[ CAS No. 766-39-2 ] {[proInfo.proName]}

Name: 766-39-2|3,4-Dimethylfuran-2,5-dione|98%
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Quality Control of [ 766-39-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 766-39-2 ]

Product Details of [ 766-39-2 ]

CAS No. :	766-39-2	MDL No. :	MFCD00005523
Formula :	C₆H₆O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MFGALGYVFGDXIX-UHFFFAOYSA-N
M.W :	126.11	Pubchem ID :	13010
Synonyms :

Calculated chemistry of [ 766-39-2 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.33
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	29.85
TPSA :	43.37 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.63 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.24
Log Po/w (XLOGP3) :	0.62
Log Po/w (WLOGP) :	0.41
Log Po/w (MLOGP) :	0.61
Log Po/w (SILICOS-IT) :	1.36
Consensus Log Po/w :	0.85

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.01
Solubility :	12.3 mg/ml ; 0.0972 mol/l
Class :	Very soluble
Log S (Ali) :	-1.11
Solubility :	9.89 mg/ml ; 0.0785 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.21
Solubility :	7.78 mg/ml ; 0.0617 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.09

Safety of [ 766-39-2 ]

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

Application In Synthesis of [ 766-39-2 ]

* 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 [ 766-39-2 ]
Downstream synthetic route of [ 766-39-2 ]

[ 766-39-2 ] Synthesis Path-Upstream 1~7

1
[ 766-39-2 ]
[ 5754-17-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrazine hydro-chloride In waterReflux	Hydrazine hydrochloride (58 g, 552 mmol) is dissolved in hot water (300 mL) and dimethyl maleic anhydride (58 g, 460 mmol) is added in portions and the suspension stirred at reflux for 16 h. The suspension is cooled down to room temperature and the precipitate is filtered, washed with water and dried at 40° C. under vacuum to yield 4,5-dimethyl-1,2-dihydro-pyridazine-3,6-dione (36) (64 g, 99percent).¹H-NMR (400 MHz, DMSO-d₆) δ=11 (br s, 2H), 2.01 (s, 6H).MS (m/z, MH+) meas. 141.1.

Reference： [1] Patent: US2010/41663, 2010, A1, . Location in patent: Page/Page column 41
[2] Journal of Organic Chemistry, 1955, vol. 20, p. 707,708
[3] Journal of the American Chemical Society, 1954, vol. 76, p. 4454,4457
[4] Patent: US2011/34451, 2011, A1, . Location in patent: Page/Page column 57
[5] Patent: US2011/34452, 2011, A1, . Location in patent: Page/Page column 36

2
[ 766-39-2 ]
[ 63751-07-5 ]
[ 5754-17-6 ]

Reference： [1] Journal of Organic Chemistry, 1955, vol. 20, p. 707,708

3
[ 766-39-2 ]
[ 34584-69-5 ]

Reference： [1] Patent: US2011/34451, 2011, A1,
[2] Patent: US2011/34452, 2011, A1,

4
[ 766-39-2 ]
[ 4282-29-5 ]

Reference： [1] Tetrahedron Letters, 2016, vol. 57, # 24, p. 2608 - 2611

5
[ 7397-06-0 ]
[ 766-39-2 ]
[ 32703-79-0 ]
[ 74186-27-9 ]
[ 95-47-6 ]

Reference： [1] J. Appl. Chem. USSR (Engl. Transl.), 1980, vol. 53, # 2, p. 353 - 355[2] Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation), 1980, vol. 53, # 2, p. 418 - 420

6
[ 766-39-2 ]
[ 487-66-1 ]

Reference： [1] Patent: US2008/275057, 2008, A1,

7
[ 766-39-2 ]
[ 245124-18-9 ]

Reference： [1] Patent: US2008/275057, 2008, A1,

[ 766-39-2 ] Synthesis Path-Downstream 1~88

1
[ 766-39-2 ]
[ 604-44-4 ]
10-chloro-2,3-dimethyl-10<i>H</i>-anthracene-1,4,9-trione [ No CAS ]

Reference： [1]Chemische Berichte,1950,vol. 83,p. 178,180

2
[ 766-39-2 ]
[ 604-44-4 ]
9-chloro-10-hydroxy-2,3-dimethyl-anthracene-1,4-dione [ No CAS ]

Reference： [1]Chemische Berichte,1950,vol. 83,p. 178,180

3
[ 766-39-2 ]
[ 156-43-4 ]
1-(4-ethoxyphenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In dimethyl sulfoxide; at 120℃; for 16h;	General procedure: A mixture of aniline GP7_1 , anhydride GP7_2 and DMSO (or AcOH) was stirred at 120 C for ~20 h. After cooling to rt, the mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgS04), filtered and concentrated in vacuo to afford maleimide GP7_3, which can be further purified by chromatography if necessary; 1-(4-Ethoxyphenyl)-3,4-dimethyl-1 /-/-pyrrole-2, 5-dione was prepared using general procedure GP7 - from p-phenetidine (2.55 ml_, 19.8 mmol) and 2,3-dimethyl maleic anhydride (5.00 g, 39.6 mmol) in DMSO (1 1.7 ml_); 120 C, 16 h. Purification by chromatography (toluene) gave 1-(4-ethoxyphenyl)-3,4-dimethyl-1 /-/-pyrrole-2, 5-dione as a bright yellow crystalline solid (4.95 g, 100%). 1 H NMR (500 MHz, CDCh) d 7.21 (d, J = 9.0, 2H), 6.94 (d, J = 9.0, 2H), 4.02 (d, J = 7.0, 2H), 2.02 (s, 6H), 1.40 (t, J = 7.0, 3H). 13C NMR (126 MHz, CDCh) d 171.20, 158.13, 137.28, 127.28, 124.48, 1 14.82, 63.65, 14.77, 8.85. HRMS calcd for C14H16N03 (M+H+) 246.1125; found 246.1127.

Reference： [1]Patent: WO2019/234418,2019,A1 .Location in patent: Paragraph 00437; 00449
[2]Gazzetta Chimica Italiana,1910,vol. 40,p. I, 545

4
[ 766-39-2 ]
[ 615-67-8 ]
6,7-dimethyl-2-chloronaphthazarin [ No CAS ]

Reference： [1]Chemische Berichte,1950,vol. 83,p. 178,180

5
[ 766-39-2 ]
[ 17825-86-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With ammonium acetate; In toluene; for 24h;Reflux;	2, 3-Dimethyl maleic anhydride (100 g, 0.8 mol)Was dissolved in 900 mL of toluene. Ammonium acetate (70 g, 0.9 mol) was added under stirring,Refluxing reaction 24h.The reaction solution was cooled to room temperature, and 500 mL of water was added. The mixture was allowed to stand and the layers were separated. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give (A1) 90 g, yield 90%.
89%	With 1,1,1,3,3,3-hexamethyl-disilazane; In methanol; N,N-dimethyl-formamide; at 20℃; for 8h;Cooling with ice;	A. Dissolve 1.0 g of 3,4-dimethylfuran-2,5-dione (formula as shown in Formula 1) in 10 mL of DMF, and add 17 mL of hexamethyldisilazane HMDS and 1.7 mL under ice bath. Methanol, added to room temperature for 1 h, and then evaporated to dryness with a rotary evaporator; B. Add 4mL DMF, 17mL HMDS and 1.7mL methanol for 7h, then add 65mL water, 45mL ethyl acetate for extraction, extraction 2 times; C. The organic phase is combined, and the extract is washed with water, washed with saturated brine, and dried with anhydrous sodium sulfate. Dry, then distill off the solvent, the oil pump is pulled dry, 0.9 g of a white solid, i.e., 2,3-dimethylbutenedimide (formula of formula 2) was obtained in a yield of 89% and a purity of 99.0%.
79%	With urea; sodium chloride; at 150℃; for 0.5h;	A mixture of 2,3-dimethylameic anhydride (2.5 g, 20 mmol), urea (1.2 g, 20 mmol) and sodium chloride (4.05 g, 70 mmol) was transferred to a flask fitted with an air condenser and was heated with stirring at 150 C. until the organic components were seen to fuse. Heating was continued for 30 min. Boiling water (10 ml) was then added. The cooled mixture was diluted with water (15 ml) and extracted (ethyl acetate, 430 ml). The combined organic layers were washed (sat.aq. NaCl, 20 ml), dried (Na2SO4) and concentrated in vacuum. The residue was crystallised from ethyl alcohol. Purification in chloroform and hexane on a silica gel column gave 2,3-dimethylmaleimide as a colourless crystalline solid (yield 79%). 1H NMR (CDCl3) delta 1.99 (6H, s, 2CH3).

Reference： [1]Tetrahedron Letters,1990,vol. 31,p. 5201 - 5204
[2]Patent: CN103274989,2016,B .Location in patent: Paragraph 0048; 0050-0052
[3]Patent: CN108623509,2018,A .Location in patent: Paragraph 0021; 0022; 0023; 0024; 0025; 0026; 0027; 0028
[4]Synthetic Communications,1998,vol. 28,p. 1885 - 1889
[5]ChemSusChem,2015,vol. 8,p. 665 - 671
[6]Patent: US9273304,2016,B2 .Location in patent: Page/Page column 15
[7]Journal of the Chemical Society. Perkin transactions I,1993,p. 2567 - 2580
[8]Justus Liebigs Annalen der Chemie,1886,vol. 234,p. 48
[9]Chemische Berichte,1885,vol. 18,p. 835
[10]Gazzetta Chimica Italiana,1906,vol. 36,p. II 863
[11]Organic Letters,2015,vol. 17,p. 5846 - 5849

6
[ 766-39-2 ]
[ 63751-07-5 ]
[ 5754-17-6 ]

Reference： [1]Journal of Organic Chemistry,1955,vol. 20,p. 707,708

7
[ 766-39-2 ]
[ 5754-17-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrazine hydro-chloride; In water;Reflux;	Hydrazine hydrochloride (58 g, 552 mmol) is dissolved in hot water (300 mL) and dimethyl maleic anhydride (58 g, 460 mmol) is added in portions and the suspension stirred at reflux for 16 h. The suspension is cooled down to room temperature and the precipitate is filtered, washed with water and dried at 40 C. under vacuum to yield 4,5-dimethyl-1,2-dihydro-pyridazine-3,6-dione (36) (64 g, 99%).1H-NMR (400 MHz, DMSO-d6) delta=11 (br s, 2H), 2.01 (s, 6H).MS (m/z, MH+) meas. 141.1.
	With hydrazine dihydrochloride; at 100.0℃; for 3.0h;Inert atmosphere; Reflux;	Hydrazine dihydrochloride (83.6 g) was dissolved in water (20 ml), heated to 100 C., and 3,4-dimethylfuran-2,5-dione (100.4 g) was introduced while stirring. Then the mixture was heated to reflux for 3 h. Subsequently, the precipitate formed was filtered off with suction, washed with water and dried. The residue was suspended in EA (2 l), filtered off with suction, and was dried. 69.7 g of the title compound were obtained. LC-MS rt: 0.19 min [M+H]+: 141.1 (met. b)
	With hydrazine dihydrochloride; In water; at 100.0℃; for 3.0h;	W5.006 4,5-Dimethyl-1,2-dihydropyridazine-3,6-dione Hydrazine dihydrochloride (83.6 g) was dissolved in water (20 ml) and heated to 100 C., and 3,4-dimethylfuran-2,5-dione (100.4 g) was introduced while stirring. Then the mixture was heated to reflux for 3 h. Subsequently, the precipitate formed was filtered off with suction, washed with water and dried. The residue was suspended in EA (2 l), filtered off with suction and dried. 69.7 g of the title compound were obtained. LC-MS rt: 0.19 min[M+H]+: 141.1 (met. b)

Reference： [1]Patent: US2010/41663,2010,A1 .Location in patent: Page/Page column 41
[2]Journal of Organic Chemistry,1955,vol. 20,p. 707,708
[3]Journal of the American Chemical Society,1954,vol. 76,p. 4454,4457
[4]Patent: US2011/34451,2011,A1 .Location in patent: Page/Page column 57
[5]Patent: US2011/34452,2011,A1 .Location in patent: Page/Page column 36

8
[ 766-39-2 ]
[ 21788-49-8 ]

Yield	Reaction Conditions	Operation in experiment
26%	With sodium hydroxide In water at 190℃; for 50h;
20%	With sodium hydroxide for 24h; Heating;
	With sodium hydroxide

With sodium hydroxide

Reference： [1]Mueller, Paul; Pfyffer, Jean [Helvetica Chimica Acta, 1992, vol. 75, # 3, p. 745 - 750]
[2]Piriniolu, Necmettin; Robinson, James J.; Mahon, Mary F.; Buchanan, J. Grant; Williams, Ian H. [Organic and Biomolecular Chemistry, 2007, vol. 5, # 24, p. 4001 - 4009]
[3]Tarbell; Bartlett [Journal of the American Chemical Society, 1937, vol. 59, p. 410] Couper; Kibler; Lutz [Journal of the American Chemical Society, 1941, vol. 63, p. 3] Lutz; Taylor [Journal of the American Chemical Society, 1933, vol. 55, p. 1585,1591]
[4]Fittig; Kettner [Justus Liebigs Annalen der Chemie, 1899, vol. 304, p. 158]

9
[ 44873-88-3 ]
[ 766-39-2 ]
[ 21788-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	at 200 - 230℃;

Reference： [1]Lutz; Taylor [Journal of the American Chemical Society, 1933, vol. 55, p. 1585,1591]

10
[ 21788-49-8 ]
[ 766-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: PCl₅ 2: AlCl₃ / 100 °C / anschl. mit H₂O

Reference： [1]Fittig; Kettner [Justus Liebigs Annalen der Chemie, 1899, vol. 304, p. 158]
[2]Lutz; Taylor [Journal of the American Chemical Society, 1933, vol. 55, p. 1585,1591]

11
[ 108-24-7 ]
[ 150-90-3 ]
[ 127-17-3 ]
[ 766-39-2 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1892,vol. 267,p. 212

12
[ 288-05-1 ]
[ 766-39-2 ]
[ 75899-41-1 ]
[ 75899-42-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	In benzene at 20℃; for 15h; Irradiation;

Reference： [1]Rivas, C.; Pacheco, D.; Vargas, F. [Journal of Heterocyclic Chemistry, 1980, vol. 17, p. 1151 - 1152]

13
[ 766-39-2 ]
[ 1617-18-1 ]
[ 114058-07-0 ]

Yield	Reaction Conditions	Operation in experiment
28%	With benzophenone In toluene for 168h; Irradiation;

Reference： [1]Winzenburg, M.L.; Fields, E.K.; Sinclair, D.P.; Ray, G.J.; Wright, M.E.; Hall, H.K. [Journal of Organic Chemistry, 1988, vol. 53, # 11, p. 2624 - 2629]

14
[ 766-39-2 ]
[ 2349-71-5 ]
6-isopropyl-2,3-dimethylnaphthazarin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; aluminium trichloride; sodium chloride 1.) 180 deg C, 3 h; 2.) r.t., 2 days; Multistep reaction;

Reference： [1]Eloeve, Guelnur A.; Schauble, J. Herman [Magnetic Resonance in Chemistry, 1987, vol. 25, p. 194 - 200]

15
[ 766-39-2 ]
[ 149-73-5 ]
[ 13314-92-6 ]

Yield	Reaction Conditions	Operation in experiment
70%	With toluene-4-sulfonic acid; In methanol;Reflux; Inert atmosphere;	Dimethyl maleic anhydride 5.30 g (42 mmol)in 50 mL methanol was taken in round-bottom flask. To this solution 5.885g(55.52mmol) of trimethyl orthoformate and 1.050g (5.530 mmol) of p-toluenesulfonic acid (pTSA) was added. The reaction mixture was refluxed for 60 h under nitrogen atmosphere. The excess of methanol was removed under reduced pressure and the crude product was purified by column chromatography (SiO2, hexane: ethyl acetate, 9:1) to give pale yellow liquid (yield 5.06 g, 70%). 1H NMR (400 MHz, CDCl3): delta 3.76 (s, 6H), 1.94 (s, 6H).13CNMR (100 MHz, CDCl3): delta15.2,51.8, 133.1, 168.9.MS (EI) m/z:172.FT-IR: 2999, 2953, 1741, 1725, 1647, 1436, 1298, 1270, 1198, 1165, 1100 cm-1.

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 975 - 980
[2]Tetrahedron Letters,2016,vol. 57,p. 2608 - 2611

16
[ 766-39-2 ]
[ 1575-54-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With lithium tri-t-butoxyaluminum hydride; In tetrahydrofuran; at -15 - 20℃; for 2h;Inert atmosphere;	A solution of LiAlH(tBuO)3 (2.84g, 11.17mmol) in 10mL of anhydrous THF was added dropwise over 10min to a stirred solution of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (3) (1.01g, 8.01mmol) in 20mL of anhydrous THF under argon atmosphere at -15C. The reaction mixture was stirred for 1h at -15C and then at room temperature for 1h. The reaction mixture was then quenched with 20mL of 1M HCl and extracted with AcOEt. Purification by silica gel column chromatography (30% AcOEt in hexane) afforded pure product 4 (829mg, 81%) as a white solid. 1H and 13C NMR are in agreement with published data.18 Rf (30% AcOEt/hexane) 0.23. MS(EI): m/z (%)=128.0 (1, M+), 127.0 (5), 111.0 (4), 100.1 (100), 99.0 (8), 83.1 (30), 82.1 (11), 69.1 (5), 56.1 (6), 55.1 (61), 54.1 (36), 53.1 (21), 43.1 (10), 39.1 (33).

Reference： [1]Angewandte Chemie - International Edition,2006,vol. 45,p. 4843 - 4848
[2]Synthesis,2009,p. 2778 - 2784
[3]Tetrahedron,2016,vol. 72,p. 3809 - 3817
[4]Journal of Organic Chemistry,2010,vol. 75,p. 5750 - 5753
[5]Tetrahedron,1989,vol. 45,p. 5247 - 5262
[6]Tetrahedron Letters,1988,vol. 29,p. 3869 - 3872

17
[ 766-39-2 ]
[ 70576-51-1 ]

Reference： [1]Journal of the American Chemical Society,1990,vol. 112,p. 5193 - 5199
[2]Helvetica Chimica Acta,1992,vol. 75,p. 745 - 750

18
[ 7397-06-0 ]
[ 766-39-2 ]
[ 32703-79-0 ]
[ 74186-27-9 ]
[ 95-47-6 ]
4-tert-butyl-phthalaldehyde [ No CAS ]

Reference： [1]Journal of applied chemistry of the USSR,1980,vol. 53,p. 353 - 355
Zhurnal Prikladnoi Khimii (Sankt-Peterburg, Russian Federation),1980,vol. 53,p. 418 - 420

19
[ 766-39-2 ]
[ 1946-82-3 ]
(S)-2-Acetylamino-6-(3,4-dimethyl-2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-hexanoic acid [ No CAS ]

Reference： [1]Journal of Agricultural and Food Chemistry,1994,vol. 42,p. 2692 - 2697

20
[ 766-39-2 ]
[ 123-01-3 ]
5-(4-Dodecyl-phenyl)-5-hydroxy-3,4-dimethyl-5H-furan-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With aluminium trichloride In carbon disulfide 1) 40 deg C, 3 h, 2) to r.t., 2 h;

Reference： [1]Nuhn; Herrmann; Radman [Pharmazie, 1999, vol. 54, # 2, p. 93 - 98]

21
[ 766-39-2 ]
[ 100-46-9 ]
[ 144173-20-6 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	In tetrahydrofuran; for 24h;Reflux;	A mixture of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (20g, 0.16mol) Dissolved in tetrahydrofuran 150 ml ,Benzylamine (17. 5 mL, 0.16 mol) was slowly added with stirring,And then refluxed for 24 h.After the reaction solution was cooled to room temperature, the solvent was recovered under reduced pressure, and the residue was stirred for 1 hour in water (50 mL), suction filtered, washed with water, dried at 45 C,To give the compound of formula IIc as a pale yellow solid, 32.5 g, yield 94.8%.
92%	In tetrahydrofuran; at 0℃;Reflux;	To a solution of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (2.5 g, 19.82 mmol) in dry THF (10 mL) was added benzylamine (2.17 mL, 19.82 mmol) at 0 oC. The resulting suspension was heated at reflux overnight, and the solvent was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with water (3 x 30 mL) and brine (1 x 30 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 12a as a yellow oil (3.93 g, 92%). lambda max (CH3OH)/nm = 223. IR: 1403, 1432, 1696, 1764, 2926, 3034 cm-1. 1H NMR: (300 MHz, CDCl3) delta 1.96 (s, 6H, CH3), 4.64 (s, 2H, NCH2Ph), 7.22-7.37 (m, 5H, ArH). 13C NMR: (CDCl3, 75 MHz) delta 8.82, 41.92, 127.94, 128.68, 128.90, 137.24, 137.66, 172.02.

Reference： [1]Tetrahedron,1999,vol. 55,p. 9439 - 9454
[2]Patent: CN103274989,2016,B .Location in patent: Paragraph 0048; 0057-0059
[3]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5916 - 5919
[4]ChemSusChem,2015,vol. 8,p. 665 - 671
[5]Organic Letters,2019,vol. 21,p. 5665 - 5669

22
[ 766-39-2 ]
hydrazine sulfate [ No CAS ]
[ 5754-17-6 ]
[ 6903-90-8 ]

Reference： [1]Journal of the American Chemical Society,1954,vol. 76,p. 4454,4457

23
[ 7446-70-0 ]
[ 44873-88-3 ]
[ 766-39-2 ]
[ 21788-49-8 ]

Yield	Reaction Conditions	Operation in experiment
	at 100℃;

Reference： [1]Lutz; Taylor [Journal of the American Chemical Society, 1933, vol. 55, p. 1585,1591]

24
[ 21788-49-8 ]
[ 874483-75-7 ]
[ 766-39-2 ]

Reference： [1]Lutz; Taylor [Journal of the American Chemical Society, 1933, vol. 55, p. 1585,1591]

25
[ 88-61-9 ]
[ 766-39-2 ]
[ 64-18-6 ]
[ 64-19-7 ]

Yield	Reaction Conditions	Operation in experiment
	at 75 - 80℃; bei der elektrolytischen Oxydation unter Verwendung eines Diaphragmas;

Reference： [1]Yokoyama [Helvetica Chimica Acta, 1929, vol. 12, p. 772]

26
[ 766-39-2 ]
[ 21788-49-8 ]
[ 27697-13-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide at 185℃; for 66h;

Reference： [1]Carman; Derbyshire; Hansford; Kadirvelraj; Robinson [Australian Journal of Chemistry, 2001, vol. 54, # 2, p. 117 - 126]

27
[ 766-39-2 ]
[ 109987-02-2 ]
(3aS,4R,7aS)-4-(tert-Butyl-dimethyl-silanyloxy)-3a,7a-dimethyl-3a,4,7,7a-tetrahydro-isobenzofuran-1,3-dione [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2002,vol. 124,p. 2080 - 2081

28
[ 766-39-2 ]
[ 1575-46-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 1 a: Synthesis of 3,4-dimethyl-2(5H)-furanone (not according to the invention); 37.8 g (1.0 mol) of sodium borohydride in 215 ml of 1 % sodium hydroxide solution (54 mmol) are slowly added to a suspension of 126 g (1.0 mol) of dimethyl maleic acid anhydride in 200 ml of water in such a way that the internal temperature of 30C is not exceeded during cooling. The mixture is stirred for a further 2.5 h at 20C. 1 18 g of 50% sulfuric acid (0.6 mol) are added to the reaction mixture and it is heated for 1 h at 90C. 250 ml of diethyl ether are added, the aqueous phase is saturated with ammonium chloride, and the organic phase is separated off and dried with sodium sulfate. After distilling off the solvent, 87.3 g of crude product are obtained which still contain around 17% of dimethyl maleic acid anhydride. The 3,4-dimethyl-2(5H)-furanone can be obtained in pure form by repeated recrystallisation from diethyl ether.MS (El): 83 (100), 112 (100), 55 (95), 39 (68), 53 (42), 54 (33), 41 (25), 51 (18), 84 (17), 56 (17), 50 (16), 113 (12), 52 (11 ), 40 (9), 38 (7), 67 (8), 69 (6).1H-NMR (CDCI3, 400 MHz): 1.82 (s, 3 H), 2.0 (s, 3 H), 4.6 (s, 2 H). 13C-NMR (CDCI3, 90 MHz): 8.3 (CH3), 12.3 (CH3), 72.5 (CH2), 123.0 (C), 156.3 (C), 175.4 (C).

Reference： [1]Patent: WO2007/131834,2007,A1 .Location in patent: Page/Page column 61

29
[ 766-39-2 ]
C₁₅H₁₈O₅ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 10772 - 10773
[2]Journal of the American Chemical Society,2003,vol. 125,p. 10772 - 10773
[3]Journal of the American Chemical Society,2003,vol. 125,p. 10772 - 10773
[4]Journal of the American Chemical Society,2003,vol. 125,p. 10772 - 10773
[5]Journal of the American Chemical Society,2002,vol. 124,p. 2080 - 2081

30
[ 766-39-2 ]
C₁₅H₁₈O₆ [ No CAS ]

31
[ 766-39-2 ]
[ 67025-97-2 ]
N-(17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl)-2,3-dimethyl-maleimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%		In 10 ml of acetic acid, 100 mg (0.29 mmol) of 6beta-naltrexamine was dissolved, and 110 mg (0.88 mmol) of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> was added thereto, followed by stirring the mixture at 125C for 20 hours. The reaction solution was allowed to cool to room temperature, and the reaction mixture was concentrated by an evaporator. To the reaction residue, aqueous saturated sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with water and saturated saline dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The thus obtained crude product was purified by silica gel column chromatography to obtain 36 mg (yield: 27%) of free form of the captioned compound 75. This product was converted to tartaric acid salt to obtain the captioned compound 75.1H-NMR (ppm) (300 MHz, CDCl3) 6.73 (brs, 1H), 6.60 (brs, 1H), 5.02 (brd, 1H, J = 7.1 Hz), 3.81-3.87 (m, 1H), 3.47 (brd, 1H, J = 5.4 Hz), 3.01-3.09 (brm, 2H), 2.64 (brs, 2H), 2.59 (brs, 1H), 2.37 (brd, 2H, J = 6.4 Hz), 2.12 (brt, 1H, J = 12.2 Hz), 1.96 (s, 6H), 1.65 (brd, 1H, J = 13.2 Hz) 1.36-1.47 (brm, 3H), 0.84 (brs, 1H), 0.52-0.54 (brm, 2H), 0.13 (brs, 2H) (free form) Mass (ESI) : 451(M++1)

Reference： [1]Patent: EP1555266,2005,A1 .Location in patent: Page/Page column 113

32
[ 766-39-2 ]
[ 67025-97-2 ]
N-(17-cyclopropylmethyl-4,5α-epoxy-3,14-dihydroxymorphinan-6α-yl)-2,3-dimethyl-maleimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7.5%		In a manner similar to the method described in Example 75, using 6alpha-naltrexamine in place of 6beta-naltrexamine, 8 mg (yield: 7.5%) of free form of the captioned compound 76 was obtained. This product was converted to tartaric acid salt to obtain the captioned compound 76.1H-NMR (ppm) (300 MHz, CDCl3) 6.78 (d, 1H, J = 8.1 Hz), 6.56 (d, 1H, J = 8.1Hz), 4.61 (dt, 1H, J = 3.9, 14.2 Hz), 4.54 (d, 1H, J = 3.9 Hz), 3.12 (d, 1H, J = 6.6 Hz), 3.04 (d, 1H, J = 18.3 Hz), 2.60-2.78 (brm, 2H), 2.22-2.41 (m, 4H), 1.99-2.12 (m, 1H), 1.95(s, 6H), 1.74-1.83 (m, 1H), 1.58-1.66 (brm, 1H), 1.50 (dd, 1H, J = 9.3, 14.9 Hz), 1.37-1.44 (m, 1H), 0.81-0.90 (m, 1H), 0.53-0.57 (m, 2H), 0.11-0.15 (m, 2H) (free form) Mass (ESI) : 451(M++1)

Reference： [1]Patent: EP1555266,2005,A1 .Location in patent: Page/Page column 113-114

33
[ 766-39-2 ]
[ 109987-02-2 ]
C₁₆H₂₆O₄Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	2,4,6-trimethyl-pyridine; methylene blue; In 1,3,5-trimethyl-benzene; at 165℃; for 60h;	Diels-Alder Adduct 13. A flask containing a mixture of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (2.520 g, 20.0 mmol), 1-(t-butyldimethylsilyloxy)-1,3-butadiene (5.53 g, 30.0 mmol), symm-collidine (150 mg), Methylene Blue (5 mg), and mesitylene (6.2 mL) was purged with argon several times and stirred under reflux in an oil bath at 165 C. for 2.5 days. The solvents were removed by Kugelrohr distillation at 100 C., and the residue was purified by flash chromatography (hexanes/EtOAc 19:1) to afford 4.604 g (74% yield) of the product which crystallized upon standing. 1H NMR (CDCl3, 400 MHz): 6-0.03 (s, 3H), 0.01 (s, 3H), 0.79 (s, 9H), 1.16 (s, 3H), 1.31 (s, 3H), 2.00 (dd, J=21, J=4, 1H), 2.99 (d, J=21, 1H), 4.13 (d, J=5.7, 1H), 5.96 (m, 2H); 13C NMR (CDCl3, 100 MHz): -5.6, -4.4, 14.7, 17.7, 25.3, 25.6, 30.0, 44.2, 53.9, 70.2, 126.9, 130.1, 175.4, 176.7; IR (NaCl, cm-1): 1784 s, 1852 m (anhydride CO); MS Found: 311.1 (M+1), Calc. 310.16; Mp 62-63 C.

Reference： [1]Patent: US2004/6121,2004,A1 .Location in patent: Page/Page column 10-11; 13

34
[ 766-39-2 ]
[ 13314-92-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sulfuric acid; In methanol; dichloromethane;	(Z)-Dimethyl 2,3-dimethyl-2-butenedioate (21): To a solution of 2 g (0.0158 mol) of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> in 40 mL of methanol was added 0.2 mL of concentrated sulfuric acid. After refluxing for 7 days, the solution was diluted with 100 mL of methylene chloride, neutralized with aqueous sodium bicarbonate solution. The methylene chloride layer was washed with 30 mL of brine, the aqueous layer was extracted with methylene chloride four times (30 mL twice and 15 mL twice). The combined methylene chloride layer and extracts were dried over anhydrous magnesium sulfate, concentrated to give 2.11 g of crude product. 1 H NMR check indicated about 25% of starting material existing, the crude mixture with 0.2 mL of concentrated sulfuric acid in 40 mL of methanol was heated at reflux again for 5 days. The solution was concentrated until 30% of methanol was left, neutralized with saturated sodium bicarbonate aqueous solution, followed by addition of 30 mL of brine solution, and the mixture was extracted with ethyl acetate four times (100 mL once, 30 mL three times). The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, concentrated to give 3.26 g of crude product 21 (~100% yield). It was of satisfactory purity for the next step. 1H NMR (CDCl3) d 3.77 (s, 6 H, OMe), 1.95 (s, 6 H, Me)

Reference： [1]Patent: US2002/91163,2002,A1

35
[ 766-39-2 ]
[ 60-34-4 ]
6-hydroxy-2,4,5-trimethylpyridazin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%	With hydrogenchloride; In water; for 3h;Reflux;	General procedure: From 1.26 (0.01 mol) of dimethylmaleic anhydride and 0.46 g(0.01 mol) of methylhydrazine. Yield 63%, mp: 167-168 C; 1HNMR (400 MHz, DMSO, TMS): d = 2.02 (s, 6H), 3.37 (s, 3H), 10.98(br. s, O H N, 1H); 13C NMR (100 MHz, CDCl3, TMS): d = 9.94,10.16, 33.96, 120.14, 120.75, 158.66, 161.56.
	In acetic acid;	PREPARATIVE EXAMPLE 24 Production of 1,6-dihydro-3-hydroxy-1,4,5-trimethylpyridazin-6-one <strong>[766-39-2]2,3-Dimethylmaleic anhydride</strong> (2.5 g) was dissolved in acetic acid (45 ml) and methylhydrazine (960 mg) was added. The mixture was stirred at room temperature for 2 hours. Acetic acid was distilled away and the residue obtained was recrystallized from dichloromethane-hexane to give 2.6 g of the title compound. 1 H-NMR(DMSO-d6 /ppm) delta1.99(3H, s), 2.00(3H, s), 3.44(3H, s).

Reference： [1]Journal of Molecular Structure,2015,vol. 1085,p. 28 - 36
[2]Patent: US5719155,1998,A

36
[ 766-39-2 ]
[ 155389-42-7 ]

Yield	Reaction Conditions	Operation in experiment
78%	With magnesium sulfate; sodium sulfate; In tetrahydrofuran; water;	A. 2,3-Dimethylbut-2-ene-1,4-diol A solution of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (6.3 g, 50 mmol) in dry tetrahydrofuran (25 mL) was added dropwise to a stirred suspension of lithium aluminum hydride (3.8 g, 100 mmol) in tetrahydrofuran (50 mL) at 0 C. The suspension was warmed to room temperature and stirred for 3 hours. Excess lithium aluminum hydride was destroyed by careful addition of freshly prepared saturated sodium sulfate solution in water at 0 C. Addition was continued until all inorganics were precipitated as white solids. Anhydrous magnesium sulfate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure to obtain diol A (4.5 g, 78%) as a colorless oil.

Reference： [1]Patent: US5827868,1998,A

37
[ 766-39-2 ]
[ 2015-19-2 ]
2-chloro-5-(2,5-dihydro-3,4-dimethyl-2,5-dioxo-1H-pyrrol-1-yl)benzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate;	SYNTHESIS EXAMPLE 4 Synthesis of preparation intermediate, 2-chloro-5-(2,5-dihydro-3,4-dimethyl-2,5-dioxo-1H-pyrrol-1-yl)benzenesulfonamide (Compound No. II-B-2) In 3 ml of pyridine, 1 mmol of <strong>[2015-19-2]5-amino-2-chlorobenzenesulfonamide</strong> and 1.05 mmol of 2,3-dimethylmaleic anhydride were stirred at 90-100 C. for 9 hours. Pyridine was then distilled off from the reaction mixture, followed by the addition of 20 ml of ice water and 0.1 ml of 35% hydrochloric acid to the solid residue. After the mixture thus formed was stirred for 20 minutes, the resulting precipitate was collected by filtration and then dried in air. Yield: 93%. Its physicochemical properties are shown in Table 8. The other compounds (Compound No. II-B-1 to Compound No. II-B-3) shown in Table 8 were also synthesised in a manner similar to Synthesis Example 4. The yield and physiocochemical properties of each of the compounds are also shown in Table 8.

Reference： [1]Patent: US5127937,1992,A

38
[ 766-39-2 ]
[ 2297-06-5 ]
methyl 2-(aminosulfonyl)-4-(2,5-dihydro-3,4-dimethyl-2,5-dioxo-1H-pyrrol-1-yl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; acetic acid;	SYNTHESIS EXAMPLE 5 Synthesis of preparation intermediate, methyl 2-(aminosulfonyl)-4-(2,5-dihydro-3,4-dimethyl-2,5-dioxo-1H-pyrrol-1-yl)benzoate (Compound No. II-B-4) In 3 ml of acetic acid, 1 mmol of methyl 4-amino-2-(aminosulfonyl)benzoate and 1.05 mmol of 2,3-dimethylmaleic anhydride were stirred at 80 C. for 40 hours. Acetic acid was then distilled off from the reaction mixture, followed by the addition of 20 ml of ice water to the oily residue. After the mixture thus formed was stirred for 2 hours, the resulting precipitate was collected by filtration and then dried in air. Yield: 43%. Its physiocochemical properties are shown in Table 8.

Reference： [1]Patent: US5127937,1992,A

39
[ 766-39-2 ]
[ 40963-14-2 ]
[ 110498-08-3 ]

Yield	Reaction Conditions	Operation in experiment
69.9%	With sodium ethanolate; triethylamine; In ethanol;	PREPARATION EXAMPLE 2B 0.48 g (3.85 mmol) of 2,3-dimethylmaleic anhydride was added to a solution of 0.5 g (3.85 mmol) of <strong>[40963-14-2]2-amino-2,3-dimethylbutyramide</strong> and 0.6 ml (4.32 mmol) of triethylamine in 5 ml of dried ethanol while cooling in an ice bath so that the temperature did not exceed 30 C., and then stirred for 1 hour. All of an ethanol solution of sodium ethoxide, prepared by adding 0.20 g (8.70 mmol) of metallic sodium to 5 ml of dried ethanol, was added at the same time to the above solution without isolation of the formed triethylammonium salt of amidocarbamoylacrylic acid, and the resulting mixture was heated under reflux for 1 hour. The solvent was distilled away under reduced pressure, and the residue was treated in the same procedure as in Preparation Example 2A to yield 0.64 g of the same compound as in Preparation Example 2 (yield: 69.9%).

Reference： [1]Patent: US4726835,1988,A

40
[ 766-39-2 ]
[ 141-43-5 ]
[ 34321-82-9 ]

Yield	Reaction Conditions	Operation in experiment
89%		EXAMPLE b 126 g (1 mol) of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> and 61 g (1 mol) of ethanolamine are reacted by heating at 180 C. for 1 hour to give 150 g of N-(2-hydroxyethyl)-2,3-dimethylmaleimide (boiling point 110 C. under 13.33 Pa; yield 89% of theory).
45%		Weigh 0.6mmol 3,4- dimethyl maleic anhydride to a three neck round bottom flask, and dissolved in 10ml of acetone, 0.5mmol ethanolamine with 10ml of acetone was dissolved by constant pressure funnel was slowly added dropwise three-necked flask, magnetic was stirred and reacted at room temperature for IH, the acetone solvent was removed by rotary evaporation, 15ml of toluene as a solvent instead, 0.02g of anhydrous sodium acetate were added to the reaction system, 0.2ml of triethylamine, 0.05 g of hydroquinone was slowly warmed to 115 deg.] C the reaction was refluxed for 2.5h, the reaction is tracked by thin layer chromatography on silica gel.After the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, to obtain a concentrate, the concentrate was subjected to silica gel column chromatography (eluent: VPetroleum ether: VEthyl acetate= 12: 1), and collecting the target fluid, the rotation solvent in vacuo to give the desired product.Yield 45%.
	In toluene;	N-(2-hydroxyethyl)maleimide was prepared in toluene from dimethylmaleic anhydride and ethanolamine using conventional methods. N-(2- hydroxyethyl)maleimide (10.15 g) and 6.68 g of triethylamine were dissolved in 100 ml of dichloromethane (DCM). Methacryloyl chloride (7 ml) diluted with DCM was added slowly with stirring to avoid heating. The triethylamine hydrochloride precipitate formed and the reaction solution was held for an additional 6 hours. The reaction solution was washed twice with 200 ml aliquots of dilute sodium bicarbonate, then 2 additional washings were carried out using distilled water and then the phases were allowed to separate. The DCM phase was dried over anhydrous magnesium sulfate. The DCM was evaporated to obtain a clear liquid suitable for polymerization. The expected ethylenically unsaturated monomer structure was confirmed by NMR.

Reference： [1]Patent: US4271074,1981,A
[2]Patent: CN107162950,2017,A .Location in patent: Paragraph 0099-0101
[3]Angewandte Chemie - International Edition,2012,vol. 51,p. 4448 - 4451
[4]Patent: WO2016/186864,2016,A1 .Location in patent: Page/Page column 55

41
[ 766-39-2 ]
[ 2365-85-7 ]
[ 115087-01-9 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid;	EXAMPLE 1 Preparation of N-(2-fluoro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide (intermediate) STR11 A mixture of 46.5 g of <strong>[2365-85-7]3-amino-4-fluorobenzoic acid</strong> and 37.8 g of dimethylmaleic anhydride in 200 ml of glacial acetic acid is stirred for 12 hours at an oil bath temperature of 130-40. After cooling, the mixture is poured onto ice-water, and the resulting precipitate is filtered with suction, washed with water and dried. Recrystallisation from ethanol/water yields 70.3 g of N-(2-fluoro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide which melts at 238-240.

Reference： [1]Patent: US4804400,1989,A

42
[ 766-39-2 ]
[ 2002-82-6 ]
[ 115086-84-5 ]

Yield	Reaction Conditions	Operation in experiment
	In acetic acid	8 Preparation of N-(2-fluoro-5-methylcarbonylphenyl)-2,3-dimethylmaleic acid imide (intermediate) STR18 EXAMPLE 8 Preparation of N-(2-fluoro-5-methylcarbonylphenyl)-2,3-dimethylmaleic acid imide (intermediate) STR18 A mixture of 3 g of 5-amino-4-fluoroacetophenone, 2.5 g of dimethylmaleic anhydride and 50 ml of glacial acetic acid is heated under reflux overnight. The reaction mixture is then poured onto ice, and the resulting precipitate is filtered with suction, washed with water and dried. 2.3 g of N-(2-fluoro-5-methylcarbonylphenyl)-2,3-dimethylmaleic acid imide having a melting point of 130°-131° are thus obtained.

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US4804400, 1989, A

43
[ 766-39-2 ]
[ 57946-56-2 ]
[ 115087-24-6 ]

Yield	Reaction Conditions	Operation in experiment
84%	With hydrogenchloride; dmap; sodium hydroxide; In o-xylene; ethyl acetate;	EXAMPLE 9 Preparation of N-(2-fluoro-4-chlorophenyl)-2,3-dimethylmaleic acid imide STR19 A mixture of 126 g (1.0 mol) of dimethylmaleic anhydride, 145.5 g (1.0 mol) of <strong>[57946-56-2]2-fluoro-4-chloroaniline</strong> and 2 g of 4-dimethylaminopyridine is heated under reflux in 800 ml of o-xylene for 16 hours using a water separator. The whole is then evaporated to dryness in vacuo and the residue is dissolved in a 1:1 mixture of ethyl acetate:ether and washed with each of 1N hydrochloric acid, 1N sodium hydroxide solution and water. Afer drying over sodium sulphate and evaporating off the solvent, the residue (227.5 g) is recrystallized from methanol. In this manner there are obtained 211.1 g (84% of the theoretical yield) of the title product in the form of colourless crystals which melt at 96-97.

Reference： [1]Patent: US4804400,1989,A

44
[ 766-39-2 ]
[ 39222-73-6 ]
[ 119096-63-8 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	With pyrrolidine; acetic acid; In toluene; for 2.5h;Reflux;	0.45 g of pyrrolidine (6.4 mmoles) and 0.38 g of glacial acetic acid (6.4 mmoles) are added to a solution of 10.00 g of 2-amino-5-tert-butyl-1 , 3 , 4- thiadiazole (63.6 mmoles) - compound having formula (IX) - and 8.02 g of 2 , 3-dimethylmaleic anhydride (63.6 mmoles) - compound having formula (VIII) - in 60 ml of toluene. The solution is refluxed for 2 h 30' . Upon completion of the reaction, 50 ml of a 10% aqueous solution of HC1 are added to the solution, obtaining a biphasic system. After separating the organic phase, the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with a 10% solution of HC1, water and a saturated NaCl solution, anhydrified with anhydrous sodium sulfate, filtered and concentrated. The solid thus obtained is washed with cold heptane. 15.98 g of the desired product are obtained. Yield 94.8% (0288) GC-MS: M+ = 265
	With potassium carbonate; In dichloromethane; acetic acid;	EXAMPLE 2 Synthesis of an intermediate: STR33 2-Amino-5-tert-butyl-1,3,4-thiadiazole (1.57 g) and 2,3-dimethylmaleic anhydride (1.51 g) were refluxed for 5 hours in glacial acetic acid (30 ml). After the reaction, acetic acid and the excess of the 2,3-dimethylmaleic anhydride were evaporated. The residue was dissolved in dichloromethane (50 ml), and the solution was washed with a 10% aqueous solution of potassium carbonate (20 ml), and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the desired N-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-2,3-dimethyl-maleinimide (2.41 g). mp. 87-91 C.

Reference： [1]Patent: WO2019/155400,2019,A1 .Location in patent: Page/Page column 54
[2]Patent: US4828604,1989,A

45
[ 766-39-2 ]
[ 138781-90-5 ]
[ 869575-37-1 ]

Yield	Reaction Conditions	Operation in experiment
21%	With 1,1,1,3,3,3-hexamethyl-disilazane; zinc dibromide; In toluene; at 80℃; for 2h;	29 mg (0.23 mmole) of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> and 86 mg (0.384 mmole) of zinc bromide were added to a 2 mL toluene solution of 50 mg (0.192 mmole) of the synthetic intermediate of Embodiment 1-III and the mixture was heated to 80 C.. While still at 80 C., 0.068 mL (0.324 mmole) of hexamethyldisilazane was gradually added and the mixture was stirred for two hours. After cooling the mixture to room temperature, it was filtered with celite and the solvent was removed under reduced pressures. The residue was purified by thin-layer chromatography, yielding 15 mg (21 percent) of Compound 73-III.

Reference： [1]Patent: US2007/105899,2007,A1 .Location in patent: Page/Page column 78

46
[ 766-39-2 ]
bovine insulin [ No CAS ]
bovine insulin, dimethylmaleic anhydride protected [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; ethylenediaminetetraacetic acid; sodium carbonate; N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid; In water; dimethyl sulfoxide; at 4℃;pH 6.8 - 6.9;	[0136] DMMA protection of insulin. The protection of insulin has previously been reported (N. J. Kavimandan et al. 2006 Bioconjugate Chem. 17: 1376-84). This procedure, slightly modified, is as follows. Insulin (25 mg, 4.3 mumol) was dissolved in 5 mL of 50 mM HEPES buffer with 25 mM EDTA. The pH was adjusted to be within the range of 6.8-6.9 with I M sodium carbonate. A three-fold molar excess of dimethylmaleic anhydride (DMMA) (5 mg, 43 mumol) was dissolved in 1 mL of DMSO. One third of the DMMA was added to the insulin and the pH was adjusted back to 6.8-6.9 with 1 M HCl. The insulin was slowly rotated at 4 C for 30 minutes. The pH was checked at the end of the 30 minutes and adjusted as before. The remaining two thirds of the DMMA solution were then added in the same fashion. The pH was again checked to be between 6.8-6.9 and the solution allowed to rotate at 4 C over night. The protected insulin was dialyzed, with gentle stirring at 4 C, against 50 mM HEPES buffer with 25 mM EDTA. One liter of buffer was changed every three-five hours for a total of four liters of buffer.; EXAMPLE 3 AKPl with CDT coupling[0175] Use of coupling agents, such as CDI or CDT for in this application coupling the B)2 to insulin is now the standard in chemistry, and review books exist on this topic, such as, for example Hermanson, G. "Bioconjugate Techniques", AP Press.[0176] Bovine insulin (0.01Og, 1.74 x 10"6 mol) was protected with a three-fold molar excess of dimethylmaleic anhydride by the previously established procedure. The protected insulin solution was then collected by precipitation in 35 mL chilled isopropyl alcohol. The resulting solid was washed in chilled isopropyl alcohol, then ether. The dried sample was then dissolved in 4 mL DMSO with 1 % triethylamine. Cyanocobalamin (0.005g, 3.69 x 10"6 mol) was activated with 1.2 molar equivalents of CDT in 2 mL dry DMSO at room temperature for 30 minutes. The insulin solution was then added to the activated cyanocobalamin and allowed to rotate gently over night at room temperature. The resulting reaction was dialyzed against 5 L of deionized water and then purified by anion exchange chromatography.; EXAMPLE 4 AKP2 synthesis[0177] Cyanocobalamin (0.005g, 3.69 x 10"6 mol) was dissolved in 2 mL dry DMSO and activated with CDT at room temperature for 30 minutes. This was then added to O,O'-Bis(2-aminoethyl)polyethylene glycol 2,000 (0.0147 g, 7.37 x 10"6 mol) and the B12- PEG product was purified by high pressure liquid chromatography using 5 mM Phosphate buffer, pH 7, and acetonitrile. The gradient went from 20 % acetonitrile to 50 % acetonitrile over 20 minutes. B)2-PEG had a Tr at 1 1 minutes and was then verified by MALDI-MS. Bi2-PEG was reacted with 50 mM sodium iodoacetate with the presence of a ten-fold molar excess of sodium iodoacetate. The reaction was run in 2 mL 500 mM phosphate buffer containing 0.15 M NaCI and 5 mM EDTA, pH 8.3. This was stirred under nitrogen atmosphere at room temperature overnight. The B\|2-PEG-acetate product was then dried in vacuo and activated with CDT in 2 mL dry DMSO for 30 minutes at room temperature.[0178] Bovine insulin (0.01 Og, 1.74 x 10"6 mol) was protected with a three-fold molar excess of dimethylmaleic anhydride by the previously established procedure. The <n="52"/>protected insulin solution was then collected by precipitation in 35 mL chilled isopropyl alcohol. The resulting solid was washed in chilled isopropyl alcohol, then ether. The dried sample was then dissolved in 4 mL DMSO with 1 % triethylamine. The insulin solution was then added to the activated B I2-PEG -acetate and allowed to rotate gently over night at room temperature. The resulting reaction was dialyzed against 5 L of deionized water and then purified by anion exchange chromatography.

Reference： [1]Patent: WO2008/109068,2008,A2 .Location in patent: Page/Page column 37; 49; 50

47
[ 766-39-2 ]
[ 13545-04-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine In various solvent(s) at 100℃;

Reference： [1]Gaviglio, Carina; Doctorovich, Fabio [Journal of Organic Chemistry, 2008, vol. 73, # 14, p. 5379 - 5384]

48
[ 766-39-2 ]
[ 98453-81-7 ]

Yield	Reaction Conditions	Operation in experiment
96%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 10h;Reflux;	The BrMMMan intermediate was synthesized by using a previousprotocol (Liu et al., 2016; Maier and Wagner, 2012). In brief, dimethylmaleicanhydride (5.04 g, 40 mmol), N-bromosuccinimide(14.24 g, 80 mmol), and benzoyl peroxide (0.2 g, 0.83 mmol) wereadded into an adaptive round-bottom flask and dissolved in carbontetrachloride (CCl4, 250 mL). The reaction was stirred for 5 h underrefluxing. Then the mixture was cooled down to room temperature,benzoyl peroxide (0.2 g, 0.83 mmol) was added as catalyst to themixture again, the reaction was stirred for another 5 h under refluxing.Then the mixture was agaun cooled down to room temperature, andsolids were removed by filtration. The obtained solution was washedtwo times with DI water (100 mL) and one time with saturated sodiumchloride solution by separating funnel, then the organic solution driedover anhydrous sodium sulfite for 3 h and concentrated to a thickyellow oil by rotary evaporator. The crude intermediate was purified bychromatography on a silica gel column (elution with petroleum ether/ethyl acetate 4:1). Finally, BrMMMan intermediate (purity 96%, 1.1 g)was obtained (Fig. S2a). BrMMMan: 1H NMR (500 MHz, CDCl3) delta(ppm) = 2.18 (s, 3H, eCH3), 4.18 (s, 2H, eCH2-Br), 7.26 (CHCl3).
	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 20℃;Heating / reflux;	A solution of starting material (5.0 g, 0.040 mol), NBS (10.6 g, 0.059 mol) BPO (296 mg) in 300 ml CCl4 was stirred under reflux for 5 hrs. The reaction mixture was then cooled to room temperature, and another portion of BPO (296 mg) was added, and the reaction was stirred under reflux for another 5 hrs. The reaction mixtures was then held at room temperature overnight. Then it was filtered and the residue was washed by CCl4 for three (3) times, and the combined organic layer was washed by water and brine, then dried and concentrated and purified by column chromatography (PE:EA=4:1) to give crude product that was then was purified by distillation. The second fraction obtained at 128 C.135 C. (3 mmHg) was intermediate 7.

Reference： [1]International Journal of Pharmaceutics,2020,vol. 582
[2]Synthesis,2009,p. 1807 - 1810
[3]Journal of the American Chemical Society,2012,vol. 134,p. 10169 - 10173
[4]Patent: US2008/275057,2008,A1 .Location in patent: Page/Page column 72

49
[ 766-39-2 ]
[ 1942-45-6 ]
[ 1094789-96-4 ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 17226 - 17227

50
[ 108-31-6 ]
[ 64-19-7 ]
[ 766-39-2 ]

Yield	Reaction Conditions	Operation in experiment
		maleic anhydride,2-aminopyridine and glacial acetic acid in accordance with the weight ratio of 1: 0.45: 2.5 mixed,Heated at a temperature of 100 under reflux conditions 0.5h,Then adding a concentration of 1.0mol / L sulfuric acid aqueous solution,Then heated to reflux 3.2h, cooled to room temperature,Followed by crystallization under stirring, filtered,Washed with water, dried at a temperature of 15 for 30min,Using NMR spectroscopy to determine the detection method,The product obtained by drying is colorless crystal dimethyl maleic anhydride;

Reference： [1]Synthesis,2009,p. 2778 - 2784
[2]Patent: CN106748956,2017,A .Location in patent: Paragraph 0073-0074; 0085-0086; 0097-0098; 0109-0110; 0121

51
[ 766-39-2 ]
[ 34584-69-5 ]

Reference： [1]Patent: US2011/34451,2011,A1
[2]Patent: US2011/34452,2011,A1

52
[ 107-10-8 ]
[ 766-39-2 ]
[ 119518-26-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	In tetrahydrofuran; at 0℃;Reflux;	To a solution of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (2.5 g, 19.82 mmol) in dry THF (10 mL) was added propylamine (1.63 mL, 19.82 mmol) at 0 oC. The resulting suspension was heated at reflux overnight, and the solvent concentrated in vacuo. The residue was disolved in EtOAc (50 mL), washed with water (3 x 30 mL) and brine (1 x 30 mL). The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give 12a as a yellow oil (3.10 g, 94%). lambda max (CH3OH)/nm = 223. IR: 1405, 1695, 1768, 2877, 2967 cm-1. 1H NMR: (300 MHz, CDCl3) delta 0.67-0.72 (t, J = 7.4 Hz, 3H, N-CH2CH2CH3), 1.33-1.46 (m, 2H, N-CH2CH2CH3), 1.78 (s, 6H, 2 x CH3-C-(C=O)-), 3.22-3.27 (t, J = 7.2 Hz, 2H, N-CH2). 13C NMR: (CDCl3, 75 MHz) delta 8.53, 11.28, 22.10, 39.73, 137.14, 172.24.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 5916 - 5919

53
[ 766-39-2 ]
2,3-dimethyl-2-butenolide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		A mixture of NaBH4 (0.60 g, 15.9 mmol) in anhydrous THF (3 mL) was stirred and cooled in an ice bath while 2.0 g (15.9 mmol) of 2,3-dimethyl-maleic anhydride, 7, dissolved in 19.3 mL of THF anhydrous was added slowly. The ice bath was removed and the stirring was continued for 1.5 h. The solution was cooled in an ice bath and acidified with 2 M aqueous HCl down to pH 5-6. The resulting mixture was concentrated, dissolved in 30 mL of water and extracted three times with 10 mL of diethyl ether. The organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated to dryness, affording 0.90 g (8.0 mmol) of 2,3-dimethyl-2-butenolide (yield 50%). 1H NMR (300 MHz; CDCl3; delta, ppm) 1.83 (3H, br s, CH3), 2.02 (3H, br s, CH3), 4.63 (2H, q, J5,7=0.8 Hz, H5). 13C NMR (100 MHz, CDCl3, delta, ppm): 175.7 (C2), 157.1 (C4), 122.8 (C3), 73.4 (C5), 15.0 (C7), 9.2 (C6). IR (film, nu, cm-1) 1031 (st. C-O), 1081 (st. C-O), 1456 (def. C-H), 1684 (st. C=C), 1751 (st. C=O), 2927 (st. C-H). GC (50 C, 1 min, 5 C/min, 250 C, 10 min) tR=7.8 min. MS (DIP, EI, m/z, %): 112.05 (M+, 100); 113.04 (8); 97.03 (M+-Me, 30); 68.06 (M+-CO2, 15). EA. Calculated for C6H8O2: C (64.27), H (7.19). Found: C (64.29), H (7.22).

Reference： [1]Tetrahedron,2012,vol. 68,p. 9982 - 9998,17

54
[ 766-39-2 ]
[ 1099-45-2 ]
[ 18515-43-0 ]

Yield	Reaction Conditions	Operation in experiment
80%		General procedure: Compounds 6b and 6c are commercially available. Compound 6a was prepared from the condensation reaction of glyoxylic acid with 3-methylbutyraldehyde, followed by oxidation of the intermediate product beta-isopropyl-gamma-hydoxybutenolide with Dess-Martin periodinate, according to the previously reported method.37 (0031) A solution of respective alkyl maleic anhydride (6a-6c, 10mmol) in anhydrous toluene (50mL) was treated with carbethoxymethylenetriphenylphosphorane (4.18g, 12mmol). The mixture was stirred for 15h at room temperature, and then concentrated under reduced pressure. The residual solids were dissolved in Et2O (30mL), and triphenylphosphine oxide was removed by filtration. The filtrate was concentrated and purified by chromatography on a short silica gel column (EtOAc/hexane, 1:4) to afford the desired butenolactone product as a mixture of isomers (90-95%). (0032) The above-prepared butenolactone (5mmol) was dissolved in anhydrous methanol (30mL), and sodium methoxide (1.5mL of 5.4M solution in methanol, 8.1mmol) was added. The mixture was stirred for 18h at room temperature, and then heated under reflux for additional 2h. The orange solution was concentrated under reduced pressure, and poured into 2M aqueous HCl solution (30mL). After stirring for 2h at 50C, the mixture was extracted with EtOAc (40mL×5). The combined organic extracts were washed with saturated aqueous NaHCO3 solution (50mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (EtOAc/hexane, 1:9) to afford the desired cyclopentadione product (7a-7c).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1766 - 1772

55
[ 766-39-2 ]
[ 2450-71-7 ]
dimethylmaleic propargylamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In tetrahydrofuran; at 20℃; for 4h;	Propargylamine (0.50 g, 9.09 mol) and <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (1.14 g, 9.09 mmol) were sequentially dissolved in anhydrous THF (25 mL), and the solution was stirred for 4 h at room temperature (Scheme S2). The final product was recrystallized in THF. Yield: 1.50 g (91%). 1H NMR (400 MHz, CD3OD): delta 3.70 (2H, -CH2-C ? CH), 2.01 (1H, -CH2-C ? CH), 1.89 (6H, -C(CH3) = C(CH3)-) (Fig. S2).

Reference： [1]Journal of Controlled Release,2015,vol. 205,p. 15 - 24

56
[ 766-39-2 ]
[ 753-90-2 ]
3,4-dimethyl-1-(2,2,2-trifluoroethyl)pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With toluene-4-sulfonic acid; In toluene;Reflux;	Step 1: Preparation of 3,4-dimethyl-1-(2,2,2-trifluoroethyl)pyrrole-2,5-dione (compound Vl-8) <strong>[766-39-2]2,3-Dimethylmaleic anhydride</strong> (2 g, 15.5 mmol) was dissolved in toluene (30 mL).2,2,2-Trifluoroethylamine (2.524 mL, 31.0 mmol) was added followed by p-toluenesulfonic acid (0.267 g, 1.55 mmol) was added and the reaction mixture was heated to reflux overnight. A spatula tip of p-toluenesulfonic acid and 0.5 mL of 2,2,2-trifluoroethylamine was added and the reaction mixture was further for 6 h. The reaction mixture was diluted withethyl acetate and washed twice with saturated NaHCO3 solution and then with brine. The organic layer was dried over Na2504 and the solvent was evaporated to give a clear oil (2.90g, quant.), which was used without further purification; 1H NMR (ODd3, 400MHz): oe ppm 4.10 (q, 2 H), 2.02 (s, 6H);

Reference： [1]Patent: WO2015/128321,2015,A1 .Location in patent: Page/Page column 48

57
[ 766-39-2 ]
[ 19763-90-7 ]
2-(3,4-dichlorophenyl)-6-hydroxy-4,5-dimethylpyridazin-3(2H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.6%	With hydrogenchloride; In water; for 6h;Reflux;	1) Take 21.1 g of <strong>[19763-90-7]3,4-dichlorophenylhydrazine hydrochloride</strong>,12.6g of 3,4-dimethyl maleic anhydride was dissolved in 200ml of purified water was added.With stirring, slowly add 40 ml of concentrated hydrochloric acid.After the addition was completed, the mixture was heated under reflux for 6 hours.After completion of the reaction, the ice water bath was cooled to precipitate a yellow solid.Filter by suction and wash the filter cake twice with water.The filter cake was taken out and dissolved in saturated NaHCO3. The insoluble matter was filtered off, and the clear liquid was adjusted to pH between 2 and 3 with concentrated hydrochloric acid to precipitate a white solid.After suction filtration and drying, 26.3 g was obtained, and the yield was 92.6%.

Reference： [1]Patent: CN107793362,2018,A .Location in patent: Paragraph 0102; 0183; 0185; 0186
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 2942 - 2961

58
[ 766-39-2 ]
2-Amino-4⁽⁵⁾-tert-butylimidazole [ No CAS ]
1-(5-tert-butyl-1H-imidazol-2-yl)-3,4-dimethyl-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With dmap; triethylamine; In toluene; at 100℃; for 16h;	A mixture of 4-tert-butyl-1H-imidazol-2-amine (3.5920 mmol, 0.5 g), DMAP (0.35920 mmol,0.043883 g), N, N-diethylethanamine (3.5920 mmol, 0.36348 g) and 3,4-dimethylfuran-2,5-dione(3.9511 mmol, 0.49828 g) was heated in toluene (120 ml) at 100C for 16h.The mixture wasdiluted with methanol (5m1) ethyl acetate (20m1), washed with saturated bicarbonate solution,brine, dried (Mg504) and concentrated. The mixture was then absorbed onto silica and purified by chromatography (silica gel column, gradient elution with mixtures of hexane containing 0 to 50 % ethyl acetate) to afford the product as a yellow solid (100 mg, 20%). NMR (400 MHz, CDCI3) 9.63, 9.52 (2xbs, 1 H), 6.68 (bs, 1 H) 2.05 (s, 3H) 2.03 (s, 3H), 1.30 (s, 9H).

Reference： [1]Patent: WO2016/71360,2016,A1 .Location in patent: Page/Page column 44

59
[ 766-39-2 ]
[ 4282-29-5 ]

Reference： [1]Tetrahedron Letters,2016,vol. 57,p. 2608 - 2611

60
[ 766-39-2 ]
[ 126-58-9 ]
C₄₆H₅₈O₂₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methoxy-phenol; In acetonitrile; for 6.5h;Reflux; Inert atmosphere;	In a 1 L flask with a condenser and a mechanical stirrer were added 1 mole of p-hydroxyanisole, 1.0 mole of dipentaerythritol, 6.0 mole of 2,3-dimethylmaleic anhydride and 300 grams of acetonitrile and the mixture was heated to reflux under nitrogen, after about 30 minutes, a light yellow clear liquid was obtained. The reaction temperature was maintained for 6 hours and then cooled to room temperature.

Reference： [1]Patent: CN105753694,2016,A .Location in patent: Paragraph 0042; 0043

61
[ 766-39-2 ]
[ 93102-05-7 ]
(3aR,6aS)-5-benzyl-3a,6a-dimethyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;	Step 1. Preparation of (3aR,6aS)-5-Benzyl-3a,6a-dimethyltetrahydro-lH-furo[3,4- c]pyrrole-l,3(3aH)-dione 123 To a cooled solution (0C) of 3,4-dimethylfuran-2,5-dione (3 g, 24 mmol) and N-benzyl- l-methoxy-N-((trimethylsilyl)methyl)methanamine (7 g, 29.8 mmol) in dichloromethane (75 mL) was slowly added trifluoroacetic acid (75 mu,). Stir overnight allowing the solution to slowly warm to room temperature as the ice bath melted. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (2 x l OOmL), dried on magnesium sulfate, filtered and concentrated to dryness. Purification by column chromatography on silica gel (gradient: 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded (3aR,6aS)-5-Benzyl-3a,6a-dimethyltetrahydro-lH-furo[3,4-c]pyrrole-l,3(3aH)- dione as a yellow oil (3.5 g, 56%).
56%	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;	To a cooled solution (0C) of 3,4-dimethylfuran-2,5-dione (3 g, 24 mmol) and N- benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (7 g, 29.8 mmol) in dichloromethane (75 mL) was slowly added trifluoroacetic acid (75 mu.). Stir overnight allowing the solution to slowly warm to room temperature as the ice bath melted. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (2 x lOOmL), dried on magnesium sulfate, filtered and concentrated to dryness. Purification by column chromatography on silica gel (gradient: 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded racemic (cis) 5-Benzyl-3a,6a- dimethyltetrahydro-lH-furo[3,4-c]pyrrole-l,3(3aH)-dione as a yellow oil (3.5 g, 56%).
56%	With trifluoroacetic acid; In dichloromethane; at 0 - 20℃;Cooling with ice;	To a cooled solution (0C) of 3,4-dimethylfuran-2,5-dione (3 g, 24 mmol) and N-benzyl- l-methoxy-N-((trimethylsilyl)methyl)methanamine (7 g, 29.8 mmol) in dichloromethane (75 mL) was slowly added trifluoroacetic acid (75 mu,). Stir overnight allowing the solution to slowly warm to room temperature as the ice bath melted. The reaction mixture was concentrated to dryness, dissolved in ethyl acetate (100 mL), washed with saturated sodium bicarbonate (2 x lOOmL), dried on magnesium sulfate, filtered and concentrated to dryness. Purification by column chromatography on silica gel (gradient: 20% ethyl acetate in hexanes to 100% ethyl acetate) afforded (3aR,6aS)-5-Benzyl-3a,6a-dimethyltetrahydro-lH-furo[3,4-c]pyrrole- l,3(3aH)-dione as a yellow oil (3.5 g, 56%)

With trifluoroacetic acid; In dichloromethane; at 25℃; for 3h;Inert atmosphere;

General procedure: To a solution of 15 (1.02 mol) in CH2Cl2 (700 mL), N-(methoxymethyl)-N-[(trimethylsilyl)methyl]benzylamine (16, 244 g, 1.03 mol) was added. To the resulting mixture, a solution of TFA (11.6 g, 0.102 mol) in CH2Cl2 (20 mL) was added dropwise at 25 C under an inert atmosphere. The mixture was stirred for 3 h, washed with H2O (400 mL) and brine (400 mL), dried (Na2SO4), and evaporated under reduced pressure to give adduct 17, which was used in the next step without purification.

Reference： [1]Patent: WO2020/93053,2020,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2020/93061,2020,A1 .Location in patent: Page/Page column 204
[3]Patent: WO2017/177326,2017,A1 .Location in patent: Page/Page column 91
[4]Patent: WO2018/191278,2018,A2 .Location in patent: Page/Page column 117; 118
[5]Patent: WO2019/51257,2019,A2 .Location in patent: Page/Page column 197-198; 258; 265
[6]Synthesis,2017,vol. 49,p. 3112 - 3117

62
[ 766-39-2 ]
[ 104-86-9 ]
N-4-chlorobenzyl-2,3-dimethylmaleimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.5%		Weigh 0.6mmol 2,3- dimethyl maleic anhydride to a three neck round bottom flask, and dissolved in 10ml of acetone, 0.5mmol 4-chloro-benzylamine were dissolved by constant pressure funnel was slowly added dropwise 10ml of acetone three flask, with magnetic stirring, at room temperature IH reaction, solvent acetone was removed by rotary evaporation, 15ml of toluene as a solvent instead, 0.02g of anhydrous sodium acetate were added to the reaction system, 0.2ml of triethylamine, 0.05 g of hydroquinone , 115 deg.] C was slowly warmed to reflux for 2.5h, the reaction is tracked by thin layer chromatography on silica gel.After the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, to obtain a concentrate, the concentrate was subjected to silica gel column chromatography (eluent: VPetroleum ether: VEthyl acetate= 12: 1), and collecting the target fluid, the rotation solvent in vacuo to give the desired product.Yield 70.5.

Reference： [1]Patent: CN107162950,2017,A .Location in patent: Paragraph 0047-0049

63
[ 766-39-2 ]
[ 6298-96-0 ]
N-(1-(4-methoxyphenyl))-2,3-dimethylethylmaleimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.5%		Weigh 0.6mmol 2,3- dimethyl maleic anhydride to a three neck round bottom flask, dissolved in 4ml acetone was 0.66mmol of (R) - (+) - 1- (4- methoxyphenoxy) ethylamine 4ml acetone was dissolved by constant pressure funnel was slowly added dropwise three-necked flask, with magnetic stirring, at room temperature IH after the reaction, the acetone solvent was removed by rotary evaporation, use 5ml of toluene as a solvent, were added to the reaction system over anhydrous 0.006g sodium acetate, 0.2ml of triethylamine, 0.012 g of hydroquinone, 115 deg.] C was slowly warmed to reflux for 2.5h, the reaction is tracked by thin layer chromatography on silica gel.After the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, to obtain a concentrate, the concentrate was subjected to silica gel column chromatography (eluent: VPetroleum ether: VEthyl acetate= 12: 1), and collecting the target fluid, the rotation solvent in vacuo to give the desired product.Yield 62.5%.

Reference： [1]Patent: CN107162950,2017,A .Location in patent: Paragraph 0083-0085

64
[ 766-39-2 ]
[ 156-87-6 ]
[ 34321-83-0 ]

Yield	Reaction Conditions	Operation in experiment
20%		Weigh 0.6mmol 2,3- dimethyl maleic anhydride to a three neck round bottom flask, and dissolved in 10ml of acetone, 0.5mmol the propanolamine is dissolved by acetone 10ml was slowly dropped into a constant pressure funnel neck flask , magnetic stirring, at room temperature IH after the reaction, the acetone solvent was removed by rotary evaporation, 15ml of toluene as a solvent instead, 0.02g of anhydrous sodium acetate were added to the reaction system, 0.2ml of triethylamine, 0.05 g of hydroquinone was slowly 115 deg.] C the reaction was warmed to reflux for 2.5h, the reaction is tracked by thin layer chromatography on silica gel.After the reaction was cooled to room temperature, the solvent was removed by rotary evaporation, to obtain a concentrate, the concentrate was subjected to silica gel column chromatography (eluent: VPetroleum ether: VEthyl acetate= 12: 1), and collecting the target fluid, the rotation solvent in vacuo to give the desired product.Yield 20%.

Reference： [1]Patent: CN107162950,2017,A .Location in patent: Paragraph 0115-0117

65
[ 766-39-2 ]
[ 85030-56-4 ]
[ 488-21-1 ]
C₁₅H₂₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 °C 2: water / aq. phosphate buffer / 37 °C / pH 7.4

Reference： [1]Su, Shan; Du, Fu-Sheng; Li, Zi-Chen [Organic and Biomolecular Chemistry, 2017, vol. 15, # 39, p. 8384 - 8392]

66
[ 766-39-2 ]
[ 85030-56-4 ]
C₁₅H₂₆NO₇^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	Stage #1: 2,3-Dimethylmaleic anhydride; 3,6,9,12-tetraoxa-tridecylamine With triethylamine In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: With sodium hydrogencarbonate

Reference： [1]Su, Shan; Du, Fu-Sheng; Li, Zi-Chen [Organic and Biomolecular Chemistry, 2017, vol. 15, # 39, p. 8384 - 8392]

67
C₁₅H₂₆NO₇^(1-)*Na⁽¹⁺⁾ [ No CAS ]
[ 766-39-2 ]
[ 85030-56-4 ]

Yield	Reaction Conditions	Operation in experiment
	With water In aq. phosphate buffer at 37℃;

Reference： [1]Su, Shan; Du, Fu-Sheng; Li, Zi-Chen [Organic and Biomolecular Chemistry, 2017, vol. 15, # 39, p. 8384 - 8392]

68
[ 766-39-2 ]
C₇H₁₅NO₄ [ No CAS ]
C₁₃H₁₉NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.6%		Weigh Jinggangmycin 0.176g (1mmol) was added to a round bottom flask, was added 16ml 0.26mol / L sodium methoxide in methanol, stirred at 30 for 20min, weighed 0.264g (2.0mmol)3,4-dimethyl maleic anhydride was added to a round bottom flask, the reaction was stirred at 30 C for 1 h,Then add 340muL triethylamine, the reaction 20min, the system was heated to 60 C to continue the reaction 2h,After the reaction was completed, the mixture was cooled to room temperature and distilled under reduced pressure to obtain a yellow oily concentrate. The concentrate was separated on a 200-mesh silica gel column and the mobile phase wasV n-propanol: V acetic acid: V water = 6: 1: 1, collecting the target solution was concentrated to give the product as a light yellow oil.The resulting product was confirmed by 1H NMR and MS spectral analyzes to be N-quincloram-3,4-dimethyl N-substituted maleimide (I-9)

Reference： [1]Patent: CN107033060,2017,A .Location in patent: Paragraph 0064-0067

69
[ 766-39-2 ]
valienamine [ No CAS ]
C₁₃H₁₇NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.3%		Weigh Jinggangmycin 0.175g (1mmol) was added to a round bottom flask, 6ml 0.26mol / L sodium methoxide in methanol was added, the reaction was stirred at 30 for 20min, the amount of 0.1512g (1.2mmol)3,4-dimethyl maleic anhydride was added into a round-bottomed flask, stirred at 30 C for 1 h, and then added with 150 muL triethylamine. After the reaction for 20 min, the system was heated to 60 C. to continue the reaction for 2 h.After the reaction was completed, the solution was cooled to room temperature and distilled under reduced pressure to obtain a yellow oily concentrate. The concentrate was separated on a 200-mesh silica gel column and the mobile phase was positiveV n-propanol: V acetic acid: V water = 6: 1: 1, collecting the target solution was concentrated to give the product as a light yellow oil.The resulting product was confirmed by 1H NMR and MS spectral analyzes as N-Jinggangmycin-3,4-dimethyl N-substituted maleimide (I-10)

Reference： [1]Patent: CN107033060,2017,A .Location in patent: Paragraph 0068-0071

70
[ 766-39-2 ]
jinggangmycin amine [ No CAS ]
C₁₃H₁₉NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53.3%		Weigh Jinggangmycin amine 0.193g (1mmol) was added to a round bottom flask, was added 6ml 0.26mol / L sodium methoxide in methanol, stirred at 30 for 20min, the amount of 0.1512g (1.2mmol)3,4-dimethyl maleic anhydride was added into a round-bottomed flask, the reaction was stirred at 30 C for 1 h, and then 150 muL of triethylamine was added. After the reaction was completed for 20 min, the system was heated to 60 C. to continue the reaction for 2 h.After the reaction was completed, the solution was cooled to room temperature and distilled under reduced pressure to obtain a yellow oily concentrate. The concentrate was separated on a 200-mesh silica gel column and the mobile phase was positiveV n-propanol: V acetic acid: V water = 6: 1: 1, collecting the target solution was concentrated to give the product as a light yellow oil.The resulting product was confirmed by 1H NMR and MS spectral analyzes to be N-wellmandecanol-3,4-dimethyl N-substituted maleimide (I-11)

Reference： [1]Patent: CN107033060,2017,A .Location in patent: Paragraph 0072-0075

71
[ 766-39-2 ]
C₆H₁₃NO₅ [ No CAS ]
C₁₂H₁₇NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.3%		Weigh 0.179g (1mmol) of glucosamine into a round bottom flask, add 6ml 0.26mol / L sodium methoxide in methanol, and stir for 30min, then take 0.179g (1.0mmol)3,4-dimethyl maleic anhydride was added into a round-bottomed flask, the reaction was stirred at 30 C for 1h, then added 170muL triethylamine, the reaction 20min, the system was heated to 60 C to continue the reaction 2h,After the reaction was completed, the solution was cooled to room temperature and distilled under reduced pressure to obtain a yellow oily concentrate. The concentrate was separated on a 200-mesh silica gel column and the mobile phase was positiveV n-propanol: V acetic acid: V water = 6: 1: 1, collecting the target solution was concentrated to give the product as a light yellow oil.The resulting product was confirmed by 1H NMR and MS spectral analyzes to be N-glucosamine-3,4-dimethyl N-substituted maleimide (I-12),

Reference： [1]Patent: CN107033060,2017,A .Location in patent: Paragraph 0076-0079

72
[ 766-39-2 ]
[ 20781-20-8 ]
1-((2,4-dimethoxyphenyl)methyl)-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	In tetrahydrofuran; at 0℃; for 2h;Reflux;	To a solution of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (126 mg, 1.0 mmol, 1.0 eq) in tetrahydrofuran (10 mL) was added 2,4-dimethoxybenzylamine (0.15 mL, 1.0 mmol, 1.0 eq) at 0 C. The reaction mixture was refluxed for 2 h until the starting material was completely consumed and then concentrated in vacuo. The residue was purified by flash column chromatography over silica gel (hexane/ethyl acetate, 10: 1, v/v) to afford the desired product IRES-J004 (153 mg, 56%) as a white powder: Rf = 0.3 (hexane/ethyl acetate, 5: 1, v/v); mp 105-107 C; NMR (CDC13, 500 MHz) delta 7.08 (d, J= 8.0 Hz, 1H), 6.41 (bs, 1H), 6.40 (dd, J= 8.0, 2.0 Hz, 1H), 4.62 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 1.95 (s, 6H) ppm; 13C NMR (CDCI3, 125 MHz) delta 172.0, 160.4, 158.1, 137.1, 129.8, 117.2, 103.9, 98.5, 55.5, 55.4, 36.3, 8.7 ppm; HRMS-ESI (m/z): [M+H]+ calcd for C15H18N04 276.12358; found, 276.12216.

Reference： [1]Patent: WO2017/192665,2017,A1 .Location in patent: Page/Page column 38; 40; 41

73
[ 766-39-2 ]
[ 912368-73-1 ]
(S)-tert-butyl 3-(3,4-dimethyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6 g	With triethylamine; In toluene; at 20℃; for 16h;Reflux;	To a stirred solution of (S)-tert-butyl 3-(methylamino)piperidine- 1 -carboxylate (5 g, 25 mmol) in toluene (150 ml) was added triethylamine (5.42 ml, 37.5 mmol) followed by 3,4- dimethylfuran-2,5-dione (3.15 g, 2Smmol) at RT and the resulting reaction mixture was heated at reflux temperature for 16 h. The reaction mixture was cooled to RT and dilutedwith EtOAc and washed with water. The organic layer was dried and evaporated. The crude product was purified by flash chromatography to obtain 6.0 g of the product.?H NMR (300 MHz, CDC13) oe ppm 1.45 (s, 9H), 1.65- 1.83 (m, 2H), 1.95 (s, 6H), 2.05 - 2.29 (m, 2H), 2.60 - 2.75 (m, 1H), 3.22-3.35 (m, 1H), 3.92 - 4.10 (m, 3H).

Reference： [1]Patent: WO2018/2437,2018,A1 .Location in patent: Page/Page column 29

74
[ 766-39-2 ]
[ 912368-73-1 ]
(3S)-tert-butyl 3-((3R,4R)-dimethyl-2,5-dioxopyrrolidin-1-yl)piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2018/2437,2018,A1

75
[ 766-39-2 ]
[ 17680-04-5 ]
5-(benzo[d][1,3]dioxol-5-yl)-5-hydroxy-3,4-dimethylfuran-2(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	In tetrahydrofuran; at 0℃; for 3h;	To a solution of <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (11, 3.03?g, 23.8?mmol) in THF (240?mL) was added 3,4-methylenedioxy phenyl magnesium bromide (48.1?mL, 0.5?M solution in THF) at 0?C. After being stirred for 3?h, the reaction was quenched with saturated NH4Cl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by recrystallization (hexane/EtOAc) to afford 13 (5.90?g, quant.) as a colorless amorphous. 1H NMR (300?MHz, CDCl3) delta 6.97 (1H, dd, J?=?8.1, 1.8?Hz), 6.89 (1H, d, J?=?1.8?Hz), 6.79 (1H, d, J?=?8.1?Hz), 5.98 (2H, s), 1.86 (6H, s). 13C NMR (75?MHz, CDCl3) delta 173.4, 159.8, 148.3, 147.9, 130.7, 123.7, 119.6, 108.2, 106.3, 106.0, 101.4, 10.7, 8.5. IR (ATR) 3334, 1739, 1504, 1491, 1246, 1038?cm-1. HRMS (EI) m/z: calcd. for C13H12O5 [M]+ 248.0685, found 248.0685.

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 148,p. 86 - 94

76
[ 766-39-2 ]
C₂₅H₂₈Cl₉NO₁₈S₃ [ No CAS ]
C₃₁H₃₂Cl₉NO₂₀S₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With triethylamine; In dichloromethane; for 72h;Reflux;	Compound (4-1) (3.916 g) was dissolved in dichloromethane (20 ml), maleic anhydride (708.5 mg) and triethylamine (1.0 ml) were added and the mixture was heated under reflux for 3 days. The precipitated target substance was dissolved with dichloromethane, washed with 1N hydrochloric acid, and the aqueous hydrochloric acid used for washing was extracted with dichloromethane. The obtained organic layer was washed successively with sodium bicarbonate water and saturated brine, and dried over magnesium sulfate. The organic layer was filtered and the filtrate was concentrated. The residue was dissolved in chloroform (40 ml), hexane (120 ml) was added dropwise over 20 minutes, and crystallization was carried out at room temperature. The crystals were collected by filtration and washed with chloroform / hexane (1/3 (v / v)) to obtain compound (5-2) (2.86 g, yield 66%).

Reference： [1]Patent: JP6273199,2018,B2 .Location in patent: Paragraph 0264; 0265; 0266

77
[ 766-39-2 ]
[ 4227-95-6 ]
5-hydroxy-3,4-dimethyl-5-(methyl-<SUP>13</SUP>C)furan-2(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%		Lithium (0.5 g, 72.00 mmol) was stirred and heated to 210 C in silicone oil under an argon atmosphere until it melted and very small particles were formed. The mixture was allowed to cool slowly under vigorous stirring and then the oil was removed by a syringe and the lithium particles were washed with anhydrous Et2O (5 9 10 cm3). The lithium was suspended in 4 cm3 Et2O and a solution of 1.0 g 13CH3I (7.05 mmol) in 2 cm3 Et2O was added dropwise. The reaction mixture was left to boil spontaneously, after which it was stirred for further 30 min at 45 C. After cooling, the solution was filtered and used for the alkylation step. A solution of 630.0 mg 3 (5.00 mmol) in 20 cm3 anhydrous Et2O under an argon atmosphere was cooled to - 70 C. Subsequently, the above solution of 13CH3Li was added dropwise, the mixture was stirred for 15 min and quenched with 20 cm3 saturated aqueous solution of NH4Cl. The mixture was extracted with AcOEt (3 9 30 cm3) and the combined organic fraction was dried with MgSO4. The solvent was removed in vacuo. Purification by column chromatography (SiO2, 30% AcOEt in petroleum ether) afforded pure 4 (384 mg, 54%) as a white solid. TLC: Rf = 0.22 (30% AcOEt in petroleum ether); 1HNMR (400 MHz, acetone-d6): d = 6.03 (d, J = 5.2 Hz,1H), 1.97 (q, J = 1.2 Hz, 3H), 1.72 (q, J = 1.2 Hz, 3H),1.55 (d, J = 128.3 Hz, 3H) ppm; 13C NMR (100 MHz,acetone-d6): d = 172.00 ([C), 159.45 (d, J = 1.9 Hz,[C), 124.24 ([C), 106.01 (d, J = 45.7 Hz, [C),23.92 (CH3), 10.45 (CH3), 8.37 (CH3) ppm; MS (EI): m/z(%) = 143.0 ([M?], 3), 127.1 (100), 115.1 (10), 99.1 (87),83.1 (16), 54.1 (53), 44.1 (61).

Reference： [1]Monatshefte fur Chemie,2018,vol. 149,p. 1475 - 1480

78
[ 766-39-2 ]
[ 487-66-1 ]

Reference： [1]Patent: US2008/275057,2008,A1

79
[ 766-39-2 ]
[ 93-14-1 ]
C₂₂H₂₆O₁₀ [ No CAS ]

Reference： [1]Chemical Biology and Drug Design,2019,vol. 93,p. 262 - 271

80
[ 766-39-2 ]
[ 106797-53-9 ]
[ 121-44-8 ]
C₁₈H₂₂O₇*C₆H₁₅N [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The structural formula of compound 4 is:2-Hydroxy-1-(4-(2-hydroxyethoxy)phenyl)-2-methylacetone (Darocur 2959) (33.69 g,0.15 mol), 2,3-dimethylmaleic anhydride (12.61 g, 0.1 mol), catalyst anhydrous AlCl3 (10.67, 0.08 mol) and 100 ml of toluene solution were added to 250 ml equipped with mechanical stirring and constant pressure dropping funnel. The mixture was stirred at 90 C for 60 min in a three-necked flask.After the reaction is completed, the solid impurities are removed by filtration, washed with water, separated by liquid three times to remove the aqueous phase, and the toluene is removed by rotary evaporation, and finally the solvent and water are removed by vacuum drying to obtain an intermediate product A;Intermediate product A and triethylamine (10.22 g, 0.1 mol) dissolved in 60 ml of pyridineAdd to a 250 ml three-necked flask equipped with a mechanical stirrer and a constant pressure dropping funnel.Stir at room temperature for 16 h.After completion of the reaction, it was washed three times with hydrochloric acid or ethyl acetate, and the solvent was removed by rotary evaporation, and further purified by a gel column to obtain a pure product 4, which was subjected to structural identification by nuclear magnetic resonance spectroscopy.

Reference： [1]Patent: CN109384670,2019,A .Location in patent: Paragraph 0037-0041

81
[ 766-39-2 ]
[ 108-91-8 ]
1-cyclohexyl-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	In tetrahydrofuran; at 55℃;Sealed tube; Inert atmosphere;	2,3-dimethyl maleic anhydride (500 mg, 3.97mmol) and cyclohexylamine (0.45mL, 4.00mmol) in 3 mL of anhydrous THF were heated in a sealed ampoule at 55C overnight. Solvent was removed under vacuum and silica gel column chromatography (30% ethyl acetate in petroleum ether) afforded pure product I as a white solid (581 mg, 71%).

Reference： [1]Phytochemistry,2019,vol. 163,p. 187 - 194

82
[ 766-39-2 ]
3-amino-5-cyclopropyl-4-methyl-4H-1,2,4-triazole [ No CAS ]
1-(5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With pyridine; triethylamine; In acetonitrile; for 6h;Reflux;	3,4-Dimethylfuran-2,5-dione (1000 mg, 7.93 mmol, 1.05 equiv) and 3-amino-5-cyclopropyl-4-methyl-4H-1,2,4-triazole (2009 mg, 7.55 mmol, 1.0 equiv) were dissolved in abs. acetonitrile (10 ml), pyridine (0.24 ml, 3.02 mmol, 0.4 equiv) and triethylamine (1.05 ml, 7.55 mmol, 1.0 equiv) were added and the mixture was stirred under reflux conditions for 6 h. After cooling to room temperature, water and, carefully, sat. sodium bicarbonate solution and ethyl acetate were added and the reaction mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 1-(5-cyclopropyl-4-methyl-4H-1,2,4-triazol-3-yl)-3,4-dimethyl-1H-pyrrole-2,5-dione in the form of a colorless solid (1530 mg, 82% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 3.50 (s, 3H), 2.08 (s, 6H), 1.79-1.75 (m, 1H), 1.21-1.18 (m, 2H), 1.09-1.04 (m, 2H).

Reference： [1]Patent: US2019/330192,2019,A1 .Location in patent: Paragraph 0198-0199

83
[ 766-39-2 ]
[ 49607-51-4 ]
3,4-dimethyl 1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	With acetic acid; for 7h;Reflux;	3,4-Dimethylfuran-2,5-dione (550 mg, 4.36 mmol, 1.05 equiv) and <strong>[49607-51-4]1-methyl-1H-1,2,4-triazole-3-amine</strong> (407 mg, 4.15 mmol, 1.00 equiv) were dissolved in concentrated acetic acid (15 ml) and stirred under reflux conditions for 7 h. After cooling to room temperature, water and ethyl acetate were added and the mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 3,4-dimethyl 1-(1-methyl-1H-1,2,4-triazol-3-yl)-1H-pyrrole-2,5-dione in the form of a colorless solid (90 mg, 10% of theory). 1H-NMR (400 MHz, d6-DMSO delta, ppm) 8.09 (s, 1H), 3.75 (s, 3H), 2.01 (s, 6H).

Reference： [1]Patent: US2019/330192,2019,A1 .Location in patent: Paragraph 0200-0201

84
[ 766-39-2 ]
[ 16681-76-8 ]
1-(1-methyl-1H-1,2,4-triazol-5-yl)-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyridine; triethylamine; In acetonitrile; for 6h;Reflux;	3,4-Dimethylfuran-2,5-dione (1500 mg, 11.89 mmol, 1.0 equiv) and 1-methyl-1H-1,2,4-triazole-5-amine (1228 mg, 11.89 mmol, 1.0 equiv) were dissolved in abs. acetonitrile (15 ml), pyridine (0.39 ml, 4.76 mmol, 0.4 equiv) and triethylamine (1.0 equiv) were added and the mixture was stirred under reflux conditions for 6 h. After cooling to room temperature, water and, carefully, sat. sodium bicarbonate solution and ethyl acetate were added and the reaction mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 1-(1-methyl-1H-1,2,4-triazol-5-yl)-3,4-dimethyl-1H-pyrrole-2,5-dione in the form of a colorless solid (1430 mg, 58% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 7.95 (s, 1H), 3.79 (s, 3H), 2.09 (s, 6H).

Reference： [1]Patent: US2019/330192,2019,A1 .Location in patent: Paragraph 0194-0195

85
[ 766-39-2 ]
[ 53132-83-5 ]
C₁₀H₁₂N₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With pyridine; triethylamine; In acetonitrile; for 6h;Reflux;	3,4-Dimethylfuran-2,5-dione (276 mg, 2.19 mmol, 1.05 equiv) and 1,3-dimethyl-1H-1,2,4-triazole-5-amine (500 mg, 2.08 mmol, 1.0 equiv) were dissolved in abs. acetonitrile (10 ml), pyridine (0.07 ml, 0.83 mmol, 0.4 equiv) and triethylamine (0.29 ml, 2.08 mmol, 1.0 equiv) were added and the mixture was stirred under reflux conditions for 6 h. After cooling to room temperature, water and, carefully, sat. sodium bicarbonate solution and ethyl acetate were added and the reaction mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 1-(1,3-dimethyl-1H-1,2,4-triazol-5-yl)-3,4-dimethyl-1H-pyrrole-2,5-dione in the form of a colorless solid (320 mg, 70% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 3.41 (s, 3H), 2.48 (s, 3H), 2.08 (s, 6H).

Reference： [1]Patent: US2019/330192,2019,A1 .Location in patent: Paragraph 0196-0197

86
[ 766-39-2 ]
[ 106-40-1 ]
1-(4-bromophenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	In acetic acid; at 100℃; for 16h;	General procedure: A mixture of aniline GP7_1 , anhydride GP7_2 and DMSO (or AcOH) was stirred at 120 C for ~20 h. After cooling to rt, the mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgS04), filtered and concentrated in vacuo to afford maleimide GP7_3, which can be further purified by chromatography if necessary; 1-(4-Bromophenyl)-3,4-dimethyl-1 /-/-pyrrole-2, 5-dione was synthesised according to general procedures GP7 - from 4-bromoaniline (1.37 g, 7.94 mmol), 3,4-dimethylfuran-2,5- dione (1.0 g, 7.94 mmol) and AcOH (8.0 ml_); 100 C, 16 h. The crude was purified by chromatography (EtOAc/cyclohexane 0 50%) to afford a white solid (1.74 g, 79%). 1 H NMR (500 MHz, Chloroform-d) d 7.61 - 7.56 (m, 2H), 7.31 - 7.26 (m, 2H), 2.07 (s, 6H). MS (ESI) m/z 280/282 (M+H)+.

Reference： [1]Patent: WO2019/234418,2019,A1 .Location in patent: Paragraph 00437; 00495

87
[ 766-39-2 ]
[ 105297-10-7 ]
1-(4-(1,1-dioxidothiomorpholino)phenyl)-3,4-dimethyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In dimethyl sulfoxide; at 120℃; for 17h;	General procedure: A mixture of aniline GP7_1 , anhydride GP7_2 and DMSO (or AcOH) was stirred at 120 C for ~20 h. After cooling to rt, the mixture was diluted with dichloromethane and washed with water. The organic phase was dried (MgS04), filtered and concentrated in vacuo to afford maleimide GP7_3, which can be further purified by chromatography if necessary; 1-(4-(1 , 1-Dioxidothiomorpholino)phenyl)-3,4-dimethyl-1 /-/-pyrrole-2, 5-dione was synthesised according to general procedures GP7 - from <strong>[766-39-2]2,3-dimethylmaleic anhydride</strong> (3.34 g, 26.5 mmol), 4-(4-aminophenyl)-thiomorpholine 1 , 1-dioxide (3.0 g, 13.3 mmol) and DMSO (6 ml_); 120 C, 17 h. The crude residue was recrystallised from DCM and diethyl ether to afford a yellow powder (3.59 g, 81 %). 1 H NMR (CDCb, 500 MHz): 2.04 (6H, s), 3.1 1 (4H, t, J = 5.2), 3.86 (4H, t, J = 5.2 Hz), 6.98 (2H, d, J = 9.0 Hz), 7.26 (2H, d, J = 9.0 Hz); 13C NMR (CDCb, 125 MHz): 8.93, 47.78, 50.45, 1 16.71 , 124.93, 127.36, 137.47, 146.52, 171.12. HRMS (ESI +ve): found 336.1046 [M+H+]; C16H19N204S requires 336.1053.

Reference： [1]Patent: WO2019/234418,2019,A1 .Location in patent: Paragraph 00437; 00459

88
[ 766-39-2 ]
[ 32039-21-7 ]
3,4-dimethyl-1-(3-(isopropyl)-1,2,4-thiadiazol-5-yl)-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With toluene-4-sulfonic acid; In toluene; at 100℃; for 0.5h;Microwave irradiation;	3,4-Dimethyl-1-(3-(isopropyl)-1,2,4-thiadiazol-5-yl)-pyrrole-2,5-dione 3,4-Dimethylfuran-2,5-dione (300 mg, 2.38 mmol, 1.0 equiv), p-toluenesulfonic acid hydrate (6.8 mg, 0.04 mmol) and 5-amino-3-isopropyl-1,2,4-thiadiazole (341 mg, 2.38 mmol, 1.0 equiv) were dissolved in toluene (8 ml) and stirred under microwave conditions at a temperature of 100 C. for 30 minutes. After cooling to room temperature, water, sat. sodium bicarbonate solution and ethyl acetate were added and the reaction mixture was extracted. The aqueous phase was repeatedly re-extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. Final purification by column chromatography of the resulting crude product (gradient ethyl acetate/heptane) gave 3,4-dimethyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione in the form of a colorless solid (160 mg, 27% of theory). 1H-NMR (400 MHz, CDCl3 delta, ppm) 3.37-3.32 (m, 1H), 2.12 (s, 6H), 1.40 (d, 6H); 13C-NMR (150 MHz, CDCl3 delta, ppm) 178.5, 178.4, 169.5, 166.9, 139.5, 32.8, 21.4, 9.1.

Reference： [1]Patent: US2020/95241,2020,A1 .Location in patent: Paragraph 0230-0231

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P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 766-39-2 ] {[proInfo.proName]}

Quality Control of [ 766-39-2 ]

Related Doc. of [ 766-39-2 ]

Product Details of [ 766-39-2 ]

Calculated chemistry of [ 766-39-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 766-39-2 ]

Application In Synthesis of [ 766-39-2 ]

[ 766-39-2 ] Synthesis Path-Upstream 1~7

[ 766-39-2 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 766-39-2 ]

Acid Anhydrides

Esters

Related Parent Nucleus of [ 766-39-2 ]

Furans

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 766-39-2 ]

Related Parent Nucleus of
[ 766-39-2 ]