[ CAS No. 461-72-3 ]

Name: 461-72-3|Imidazolidine-2,4-dione|95%
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{[proInfo.proName]} (Synonyms:imidazole-2,4-dione) ,{[proInfo.pro_purity]}

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Quality Control of [ 461-72-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 461-72-3 ]

Product Details of [ 461-72-3 ]

CAS No. :	461-72-3	MDL No. :	MFCD00005259
Formula :	C₃H₄N₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WJRBRSLFGCUECM-UHFFFAOYSA-N
M.W :	100.08	Pubchem ID :	10006
Synonyms :	imidazole-2,4-dione

Calculated chemistry of [ 461-72-3 ]

Physicochemical Properties

Num. heavy atoms :	7
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.33
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	28.64
TPSA :	58.2 Å²

Pharmacokinetics

GI absorption :	Low
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) :	-8.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.33
Log Po/w (XLOGP3) :	-1.69
Log Po/w (WLOGP) :	-1.94
Log Po/w (MLOGP) :	-1.79
Log Po/w (SILICOS-IT) :	0.07
Consensus Log Po/w :	-1.0

Druglikeness

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

Water Solubility

Log S (ESOL) :	0.6
Solubility :	402.0 mg/ml ; 4.02 mol/l
Class :	Highly soluble
Log S (Ali) :	0.98
Solubility :	956.0 mg/ml ; 9.56 mol/l
Class :	Highly soluble
Log S (SILICOS-IT) :	-0.51
Solubility :	30.8 mg/ml ; 0.308 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.02

Safety of [ 461-72-3 ]

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

Application In Synthesis of [ 461-72-3 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 461-72-3 ]
Downstream synthetic route of [ 461-72-3 ]

[ 461-72-3 ] Synthesis Path-Upstream 1~5

1
[ 461-72-3 ]
[ 5918-93-4 ]

Reference： [1] Synlett, 2013, vol. 24, # 18, p. 2443 - 2445
[2] Angewandte Chemie - International Edition, 2018, vol. 57, # 18, p. 5120 - 5123[3] Angew. Chem., 2018, vol. 130, p. 5214 - 5217,4
[4] Tetrahedron, 2008, vol. 64, # 1, p. 204 - 218
[5] Tetrahedron Letters, 1981, vol. 22, # 22, p. 2063 - 2066

2
[ 461-72-3 ]
[ 120-92-3 ]
[ 699-51-4 ]

Reference： [1] Journal of Medicinal Chemistry, 1999, vol. 42, # 14, p. 2504 - 2526

3
[ 461-72-3 ]
[ 144-55-8 ]
[ 106412-35-5 ]
[ 28121-73-5 ]
[ 13625-39-3 ]

Reference： [1] Patent: US6291469, 2001, B1,

4
[ 461-72-3 ]
[ 2078-71-9 ]

Reference： [1] Journal of Organic Chemistry, 1968, vol. 33, # 1, p. 206 - 212

5
[ 461-72-3 ]
[ 555-16-8 ]
[ 38335-24-9 ]

Reference： [1] RSC Advances, 2017, vol. 7, # 7, p. 4203 - 4208

[ 461-72-3 ] Synthesis Path-Downstream 1~68

1
[ 461-72-3 ]
[ 120-89-8 ]
[ 6712-62-5 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1933,vol. <2>136,p. 217,227,228

2
[ 461-72-3 ]
[ 52562-50-2 ]
5-(5-methyl-indol-3-ylmethylene)-imidazolidine-2,4-dione [ No CAS ]

Reference： [1]Journal of the Chemical Society,1949,p. Spl. 231

3
[ 461-72-3 ]
[ 78610-70-5 ]
5-(2-oxo-indolin-3-ylmethylene)-imidazolidine-2,4-dione [ No CAS ]

Reference： [1]Nippon Kagaku Kaishi/Journal of the Chemical Society of Japan,1939,vol. 60,p. 454
Chem.Abstr.,1941,p. 5107

4
[ 461-72-3 ]
[ 1477-49-2 ]
[ 117490-34-3 ]

Reference： [1]Patent: US2305501,1940,

5
[ 461-72-3 ]
[ 100-39-0 ]
[ 2301-40-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate; In N,N-dimethyl-formamide; for 10h;Heating;	General procedure: To a solution of imidazolidine-2,4-dione (1.0 g, 10 mmol) in DMF (10 mL) was added potassium carbonate (1.38 g, 10 mmol) and either (2-bromoethyl)benzene (1.85 g, 10 mmol) or benzyl bromide (1.71 g, 10 mmol). The mixture was heated at 90 oC for 10 h. The solution was concentrated to quarter volume and ice was added. The precipitate was filtered off and recrystallized from ethanol to give 3-benzylimidazolidine-2,4-dione 3a (1.69 g, 89%) and 3-phenethylimidazolidine-2,4-dione 3b (1.75 g, 86%) as pale yellow microcrystal.
65%		A solution of hydantoin (6.00 g, 60 mmol) and sodium methoxide (3.66 g, 68 mmol) in anhydrous methanol (60 ml) was heated at 60 C for 1 h under inert atmosphere. Benzyl bromide (12.24 g, 72 mmol) was then added and the mixture was stirred at the same temperature for 14 h. After cooling at rt, the solvent was eliminated under reduced pressure, and the obtained solid was stirred with water (100 ml) for 12 h, filtered and dried under vacuum. 3-Benzylhydantoin (7.5 g, 65% yield) was obtained as a white solid. Elemental analysis (C10H10N2O2): theoretical C 63.15, H 5.30, N 14.73; experimental: C 63.26, H 5.24, N 14.59. 1H NMR (DMSO-d6, delta ppm): 8.12 (s, 1H), 7.32-7.26 (m, 5H), 4.53 (s, 2H), 3.98 (s, 2H). 13C NMR (DMSO-d6, delta ppm): 171.8, 157.3, 136.7, 128.3, 127.3, 127.2, 45.9, 40.9.
40%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 18h;	2,4-imidazolinedione (1.0 equiv),Benzyl bromide (1.0 equiv),Sodium hydride (1.1 equiv) in DMF (20 mL) at room temperature for 18 h,The reaction solution was diluted with water and extracted with ethyl acetate,The organic phase was washed with water 6 times and dried over anhydrous sodium sulfate.Acetone and n-hexane to give 3-benzylimidazolidine-2,4-dione (3-benzyl-imidazoline-2,4-dione) in 40% yield.

31%	With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18.5h;	To a solution of imidazolidine-2,4-dione (2.3, 5.00 g, 50 mmol) in N,N-dimethylformamide (100 mL) was added K2C03 (20.7 g, 150 mmol) and the reaction mixture was cooled to 00 C. Bromomethylbenzene (2.3a, 6.5 mL, 55 mmol) was added slowly over 30 mm at 0 C and the reaction mixture was warmed and stirred at room temperature for 18 h. The reaction mixture was quenched with water (200 mL) and the mixture was extracted with ethyl acetate (500 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by silica gel (23 0-400 mesh) column chromatography eluting with 40% ethyl acetate in hexanes to afford 3-benzylimidazolidine-2,4-dione (2.2) as an off-white solid. Yield: 3.00 g, 3 1.0%.
	With potassium hydroxide; In N-methyl-acetamide; ethanol; chloroform;	EXAMPLE 44 3-Benzyl-2,4-imidazolidinedione Hydantoin (2,4-imidazolidinedione; 25 g, 0.25 mole) was dissolved in 1 liter of 90% ethanol. Potassium hydroxide (15 g, 0.27 mole) in 125 ml of ethanol was added and the mixture stirred for 16 hours. The potassium salt was recovered by filtration and dried at 80 C. at reduced pressure [25.2 g, m.p. 271-2 C. (dec)]. Potassium salt (5.5 g, 0.04 mole) and benzyl bromide (17.1 g, 11.9 ml, 0.10 mole) were combined with 40 ml of dimethylformamide and the mixture stirred for 16 hours at room temperature and then refluxed for 4 hours. The cooled reaction mixture was filtered and the filtrate evaporated to an oil. The oil was dissolved in chloroform. The chloroform solution was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to solids. Trituration of the solids with ether gave the title product (3.0 g, m.p. 139-140 C., m/e 190). By the same method, but generating a sodium salt in situ by the use of one equivalent of sodium hydride, uracil and dihydrouracil are converted to 3-benzyl-2,3(1H,3H)-pyrimidinedione and 3-benzyl-5,6-dihydro-2,3(1H,3H)-pyrimidinedione.

Reference： [1]Tetrahedron Letters,2009,vol. 50,p. 1395 - 1398
[2]Bioorganic Chemistry,2020,vol. 99
[3]Tetrahedron,2011,vol. 67,p. 8639 - 8647
[4]Journal of Organic Chemistry,2012,vol. 77,p. 8071 - 8082,12
[5]Journal of Medicinal Chemistry,2005,vol. 48,p. 7103 - 7112
[6]Journal of Medicinal Chemistry,2013,vol. 56,p. 3115 - 3119
[7]Patent: CN106279132,2017,A .Location in patent: Paragraph 0093; 0094; 0095
[8]Patent: WO2018/126072,2018,A1 .Location in patent: Paragraph 0213; 0216; 0217
[9]Patent: US2759002,1954,
[10]Patent: US4337250,1982,A

6
[ 461-72-3 ]
[ 120-89-8 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 5494 - 5503
[2]Justus Liebigs Annalen der Chemie,1906,vol. 348,p. 89
[3]Journal of the Chemical Society. Perkin transactions I,1982,p. 2341 - 2346
[4]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2005,vol. 62,p. 1131 - 1139

7
[ 120-89-8 ]
[ 120-93-4 ]
[ 461-72-3 ]

Reference： [1]Chemische Berichte,1901,vol. 34,p. 3288

8
[ 120-89-8 ]
[ 461-72-3 ]

Reference： [1]Chemische Berichte,1901,vol. 34,p. 3288

9
[ 461-72-3 ]
[ 2078-71-9 ]

Reference： [1]Journal of Organic Chemistry,1968,vol. 33,p. 206 - 212

10
[ 98-01-1 ]
[ 461-72-3 ]
[ 136949-32-1 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium acetate; In acetic acid;	EXAMPLE 3 A solution of hydantoin (10 g), fused sodium acetate (20 g), and freshly distilled furfural (12 g) in acetic acid (40 ml) was heated under reflux for 11/4 hours. The dark solution was poured into cold water (400 ml) to precipitate the dark green/yellow product, which was washed with water until neutral and then with cold ethanol to give 14 g (80% theoretical yield) of 5-furfurylidenehydantoin m.p. 232-5 (decomp.) (H. L. Wheeler and C. Hoffman, Amer. Chem. J., 1911, 45, 368, quote m.p. 232.) The material was used without further purification.

Reference： [1]Patent: US4124760,1978,A
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 743 - 753
[3]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[4]Journal of Organic Chemistry,1993,vol. 58,p. 5994 - 5999

11
[ 461-72-3 ]
[ 100-52-7 ]
[ 3775-01-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With ethanolamine; In ethanol; water; for 24h;Schlenk technique; Inert atmosphere; Reflux;	General procedure: A 250mL flask was charged with hydantoin (10.0g, 100mmol), aromatic aldehyde (100mmol), ethanolamine (3.05g, 50mmol) and 100mL of solvent (ethnol/water=1/1, v/v). The reaction mixture was then heated and stirred at reflux for 24h. After cooling to room temperature, a large amount of crystals were formed. The mixture was filtered and the filter cake was washed with 20mL of cold ethanol. The crystals were then collected and dried under reduced pressure. Yield: 85%; Colorless crystal, mp=224.0-225.1C; 1H NMR (300MHz, d6-DMSO) delta (ppm): 6.41 (s, 1H), 7.32-7.43 (m, 3H), 7.63 (t, J=1.5Hz, 2H), 10.52 (br s, 1H), 11.18 (br s, 1H); 13C NMR (125MHz, d6-DMSO) delta (ppm): 166.0, 156.1, 133.4, 129.8, 129.2, 128.8, 128.4, 108.7
74%	With sodium acetate; acetic acid;Reflux;	General procedure: Starting materials and compound 1e were synthesized by means of previously publishedprocedures [62]. Glacial acetic acid (100 mL) was mixed with anhydrous sodium acetate (33.3 g) inround-bottom flask. Then hydantoin (10.1 g, 0.11 mole) was added and mixture was heated under reflux. After achieving boiling point, the appropriate aldehyde (0.1 mole) was added and the mixturewas heated for the next 4-8 h. After cooling the mixture was filtered and the obtained solid was washedwell with water. Dried crude product was crystallized from ethanol or ethanol/acetic acid (1:1).
57%	With ammonium acetate; acetic acid; for 20h;Reflux;	General procedure: To a stirred suspension of the corresponding benzaldehydes (3.33 mmol) and imidazolidine-2,4-dione (500 mg, 5 mmol) or 2-thioxoimidazolidin-4-one (580 mg, 5 mmol) in glacial acetic acid (5 mL) ammonium acetate (507 mg, 6.6 mmol) was added and the reaction mixture was heated under reflux for 20 h. The solution was cooled, and the precipitate was filtered off, washed with water and ethanol, and dried.

Reference： [1]Tetrahedron,2011,vol. 67,p. 8639 - 8647
[2]Synthetic Communications,2006,vol. 36,p. 1575 - 1584
[3]Tetrahedron Asymmetry,2017,vol. 28,p. 47 - 53
[4]European Journal of Organic Chemistry,1999,p. 2609 - 2621
[5]Molecules,2019,vol. 24
[6]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[7]Acta Chimica Slovenica,2014,vol. 61,p. 637 - 644
[8]Journal of Organic Chemistry,1993,vol. 58,p. 5994 - 5999
[9]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2516 - 2530
[10]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4245 - 4257
[11]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 135 - 145
[12]ChemMedChem,2020

12
[ 461-72-3 ]
[ 5918-93-4 ]

Reference： [1]Synlett,2013,vol. 24,p. 2443 - 2445
[2]Angewandte Chemie - International Edition,2018,vol. 57,p. 5120 - 5123
Angew. Chem.,2018,vol. 130,p. 5214 - 5217,4
[3]Tetrahedron,2008,vol. 64,p. 204 - 218
[4]Tetrahedron Letters,1981,vol. 22,p. 2063 - 2066

13
[ 461-72-3 ]
[ 1122-91-4 ]
(Z)-5-(4-bromobenzylidene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With ethanolamine; In ethanol; water; for 24h;Schlenk technique; Inert atmosphere; Reflux;	General procedure: A 250mL flask was charged with hydantoin (10.0g, 100mmol), aromatic aldehyde (100mmol), ethanolamine (3.05g, 50mmol) and 100mL of solvent (ethnol/water=1/1, v/v). The reaction mixture was then heated and stirred at reflux for 24h. After cooling to room temperature, a large amount of crystals were formed. The mixture was filtered and the filter cake was washed with 20mL of cold ethanol. The crystals were then collected and dried under reduced pressure. Yield: 89%; Colorless crystal, mp >250.0C; 1H NMR (300MHz, d6-DMSO) delta (ppm): 6.38 (s, 1H), 7.57 (s, 4H), 10.58 (br s, 1H), 11.25 (br s, 1H); 13C NMR (125MHz, d6-DMSO) delta (ppm): 165.9, 156.1, 132.7, 132.1, 131.7, 129.0, 121.9, 107.3

Reference： [1]Tetrahedron Asymmetry,2017,vol. 28,p. 47 - 53
[2]Journal of Medicinal Chemistry,2010,vol. 53,p. 273 - 281
[3]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[4]Il Farmaco,1999,vol. 54,p. 77 - 82
[5]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2516 - 2530
[6]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 135 - 145

14
[ 461-72-3 ]
[ 120-92-3 ]
[ 699-51-4 ]

Reference： [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 2504 - 2526

15
[ 461-72-3 ]
[ 7726-95-6 ]
[ 64-19-7 ]
[ 120-89-8 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1906,vol. 348,p. 89

16
[ 7647-01-0 ]
[ 496-46-8 ]
[ 461-72-3 ]
[ 57-13-6 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1904,vol. 333,p. 135

17
[ 6940-78-9 ]
[ 461-72-3 ]
3-(4-chlorobutyl)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydride; In N,N-dimethyl-formamide; at 50℃; for 18h;	Example 3Scheme 3 shows a method for making radiolabeled compounds of formula (I) for preparation of l-(2-fluoroethyl)-3-(4-(4-(2-methoxyphenyl)piperazin-l- yl)butyl)imidaz-olidine-2,4-dioneScheme 3Preparation of 3-(4-Chlorobutyl)imidazolidine-2,4-dioneTo hydantoin (1.06 g, 10.5 mmol) in dimethylformamide (20 mL) at 50 C was added a 60% suspension of sodium hydride (420 mg, 10.5 mmol). After stirring for 60 minutes l-bromo-4-chlorobutane (4.5 g, 26.3 mmol) was added, and the mixture stirred for 18h. The reaction was quenched with 1 N HCl (20 mL, 20 mmol) and concentrated to give a yellow oil. This was purified by chromatography on silica gel (40 g) eluting with ethyl acetate at 40 mL/min. The product eluted in fraction 3-7. These were concentrated to give a pale orange solid (1.9 g, 95%)..H (CDC13, 300 MHz): delta 1.65 (4H, m), 3.36 (2H, t), 3.62 (2H, t), 3.89 (2H, s), and 8.02 (IotaEta, ).

Reference： [1]Patent: WO2011/150183,2011,A1 .Location in patent: Page/Page column 78-79; 179-180
[2]Journal of Medicinal Chemistry,2000,vol. 43,p. 1892 - 1897

18
[ 461-72-3 ]
[ 613-69-4 ]
(Z)-5-(2-ethoxybenzylidene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With ethanolamine; In ethanol; water; for 24h;Schlenk technique; Inert atmosphere; Reflux;	General procedure: A 250mL flask was charged with hydantoin (10.0g, 100mmol), aromatic aldehyde (100mmol), ethanolamine (3.05g, 50mmol) and 100mL of solvent (ethnol/water=1/1, v/v). The reaction mixture was then heated and stirred at reflux for 24h. After cooling to room temperature, a large amount of crystals were formed. The mixture was filtered and the filter cake was washed with 20mL of cold ethanol. The crystals were then collected and dried under reduced pressure. Yield: 81%; Colorless crystal, mp=219.4-220.7C; 1H NMR (300MHz, d6-DMSO) delta (ppm): 1.37 (t, J=6.9Hz, 3H), 4.06-4.13 (m, 2H), 6.66 (s, 1H), 6.93-7.04 (m, 1H), 7.27-7.33 (m, 1H), 7.57-7.60 (m, 1H), 7.58 (dd, J1=7.8Hz, J2=1.5Hz, 1H), 10.31 (br s, 1H), 11.15 (br s, 1H); 13C NMR (125MHz, d6-DMSO) delta (ppm): 166.0, 156.9, 155.9, 130.5, 129.8, 128.4, 122.0, 120.9, 112.4, 103.4, 64.1, 15.0

Reference： [1]Tetrahedron Asymmetry,2017,vol. 28,p. 47 - 53
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535

19
[ 461-72-3 ]
[ 100-39-0 ]
[ 16935-43-6 ]

Yield	Reaction Conditions	Operation in experiment
93%		General procedure: A mixture of 50 mg of imide and the required amount of K2CO3 were placed in a 10 mL stainlesssteel grinding jar and milled for 1 hour at 30 Hz. Upon completion, the required amount of alkylhalide was added and milling was continued for 1 hour in the presence of 100 muL of dry DMF(LAG experiment, eta = 2 muL mg-1). The obtained mixture was suspended in dichloromethane andwashed with water. The organic layers were collected and the solvent was evaporated. Where itwas necessary, the products were separated by using column chromatography

Reference： [1]Beilstein Journal of Organic Chemistry,2017,vol. 13,p. 1745 - 1752
[2]Tetrahedron Letters,2004,vol. 45,p. 1047 - 1050
[3]Tetrahedron,2008,vol. 64,p. 11768 - 11775
[4]Journal of Organic Chemistry,2012,vol. 77,p. 8071 - 8082,12

20
[ 461-72-3 ]
[ 104-88-1 ]
[ 10040-86-5 ]

Yield	Reaction Conditions	Operation in experiment
88%	With ethanolamine; In ethanol; water; for 24h;Schlenk technique; Inert atmosphere; Reflux;	General procedure: A 250mL flask was charged with hydantoin (10.0g, 100mmol), aromatic aldehyde (100mmol), ethanolamine (3.05g, 50mmol) and 100mL of solvent (ethnol/water=1/1, v/v). The reaction mixture was then heated and stirred at reflux for 24h. After cooling to room temperature, a large amount of crystals were formed. The mixture was filtered and the filter cake was washed with 20mL of cold ethanol. The crystals were then collected and dried under reduced pressure. Yield: 88%; Colorless crystal, mp >250.0C; 1H NMR (300MHz, d6-DMSO) delta (ppm): 6.40 (s, 1H), 7.42-7.46 (m, 2H), 7.61-7.66 (m, 2H), 10.60 (br s, 1H), 11.21 (br s, 1H); 13C NMR (125MHz, d6-DMSO) delta (ppm): 165.9, 156.1, 133.2, 132.4, 131.5, 129.2, 128.9, 107.2
78%	With sodium carbonate; 3-amino-butan-2-one; In water;Reflux;	General procedure: Two synthetic methods were used. In the first method (Method A), a flat-bottom flask was charged with hydantoin (100-200 mmol), alanine (100-200 mmol), sodium carbonate (50-100 mmol), distilled water (100-200 mL) and appropriate aldehyde (100-200 mmol). The entire mixture was stirred using a magnetic stirrer with thermal regulation at boiling point under reflux condenser for 7.5-20 hours. The resulting mixture was pured into a beaker, diluted with distilled water (100-200 mL)and acidified with 10% HC1. The precipitate was filtered off and rinsed with distilled water until neutral pH of the filtrate was obtained. If required, the precipitate waspurified by washing several times with acetone to remove unreacted aldehyde.:_The compound was synthesized according to Method A. 78%, m.p.: 293-297 C, Rf (ICH3COOC2H5 : CHC13, 1:1): 0.49; C10H7C1N202, (M: 222.63); ?H-NMR (DMSO-d6) oe [ppm]:6.38 (s, 1H,CH=C), 7.40-7.45 (d, J= 8.40 Hz, 2H, Ar-3,5-H), 7.60-7.62 (d, J= 8.5 Hz, 2H, Ar-2,6-H), 10.58 (br.s, 1H,N1-H), ii.26 (br.s, iH,N3-H

Reference： [1]Synthetic Communications,2006,vol. 36,p. 1575 - 1584
[2]Tetrahedron Asymmetry,2017,vol. 28,p. 47 - 53
[3]Patent: WO2015/65212,2015,A1 .Location in patent: Page/Page column 7; 8
[4]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[5]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6032 - 6039
[6]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2516 - 2530
[7]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4245 - 4257
[8]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 135 - 145

21
[ 461-72-3 ]
[ 123-11-5 ]
[ 5349-42-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With ethanolamine; In ethanol; water; for 24h;Schlenk technique; Inert atmosphere; Reflux;	General procedure: A 250mL flask was charged with hydantoin (10.0g, 100mmol), aromatic aldehyde (100mmol), ethanolamine (3.05g, 50mmol) and 100mL of solvent (ethnol/water=1/1, v/v). The reaction mixture was then heated and stirred at reflux for 24h. After cooling to room temperature, a large amount of crystals were formed. The mixture was filtered and the filter cake was washed with 20mL of cold ethanol. The crystals were then collected and dried under reduced pressure. Yield: 87%; Pale yellow crystal, mp >250.0C; 1H NMR (300MHz, d6-DMSO) delta (ppm): 3.80 (s, 3H), 6.39 (s, 1H), 6.93-6.98 (m, 2H), 7.56-7.60 (m, 2H), 10.39 (br s, 1H), 11.12 (br s, 1H); 13C NMR (125MHz, d6-DMSO) delta (ppm): 166.0, 159.9, 156.1, 131.5, 126.5, 125.9, 114.7, 109.1, 55.7
72%	With sodium acetate; acetic acid;Reflux;	General procedure: Starting materials and compound 1e were synthesized by means of previously publishedprocedures [62]. Glacial acetic acid (100 mL) was mixed with anhydrous sodium acetate (33.3 g) inround-bottom flask. Then hydantoin (10.1 g, 0.11 mole) was added and mixture was heated under reflux. After achieving boiling point, the appropriate aldehyde (0.1 mole) was added and the mixturewas heated for the next 4-8 h. After cooling the mixture was filtered and the obtained solid was washedwell with water. Dried crude product was crystallized from ethanol or ethanol/acetic acid (1:1).
49%	With boric acid; In neat (no solvent); at 180℃; for 0.666667h;Microwave irradiation; Sealed tube; Green chemistry;	General procedure: A mixture of substrate (1 mmol), aldehyde (1.2 mmol) and boric acid (0.2 mmol) was placed in a cylindrical quartz reactor ( theta = 4 cm). The reactor was introduced into an Explorer24 CEM apparatus. The stirred mixture was heated at 160 C (P = 300 W) for 40 min, except for 3c (180 C). After microwave dielectric heating, the crude reaction mixture was allowed to cool down at room temperature and ethanol (10 mL) or mixture of H2O/EtOH (10 mL) was directly added in the cylindrical quartz reactor. The resulting precipitated product was filtered off and was purified by recrystallization from ethanol if necessary.

26%		Hydantoine (0.400 g, 4 mmol) was dissolved in 4 mL of water stirring. After complete dissolution, the pH of the mixture was buffered to 7.0 with saturated NaHCO3 solution. Ethanolammine (0.36 mL) was added at the reaction mixture, and the temperature was increased to 90C gradually. The 4-methoxybenzaldehyde solution (0.544 g, 0.486 mL, 4 mmol) in 4 mL of ethanol was added dropwise with continuous stirring. The temperature was raised to 120C and kept under reflux for 48h. On cooling, a precipitate was formed and it was filtered and washed with H20/EtOH 5:1. Yield: 26%. Mp: 255C. 1H NMR (500 MHz, DMSO-d6) delta ppm 3.79 (s, 3 H) 6.39 (s, 1 H) 6.96 (d, J=8.83 Hz, 2 H) 7.59 (d, J=8.83 Hz, 2 H) 10.18 - 10.61 (m, 1 H) 10.95 - 11.28 (m, 1 H) 13C NMR (126 MHz, DMSO-d6) delta ppm 55.25 (s, 1 C) 108.61 (s, 1 C) 114.27 (s, 2 C) 125.42 (s, 1 C) 126.06 (s, 1 C) 131.07 (s, 2 C) 155.63 (s, 1 C) 159.41 (s, 1 C) 165.59 (s, 1 C). LC-MS (ESI): m/z MH+ = 219.
17.4%	With piperidine; for 4h;Reflux;	General procedure: Synthesis of Compounds 25 to 28, 30, 31, 33, and 35, which are (Z)-5-(substitutedbenzylidene)imidazolidine-2,4-dione derivatives), was performed as follows. In detail, in a piperidine (1 mL/4 mmol of benzaldhehyde) solution, a suspension including a substituted benzaldhehyde (2.42 to 7.70 mmol) and hydantoin (1.1 eq.) was refluxed for 30 minutes to 8 hours. The reaction mixture was cooled, and at a temperature of 60 C., water (in a volume 20 times greater than that of piperidine used) was added thereto. Filtering was performed to remove a small amount of soft tarry material. A filtrate was acidified at room temperature by using 12N HCl. The mixture was maintained for several hours at room temperature, and then, the produced precipitate was filtered, and the resultant product was washed with cold water and/or methylene chloride. The result was dried under reduced pressure to obtain a target compound (yield: 9.7 to 79%). [0160] Yellow solid; a reaction time of 4 hours; a yield17.4%; a melting point of 241.8-242.9 C.; ?H NMR (400MHz, DMSO-d5) oe 11.13 (s, 1H), 10.40 (s, 1H), 7.55 (d, 2H,J=8.8 Hz), 6.92 (d, 2H, J=8.8 Hz), 6.35 (s, 1H), 3.75 (s, 3H); 13C NMR(100 MHz, DMSO-d5) oe 166.3, 160.1, 156.3, 131.8, 126.7, 126.1, 115.0, 109.3, 55.9; LRMS (ES) mlz 217(M-H)-.
17.4%	With piperidine; for 4h;Reflux;	General procedure: Synthesis of Compounds 25 to 28, 30, 31, 33, and 35, which are (Z)-5-(substitutedbenzylidene)imidazolidine-2,4-dione derivatives), was performed as follows. In detail, in a piperidine (1 mL/4 mmol of benzaldhehyde) solution, a suspension including a substituted benzaldhehyde (2.42 to 7.70 mmol) and hydantoin (1.1 eq.) was refluxed for 30 minutes to 8 hours. The reaction mixture was cooled, and at a temperature of 60 C., water (in a volume 20 times greater than that of piperidine used) was added thereto. Filtering was performed to remove a small amount of soft tarry material. A filtrate was acidified at room temperature by using 12N HCl. The mixture was maintained for several hours at room temperature, and then, the produced precipitate was filtered, and the resultant product was washed with cold water and/or methylene chloride. The result was dried under reduced pressure to obtain a target compound (yield: 9.7 to 79%).

Reference： [1]Synthetic Communications,2006,vol. 36,p. 1575 - 1584
[2]Tetrahedron Asymmetry,2017,vol. 28,p. 47 - 53
[3]Molecules,2019,vol. 24
[4]Journal of Medicinal Chemistry,2012,vol. 55,p. 743 - 753
[5]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[6]Molecules,2015,vol. 20,p. 11617 - 11631
[7]European Journal of Medicinal Chemistry,2016,vol. 112,p. 209 - 216
[8]Journal of Medicinal Chemistry,2010,vol. 53,p. 273 - 281
[9]Biochimica et Biophysica Acta - General Subjects,2011,vol. 1810,p. 612 - 619
[10]Patent: US2014/23603,2014,A1 .Location in patent: Paragraph 0153; 0160
[11]Patent: KR101677122,2016,B1 .Location in patent: Paragraph 0183; 0195
[12]European Journal of Medicinal Chemistry,2010,vol. 45,p. 2516 - 2530
[13]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 135 - 145

22
[ 461-72-3 ]
[ 874-42-0 ]
(5Z)-5-(2,4-dichlorobenzylidene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With copper(II)-Para-aminobenzoic acid complex supported on Fe3O4 Magnetic nanoparticle; In ethanol; for 1.61667h;Reflux; Green chemistry;	General procedure: Fe3O4PABA-Cu(II) (0.05 g) was added to a mixtureof various aldehydes (1mmol), with hydantoin or TZD(1mmol), in Ethanol (10mL), and this mixture was refluxedfor the times reported in Table2. the progress of the reactionmonitored by TLC, after completion of the reactionthe mixture was diluted with ethanol and the catalyst waseasily separated from the reaction mixture by an externalmagnet, washed with hot ethanol, dried and reused for aconsecutive run under the same reaction conditions. Afterwards,the reaction mixture was cooled to room temperatureand the crude product obtained was collected by filtrationand washed with cold ethanol to give the pure solid.

Reference： [1]Catalysis Letters,2020
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[3]Journal of Medicinal Chemistry,2012,vol. 55,p. 743 - 753

23
[ 461-72-3 ]
[ 613-45-6 ]
(Z)-5-(2,4-dimethoxybenzylidene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With sodium acetate; acetic acid;Reflux;	General procedure: Starting materials and compound 1e were synthesized by means of previously publishedprocedures [62]. Glacial acetic acid (100 mL) was mixed with anhydrous sodium acetate (33.3 g) inround-bottom flask. Then hydantoin (10.1 g, 0.11 mole) was added and mixture was heated under reflux. After achieving boiling point, the appropriate aldehyde (0.1 mole) was added and the mixturewas heated for the next 4-8 h. After cooling the mixture was filtered and the obtained solid was washedwell with water. Dried crude product was crystallized from ethanol or ethanol/acetic acid (1:1).
71.4%	In ethanol; water; at 80℃; for 30h;	[0154] Compounds 29, 32, and 34 were synthesized as follows. In detail, in a solvent including ethanol (2 to 4 mE) and H20 (2 to 4 mE), a suspension including a substituted benzaldhehyde (1.08 to 1.28 mmol) and a hydantoin (1.1 eq.) was heated to a temperature of 80 C. The reaction mixture was heated at the same temperature as described above for 30 to 50 hours, and then, the produced precipitate was filtered, and the filtered product was washed with water to remove the remaining unreacted hydantoin. In consideration of the residual substituted benzaldhehyde, the resultant product was washed with water and/or methylene chloride and/or ethyl acetate to obtain a target product (yield: 11.4 to 71.4%). [0162] White solid; a reaction time of 30 hours; a yield of 71.4%; a melting point of 234.1-237.2 C.; ?H NMR (500MHz, DMSO-d5) oe 11.09 (s, 1H), 10.28 (s, 1H), 7.55 (d, 1H,J=8.5 Hz), 6.60 (s, 1H), 6.59 (d, 1H, J=2.5 Hz), 6.54 (dd, 1H,J=2.0, 8.5 Hz), 3.83 (s, 3H), 3.79 (s, 3H); ?3C NMR (100MHz, DMSO-d5) oe 166.3, 161.8, 159.3, 156.2, 130.8, 126.7,114.9, 106.2, 103.7, 98.9, 56.4, 56.1; LRMS (ES) mlz 247(M-H)-.

Reference： [1]Molecules,2019,vol. 24
[2]Biochimica et Biophysica Acta - General Subjects,2011,vol. 1810,p. 612 - 619
[3]Patent: US2014/23603,2014,A1 .Location in patent: Paragraph 0154; 0162
[4]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535
[5]Patent: KR101677122,2016,B1 .Location in patent: Paragraph 0184; 0199
[6]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4245 - 4257
[7]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 135 - 145

24
[ 461-72-3 ]
[ 5736-88-9 ]
(Z)-5-(4-butoxybenzylidene)imidazolidine-2,4-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 1527 - 1535

25
[ 461-72-3 ]
[ 121-33-5 ]
(5Z)-5-(4-hydroxy-3-methoxybenzylidene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With copper(II)-Para-aminobenzoic acid complex supported on Fe3O4 Magnetic nanoparticle; In ethanol; for 1.46667h;Reflux; Green chemistry;	General procedure: Fe3O4PABA-Cu(II) (0.05 g) was added to a mixtureof various aldehydes (1mmol), with hydantoin or TZD(1mmol), in Ethanol (10mL), and this mixture was refluxedfor the times reported in Table2. the progress of the reactionmonitored by TLC, after completion of the reactionthe mixture was diluted with ethanol and the catalyst waseasily separated from the reaction mixture by an externalmagnet, washed with hot ethanol, dried and reused for aconsecutive run under the same reaction conditions. Afterwards,the reaction mixture was cooled to room temperatureand the crude product obtained was collected by filtrationand washed with cold ethanol to give the pure solid.

Reference： [1]Catalysis Letters,2020
[2]Synthetic Communications,2006,vol. 36,p. 1575 - 1584
[3]Biochimica et Biophysica Acta - General Subjects,2011,vol. 1810,p. 612 - 619
[4]Journal of Medicinal Chemistry,2012,vol. 55,p. 743 - 753
[5]Journal of Medicinal Chemistry,2010,vol. 53,p. 273 - 281
[6]Chemistry and biodiversity,2011,vol. 8,p. 1470 - 1485

26
[ 461-72-3 ]
PhCH₂-X [ No CAS ]
[ 2301-40-8 ]

Reference： [1]Arzneimittel-Forschung/Drug Research,2007,vol. 57,p. 532 - 536

27
[ 461-72-3 ]
[ 220364-34-1 ]
C₁₆H₂₁N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetra-(n-butyl)ammonium iodide; In N,N-dimethyl-formamide; at 20℃; for 24h;	The mixture of the title compound from Step A above (90 mg), hydantoin (36 mg), potassium carbonate (150 mg) and tetrabutylammonium iodide (1 mg) in N,N-dimethylformamide was stirred at room temperature for 24 h. The solution was concentrated to dryness, and then dissolved in ethyl acetate (20 mL). The solution was washed with water and brine, dried over magnesium sulfate and concentrated to give the title compound (90 mg) as a yellow solid.

Reference： [1]Patent: US2006/173183,2006,A1 .Location in patent: Page/Page column 113

28
[ 461-72-3 ]
[ 107622-80-0 ]
[ 477583-00-9 ]

Yield	Reaction Conditions	Operation in experiment
		Example 104 2-(4-methyl-2,5-dioxo-4-imidazolidinyl)-N-(4-phenoxybenzyl)acetamide Hydantoin 103a (50 mg, 0.30 mmol) was coupled to <strong>[107622-80-0]4-phenoxybenzylamine</strong> using general coupling method A to give 45 mg of the product hydantoin. MS found:(M+H)+=354.

Reference： [1]Patent: US2003/130273,2003,A1

29
[ 29943-42-8 ]
[ 461-72-3 ]
barium hydroxide octahydrate [ No CAS ]
[ 39124-20-4 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium carbonate; In water;	(b) 4-Amino-4H-tetrahydropyran-4-carboxylic acid can be prepared as follows: A mixture of tetrahydro-4H-pyran-4-one (15.0 g, 0.15 mole), sodium cyanide (22.0 g, 0.45 mole) and ammonium carbonate (216 g, 2.25 mole) in distilled water (500 mL) is stirred at 60 C. under N2 for 24 hours. The reaction mixture is heated to reflux to destroy the excess ammonium carbonate. The solution is then evaporated down to a volume of 100 mL and cooled to 0 C. The white crystalline hydantoin is filtered and rinsed with two 50 ml portions of distilled water at 0 C. A solution of the hydantoin (20.0 g, 0.12 mole) and barium hydroxide octahydrate (111 g, 0.35 mole) in distilled water (650 mL) is refluxed for 24 hours. Carbon dioxide gas is bubbled through the mixture until the pH is 7. The mixture is warmed to 50 C. and filtered to remove the barium carbonate. The clear solution is evaporated to dryness. The crude product is dissolved in a minimal amount of refluxing distilled water and filtered to remove more barium salts. The 4-amino-4H-tetrahydropyran-4-carboxylic acid crystallizes from the solution.

Reference： [1]Patent: US5977075,1999,A

Yield	Reaction Conditions	Operation in experiment
		B (R,S)-2-Amino-2-cyclohexylpropionic acid This compound is prepared according to J. Org. Chem., 1960, 25, 1920-1924. A mixture containing 7 g of the hydantoin prepared in the previous step and 28 g of barium hydroxide octahydrate in 150 ml of water is heated at 160 C. for 5 hours in a steel tube. The reaction medium is saturated with dry ice, the insoluble material formed is filtered off and the filtrate is then concentrated under vacuum. The solid residue is taken up in acetone, filtered off and dried to give 5.25 g of the expected acid, which is identified by its IR and NMR spectra. The product melts at 350 C. with decomposition.
		B (R,S)-2-Amino-2-cyclohexylpropionic acid This compound is prepared according to J. Org. Chem., 1960, 25, 1920-1924. A mixture containing 7 g of the hydantoin prepared in the previous step and 28 g of barium hydroxide octahydrate in 150 ml of water is heated at 160 C. for 5 hours in a steel tube. The reaction medium is saturated with dry ice, the insoluble material formed is filtered off and the filtrate is then concentrated under vacuum. The residue is taken up in acetone, filtered off and dried to give 5.25 g of the expected acid, which is identified by its IR and NMR spectra. The product melts at 350 C. with decomposition.

31
[ 461-72-3 ]
[ 116313-85-0 ]
4-[(3,4-dihydroxy-5-nitrophenyl)methylidene]-2,5-imidazolidindione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
0.56 g (42%)	With ammonium acetate; In acetic acid;	EXAMPLE 8 4- [(3,4-Dihydroxy-5-nitrophenyl)methylidene]-2,5-imidazolidindione A solution containing 0.65 g of hydantoin, 0.92 g of <strong>[116313-85-0]3,4-dihydroxy-5-nitrobenzaldehyde</strong> and 0.15 g of ammonium acetate in 15 ml of acetic acid was refluxed overnight. The product was filtered and washed with acetic acid and 2-propanol. Yield 0.56 g (42%), mp>350 C.

Reference： [1]Patent: US5362733,1994,A

32
[ 461-72-3 ]
[ 3587-60-8 ]
[ 70384-51-9 ]
[ 151918-26-2 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium hydroxide; In water; 4-methyl-2-pentanone;	Reference Example 1 In 5 ml of methyl isobutyl ketone were suspended 216 mg (3.85 mmoles) of potassium hydroxide and 73 mg (0.226 mmoles) of tris[2-(2-methoxyethoxy)ethyl]-amine followed by addition of 900 mg (8.99 mmoles) of imidazolidine-2,4-dione, and the mixture was stirred at room temperature for 10 minutes. Then, 704 mg (4.50 mmoles) of benzyloxymethyl chloride was added dropwise at 0° C. and the mixture was stirred at room temperature for 3 hours. To this reaction mixture was added water and the organic layer was separated and washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was subjected to silica gel chromatography (eluent: hexane:ethyl acetate =1:1) to give 687 mg (3.12 mmoles) of 3-benzyloxymethylimidazolidine-2,4-dione. Yield 70percent (based on benzyloxymethyl chloride) 1 H-NMR, delta(CDCl3): 3.90 (2H, s), 4.60 (2H, s), 5.05 (2H, s), 6.00-6.20 (1H, brs, -NH), 7.20-7.45 (5H, m)

Reference： [1]Patent: US5350859,1994,A

33
[ 461-72-3 ]
[ 144-55-8 ]
[ 106412-35-5 ]
[ 28121-73-5 ]
[ 13625-39-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogen; acetic acid;palladium-carbon; In ethanol;	Step A Preparation of 1,3,8-triaza-spiro[4.5]decan-2,4-dione To a solution of 14.6 g (48.1 mmol) <strong>[28121-73-5]benzyl 2,4-dioxo-1,3,8-triaza-spiro[4.5]decan-8-carboxylate</strong> (prepared from N-(benzyloxycarbonyl)piperidone by the method from J. Med. Chem. 1995, 38, 3772) in 250 ml dry ethanol were added 500 mg 10% Pd/C, and the mixture was filled into an autoclave. After stirring at 60 C. and 10 atm of hydrogen for 3 h no starting hydantoin could be detected by TLC. A precipitate had been formed which was redissolved by addition of 100 ml acetic acid. The catalyst was removed by filtration and the solution was concentrated in vacuo. Aqueous sodium bicarbonate solution was added until the mixture became a clear solution, and the title compound precipitated in two crops upon concentration in vacuo. total yield: 8.1 g (99%), white powder, m.p. 303-304 C. (dec.)

Reference： [1]Patent: US6291469,2001,B1

34
[ 461-72-3 ]
[ 107834-03-7 ]
[ 1134426-49-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1731 - 1738

35
[ 34557-54-5 ]
[ 57-13-6 ]
[ 461-72-3 ]
[ 29410-13-7 ]
[ 120-89-8 ]
[ 470-44-0 ]
[ 462-60-2 ]

Reference： [1]Chemistry - A European Journal,2009,vol. 15,p. 4411 - 4418

36
[ 461-72-3 ]
[ 120-14-9 ]
5-(3,4-dimethoxybenzylidene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium acetate; acetic acid;Reflux;	General procedure: Starting materials and compound 1e were synthesized by means of previously publishedprocedures [62]. Glacial acetic acid (100 mL) was mixed with anhydrous sodium acetate (33.3 g) inround-bottom flask. Then hydantoin (10.1 g, 0.11 mole) was added and mixture was heated under reflux. After achieving boiling point, the appropriate aldehyde (0.1 mole) was added and the mixturewas heated for the next 4-8 h. After cooling the mixture was filtered and the obtained solid was washedwell with water. Dried crude product was crystallized from ethanol or ethanol/acetic acid (1:1).
67%	With sodium hydrogencarbonate; ethanolamine; In ethanol; water; at 70 - 120℃; for 2h;pH 7;	General procedure: The title compounds: 5-(3,4-dimethoxybenzylidene)imidazolidine-2,4-dione (3) and 5-(3-cyclopentyloxy-4-methoxybenzylidene)imidazolidine-2,4-dione (4) were prepared in line with procedure described elsewhere. 23 Hydantoin (1.25 g, 12.5 mmol) was dissolved in 16.3 mL of water at 70C, and two drops of saturated NaHCO3 solution was added (pH = 7.0) followed by 1.23 mL of ethanolamine (20 mmol). Then the temperature of the reaction mixture was increased to 90C. Upon dissolution of appropriate aldehyde (12.5 mmol) in ethanol (20.4 mL), it was added as one portion to the reaction mixture The temperature was again increased to 120C and kept under refluxed for 2 hours. After cooling to room temperature, the reaction mixture was acidified with 16% H2SO4 to pH 5. The resulting precipitate was filtered and washed with 1:5 solution of ethanol/water. 10.1.2.1 5-(3,4-Dimethoxybenzylidene)imidazolidine-2,4-dione (3)Yellow powdery crystals. Yield: 67%; mp 283.3-284.6C; TLC: Rf = 0. 37 (S2); HPLC: tR = 0.936; MS calcd for [M + H]+: C12H12N2O4 m/z: 248.23, found: 249.19; 1H NMR (300 MHz, CDCl3-d) delta ppm 3.79 (s, 3 H), 3.83 (s, 3 H), 6.39 (s, 1 H), 6.97 (d, J=8.46 Hz, 1 H), 7.13 (d, J=2.05 Hz, 1 H), 7.20 (dd, J=8.46, 2.05 Hz, 1 H), 10.47 - 11.08 (m, 2 H).
17.4%	With piperidine; for 6h;Reflux;	General procedure: Synthesis of Compounds 25 to 28, 30, 31, 33, and 35, which are (Z)-5-(substitutedbenzylidene)imidazolidine-2,4-dione derivatives), was performed as follows. In detail, in a piperidine (1 mL/4 mmol of benzaldhehyde) solution, a suspension including a substituted benzaldhehyde (2.42 to 7.70 mmol) and hydantoin (1.1 eq.) was refluxed for 30 minutes to 8 hours. The reaction mixture was cooled, and at a temperature of 60 C., water (in a volume 20 times greater than that of piperidine used) was added thereto. Filtering was performed to remove a small amount of soft tarry material. A filtrate was acidified at room temperature by using 12N HCl. The mixture was maintained for several hours at room temperature, and then, the produced precipitate was filtered, and the resultant product was washed with cold water and/or methylene chloride. The result was dried under reduced pressure to obtain a target compound (yield: 9.7 to 79%).

9.7%

With piperidine; for 6h;Reflux;

General procedure: Synthesis of Compounds 25 to 28, 30, 31, 33, and 35, which are (Z)-5-(substitutedbenzylidene)imidazolidine-2,4-dione derivatives), was performed as follows. In detail, in a piperidine (1 mL/4 mmol of benzaldhehyde) solution, a suspension including a substituted benzaldhehyde (2.42 to 7.70 mmol) and hydantoin (1.1 eq.) was refluxed for 30 minutes to 8 hours. The reaction mixture was cooled, and at a temperature of 60 C., water (in a volume 20 times greater than that of piperidine used) was added thereto. Filtering was performed to remove a small amount of soft tarry material. A filtrate was acidified at room temperature by using 12N HCl. The mixture was maintained for several hours at room temperature, and then, the produced precipitate was filtered, and the resultant product was washed with cold water and/or methylene chloride. The result was dried under reduced pressure to obtain a target compound (yield: 9.7 to 79%). [0161] Light yellow solid; a reactiontime of 6 hours; a yieldof 9.7%; a melting point of 271.3-273.9 C.; 1H NMR (500MHz, DMSO-d5) oe 11.15 (s, 1H), 10.48 (s, 1H), 7.18 (dd, 1H,J=1.5, 8.0 Hz), 7.11 (d, 1H, J=2.OHz), 6.95 (d, 1H, J=8.5 Hz),6.37 (s, 1H), 3.81 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz,DMSO-d5) oe 166.3, 156.4, 150.0, 149.4, 126.8, 126.3, 123.7,113.2, 112.4, 109.9, 56.3, 56.2; LRMS (ES) mlz 247 (M-H)-.

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 743 - 753
[2]Molecules,2019,vol. 24
[3]Bioorganic and Medicinal Chemistry,2019,vol. 27,p. 4163 - 4173
[4]Journal of Medicinal Chemistry,2010,vol. 53,p. 273 - 281
[5]Patent: KR101677122,2016,B1 .Location in patent: Paragraph 0183; 0197
[6]Biochimica et Biophysica Acta - General Subjects,2011,vol. 1810,p. 612 - 619
[7]Patent: US2014/23603,2014,A1 .Location in patent: Paragraph 0153; 0161
[8]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 4245 - 4257
[9]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 135 - 145

37
[ 461-72-3 ]
[ 54221-96-4 ]
[ 1256244-73-1 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 5397 - 5405

38
[ 461-72-3 ]
[ 33515-62-7 ]
[ 1256244-76-4 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 5397 - 5405

39
[ 461-72-3 ]
[ 68282-53-1 ]
[ 1256244-67-3 ]

Reference： [1]European Journal of Medicinal Chemistry,2010,vol. 45,p. 5397 - 5405

40
[ 2078-71-9 ]
[ 3720-97-6 ]
[ 461-72-3 ]
[ 125577-52-8 ]

Reference： [1]Russian Chemical Bulletin,2009,vol. 58,p. 1264 - 1269

41
[ 461-72-3 ]
[ 1074-68-6 ]
[ 1332366-24-1 ]

Yield	Reaction Conditions	Operation in experiment
48%	With piperidine; In ethanol; at 80℃; for 20h;	A 40 mL round bottomed vial was charged with <strong>[1074-68-6]2-(methylthio)pyrimidine-4-carbaldehyde</strong> (4) (771 mg, 5 mmol), imidazolidine-2,4-dione (500 mg, 5 mmol, 1 .0 equiv.), and piperidine (400 muL·, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixture was heated to 80C and shaken for 20 h. The resulting yellow precipitate was isolated by filtration and washed with ethanol ( 1 x 20 mL) and dried in vacuo to afford (Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)imidazolidine-2,4-dione (5a) as a yellow solid (565 mg, 1 . 18 mg theoretical, 48%). LC-MS m/z 237 (M+ 1 ). The same procedure can be used to prepare 5b or 5c by replacing imidazolidine-2,4-dione with 1 -benzylimidazolidine- 2,4-dione or l -methylimidazolidine-2,4-dione respectively.

Reference： [1]Patent: WO2011/103289,2011,A2 .Location in patent: Page/Page column 74

42
[ 461-72-3 ]
[ 107-75-5 ]
[ 1333480-84-4 ]

Reference： [1]Chemistry and biodiversity,2011,vol. 8,p. 1470 - 1485

43
[ 461-72-3 ]
[ 1343454-08-9 ]
[ 1343454-15-8 ]

Yield	Reaction Conditions	Operation in experiment
38%	With potassium carbonate;copper(l) iodide; N,N-dimethylglycine hydrochoride; In dimethyl sulfoxide; at 120℃; for 12h;	Example 192-[3-(2,4-Dioxo-imidazolidine-l-yl)-phenyl]-3,3-dimethyl-l,2,3>4-tetrahydro- quinoline-6-carboxylic acidA mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), imidazolidine-2,4-dione (500 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N, N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120C for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2 x 150 mL), washed with water (2 x 50 mL) and saturated aqueous ammonium chloride solution (2 x 50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm x 100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(2,4-dioxo- imidazolidine-l-yl) -phenyl] -3,3-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (145 mg, 38%) as a light yellow solid: LC/MS m/e calcd for C21H21N3O4 (M+H)+: 380.42, observed: 380.0.
38%	With potassium carbonate;copper(l) iodide; N,N-dimethylglycine hydrochoride; In dimethyl sulfoxide; at 120℃; for 12h;	A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), imidazolidine-2,4-dione (500 mg, 5 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120 C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-[3-(2,4-dioxo-imidazolidine-1-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (145 mg, 38%) as a light yellow solid: LC/MS m/e calcd for C21H21N3O4 (M+H)+: 380.42, observed: 380.0.

Reference： [1]Patent: WO2011/128251,2011,A1 .Location in patent: Page/Page column 87
[2]Patent: US2011/257151,2011,A1 .Location in patent: Page/Page column 33

44
[ 461-72-3 ]
[ 103-63-9 ]
[ 52632-02-7 ]

Yield	Reaction Conditions	Operation in experiment
86%	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 10h;	To a solution of imidazolidine-2,4-dione 8 (1.0 g, 10 mmol) in DMF (10 mL) was added potassium carbonate (1.38 g, 10 mmol) and (2-bromoethyl)benzene 9 (1.85 g, 10 mmol). The mixture was heated at 90 oC for 10 h. The solution was concentrated to quarter volume and ice was added. The precipitate was filtered off and recrystallized from ethanol to give 3-phenethylimidazolidine-2,4-dione 7a (1.75 g, 86%) as pale yellow microcrystals; mp 145-147 oC (lit.1 mp 155-156). 1H NMR (DMSO-d6) 2.83 (t, J = 7.2 Hz, 2H), 3.57 (t, J = 7.2 Hz, 2H), 3.87 (s, 2H), 7.05-7.48 (m, 5H), 8.04 (s, 1H); 13NMR (DMSO-d6) 32.7, 33.8, 42.3, 126.5, 128.4, 128.6, 137.8, 171.7, 172.0.
86%	With potassium carbonate; In N,N-dimethyl-formamide; for 10h;Heating;	General procedure: To a solution of imidazolidine-2,4-dione (1.0 g, 10 mmol) in DMF (10 mL) was added potassium carbonate (1.38 g, 10 mmol) and either (2-bromoethyl)benzene (1.85 g, 10 mmol) or benzyl bromide (1.71 g, 10 mmol). The mixture was heated at 90 oC for 10 h. The solution was concentrated to quarter volume and ice was added. The precipitate was filtered off and recrystallized from ethanol to give 3-benzylimidazolidine-2,4-dione 3a (1.69 g, 89%) and 3-phenethylimidazolidine-2,4-dione 3b (1.75 g, 86%) as pale yellow microcrystal.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6895 - 6898
[2]Bioorganic Chemistry,2020,vol. 99
[3]Archiv der Pharmazie,2020

45
[ 461-72-3 ]
[ 123-08-0 ]
[ 80171-33-1 ]

Yield	Reaction Conditions	Operation in experiment
79.5%	With piperidine; at 130℃; for 0.5h;	4-hydroxybenzaldehyde (50 mmol) and hydantoin (55 mmol) were dissolved in 10 ml piperidine. The mixture was heated to 130 C for 0.5 h, and TLC analysis indicated that the reaction was complete. Water (200 ml) was added to the mixture after it was cooled to the room temperature. Then, stirring until the mixture was dissolved and filtrating to remove the undissolved substance. Subsequently, 20 ml10 N HCl was dropwise added to the filtrate and the precipitate was filtrated, washed with water and dried to give compound 3. 5.1.1.1 5-(4-hydroxybenzylidene)imidazolidine-2,4-dione(3) A yellow solid with the following characteristics: 79.5% yield; m.p. 316-318 C; 1H NMR (DMSO-d6, 400 Hz): delta 11.089 (s, 1H, N1H); 10.299 (s, 1H, N3H); 9.856 (s, 1H, OH); 7.469 (d, 2H, J = 8.4 Hz, Ar-H); 6.767 (q, 2H, J = 8.4 Hz, Ar-H); 6.346 (s, 1H, Ar-CH); MS (m/z): 205.0 (M + 1).
20.3 g	With ammonia; In water; at 90℃; for 12h;	In a 200 mL egg-plant shaped flask, 14.7 g (120 mmol) of 4-hydroxybenzaldehyde was mixed with 15.6 g (156 mmol) of hydantoin, 80 mL of water, and 14.4 g of 28% ammonia water, and the mixture was heated at 90C for 12 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated crystals were collected by filtration. The crystals were then washed twice with water and twice with ethanol. The crystals were dried to give 20.3 g of 5-(4-hydroxybenzylidene)hydantoin. Subsequently, 18.8 g (92.2 mmol) of the product was added to a 500 mL egg-plant shaped flask and then dissolved in 180 mL of N,N-dimethylformamide. To the solution were added to 27.1 g (221 mmol) of ethyl chloroacetate and 30.5 g (221 mmol) of potassium carbonate. The mixture was heated at 120C for 2 hours with stirring. After the liquid reaction mixture was cooled to room temperature, the solvent was removed by distillation under reduced pressure. Water was added to the residue, and then the mixture was extracted three times with ethyl acetate. The organic layers were collected, washed twice with water and once with saturated brine, and then dried with sodium sulfate. The sodium sulfate was then removed by filtration. After the solvent was removed by distillation under reduced pressure, the resulting brown crystals were recrystallized with a mixed solvent of ethyl acetate and hexane. The crystals were then dried to give 9.96 g of 5-[4-(2-ethoxy-2-oxoethoxy)benzylidene]-3-(2-ethoxy-2-oxoet hyl) hydantoin. In a 50 mL egg-plant shaped flask, 4.50 g (12.0 mmol) of the product was mixed with 7.57 g (72.0 mmol) of diethanolamine, and the mixture was heated at 120C for 1 hour with stirring. After the liquid reaction mixture was cooled to room temperature, the precipitated yellow crystals were recrystallized with a mixed solvent of ethanol and water. The crystals were then dried to give 4.46 g of compound 3 (yield: 18%). The 1H-NMR spectrum chart of compound 3 was obtained as in Example 1. The resulting spectrum chart showed that compound 3 has the following structure. Important chemical shift peaks of compound 3 for DMSO-d6 (standard substance) are as follows. 3.33-3.36 (m, 4H), 3.42-3.51 (m, 8H), 3.57-3.60 (m, 4H), 4.49(s, 2H), 4.71-4.74(t, 1H × 2), 4.97(s, 2H), 5.00(t, 1H), 5.05(t, 1H), 6.53(s, 1H), 6.94(d, 2H), 7.60(d, 2H), 10.72(s, 1H) The UV absorbing properties and the hydrophilicity of compound 3 were then evaluated as in Example 1. Table 1 shows the results.
	With ethanolamine; In ethanol; water; at 70 - 120℃;pH 7;Alkaline conditions;	General procedure: Hydantoin (15.0 mmol) was dissolved in water (15.0 ml) at 70 C. The solution was adjusted to pH 7 using saturated sodium bicarbonate solution. Ethanolamine (1.4 ml) was added and the temperature was raised to 90 C. The corresponding aldehyde (15.0 mmol) in ethanol (15.0 ml) was added drop wise to the reaction mixture. The reaction was refluxed at 120 C for 5-10 h. After being cooled to room temperature, the product was filtered, washed with alcohol/water (1:5) and dried to give the corresponding benzyl hydantoin intermediate. This corresponding benzylhydantoin(8.98 mmol) was dissolved in 20% aqueous NaOH solution(28.4 ml) and refluxed at 100 C for 3 h. After being cooled to room temperature, 12 N HCl (11.8 ml) was added. Sodium bicarbonate was added to bring the pH to 7. The reaction mixture was extracted with ether until the ether layer was clear. This layer was discarded. To the aqueous layer, 12 N HCl (7.1 ml) was added. It was extracted with ether until no more acid was obtained. The ether layer was dried to give the crude keto-acid. It was recrystallized in water to give pure product, which was judged by proton NMR to existas the enol tautomer.

	With ethanolamine; In ethanol; water; at 70℃; for 5h;Reflux;	General procedure: Hydantoin (5.0 g, 49.8 mmol) was dissolved in 50 mL water at 70C with stirring. Ethanolamine (4.4 mL) was added to the mixture, and the temperature was increased to 90C. An equimolar quantity of the appropriate benzaldehyde solution (1a-k, 49.8 mmol in 50 mL ethanol) was added drop-wise with continuous stirring. Next, the temperature was increased to reflux for 5 h. When the mixture was cooled to room temperature, the precipitate was filtered and washed with water (20 mL × 3) to remove the soluble impurities. The crude products were obtained as a white to yellow solid with yields of 82% to 98%.
20.3 g	With ammonia; In water; at 90℃; for 12h;	In a 200 mL eggplant-shaped flask, 14.6 g (120 mmol) of 4-hydroxybenzaldehyde were added 15.6 g (156 mmol) of hydantoin,80 mL of water and 14.4 g of 28% ammonia water were added,And heated with stirring at 90 C. for 12 hours. After the reaction mixture cooled to room temperature,Crystals precipitated by filtration were recovered.Thereafter, the crystals were washed twice with water and twice with ethanol.After drying, 20.3 g of 5- (4-hydroxybenzylidene) hydantoin was obtained.

Reference： [1]Asian Journal of Chemistry,2011,vol. 23,p. 4114 - 4116
[2]European Journal of Medicinal Chemistry,2015,vol. 103,p. 91 - 104
[3]Patent: EP2832727,2015,A1 .Location in patent: Paragraph 0127-0130
[4]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2707 - 2715
[5]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4372 - 4376
[6]Patent: JP6254808,2017,B2 .Location in patent: Paragraph 0139

46
[ 461-72-3 ]
[ 1538-75-6 ]
[ 2301-40-8 ]

Reference： [1]Journal of Organic Chemistry,2012,vol. 77,p. 8071 - 8082,12

47
[ 461-72-3 ]
[ 676500-39-3 ]
[ 1617504-91-2 ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 5295 - 5303

48
[ 461-72-3 ]
[ 100-39-0 ]
[ 2301-40-8 ]
[ 16935-43-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃;	Synthesis of 8d-e [16]: In ice bath, imidazolidine-2,4-dione (1.0 mmol) wasdissolved in 10 mL DMF and NaH (1.5 mmol, 60%) was slowly added into the mixture. Then, (bromomethyl)benzene (1.1 mmol) was added and stirred overnight. The mixture was evaporated to dryness. The residue was purified by silica gel column chromatography to give 8d and 8e.

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 92,p. 178 - 190

49
[ 461-72-3 ]
[ 108940-96-1 ]
(E)-5-(3,5-dibromo-4-methoxybenzylidene)imidazolidine-2,4-dione [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2015,vol. 80,p. 3929 - 3939

50
[ 461-72-3 ]
[ 391-12-8 ]
[ 109-77-3 ]
(±)-(7R,7a'S)-5'-amino-1',2,3'-trioxo-7-(trifluoromethyl)-1',2',3′,7a'-tetrahydrospiro[indoline-3,7'-pyrrolo[1,2-c]imidazole]-6'-carbonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydrogencarbonate; In water; for 24h;Reflux;	General procedure: A mixture of isatin 1(2 mmol), hydantoin 2/2-thiohydantoin 2a (2 mmol), malononitrile 3 (2 mmol) and NaHCO3 (0.2 mmol) were stirred in water for the appropriate time under reflux conditions. After completion of the reaction (TLC), the solid that separated from the reaction mixture was filtered and washed with ethanol (5 mL) without further purification.

Reference： [1]Journal of Chemical Research,2015,vol. 39,p. 115 - 119

51
[ 461-72-3 ]
5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde [ No CAS ]
(Z)-5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With piperidine; In ethanol; at 90℃; for 3h;	Example 27 Synthesis of 5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione 5-(Cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.0 eq, 20 mg, 0.070 mmol) was mixed in a vial with hydantoin (2.8 eq, 20 mg, 0.20 mmol) in Ethanol (0.3 ml). Piperidine (2.9 eq, 20 ul, 0.202 mmol) was added and the mixture was stirred at 90 C. for 3 hours. The mixture was cooled down, the precipitate was filtered, washed with ethanol and dried. (Z)-5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (25 mg, 100%). LCMS (ES): >95% pure, m/z 368 [M+H]+.
100%	With piperidine; In ethanol; at 90℃; for 3h;	5-(Cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.0 eq, 20 mg, 0.070 mmol) was mixed in a vial with hydantoin (2.8 eq, 20 mg, 0.20 mmol) in Ethanol (0.3 ml). Piperidine (2.9 eq, 20 ul, 0.202 mmol) was added and the mixture was stirred at 90 C. for 3 hours. The mixture was cooled down, the precipitate was filtered, washed with ethanol and dried. (Z)-5-((5-(cyclopentylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione was isolated as a solid (25 mg, 100%).

Reference： [1]Patent: US9303033,2016,B2 .Location in patent: Page/Page column 91
[2]Patent: JP5802676,2015,B2 .Location in patent: Paragraph 0314

52
[ 461-72-3 ]
7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde [ No CAS ]
5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With piperidine; In ethanol; at 80℃; for 72h;	Example 68 Synthesis 5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione To the reaction flask, 7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.7 g, 9.3 mmol) was added to ethanol (31 mL) along with hydantoin (933 mg, 9.3 mmol) and piperidine (920 muL, 9.3 mmol). The reaction was heated at 80 C. for 3 days then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, 5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was recovered as a yellow solid in 92% yield. LCMS (M+1=477)
92%	With piperidine; In ethanol; at 80℃; for 72h;	To the reaction flask, 7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (3.7 g, 9.3 mmol) was added to ethanol (31 mL) along with hydantoin (933 mg, 9.3 mmol) and piperidine (920 muL, 9.3 mmol). The reaction was heated at 80 C. for 3 days then cooled to room temperature and diluted with water. The solid was collected by filtration, washed with water, 50% ethanol/water, and then 100% ethanol. The material was dried under vacuum overnight. The product, 5-((7-(benzylthio)-5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione, was recovered as a yellow solid in 92% yield.

Reference： [1]Patent: US9303033,2016,B2 .Location in patent: Page/Page column 150
[2]Patent: JP5802676,2015,B2 .Location in patent: Paragraph 0384

53
[ 461-72-3 ]
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid [ No CAS ]
(Z)-4-(7-(cyclopropyl)amino)-3-(((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With piperidine; In ethanol; at 80℃; for 15h;	Example 164 Synthesis of (Z)-4-(7-(cyclopropyl)amino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid Hydantoin (292 mg, 2.92 mmol) and piperidine (285 muL, 2.89 mmol) were added to 4-(7-(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (315 mg, 0.96 mmol) dissolved in ethanol (5 mL). The reaction was heated at 80 C. After 15 h, the reaction was cooled to r.t., then diluted with water (10 mL). The pH was adjusted to pH=3 by addition of 1N HCl. The yellow precipitate was collected and washed with 1:1 ethanol:water (10 mL) and then ethanol (10 mL). The solid was dried in vacuo to give (Z)-4-(7-(cyclopropyl)amino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (362 mg, 92%). LCMS (ES): >95% pure, m/z 411 [M+1]+.
92%	With piperidine; In ethanol; at 80℃; for 15h;	Hydantoin (292 mg, 2.92 mmol) and piperidine (285 muL, 2.89 mmol) were added to 4-(7-(cyclopropyl)amino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (315 mg, 0.96 mmol) dissolved in ethanol (5 mL). The reaction was heated at 80 C. After 15 h, the reaction was cooled to r.t., then diluted with water (10 mL). The pH was adjusted to pH=3 by addition of 1N HCl. The yellow precipitate was collected and washed with 1:1 ethanol:water (10 mL) and then ethanol (10 mL). The solid was dried in vacuo to give (Z)-4-(7-(cyclopropyl)amino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (362 mg, 92%).

Reference： [1]Patent: US9303033,2016,B2 .Location in patent: Page/Page column 255
[2]Patent: JP5802676,2015,B2 .Location in patent: Paragraph 0496

54
[ 461-72-3 ]
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile [ No CAS ]
[ 1309846-06-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With piperidine; In ethanol; at 80℃; for 15h;	Example 248 Synthesis of (Z)-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (75 mg, 0.24 mmol) was suspended in EtOH (2.4 mL). Hydantoin (36 mg, 0.35 mmol) and piperidine (36 muL, 0.35 mmol) were added and the reaction was heated to 80 C. After 15 h, the solution was filtered while warm and the filter cake was washed with warm EtOH (3 mL) to give (Z)-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (76 mg, 80%) as a bright yellow solid. LCMS (ES): >90% pure, m/z 401 [M+1]+.
80%	With piperidine; In ethanol; at 80℃; for 15h;	4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (75 mg, 0.24 mmol) was suspended in EtOH (2.4 mL). Hydantoin (36 mg, 0.35 mmol) and piperidine (36 muL, 0.35 mmol) were added and the reaction was heated to 80 C. After 15 h, the solution was filtered while warm and the filter cake was washed with warm EtOH (3 mL) to give (Z)-4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (76 mg, 80%) as a bright yellow solid.

Reference： [1]Patent: US9303033,2016,B2 .Location in patent: Page/Page column 525; 526
[2]Patent: JP5802676,2015,B2 .Location in patent: Paragraph 0663

55
[ 461-72-3 ]
7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde [ No CAS ]
(Z)-5-((7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With piperidine; In ethanol; at 80℃;	Example 264 Synthesis of (Z)-5-((7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione The above product 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde was dissolved in 20.0 mL ethanol, added hydantoin (2.82 g, 28.17 mmol) and piperidine (2.70 mL). The reaction was heated to 80 C. for overnight. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-5-((7-(cyclopropylamino)-5-(methylthio) pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione 4.18 g (90% yield). LCMS (M+1=331)
90%	With piperidine; In ethanol; at 80℃;	The above product 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde was dissolved in 20.0 mL ethanol, added hydantoin (2.82 g, 28.17 mmol) and piperidine (2.70 mL). The reaction was heated to 80 C. for overnight. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-5-((7-(cyclopropylamino)-5-(methylthio) pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione 4.18 g (90% yield).

Reference： [1]Patent: US9303033,2016,B2 .Location in patent: Page/Page column 546
[2]Patent: JP5802676,2015,B2 .Location in patent: Paragraph 0695

56
[ 461-72-3 ]
tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate [ No CAS ]
(Z)-tert-butyl 4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)me-thyl)pyrazolo[1 ,5-a]pyrimidin-5-yl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With piperidine; In ethanol; at 80℃; for 3h;	Example 290 Synthesis of (Z)-5-((7-(cyclopropylamino)-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione The above product tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (250 mg, 0.645 mmol) was dissolved in 2.0 mL ethanol, added hydantoin (129 mg, 1.288 mmol) and piperidine (127 ul). The reaction was heated to 80 C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-tert-butyl 4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (264 mg, 87% yield). The above product was further dissolved in 1:1 mixture of DCM:TFA and stirred at room temperature for 30 minutes. Mixture was concentrated and dried to yield yellow solid of (Z)-5-((7-(cyclopropylamino)-5-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene) imidazolidine-2,4-dione. LCMS (M+1=369)
87%	With piperidine; In ethanol; at 80℃; for 3h;	The above product tert-butyl 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (250 mg, 0.645 mmol) was dissolved in 2.0 mL ethanol, added hydantoin (129 mg, 1.288 mmol) and piperidine (127 ul). The reaction was heated to 80 C. for three hours. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-tert-butyl 4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-yl)piperazine-1-carboxylate (264 mg, 87% yield).

Reference： [1]Patent: US9303033,2016,B2 .Location in patent: Page/Page column 593; 594
[2]Patent: JP5802676,2015,B2 .Location in patent: Paragraph 0747

57
[ 461-72-3 ]
[ 108-70-3 ]
3,5-dichlorophenyl hydantoin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96.5%	With triethylamine; In toluene; for 8h;Reflux;	500 ml of xylene, 55 g of hydantoin, 100 g of m-trichlorobenzene were placed in a 1000 ml four-necked flask equipped with a stirrer90 g of triethylamine and 45 g of triethylamine. Slowly heated to reflux, refluxing reaction 8 hours, chromatography tracking raw materials, the content of trichlorobenzene, when less than0.5%, the reaction was completed. The reaction solution was washed with water, dissolved, crystallized and filtered. The filter cake was dried to give 3,5-dichlorophenyl-hydantoinL05g, content of 96.5%.

Reference： [1]Patent: CN105777647,2016,A .Location in patent: Paragraph 0024; 0027

58
[ 461-72-3 ]
[ 1011-40-1 ]
C₁₃H₉N₃O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With piperidine; In ethanol; for 24h;Reflux;	Weighed 2,4-imidazolinedione 20 mmol,2-Phenylthiazole-5-carbaldehyde (<strong>[1011-40-1]2-phenylthiazole-5-carbaldehyde</strong>)Piperidine 16 mmol in a round bottom flask,Was dissolved in EtOH (150 mL)The mixture was refluxed for 24 h.A small amount of water was added and acidified with acetic acid to give the crude product. After recrystallization from methanol, compound 57 was obtained in a yield of 41%.

Reference： [1]Patent: CN106279132,2017,A .Location in patent: Paragraph 0146; 0147; 0149; 0150

59
[ 875003-43-3 ]
[ 461-72-3 ]
[ 109-77-3 ]
(trans-3,7a')-5'-amino-7-fluoro-1-methyl-1',2,3'-trioxo-1',2',3',7a'-tetrahydrospiro[indoline-3,7'-pyrrolo[1,2-c]imidazole]-6'-carbonitrile [ No CAS ]

Reference： [1]ACS Combinatorial Science,2017,vol. 19,p. 455 - 463

60
[ 461-72-3 ]
[ 2058-72-2 ]
[ 109-77-3 ]
(trans-3,7a')-5'-amino-5-bromo-1-methyl-1',2,3'-trioxo-1',2',3',7a'-tetrahydrospiro [indoline-3,7'-pyrrolo[1,2-c]imidazole]-6'-carbonitrile [ No CAS ]

Reference： [1]ACS Combinatorial Science,2017,vol. 19,p. 455 - 463

61
[ 461-72-3 ]
[ 90050-59-2 ]
[ 64-19-7 ]
3-(5-bromo-2-methylphenyl)-2-oxopropionic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium acetate;Reflux;	To a 250 mL reaction flask was added <strong>[90050-59-2]2-methyl-5-bromobenzaldehyde</strong> (20 g, 100 mmol), Hydantoin (15 g, 150 mmol),Sodium acetate (20 g, 244 mmol) and 150 mL glacial acetic acid. The reaction system was heated to reflux overnight. The system was cooled to room temperature, slowly poured into a 500 mL ice-water system, cooled to room temperature, filtered, and the filter cake washed with 500 mL of water until neutral. Collect the solid and add the solid to a 250 mL reaction flask.Add 20% NaOH solution 100mL, the system is refluxed under nitrogen protection for 3h, cooled to 20 ~ 30 C, the system is neutralized with 6N aqueous hydrochloric acid to pH = 7 ~ 8, 10g of sodium bicarbonate solids, the system with ethyl acetate Extract three times. The aqueous phase was further adjusted to pH<2 with 6N hydrochloric acid, and the aqueous phase was extracted with 500 mL of ethyl acetate. The organic phase was concentrated and purified by column chromatography (PE/EA/TEA=1/3/0.01) to give 16 g of the product in 63% yield.

Reference： [1]Patent: CN104072348,2018,B .Location in patent: Paragraph 0029-0031

62
[ 461-72-3 ]
[ 17826-04-9 ]
[ 117490-29-6 ]

Yield	Reaction Conditions	Operation in experiment
18%	With piperidine; for 1h;Reflux;	A mixture of hydantoin (446 mg, 4.46 mmol, 2.5 eq.) and <strong>[17826-04-9]6-bromoindole-3-carboxaldehyde</strong> (400 mg, 1.78 mmol, 1.0 eq.) in piperidine(2 mL) was refluxed during 1 h. The mixture was cooled to room temperature,then diluted with acetone and ethyl acetate. The organic layerwas washed with a 1M HCl, dried over Na2SO4 and then evaporatedunder reduced pressure. The residue was triturated with ethyl acetate,ethanol and MTBE to afford 28 as an orange solid (250 mg, 18%). 1HNMR (DMSO-d6, 400 MHz): delta (ppm): 6.70 (s, 1H), 7.22 (dd, J=8.4 Hz,J=1.6 Hz, 1H), 7.61 (d, J=1.6 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.13(s, 1H), 10.14 (bs, 1H), 11.01 (bs, 1H), 11.92 (s, 1H). 13C NMR(DMSO-d6, 100 MHz): delta (ppm): 100.9, 108.6, 114.4, 115.0, 120.1,122.9, 124.3, 125.9, 127.5, 136.6, 155.2, 165.3. MS: FTMS (-ESI): calcdfor C12H7N3O279Br-: m/z=303.9727, found: 303.9726.

Reference： [1]Bioorganic Chemistry,2019,vol. 84,p. 106 - 114

63
[ 461-72-3 ]
[ 298-12-4 ]
[ 65-86-1 ]

Yield	Reaction Conditions	Operation in experiment
91.9%	With sodium hydroxide; In water; at 115 - 120℃; for 2h;Large scale;	S1. Control the temperature in the reaction channel at 115-120 C, adjust the flow rate of the double pump, and simultaneously pump 1.5 kg of hydantoin 10 kg of water,2.5 kg of 50% mixed solution of glyoxylic acid and 7.5 liters of 8N sodium hydroxide solution, after heating and circulating for 2 hours,Stop heating, and when the temperature drops to 70-80 C, transfer the reaction solution to a 50 liter purification reactor.Maintain the internal temperature at 60-65 C, add concentrated hydrochloric acid dropwise to adjust the pH to 9-9.5, and centrifuge the precipitated solid.A crude white sodium orotate is obtained, and the crude product is added to 6 liters of water.Incubate at 60-65 C, add concentrated hydrochloric acid to adjust the pH to 1-2, stir for half an hour, centrifuge the precipitated solid to obtain 3 kg of crude orotic acid;S2. Add the above crude sodium orotate to 90 liters of water, raise the temperature to 90-95 C, add concentrated ammonia water to adjust the pH to 4-5.To the solid solution, add 50 g of acidic activated carbon, decolorize for 15 minutes, then filter while hot.The filtrate was added with concentrated hydrochloric acid at 80 C to adjust the pH to 1, and after slowly stirring for 2 minutes, the temperature was naturally lowered.The crystal is allowed to stand, and when the temperature is lowered to 50-55 C, centrifugation is started, and the filter cake is washed with water.The air was dried at 100 C to obtain 2.15 kg of anhydrous orotic acid, and the yield was 91.9%.

Reference： [1]Patent: CN109761916,2019,A .Location in patent: Paragraph 0032-0059

64
[ 461-72-3 ]
[ 936326-60-2 ]
[ 2221-13-8 ]

Reference： [1]Organic Letters,2020,vol. 22,p. 2687 - 2691

65
[ 461-72-3 ]
C₁₅H₁₆IO₃⁽¹⁺⁾*Br^(1-) [ No CAS ]
[ 2221-13-8 ]

Reference： [1]Organic Letters,2020,vol. 22,p. 2687 - 2691

66
[ 461-72-3 ]
(2,4,6-trimethylphenyl)(phenyl)iodonium tosylate [ No CAS ]
[ 2221-13-8 ]

Reference： [1]Organic Letters,2020,vol. 22,p. 2687 - 2691

67
[ 461-72-3 ]
[ 4521-33-9 ]
(Z)-5-((5-nitrothiophen-2-yl)methylene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With copper(II)-Para-aminobenzoic acid complex supported on Fe3O4 Magnetic nanoparticle; In ethanol; for 1.55h;Reflux; Green chemistry;	General procedure: Fe3O4PABA-Cu(II) (0.05 g) was added to a mixtureof various aldehydes (1mmol), with hydantoin or TZD(1mmol), in Ethanol (10mL), and this mixture was refluxedfor the times reported in Table2. the progress of the reactionmonitored by TLC, after completion of the reactionthe mixture was diluted with ethanol and the catalyst waseasily separated from the reaction mixture by an externalmagnet, washed with hot ethanol, dried and reused for aconsecutive run under the same reaction conditions. Afterwards,the reaction mixture was cooled to room temperatureand the crude product obtained was collected by filtrationand washed with cold ethanol to give the pure solid.

Reference： [1]Catalysis Letters,2020

68
[ 60032-57-7 ]
[ 461-72-3 ]
(Z)-5-((2-methylpyridin-3-yl)methylene)imidazolidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With copper(II)-Para-aminobenzoic acid complex supported on Fe3O4 Magnetic nanoparticle; In ethanol; for 1.56667h;Reflux; Green chemistry;	General procedure: Fe3O4PABA-Cu(II) (0.05 g) was added to a mixtureof various aldehydes (1mmol), with hydantoin or TZD(1mmol), in Ethanol (10mL), and this mixture was refluxedfor the times reported in Table2. the progress of the reactionmonitored by TLC, after completion of the reactionthe mixture was diluted with ethanol and the catalyst waseasily separated from the reaction mixture by an externalmagnet, washed with hot ethanol, dried and reused for aconsecutive run under the same reaction conditions. Afterwards,the reaction mixture was cooled to room temperatureand the crude product obtained was collected by filtrationand washed with cold ethanol to give the pure solid.

Reference： [1]Catalysis Letters,2020

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[ 461-72-3 ] Synthesis Path-Upstream 1~5

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Amides

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