[0533] Into a 3000-mL 3-necked round-bottom flask were placed a solution of sodium ethoxide (155 g, 2.28mol, 4.00 equiv) in ethanol (2000 mL), malonamide (233 g, 2.28mol, 4.00 equiv) and 5-chloro-l,3-dimethylpyrimidine-2,4(lH,3H)-dione (100 g, 571.43 mmol, 1.00 equiv). The resulting solution was heated to reflux for 20 min. Then it was cooled and concentrated under vacuum. The residue was diluted with 500 mL of H20, and then adjusted to pH 2 with HCl. The solid was collected by filtration and dried in an oven under reduced pressure. This resulted in 50 g (crude) of 5-chloro-2,6-dihydroxynicotinamide as a white solid.

Reference： [1]Journal of Organic Chemistry,1981,vol. 46,p. 846 - 851
[2]Patent: WO2011/94450,2011,A1 .Location in patent: Page/Page column 157

16
[ 108-13-4 ]
[ 1158799-88-2 ]
[ 116548-07-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With hydrogenchloride; sodium ethanolate In ethanol Heating;

Reference： [1]Lang; Wenk [Helvetica Chimica Acta, 1988, vol. 71, # 3, p. 596 - 601]

17
[ 108-13-4 ]
[ 6944-34-9 ]

Reference： [1]Journal of the Chemical Society, Dalton Transactions,1984,p. 1975 - 1980
[2]Tetrahedron Letters,2004,vol. 45,p. 299 - 301
[3]Chemistry of Heterocyclic Compounds,1992,vol. 28,p. 931 - 936
Khimiya Geterotsiklicheskikh Soedinenii,1992,p. 1106 - 1112
[4]Tetrahedron,1989,vol. 45,p. 7329 - 7340
[5]Gazzetta Chimica Italiana,1994,vol. 124,p. 301 - 308

18
[ 108-13-4 ]
[ 2345-56-4 ]

Reference： [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,1991,vol. 30,p. 144 - 147

19
[ 108-13-4 ]
[ 10128-99-1 ]
[ 141946-12-5 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1992,p. 1139 - 1144

20
[ 108-13-4 ]
[ 26866-49-9 ]
[ 62749-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In N-methyl-acetamide; methanol; water;	E-2. 1,2-Dihydro-5-(4-pyridinyl)nicotinamide -- A reaction mixture containing 17.6 g. of alpha-(4-pyridinyl)-beta-dimethylaminoacrolein, 10.0 g. of malonamide, 10.8 g. of sodium methoxide and 200 ml. of methanol was refluxed for thirty minutes and allowed to cool. The separated product was collected and dried to yield "A". The mother liquor was concentrated in vacuo to remove the solvent and the residual material was diluted with water. The mixture was neutralized with acetic acid and the solid was collected, washed with water and dried to yield "B". "A" was dissolved in water and the solution was neutralized with acetic acid and the mixture cooled. The separated solid was collected, washed with water and dried. "A" and "B" were combined and recrystallized from 400 ml. of dimethylformamide to yield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300 C. The product obtained by this procedure was identical with the compound obtained in the immediately preceding Example E-1.
	With sodium methylate; In N-methyl-acetamide; methanol; water;	E-2. 1,2-Dihydro-5-(4-pyridinyl)nicotinamide -- A reaction mixture containing 17.6 g. of alpha-(4-pyridinyl)-beta-dimethylaminoacrolein, 10.0 g. of malonamide, 10.8 g. of sodium methoxide and 200 ml. of methanol was refluxed for 30 minutes and allowed to cool. The separated product was collected and dried to yield "A". The mother liquor was concentrated in vacuo to remove the solvent and the residual material was diluted with water. The mixture was neutralized with acetic acid and the solid was collected, washed with water and dried to yield "B". "A" was dissolved in water and the solution was neutralized with acetic acid and the mixture cooled. The separated solid was collected, washed with water and dried. "A" and "B" were combined and recrystallized from 400 ml. of dimethylformamide to yield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300 C. The product obtained by this procedure was identical with the compound obtained in the immediately preceding Example E-1.

Reference： [1]Archiv der Pharmazie,1984,vol. 317,p. 183 - 185
[2]Patent: US4072746,1978,A
[3]Patent: US4004012,1977,A

21
[ 108-13-4 ]
[ 5486-55-5 ]
[ 64-19-7 ]
[ 134255-29-1 ]
[ 134255-28-0 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1991,vol. 64,p. 851 - 856

22
[ 108-13-4 ]
[ 10103-06-7 ]
[ 64-19-7 ]
[ 134255-33-7 ]
[ 134255-32-6 ]

Reference： [1]Bulletin of the Chemical Society of Japan,1991,vol. 64,p. 851 - 856

23
[ 107-91-5 ]
[ 108-13-4 ]

Reference： [1]Synthetic Communications,2015,vol. 45,p. 760 - 767
[2]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1999,vol. 38,p. 974 - 975
[3]Synthetic Communications,1993,vol. 23,p. 3149 - 3155

24
[ 108-13-4 ]
[ 4637-24-5 ]
[ 123-54-6 ]
[ 52600-60-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride 1.) DMF, r.t., 24 h, 2.) DMF, r.t., 24 h; Yield given. Multistep reaction;
	With sodium hydride multistep reaction; further diones;

Reference： [1]Abu-Shanab; Aly; Wakefield [Synthesis, 1995, # 8, p. 923 - 925]
[2]Abu-Shanab; Aly; Wakefield [Synthesis, 1995, # 8, p. 923 - 925]

25
[ 108-13-4 ]
[ 104-87-0 ]
2-p-tolyl-dihydro-pyrimidine-4,6-dione [ No CAS ]

Reference： [1]Journal of Fluorine Chemistry,1999,vol. 93,p. 69 - 71

26
[ 897-38-1 ]
[ 7664-41-7 ]
[ 108-13-4 ]
[ 88-96-0 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1887,vol. 242,p. 46

28
[ 7597-56-0 ]
[ 7664-41-7 ]
[ 108-13-4 ]

Reference： [1]Journal of Organic Chemistry,1938,vol. 3,p. 313

29
[ 7597-56-0 ]
ammonium chloride [ No CAS ]
[ 7664-41-7 ]
[ 108-13-4 ]

Reference： [1]Journal of Organic Chemistry,1938,vol. 3,p. 313

30
[ 71-33-0 ]
[ 108-13-4 ]
1,2,3,4,5,6-hexahydro-6-(dicarbamoylmethyl)-1,3,5-triazine-2,4-dione [ No CAS ]

Reference： [1]Mendeleev Communications,2001,vol. 11,p. 234 - 235
[2]Pharmaceutical Chemistry Journal,2002,vol. 36,p. 146 - 150

31
vanadium sulfate [ No CAS ]
[ 108-13-4 ]
bis(acetylacetanato-bisNHz)oxovanadium(IV) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; In water; at 4℃;	VO(acac- is synthesized as follows. One equivalent of vanadyl sulfate is dissolved in water <n="20"/>followed by the addition of 3 equivalents of malonamide under constant stirring. A solution of 10% sodium bicarbonate is then added dropwise to raise the pH in order to form a suspension. A bluish precipitate is obtained after standing the solution for one day at 4 0C. The precipitate is filtered off, washed with a small amount of chloroform, and dried under vacuum. VO(acac-(NH2)2)2 is completely soluble in aqueous solutions at physiological pH.

Reference： [1]Patent: WO2007/126896,2007,A2 .Location in patent: Page/Page column 17-18

32
[ 108-13-4 ]
[ 141-52-6 ]
[ 28215-45-4 ]

Yield	Reaction Conditions	Operation in experiment
33%		a). To a solution of NaOEt (21% in EtOH, 167 ml, 450 mmol) in EtOH (170 ml) was added malonamide (22.9 g, 224 mmol). After being refluxed for 2 h, half of EtOH was removed under reduced pressure and the precipitated solid was filtered and dried under high vacuum for overnight. The dried solid sodium salt (24 g) was dissolved in ice-cold H2O (70 mL) and brought to pH 2-3 using 3 N aqueous HCl (50 mL). Recrystallization from water (0 C., 6 h) gave 2-(4,6-dihydroxypyrimidin-2-yl)acetamide (6.28 g, 37.1 mmol, 33%) as a pale yellow solid.

Reference： [1]Patent: US2007/299080,2007,A1 .Location in patent: Page/Page column 80-81

33
[ 726197-67-7 ]
[ 108-13-4 ]
2-[4-(trimethylsilanylmethoxy)benzylidene]malonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	piperidine; acetic acid; In toluene; for 3h;Heating / reflux;	4-(trimethylsilanylmethoxy)benzaldehyde (obtained in step 1 of Example 1) (10.4 g, 0.005 mol) and malonamide (5.5 g, 0.055 mol) in 20 ml of dry toluene in the presence of 0.5 ml of piperidine and 0.3 g of acetic acid are refluxed for 3 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The mixture is cooled and the organic phase is washed twice with water. The organic phase is dried over sodium sulphate and filtered, and the solvent is evaporated off under vacuum. After recrystallization from ethanol, 7.2 g (yield: 49%) of the derivative of Example 10 are obtained in the form of an off-white powder: - m. p. 163-164C - UV (ethanol) lambdamax = 310 nm, epsilonmax = 20 350, E1% = 696.

Reference： [1]Patent: WO2004/67539,2004,A1 .Location in patent: Page 43-44

34
[ 108-13-4 ]
[ 383-63-1 ]
[ 672-47-9 ]

Yield	Reaction Conditions	Operation in experiment
44.4%	With NaH; In toluene; mineral oil; butan-1-ol;	EXAMPLE 3 4,6-Dihydroxy-2-trifluoromethylpyrimidine, Compound VI, starting material for Step 2 Sodium hydride (900 g, 57.5% dispersion in mineral oil; 518 g active NaH; 22.5M) was stirred with 7.5 L toluene in a 22 L round-bottomed flask. Butanol was added over 5 hr. so that the pot temperature was maintained at 40. The mixture was stirred an additional 16 hr. <strong>[108-13-4]Malonamide</strong> (765 g; 7.5 M) was added, followed by ethyl trifluoroacetate (1065 g; 7.5 M). The ensuing reaction was exothermic; the mixture was then heated on a steam-bath for 3.5 hrs. It was then stirred at 23-25 for an additional 16 hrs. The mixture was extracted with water (14 L and 12 L). The combined aqueous extracts were treated with activated charcoal and filtered. The filtrate was maintained at 10-15 as it was acidified to pH 1-2 with 37% hydrochloric acid. The mixture was chilled to 5. The solid was isolated by filtration and dried at 50 in vacuo to give 600 g (44.4% yield) VI m.p. 255-256 (Lit. 265).
		To a suspension of 60% NaH in oil (11.7 g) in toluene (98 mL) was added BuOH (21. 8 g). The mixture was stirred at ambient temperature for 16 hr. To the mixture were added malonamide (10.0 g) and trifluoro-acetic acid ethyl ester (13.9 g). The mixture was stirred at 100C for 3.5 hr and ambient temperature for 16 hr. The organic layer was extracted with water (two times) and the aqueous layer was filtrated through activated carbon. To the aqueous layer was added conc. HCI (pH 1) and the suspension was stirred at 4C for 2 hr. The precipitate was collected by filtration and dried at 80C under reduced pressure to give 2-trifluoromethyl-pyrimidine-4, 6-diol (3.25 g). ESI MS m/e 178, M-H+ ;'H NMR (300 MHz, CDC13) 8 6.00 (s, 1 H), 12.48 (brs, 2 H).

Reference： [1]Patent: US4963678,1990,A
[2]Patent: WO2005/95357,2005,A2 .Location in patent: Page/Page column 140
[3]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

35
3-dimethylamino-2-(4-methoxyphenyl)-2-propenal [ No CAS ]
[ 108-13-4 ]
1,2-dihydro-5-(4-methoxyphenyl)-2-oxonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol;	B-1. 1,2-Dihydro-5-(4-methoxyphenyl)-2-oxonicotinamide--A mixture containing 82.1 g. of 3-dimethylamino-2-(4-methoxyphenyl)-2-propenal, 63.15 g. of malonamide (97%), 54.0 g. of sodium methoxide and 800 ml. of methanol was refluxed with stirring for about 17 hours and chilled. The reaction mixture was filtered and the filtrate concentrated in vacuo to a volume of about 500 ml., acidified with acetic acid and chilled. The resulting solid was collected, dried at 90 C. in a vacuum oven to yield 25.25 g. of 1,2-dihydro-5-(4-methoxyphenyl)-2-oxonicotinamide, m.p. 283-286 C.

Reference： [1]Patent: US4515797,1985,A

36
[ 108-13-4 ]
[ 85907-71-7 ]
1,2-dihydro-5-(3,4-dimethoxyphenyl)-2-oxonicotinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol; water;	B-5. 1,2-Dihydro-5-(3,4-dimethoxyphenyl)-2-oxonicotinamide--A mixture containing 235 g. of 2-(3,4-dimethoxyphenyl)-3-dimethylamino-2-propenal, 2 liters of methanol, 108 g. of sodium methoxide and 150 g. of malonamide was refluxed with stirring for about 30 minutes and the reaction mixture heated in vacuo to remove the solvent. The residue was dissolved in water and neutralized with acetic acid. The separated solid was collected, washed with water, dried, recrystallized from dimethylformamide and dried at 70 C. to yield 81 g. of 1,2-dihydro-5-(3,4-dimethoxyphenyl)-2-oxonicotinamide. A 20 g. sample of the material was recrystallized a second time from dimethylformamide to yield 16 g. of the product, m.p. 266-268 C. The intermediate 2-(3,4-dimethoxyphenyl)-3-dimethylamino-2-propenal was prepared as follows:

Reference： [1]Patent: US4515797,1985,A

37
2-(3,4-Dichloro-phenoxy)-3-dimethylamino-propenal [ No CAS ]
[ 108-13-4 ]
5-(3,4-dichlorophenoxy)-2-hydroxy-3-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium tert-butylate; In ice-water; dimethyl sulfoxide;	(c) Preparation of 5-(3,4-dichlorophenoxy)-2-hydroxy-3-pyridinecarboxamide 2-(3,4-Dichlorophenoxy)-3-dimethylaminopropenal (13 g), malonamide (5.6 g), and t-BuOK (6.2 g) were mixed in 50 ml of DMSO and heated at 45 C. for 30 minutes. This mixture was then stirred at room temperature for an additional 24 hours after which it was poured into 200 g of an ice-water mixture and acidified with concentrated HCl. A solid formed which was collected by centrifugation, vacuum dried, and recrystallized from 2-propanol to give 6.5 g of the desired 5-(3,4-dichlorophenoxy)-2-hydroxy-3-pyridinecarboxamide, m.p. 246-249 C.

Reference： [1]Patent: US4558134,1985,A

38
3-(dimethylamino)-2-[3-(trifluoromethyl)phenyl]-2-propenal [ No CAS ]
[ 108-13-4 ]
1,2-Dihydro-2-oxo-5-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium methylate; In methanol;	EXAMPLE 45 1,2-Dihydro-2-oxo-5-[3-(trifluoromethyl)phenyl]-3-pyridinecarboxamide To a solution of 1.1 g. of malonamide and 1.1 g. of sodium methoxide in 50 ml. of methanol is added 2.43 g. of 3-(dimethylamino)-2-[3-(trifluoromethyl)phenyl]-2-propenal. The resulting mixture is heated at reflux temperature for 12 hours. The mixture is cooled, concentrated and acidified with hydrochloric acid to yield 800 mg. of the product of the Example as a yellow solid m.p. 276.5-278.5 C.

Reference： [1]Patent: US4209626,1980,A

39
1,2-dihydro-5-phenyl-2(1H)-oxo-3-pyridinecarboxamide [ No CAS ]
[ 108-13-4 ]
[ 10177-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid;	EXAMPLE 43 1,2-Dihydro-2-oxo-5-phenyl-3-pyridinecarboxylic acid A 8.4 g. portion of 1,2-dihydro-5-phenyl-2(1H)-oxo-3-pyridinecarboxamide (prepared in a manner similar to that described in Example 9 with the substitution of malonamide for cyanoacetamide) is heated with 150 ml. of 80percent aqueous sulfuric acid for 6 hours. The reaction mixture is poured onto cracked ice and chilled to yield 450 mg. of the product of the Example as a gray solid.

Reference： [1]Patent: US4242515,1980,A

40
[ 108-13-4 ]
[ 59938-06-6 ]
[ 116548-03-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step A:; To a solution of anyhydrous methanol (50 mL), sodium methoxide/methanol solution (61.47 mmol) and malonamide (4.50 g, 44.08 mmol) was added (E)-4-ethoxy-l,l,l-trifluoro-3-butene-2-one V-I (7.781 g, 46.28 mmol) and the mixture was heated to reflux for 2 hours. When the reaction was quenched by addition of water and the aqueous layer pH was adjusted to pH 1-3 with HCl. The mixture was concentrated to give compund V-2 (m/z (ES) (M+H)+= 207), which was used in the next step without further purification.

Reference： [1]Patent: WO2007/41052,2007,A2 .Location in patent: Page/Page column 82

41
[ 108-13-4 ]
[ 4637-24-5 ]
[ 950171-59-2 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 50℃; for 3h;	To a solution of malonic-acid diamide (1 g) in DMF (15 mL), N, N dimethylformamide- dimethylacetal (1.4 g) added slowly. Then the mixture heated up to 50 0C and stirred for 3 h. The product isolated after concentration the mixture followed by crystallization (410 mg).IH NMR. (DMSO d6) delta: 7.45 and 7.02 (each bs, 4 H, 2 x -NH2), 7.40 (s, 1 H, -CH=), 2.94 and 2.89 (2 x s, each 3 H, 2 x -NCH3).13C NMR (DMSO d6) delta: 169.16 and 169.15 (2 x CO), 151.08 (-HN-CH=), 96.37 (C qvat.), 43.07 and 42.95 (2 x NCH3).
	In N,N-dimethyl-formamide; at 50℃;	To a solution of malonic-acid diamide (1 g) in DMF (15 mL), N,N dimethylformamide-dimethylacetal (1.4 g) added slowly. Then the mixture heated up to 50 C. and stirred for 3 h. The product isolated after concentration the mixture followed by crystallization (410 mg).1H NMR. (DMSO d6) delta: 7.45 and 7.02 (each bs, 4H, 2×-NH2), 7.40 (s, 1H, -CH), 2.94 and 2.89 (2×s, each 3H, 2×-NCH3).13C NMR (DMSO d6) delta: 169.16 and 169.15 (2×CO), 151.08 (-HN-CH), 96.37 (C qvat.), 43.07 and 42.95 (2×NCH3).

Reference： [1]Patent: WO2007/104311,2007,A1 .Location in patent: Page/Page column 22
[2]Patent: US2009/234111,2009,A1 .Location in patent: Page/Page column 8

42
[ 108-13-4 ]
[ 59938-06-6 ]
[ 116548-03-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium methylate; In methanol; at 20 - 30℃; for 2h;Heating / reflux;	(1) Production of 1,2-dihydro-2-oxo-6-(trifluoromethyl)pyridine-3-carboxamide; Sodium methoxide (74g, 1.37 mol) was dissolved in methanol (1,000 mL), and malon diamide (100g, 0.979 mol) was added to this solution at room temperature. To this mixture, 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (191g, 1.14 mol) was added dropwise at a temperature between 25 and 30C, and the resultant mixture was refluxed under heating for 2 hours. After cooling to 45C, concentrated hydrochloric acid was added to the mixed solution to give a pH of 3 to 4, and 500 mL of methanol was distilled off at normal pressure. To the residue, water (500 mL) was added, and the mixture was stirred for a day at room temperature. The resultant product was precipitated while cooling with ice. Thus obtained crystal was collected by filtration, washed with water, and then dried under reduced pressure, to obtain 167g of a subject compound (yield: 83%).

Reference： [1]Patent: EP1982978,2008,A1 .Location in patent: Page/Page column 80

43
[ 108-13-4 ]
[ 120407-73-0 ]
[ 116548-03-9 ]

Yield	Reaction Conditions	Operation in experiment
61%		1.2) 2-Oxo-6-trifluoromethyl-1,2-dihydropyridine-3-carboxamide 2.81 g (0.122 mol) of sodium were dissolved in 200 ml of ethanol, 20.0 g (0.102 mol) of 4-butoxy-1,1,1-trifluorobut-3-en-2-one and 10.41 g (0.102 mol) of malonamide were then added, and the mixture was heated under reflux for 7 h. The mixture was then concentrated slightly (about 50 ml), and 1N hydrochloric acid was added. The resulting precipitate was filtered off with suction and dried. This gave 12.9 g (61% of theory) of a yellow powder. 1H-NMR: [DMSO] 7.40 (br, 1H); 8.10 (br, 1H); 8.45 (d, 2H); 13.7 (br, 1H).

Reference： [1]Patent: US2008/269052,2008,A1 .Location in patent: Page/Page column 25

44
[ 108-13-4 ]
[ 119352-49-7 ]
[ 191595-68-3 ]

Yield	Reaction Conditions	Operation in experiment
41%		2.2) 6-Chloro(difluoro)methyl-2-oxo-1,2-dihydropyridine-3-carboxamide 1.29 g (55.9 mmol) of sodium were dissolved in 150 ml of ethanol, 9.90 g (46.6 mol) of 4-butoxy-1-chloro-1,1-difluorobut-3-en-2-one and 4.90 g (46.6 mmol) of malonamide were then added, and the mixture was heated under reflux for 5 h. The mixture was then concentrated slightly (about 50 ml), and 1N hydrochloric acid was added. The resulting precipitate was filtered off with suction and dried. This gave 4.2 g (41% of theory) of a yellow powder. 1H-NMR: [DMSO] 7.35 (d, 1H); 8.10 (br, 1H); 8.40 (d, 1H); 8.41 (br, 1H); 13.6 (br, 1H).

Reference： [1]Patent: US2008/269052,2008,A1 .Location in patent: Page/Page column 25

45
[ 108-13-4 ]
[ 822-06-0 ]
poly(hexamethylehe diisocyanate-co-malonic acid diamide) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Nach dem in Beispiel 1 beschriebenen Verfahren wurden ausgehend von HDI unter Verwendung unterschiedlicher Stabilisatoren Uretdionpolyisocyanate hergestellt. Zur besseren Handhabung wurden die Stabilisatoren dabei jeweils in Form einer Loesung im alkoholischen Cokatalysator 1,3-Butandiol eingesetzt. Der Oligomerisierungsgrad betrug in allen Faellen zwischen 18 und 19 %. Die nachfolgende Tabelle zeigt Art und Menge der eingesetzten Stabilisatoren (jeweils bezogen auf die Menge an eingesetztem Ausgangsdiisocyanat) sowie Kenndaten und Lagerstabilitaet der nach Duennschichtdestillation erhaltenen Harze.

Reference： [1]Patent: EP1174428,2002,A2 .Location in patent: Page 8

46
[ 108-13-4 ]
[ 1072027-80-5 ]
[ 1072023-83-6 ]

Yield	Reaction Conditions	Operation in experiment
73%	With methanol; sodium; for 6h;Heating / reflux;	A18.1) 6-(2-Chloro-1,1,2,2-tetrafluoroethyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; 0.53 g (22.8 mmol) of sodium were dissolved in 50 ml of methanol, 5.0 g (19.0 mmol) of 1-butoxy-5-chloro-4,4,5,5-tetrafluoropent-1-en-3-one and 2.0 g (19.0 mmol) of malonamide were then added and the mixture was heated under reflux for 6 h. The mixture was concentrated, and 1 N hydrochloric acid was then added. The resulting precipitate was filtered off with suction and dried. This gave 3.8 g (73% of theory) of a brownish powder.1H-NMR: [DMSO] 7.42 (br, 1H); 8.10 (br, 1H); 8.40 (br, 1H); 8.46 (d, 1H), 13.6 (br, 1H).

Reference： [1]Patent: US2008/269059,2008,A1 .Location in patent: Page/Page column 25

47
[ 108-13-4 ]
[ 1072027-60-1 ]
[ 1072021-29-4 ]

Yield	Reaction Conditions	Operation in experiment
94%	With ethanol; sodium; for 7h;Heating / reflux;	Example A5; 2-Oxo-6-(pentafluoroethyl)-1,2-dihydropyridine-3-carboxamide; 0.22 g (9.7 mmol) of sodium was dissolved in 50 ml of ethanol, 2 g (8.1 mmol) of 1-butoxy-4,4,5,5,5-pentafluoropent-1-en-3-one and 0.86 g (8.1 mmol) malonamide were added and the mixture was heated under reflux for 7 h. The mixture was concentrated, and 1 N hydrochloric acid was added. The resulting precipitate was filtered off with suction and dried. This gave 1.9 g (94% of theory) of a yellow powder.1H-NMR: [DMSO] 7.45 (d, 1H); 8.15 (br, 1H); 8.45 (br, 1H); 8.50 (d, 1H); 13.7 (br, 1H).

Reference： [1]Patent: US2008/269059,2008,A1 .Location in patent: Page/Page column 20-21

48
[ 454-31-9 ]
[ 108-13-4 ]
[ 929903-21-9 ]

Yield	Reaction Conditions	Operation in experiment
		Reference Example 185 2-Difluoromethyl-4,6-dihydroxy-5-nitropyrimidine A mixture of malonamide (5.1 g) and sodium ethoxide (20% ethanol solution, 34.3 g) in methanol (125 mL) was stirred at room temperature for 1 hour. To the mixture was added ethyl 2,2-difluoroacetate (6.31 mL), and the mixture was heated at reflux for 10 hours, and then stirred at room temperature overnight. To the mixture was added 1 mol/L hydrochloric acid until the pH became 3. The mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with ethyl acetate thrice. The extracts were washed with brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residual solids were suspended in a mixed solvent (n-hexane/ethyl acetate = 2/1), and collected by filtration. The collected solids were dried under reduced pressure to give 2-difluoromethyl-4,6-dihydroxypyrimidine (2.36 g). The title compound was prepared in a similar manner to that described in Reference Example 177 using this material instead of 4,6-dihydroxy-2-methylpyrimidine.

Reference： [1]Patent: EP2143724,2010,A1 .Location in patent: Page/Page column 44
[2]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

49
[ 108-13-4 ]
[ 656-73-5 ]
[ 1269416-70-7 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: 9,10-Diketo stearic acid (0.01 mol) was refluxed with thiourea (0.01 mol) (1)/urea (0.03 mol) (2)/thiosemicarbazide (0.01 mol) (5)/malonamide (0.01 mol) (6) in pyridine for 8-12 h. The cooled mixture was poured onto cold dilute HCl and extracted with ether. The crude product was recrystallized from ethyl acetate to petroleum ether.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 384 - 392

50
[ 349-43-9 ]
[ 108-13-4 ]
[ 1313546-74-5 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

51
[ 108-13-4 ]
[ 583-02-8 ]
4,6-dihydroxy-2-(4'-trifluoromethylphenyl)pyrimidine [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

52
[ 108-13-4 ]
[ 4606-07-9 ]
[ 7024-58-0 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

53
[ 108-13-4 ]
[ 7605-30-3 ]
[ 1313546-77-8 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

54
[ 108-13-4 ]
[ 109-94-4 ]
[ 1193-24-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 171 - 176

55
[ 108-13-4 ]
[ 431-47-0 ]
[ 672-47-9 ]

Yield	Reaction Conditions	Operation in experiment
		-(Trifluoromethyl)pyrimidine-4,6-diol (15) Sodium hydride (57 g of a 60% dispersion in mineral oil, 1430 mmol) was stirred in toluene under nitrogen and cooled with a wet ice bath. Butanol (130 mL, 1430 mmol) was added drop-wise and mixture was stirred for 30 min.<strong>[108-13-4]Malonamide</strong> (50 g, 480 mmol) was added in one portion followed by the drop-wise addition of methyl trifluoroacetate (14) (67.5 g, 475 mmol), which led to an immediate exotherm. When the addition was complete, the reaction mixture was stirred at 40 C overnight and then cooled to RT. The reaction was diluted with 1 N HCI (300 mL) and then concentrated HCI was added until pH = 2. The layers were separated and the aqueous layer was extracted with ethyl acetate (3X), dried over magnesium sulfate, and concentrated. The resulting orange solid was triturated with 2:1 heptane: DCM (2 x 100 mL), collected by filtration, and dried under vacuum overnight to provide 28.1 g of 15 as a light orange solid. LCMS m/z 181.1 (M+1 ). H NMR (400 MHz, CD3OD) delta 5.90 (s, 1 H).
		To the reaction flask was added 500 mL methanol, cooled to 0 ~ 5 C, 118.6 g sodium methoxide was added,Stirring until substantially clear, adding 102.1g malonamide, stirring, warmed to 35 ,153.7 g of methyl trifluoroacetate was added, and after completion of the addition, the mixture was stirred for 30 minutes,The temperature was raised to 65 to 70 C and refluxed for 15 hours. After the reaction, cooling to 25 ~ 35 ,100 mL methyl tertiary ether was added dropwise and the temperature dropped to 5 ~ 10 C. After stirring, the filter cake was rinsed with ruthenium ether. After filtration, the solid was transferred to a single-necked flask and concentrated under reduced pressure. Add water, stir until clear, add concentrated hydrochloric acid to adjust pH = 1 ~ 2, filter to obtain filter cake 95g. The filter cake was added with 250 mL of ethyl acetate, heated to reflux, stirred, filtered and concentrated under reduced pressure to constant weight to give 118.4 g of an off-white solid in a yield of 65.8% and HPLC of 94.3%.

Reference： [1]Patent: WO2011/58478,2011,A1 .Location in patent: Page/Page column 35
[2]Patent: CN106883185,2017,A .Location in patent: Paragraph 0017

56
[ 109-77-3 ]
[ 108-13-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With Acetaldehyde oxime; In methanol; at 65℃; for 4h;	General procedure: A typical reaction was carried out in a 10 mL flask. Benzonitrile (2 mmol), CuII-4 A (0.2 g), acetaldoxime (6 mmol) and MeOH (4 mL) were stirred at 65 C for 4 h. The solid was filtered, washed with MeOH and the filtrate evaporated. The residue was subjected to GC-MS analysis and NMR spectroscopy. The filtered catalyst can be recycled after drying at about 150 C for 1 h.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 6021 - 6023
[2]Organic Letters,2014,vol. 16,p. 1060 - 1063

57
[ 108-13-4 ]
[ 1522-22-1 ]
[ 209392-84-7 ]

Yield	Reaction Conditions	Operation in experiment
75%	In sulfolane; at 80 - 155℃; for 7h;	This procedure was adapted from Umemoto and Tomisawa, JP 10168061 A, June 23, 1998. In a 250 mL round bottom flask, a suspension of malonamide (9.81 g, 96 mmol) and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (20 g, 96 mmol) in tetrahydrothiophene 1,1-dioxide (Sulfolane; 40 mL, 420 mmol) was heated at 80 C for 2 h forming a clear, colorless solution. To the flask was added a short path distillation head equipped with a 20 mL receiver, and the mixture was heated at 155 C for 5 h. The hot solution was poured into ice-H2O (400 mL), and the mixture was stirred vigorously to form a white solid suspension. After stirring for 30 min, the suspension was filtered over a Biichner funnel, and the white solid was washed with distilled water (a total of 500 mL). The solid was air-dried and then dried in a vacuum oven at 50 C for 72 h to give the title compound as a white solid (20.1 g, 75%): 1H NMR (400 MHz, CD3CN) delta 9.62 (s, 1H), 7.56 (s, 1H), 6.69 (s, 1H), 6.54 (s, 1H); 19F NMR (376 MHz, CD3CN) delta -62.46 (s), -69.14 (s); ESIMS m/z 273.6 ([M-1]-).
75%	With sulfolane; at 80℃; for 2h;	This procedure was adapted from Umemoto and Tomisawa, JP 10168061 A, June 23, 1998. In a 250 mL round bottom flask, a suspension of malonamide (9.81 g, 96 mmol) and l,l,l,5,5,5-hexafluoropentane-2,4-dione (20 g, 96 mmol) in tetrahydrothiophene 1,1-dioxide (Sulfolane; 40 mL, 420 mmol) was heated at 80 C for 2 h forming a clear, colorless solution. To the flask was added a short path distillation head equipped with a 20 mL receiver, and the mixture was heated at 155 C for 5 h. The hot solution was poured into ice-H20 (400 mL), and the mixture was stirred vigorously to form a white solid suspension. After stirring for 30 min, the suspension was filtered over a Biichner funnel, and the white solid was washed with distilled water (a total of 500 mL). The solid was air-dried and then dried in a vacuum oven at 50 C for 72 h to give the title compound as a white solid (20.1 g, 75%): ]H NMR (400 MHz, CD3CN) delta 9.62 (s, 1H), 7.56 (s, 1H), 6.69 (s, 1H), 6.54 (s, 1H); 19F NMR (376 MHz, CD3CN) delta -62.46 (s), -69.14 (s); ESIMS mJz 273.6 ([M-l]").

Reference： [1]Patent: WO2013/106254,2013,A1 .Location in patent: Page/Page column 53; 54
[2]Patent: WO2014/126580,2014,A1 .Location in patent: Page/Page column 52; 53

58
[ 108-13-4 ]
[ 150-13-0 ]
4-(dicarbamoylmethylene-hydrazino)-benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.4%		To 10.0 parts of the compound (22), 100 parts of methanol and 14.0 parts of concentrated hydrochloric acid were added, and the resulting solution was ice cooled to 10C or below. To the solution, a solution prepared by dissolving 5.2 parts of sodium nitrite in 15.0 parts of water was added, and the solution was allowed to react at the same temperature for 1 hour (diazonium salt solution) . To 200.0 parts of methanol, 7.4 parts of the compound (23) was added, the resulting solution was ice cooled to 10C or below, and to the cooled solution, the foregoing diazonium salt solution was added. Then, a solution prepared by dissolving 14.8 parts of sodium acetate in 50.0 parts of water was added to the foregoing solution, and the resulting solution was allowed to react at 10C or below for 2 hours. After completion of the reaction, the solid obtained by filtering the precipitated solid was dispersed and washed in water, and then filtered, and thus 14.7 parts of the coloring matter compound (24) was obtained (yield: 81.4%) .

Reference： [1]Patent: WO2013/129696,2013,A1 .Location in patent: Paragraph 0154; 0155

59
[ 108-13-4 ]
[ 155377-05-2 ]
2-(6-trifluoromethyl-pyridin-2-yl)-1H-pyrimidine-4,6-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; In ethanol; for 1h;Reflux;	Step 1: Preparation of 2-(6-Trifluoromethyl-pyridin-2-yl)-1H-pyrimidine-4, 6-dione To a solution of sodium (32 g, 0.16 mol) in ethanol (500 mL) was added 6-trifluoro- methylpyridine-2-carboxylic acid methyl ester (6.15 g, 3 mmol) and malonamide (1.02 g, 1 mmol). The mixture was heated to reflux for 1 hour, then concentrated to give a residue which was poured to water (100 mL). Saturated NaHCO3 solution was added to adjust to pH 7, the mixture was filtered, and then added iN HC1 solution to adjust pH to 3. DCM (20 mL) was added, and the precipitated solid was collected by filtration and dried to give 2-(6-trifluoromethyl-pyridin-2-yl)- 1 H-pyrimidine-4,6-dione. LCMS: [M+ 1] = 257.9

Reference： [1]Patent: WO2015/6591,2015,A1 .Location in patent: Page/Page column 122

60
[ 507-19-7 ]
[ 108-13-4 ]
N-tert-butylpropanediamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dimanganese decacarbonyl; at 130℃; for 2h;Inert atmosphere; Sealed tube;	General procedure: A 17-mL stainless steel high-pressure micro reactor or a glass ampule (the results of parallel runs differed insignificantly) was charged under argon with 0.3 mmol of manganese catalyst, 10 mmol of tert-butyl bromide (1), and 30 mmol of the corresponding amide. The reactor was hermetically closed (the ampule was sealed) and heated for 3-4 h at 120-130C under continuous stirring. When the reaction was complete, the reactor (ampule) was cooled to room temperature and opened, the mixture was washed with water and extracted with methylene chloride (3 × 5 mL), the extract was evaporated under reduced pressure, and the residue was recrystallized.

Reference： [1]Russian Journal of Organic Chemistry,2015,vol. 51,p. 1502 - 1504
Zh. Org. Khim.,2015,vol. 51,p. 1532 - 1534,3

61
[ 108-13-4 ]
[ 123-29-5 ]
2-octylpyrimidine-4,6-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With ethanol; sodium; for 3h;Reflux;	Sodium (250 mg) was dissolved in ethanol (8 mE), then added compound 5 (500 mg, 4.9 mmol, 1 eq). After the solid was dissolved, compound 6-1 (1.1 g, 5.89 mmol, 1.2 eq.) in ethanol (5 mE) was slowly added dropwise. A white solid was precipitated. Afier heated to reflux for 3 hours, the reaction mixture was then cooled and filtered. The filtrate was concentrated and added 3 mE of H20 to dissolve the solid. A dilute hydrochloric acid (2M) was slowly added dropwise to adjust pH to 3-5. A white precipitation was filtered. The filter cake was added 5 mE of methanol, stirred for 1 h, filtered and dried to obtain compound EY224-b (white solid, 1.0 g, 91%). ?H NMR (300 MHz, DMSO-d5) oe 11.64 (s, 2H), 5.02 (s, 1H), 2.52 (t, J=7.5 Hz, 2H), 1.62 (q, J=6.6 Hz 2H), 1.25 (m, 1OH), 0.84 (t, J=6.6 Hz, 3H).

Reference： [1]Patent: US2018/237399,2018,A1 .Location in patent: Paragraph 0122; 0123
[2]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 579 - 583

62
[ 108-13-4 ]
[ 110-38-3 ]
2-nonylpyrimidine-4,6-diol [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 579 - 583

63
[ 108-13-4 ]
ethyl 3-(4-ethylphenyl)propanoate [ No CAS ]
2-(4-ethylphenethyl)pyrimidine-4,6-diol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35%	With ethanol; sodium; at 80℃; for 3h;	Sodium (250 mg) was dissolved in ethanol (8 mE), then added compound 2 (212 mg, 2.08 mmol, 1.1 eq.). After the solid was dissolved, compound 10-1 (390 mg, 1.89 mmol, 1 eq.) in ethanol (5 mE) was slowly added dropwise. A white solid was precipitated. After heated to reflux for 3 h, the reaction was cooled to room temperature, filtered, concentrated, dissolved with 3 mE of H20. A dilute hydrochloric acid (2M) was slowly added dropwise to the residue to adjust pH to 3-5. A white precipitation was filtered. The filter cake was added in 5 mE of methanol, stirred for 1 h, filtered and dried to obtain compound EY244 (white solid, 147 mg, 35%). H NMR (300 MHz, DMSO) oe 11.50 (s, 2H),7.12 (m, 4H), 5.06 (s, 1H), 2.95-2.88 (t, J=7.5 Hz, 2H),2.78-2.69 (t, J=8.1 Hz, 2H), 2.60-2.53 (q, J=7.5 Hz, 2H),1.15 (t, J=7.5 Hz, 1H).

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 579 - 583
[2]Patent: US2018/237399,2018,A1 .Location in patent: Paragraph 0125; 0129

64
[ 67-56-1 ]
[ 598-42-5 ]
[ 108-13-4 ]
[ 598-41-4 ]

Yield	Reaction Conditions	Operation in experiment
		Into a ??Methanol ammoxidation reactor"(fluidized bed) pumped methanol, meanwhile feed air and ammonia gas,first causing methanol oxidativedehydrogenation as formaldehyde then partially Ammoniated as hydrocyanic acid. Methanolweight space velocity 0.5h-1, ammonia alcohol ratio is 1.2 (Because some of the ammonia is oxidizedto nitrogen, ammonia alcohol ratio higher than the theoretical value of thereaction formula) . The reaction temperature is 420 C. The reaction pressureis 0.3MPa, the methanol concentration of about 6.5%, the gas space velocity8000 h-1 . methanol conversion rate98%. The main Built-in component of catalyst is Fe1Mo2.5Bio0.15 P0.1 Si10Ox. SiO2as a supported catalyst. The reason for choosing fluidized bed is heatrelease of oxidation and ammoniation reactions are large. Fluidized bed caneffectively reduce the temperature of the hot bed and to avoid the loss of Mosublimation. from?Methanol ammoxidation reactor? gas which came out entered into ?Condensationreactor ? (Microchannel reactor) equipped with alkali catalyst for reaction toproduce an Amide. the reactiontemperature is 300 C. The reaction pressure 0.25MPa, gas aid speed 2000h-1. The catalyst is a solid alkaliMgO/Al2O3.in the solid reaction product hydroxyacetamideis 13%, amino Acetamide 50%,Iminodiacetic acid amide 5 % and Malonamide 30%. The purpose of selection ofmicro-channel reactor is to improve the selectivity of a particular product
	With ammonia; at 400℃; under 1500.15 Torr;	Into ?Amide synthesis reactor? (Fixed bed) pumped methanol meanwhile feed airand ammonia gas ,first causing methanol oxidativedehydrogenation as formaldehyde then partially Ammoniated as hydrocyanicacid at last condensation as amide andall are done in the same reactor. Methanol weight space velocity 0.5h-1 , ammonia alcohol ratio is 0.8 and the reaction temperature is 400 C. Thereaction pressure is 0.2MPa, the methanol concentration of about 7%, the gasspace velocity 5000 h-1 . methanol conversion rate 96%. The main Built-in component of catalystis Fe1Mo2.5 Bio0.15 P0.1 Ox/ MgO/Al2O3. in the solid reaction product hydroxyacetamideis 50%, amino Acetamide 30%,Iminodiacetic acid amide 5 % and Malonamide 12%.

Reference： [1]Patent: CN102295571,2016,B .Location in patent: Paragraph 0039; 0040; 0041
[2]Patent: CN102295571,2016,B .Location in patent: Paragraph 0042; 0043

65
[ 108-13-4 ]
[ 645-36-3 ]
[ 84661-56-3 ]

Yield	Reaction Conditions	Operation in experiment
	With nitric acid; In water; at 160℃; for 13h;	(1) In a reaction vessel, 330 g of aminoacetaldehyde diethyl acetal was dissolved in 4 L of water, stirred at 60 revolutions per minute, and 70 mL of 1.7 mol / L nitric acid aqueous solution was added dropwise;(2) To 100 g of malonamide was added to the mixed system obtained in step (1), and the mixture was allowed to react at 160 C for 13 hours.(3) adding 4L of chloroform to the mixed system obtained in step (2) to extract the organic phase;(4) To the organic phase obtained in the step (3), 80 mL of glacial acetic acid was added, and the mixture was sufficiently charged and the lithium tetrahydride was slowly added, and the mixture was stirred at 40 revolutions per minute for 4.5 hours.(5) the mixture obtained in step (4) is filtered and the residue is discarded, and the resulting liquid phase is distilled at atmospheric pressure to obtain imidazole.In the preparation conditions described in the present Example, 106.8 g of imidazole was prepared in a yield of 91%.

Reference： [1]Patent: CN104496906,2016,B .Location in patent: Paragraph 0031-0035

66
[ 108-13-4 ]
[ 28215-45-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium ethanolate; In ethanol; for 2h;Reflux;	To a solution of NaOEt (21o in EtOH, 167 mL, 450 mmol) in EtOH (170 mL) was added malonamide (22.9 g, 224 mmol). After being refluxed for 2 hours, half of EtOH was removed under reduced pressure and the precipitated solid was filtered and dried under high vacuum for overnight. The dried solid sodium salt (24 g) was dissolved in ice-cold H20 (70 mL) and brought to pH 23 using 3N. HC1 (50 mL), recrystallization from water gave 2-(4,6- dihydroxypyrimidin-2-yl)acetamide as a pale yellow solid (6.28 g, 330 o).

Reference： [1]Patent: WO2016/206573,2016,A1 .Location in patent: Paragraph 081; 082; 083

67
[ 108-13-4 ]
2-(4-(diphenylamino)phenyl)benzofuran-6-carbaldehyde [ No CAS ]
2-((2-(4-(diphenylamino)phenyl)benzofuran-6-yI)methylene)malonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.64 g	With piperidine; In 1,2-dichloro-ethane; acetonitrile; for 60h;Reflux;	[0139] To 2-(4-(diphenylamino)phenyl)benzofuran-6-carbaldehyde (0.16 g) and malonamide (0.046 g) was added acetonitrile (2.1 mL) and piperidine (0.020 mL). The reaction was heated to reflux for 24 hours, then additional malonamide (0.046 g), piperidine (0.02 mL) and 1 ,2-dichloroethane (1.0 mL) were added and the reaction heated at reflux for an additional 12 hours. A third portion of malonamide (0.046 g) and of piperidine (0.04 mL) was added and the reaction heated for an additional 24 hours. The reaction was cooled to room temperature and water (10 mL) and ethyl acetate (15 mL) were added. The reaction mixture was stirred at room temperature for 1 hour and then the precipitate collected by filtration. The precipitate was dried under vacuum at 60C to afford 2-((2-(4-(diphenylamino)phenyl)benzofuran-6- yl)methylene)malonamide (BC-155, 0.64 g). 1 H NMR (400 MHz, DMSO-d6) delta 7.86 (s, 1 H), 7.82 - 7.75 (m, 3H), 7.58 (d, 1 H), 7.54 (s, 1 H), 7.43 - 7.36 (m, 2H), 7.36 - 7.29 (m, 4H), 7.26 (broad s, 1 H), 7.25 (d, 1 H), 7.13 (broad s, 1 H), 7.12 - 7.03 (m, 6H), 6.98 (d, 2H). Mass (m/z): 474 (M + 1)+.
0.64 g	With piperidine; In 1,2-dichloro-ethane; acetonitrile; for 60h;Reflux;	To 2-(4-(diphenylamino)phenyl)benzofuran-6-carbaldehyde (0.16 g) and malonamide (0.046 g) was added acetonitrile (2.1 mL) and piperidine (0.020 mL). The reaction was heated to reflux for 24 hours, then additional malonamide (0.046 g), piperidine (0.02 mL) and 1,2-dichloroethane (1.0 mL) were added and the reaction heated at reflux for an additional 12 hours. A third portion of malonamide (0.046 g) and of piperidine (0.04 mL) was added and the reaction heated for an additional 24 hours. The reaction was cooled to room temperature and water (10 mL) and ethyl acetate (15 mL) were added. The reaction mixture was stirred at room temperature for 1 hour and then the precipitate collected by filtration. The precipitate was dried under vacuum at 60C to afford 2-((2-(4-(diphenylamino)phenyl)benzofuran-6-yl)methylene)malonamide (BC-155 , 0.64 g). 1 H NMR (400 MHz, DMSO-d6) delta 7.86 (s, 1H), 7.82 - 7.75 (m, 3H), 7.58 (d, 1H), 7.54 (s, 1H), 7.43 - 7.36 (m, 2H), 7.36 - 7.29 (m, 4H), 7.26 (broad s, 1H), 7.25 (d, 1H), 7.13 (broad s, 1H), 7.12 - 7.03 (m, 6H), 6.98 (d, 2H). Mass (m/z): 474 (M + 1)+.

Reference： [1]Patent: WO2017/83488,2017,A1 .Location in patent: Paragraph 0139
[2]Patent: WO2018/208712,2018,A1 .Location in patent: Paragraph 0099

68
[ 108-13-4 ]
[ 77-78-1 ]
C₅H₁₀N₂O₂*2CH₄O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.8%	With boron trifluoride; tetra(n-butyl)ammonium hydrogensulfate; at 80℃; for 15h;Large scale;	Pump the 260L solid-liquid separation mother liquor into the 500L glass-lined kettle. Start the mixing. Add 98% malonamide 20 kg. Add 0.3 kg 1st catalyst tetrabutylammonium hydrogen sulfate and 0.2 kg 2nd catalyst boron trifluoride. At room temperature through expansion tank into the kettle was added by drops 54 kg dimethyl sulfate. Dropping time was 15 minutes. Open steam and slowly heat. At 80 C maintain temperature and react for 15 hours. gas phase tracking detection malonamide content is less than 1%, lowering the temperature to -0 C, for totally enclosed multi-functional stainless steel double-cone for solid-liquid separation, and in the vacuum degree -0.095 mpa, temperature 100 C drying to obtain 71 kg white powdery solid dimethoxypropylenediimide dimethyl hydrogen sulfate, purity HPLC detection 94.63%, with malonamide as basis production yield is 98.80%.

Reference： [1]Patent: CN105037205,2017,B .Location in patent: Paragraph 0018; 0035-0042

69
[ 108-13-4 ]
[ 132971-93-8 ]
2-(4-chlorophenyl)-4H-chromeno[3,4-c]pyridine-4,5(3H)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With ethanol; sodium; for 7h;Reflux;	General procedure: A mixture of 7b (2.58 g, 10 mmol) and/or cyanoacetamide,malonamide (10 mmol) in 50 mL ethoxide solution[prepared by dissolving (0.46 g, 20 mmol) of Na in 50 mLabs. ethanol] was heated under reflux for 7 h. After removal of the solvent under vacuum, water was added and thealkaline solution was neutralized with diluted HCl. Theproduct formed was filtered off, washed with cold water,dried and recrystallized from the proper solvent to give 13and 14, respectively.

Reference： [1]Croatica Chemica Acta,2017,vol. 90,p. 461 - 469

70
[ 141-82-2 ]
[ 108-13-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; at 100℃; for 0.5h;	General procedure: In a 1L open reactor, 500g of carboxylic acid raw material (chemically pure) was added and stirring (600r/min) was turned on from the reactorThe bottom is continuously fed with ammonia gas (chemical purity, water content 5.1 wt%, flow rate 100 g/min) to the carboxylic acid feed. After the reaction was allowed to proceed for TC hours at the reaction temperature TA, ammonia gas flow was stopped. The contents of the reactor were sampled and nuclear magnetic proton spectra and elemental analysis were performed to characterize the amide intermediate. Specific reaction conditions and characterization results are shown in the following Table A-1, Table A-2, Table A-3, Table A-4 and Table A-5. These characterization results show that the amide intermediates obtained have a very high purity (above 99%).
	With ammonium; for 0.5h;Heating;	General procedure: Add 500 g of carboxylic acid starting material (chemically pure) to a 1 L reactor.And charged with a molar amount of ammonia which is 1.3 times the carboxyl group contained in the carboxylic acid raw material.(water content: 0.5 wt%, industrial product), or ammonium bicarbonate powder (chemically pure) having a molar number of ammonium ions of 1.4 times that of the carboxylic acid raw material, and the reaction vessel is closed.Turn on the stirring (600r/min). After the reaction is carried out at the reaction temperature TA for TC hours,The contents of the autoclave were sampled and subjected to nuclear magnetic resonance spectroscopy and elemental analysis to characterize the amide intermediate.The specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3 below.Table A-4 and Table A-5. These characterization results indicate that the obtained amide intermediate has an extremely high purity (99% or more).
	With ammonium; for 0.5h;Heating;	General procedure: Adding 500 g of carboxylic acid raw material (chemically pure) and NH3 molar number to the carboxyl group containing the carboxylic acid raw material in a 1 L reactor1.4 times of ammonia (NH3 content is 25wt%, industrial product) or the number of moles of ammonium ion is 1.6 of the carboxyl group contained in the carboxylic acid raw materialThe aqueous solution of ammonium hydrogencarbonate (30% by weight of ammonium hydrogencarbonate) was closed, and the reaction vessel was closed, and stirring was started (600 r/min). ReactAfter TC hours at the reaction temperature TA, the contents of the reactor were sampled, and nuclear magnetic resonance spectroscopy and elemental analysis were performed to characterize the acyl group.Amine intermediate. The specific reaction conditions and characterization results are shown in Table A-1, Table A-2, Table A-3, Table A-4 and Table A-5 below. These tablesThe results show that the obtained amide intermediate has an extremely high purity (99% or more).

Reference： [1]Patent: CN105016945,2018,B .Location in patent: Paragraph 0124; 0125; 0127
[2]Patent: CN105001033,2018,B .Location in patent: Paragraph 0124; 0125; 0126; 0127
[3]Patent: CN105016941,2018,B .Location in patent: Paragraph 0125; 0126; 0127; 0128

71
[ 108-13-4 ]
[ 74553-29-0 ]
6-bromo-2-oxo-1,2-dihydroquinoline-3-carboxamide [ No CAS ]