Name: 616-02-4|3-Methylfuran-2,5-dione|97%
Brand: Ambeed
SKU: A281350
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1
[ 97-65-4 ]
[ 616-02-4 ]

Yield	Reaction Conditions	Operation in experiment
99.3%	With calcium In 5,5-dimethyl-1,3-cyclohexadiene at 120℃; for 1.5h;	1 Example 1 0.1 g of calcium, 20 g of itaconic acid and 20 g of xylene were charged to a reaction flask equipped with a thermometer,Stirrer and oil-water separator reactor,Heated to 120 ° C in an oil bath and subjected to a water splitting reaction for 1.5 h at a reduced pressure of 0.1 MPa.The reaction product was distilled off at a vacuum of 500 Pa and a temperature of 100 ° C for recovery.The recovered product was added to the reactor,10 g of itaconic acid and 0.1 g of calcium were heated in an oil bath to 130 ° C.,Decompression in the vacuum degree of vacuum 0.1h reaction 0.5h. The reaction product was distilled under reduced pressure,In the vacuum 500Pa, the temperature of 75 ° C, the color of the effluent slightly pale yellow that is evaporated solvent,Recyclable to continue to use. The product was collected at 100 ° C and the resulting product was a colorless liquid product, citraconic anhydride, yield 99.3%, purity 99.8%.
94%	Stage #1: 2-methylenesuccinic acid With acetic anhydride at 80℃; Stage #2: at 230℃; for 4h;	1.2 Stage 1: Itaconic Acid Anhydride 612 g (6.0 mol) of acetic anhydride were placed in a 2-litre three-necked flask with KPG stirrer, 15-Vigreux column and column head and 780 g (6.0 mol) of solid itaconic acid was added while stirring. The mixture was then slowly heated to 80° C. until the solid was dissolved and stirred for another 30 minutes at this temperature. Subsequently, approx. 680 g acetic acid was distilled off at a vacuum between 150 and 10 mbar and a sump temperature of 80 to 82° C. The acetic acid was then removed from the sample. Approx. 690 g of sump bottom product remained, the raw yield being 680 g. The raw product was used directly in stage 2. A 5 g sample of the ester was purified by ball tube distillation and analyzed by gas chromatography and had a composition of 11 wt. % citraconic acid anhydride and 89 wt. % itaconic acid anhydride. In a 2-liter three-necked flask with KPG stirrer, 15 Vigreux column and column head, 100 g of a high-boiling solvent (Synalox 50-B) were placed in the flask and heated to 230° C. while stirring. Subsequently, 690 g of itaconic acid anhydride (crude product stage 1), dissolved in 100 g Synalox, were dosed at a vacuum of approx. 350 mbar within 4 hours. The isomerization product citraconic acid anhydride was continuously extracted with an R/D ratio of 1:1. At the end of the dosing process, the vacuum was increased to 10 mbar and a total of 630 g distillate was obtained, which corresponded to a yield of 94% over both stages. The GC purity was 99%.
92.5%	at 170 - 200℃; for 5.5h;	4 100 g of itaconic acid, and 1 g of heteropolyacid Cs4SiW12O40 were mixed and added into a 100 ml reaction bottle without a solvent. The mixture was heated at 190-200° C. for 15 min, and the itaconic acid was at a melting state. After reacting for 30 min, the reaction temperature was reduced to 170° C. and reduced pressure distillation was simultaneously performed with aforementioned reaction to remove the water byproduct with a pressure of 50-100 torr. After reacting further for 5 hrs, the yield of the citraconic anhydride was measured by gas chromatography and was 92.5%. After isolating the citraconic anhydride, 50 ml of ethyl acetate was added into the residual reaction solution to separate the heteropolyacid or heteropolyacid salt catalyst via sedimentation. After filtering, the collected solid was dried to recycle the catalyst Cs4SiW12O40. The ratio between reactants and the reaction conditions are shown in Table 2.

88%	With N,N,N,N,-tetramethylethylenediamine at 175℃;	2 Example 2: Into a 250 ml three-necked flask was sequentially added itaconic acid 260 g (2 mol) and tetramethylethylenediamine 6.5 g (2.5% wt).The oil bath is heated to 175°C and gradually melted with itaconic acid.Atmospheric distillation removes the water produced by the reaction.Continue to react until no more water has evaporated and stop the reaction.Lower the reaction temperature to around 130°C,The device was changed to vacuum distillation.The pale yellow oily liquid was 197.1 g of 2-methylmaleic anhydride with a yield of 88%.Purity up to 99.5% by gas phase detection.
	durch Destillation;
	bzw. Reaktion des Anhydrids bei der Destillation;
	Multi-step reaction with 2 steps 1: acetyl chloride / toluene / Heating 2: N,N-dimethylaniline / CHCl₃ / 21 °C / var. amines, var. amine conc., other solvent
	Multi-step reaction with 2 steps 1: water / 180 - 200 °C
	Multi-step reaction with 2 steps 1: Citraconsaeureanhydrid entsteht bei der Destillation 2: durch Destillation
	Multi-step reaction with 2 steps 1: acetyl chloride 2: bei der Destillation
	durch Destillation;
345 g	With disodium hydrogenphosphate In dimethyl sulfoxide at 180℃;	1 1) In a 1000 ml three-necked flask equipped with a water separator, a condenser and a mechanical stirrer, 500 g of itaconic acid, 450ml dimethyl sulfoxide, catalyst 10 grams of disodium hydrogen phosphate, stirring and mixing, the rapid temperature rise to 180 ° C insulation reaction 1 ~ 2h, so that Itaconic acid becomes a clear and transparent solution and is cyclized under the catalysis of disodium hydrogen phosphate to give a mixture of 2-methylmaleic anhydride Liquid, the solvent was removed and dehydrated to give 345 g of liquid 2-methylmaleic anhydride. The process of removing the solvent and dehydrating is: the water in the mixture containing 2-methylmaleic anhydride is roughly separated by a water separator Min, and then in the three bottles and then add 150ml xylene, mixed with the crude water mixture, further water (due to xylene Of the density is smaller than the water, while not soluble in water, but can be close to the density and water and water can be miscible dimethyl Sulfone is miscible and floated over water for further dewatering), and then the further separated mixture is cooled to 100 ° C, distillation under reduced pressure, distillation of xylene, dimethyl sulfoxide and other solvents, and then vacuum To 20 Pa and distilled to give 345 g of 2-methylmaleic anhydride.
170 g	With 1,2,4-Trimethylbenzene; pyridinium p-toluenesulfonate at 140℃; for 3h;	1.1; 2.1; 3.1; 4.1; 5.1; 6.1 1. In a 1000ml four-necked flask connected with a water separator, a condenser, a thermometer and a stirrer, add 200g of itaconic acid, 600g of 1,2,4-trimethylbenzene solvent, and 20g of p-toluenesulfonic acid pyridinium salt catalyst. Stir and mix The temperature was quickly raised to 140 ° C, and the reaction was maintained for about 3 hours. During the period, the dehydrated water was continuously taken out by 1,2,4-trimethylbenzene. After reaching the theoretical water output of 27.5g, the heating was stopped to obtain citraconic anhydride, 1,2,4- Mixed solution of xylene and catalyst. Continue heating the mixed solution in the three-necked flask to 180 ° C., and distill off 1,2,4-trimethylbenzene under normal pressure. After cooling to room temperature, the pyridinium p-toluenesulfonate catalyst was removed by filtration to obtain 170 g of citraconic anhydride.

Reference： [1]Current Patent Assignee: SHANDONG STAIR CHEMICAL & TECHNOLOGY CO LTD - CN106831670, 2017, A Location in patent: Paragraph 0015; 0016; 0017; 0018; 0019; 0020; 0021
[2]Current Patent Assignee: SYMRISE AG - US2020/10402, 2020, A1 Location in patent: Paragraph 0317-0321; 0335-0339
[3]Current Patent Assignee: INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE - US2011/160466, 2011, A1 Location in patent: Page/Page column 3
[4]Current Patent Assignee: LANXI BAIGAO CHEMICAL; ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN105017186, 2018, B Location in patent: Paragraph 0013; 0014; 0015; 0016; 0017; 0018; 0019; 0020
[5]Anschuetz; Petri [Chemische Berichte, 1880, vol. 13, p. 1540] Crasso [Justus Liebigs Annalen der Chemie, 1840, vol. 34, p. 70] Fittig [Justus Liebigs Annalen der Chemie, 1899, vol. 304, p. 136,138][Justus Liebigs Annalen der Chemie, 1904, vol. 330, p. 296,298]
[6]Anschuetz; Petri [Chemische Berichte, 1880, vol. 13, p. 1540] Crasso [Justus Liebigs Annalen der Chemie, 1840, vol. 34, p. 70] Fittig [Justus Liebigs Annalen der Chemie, 1899, vol. 304, p. 136,138][Justus Liebigs Annalen der Chemie, 1904, vol. 330, p. 296,298]
[7]Galanti, Michele C.; Galanti, Anthony V. [Journal of Organic Chemistry, 1982, vol. 47, # 8, p. 1572 - 1574]
[8]Swarts [Jahresbericht ueber die Fortschritte der Chemie und Verwandter Theile Anderer Wissenschaften, 1873, p. 579]
[9]Crasso [Justus Liebigs Annalen der Chemie, 1840, vol. 34, p. 70]
[10]Anschuetz; Petri [Chemische Berichte, 1880, vol. 13, p. 1540]
[11]Fittig [Organic Syntheses, Vol. XI <New York 1931>, S. 28]
[12]Current Patent Assignee: WUHAN JINGHE CHEMICAL - CN103739539, 2016, B Location in patent: Paragraph 0015; 0016; 0017; 0018; 0019
[13]Current Patent Assignee: SHANDONG YANGGU HUATAI CHEMICAL COMPANY LIMITED; SHANDONG DEREK NEW MAT - CN110845387, 2020, A Location in patent: Paragraph 0025; 0028; 0031; 0034; 0037; 0040;

2
[ 616-02-4 ]
[ 123-30-8 ]
[ 129698-36-8 ]

Yield	Reaction Conditions	Operation in experiment
58.5%	Stage #1: citraconic acid anhydride; 4-amino-phenol In acetone at 20℃; for 1h; Stage #2: With sodium acetate; triethylamine; hydroquinone In toluene at 115℃; for 2.5h;	8 Synthesis of N-4- hydroxy-3-methyl maleimide 0.6mmol citraconic anhydride was weighed into three neck round bottom flask, 10ml of acetone was dissolved, 0.5mmol aminophenol dissolved by constant pressure funnel was slowly added dropwise three-necked flask, with magnetic stirring, at room temperature for 1h the reaction 10ml of acetone after 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, 115 deg.] C was slowly warmed to reflux for 2.5h during the reaction by thin layer chromatography silica gel plate track.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 58.5%.
	at 150℃;
10.77 g	With triethylamine In tetrahydrofuran at 25 - 60℃; for 8h;	2 Preparation Example 2 It is used to explain the monomer compound M2 provided by the present invention and the preparation method thereof. Add p-hydroxyaniline (10.9124g, 100mmol) to the dry three-necked flask, then add 250mL of anhydrous THF to dissolve, then add triethylamine (11.1301g, 110mmol), adjust the pH value to 9.5, stir and dissolve at room temperature 25 , The whole system was heated to 60 , methyl maleic anhydride (12.3288g, 110mmol) was slowly added dropwise, while keeping the temperature unchanged. After the completion of the dropwise addition, heating was continued, and the reaction was continued for 8 hours. After the completion of the reaction, the temperature was naturally lowered to room temperature 25 ° C. Water (100 mL) was added dropwise to quench the reaction system, after which the reaction product was extracted with ether (75 mL × 3), and the organic phase was dried with Na2SO4 After concentration, the solvent was removed and recrystallization was carried out (the recrystallization solvent was a mixture obtained by mixing n-hexane and dichloromethane in a volume ratio of 4: 1) to obtain N-(p-hydroxyphenyl)-3-methylmaleimide(10.7691g, 53mmol) as a white solid.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107162950, 2017, A Location in patent: Paragraph 0059-0061
[2]Piutti [Gazzetta Chimica Italiana, 1910, vol. 40 I, p. 528] Piutti [Gazzetta Chimica Italiana, 1906, vol. 36, p. II 365][Gazzetta Chimica Italiana, 1910, vol. 40 I, p. 542]
[3]Current Patent Assignee: CHINA PETROCHEMICAL CORPORATION - CN110938026, 2020, A Location in patent: Paragraph 0095; 0096; 0097; 0100; 0101

3
[ 616-02-4 ]
[ 62-53-3 ]
[ 3120-04-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With acetic acid Reflux;
85%	With acetic acid at 90℃; for 2h;
77%	With acetic acid at 120℃; Inert atmosphere;

77%	With acetic acid Reflux; Inert atmosphere;
41%	Stage #1: citraconic acid anhydride; aniline In diethyl ether at 20℃; for 1h; Stage #2: With sodium acetate; acetic anhydride for 3h; Reflux;
37%	Stage #1: citraconic acid anhydride; aniline In diethyl ether at 20℃; Stage #2: With sodium acetate; acetic anhydride for 0.5h; Heating;
	In acetic acid for 2h; Heating;
	Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / Reflux 2: triethylamine; thionyl chloride / tetrahydrofuran / 6 h / Reflux

Reference： [1]Xu, Wen-Lei; Tang, Lei; Ge, Chen-Yu; Chen, Jie; Zhou, Ling [Advanced Synthesis and Catalysis, 2019, vol. 361, # 10, p. 2268 - 2273]
[2]Choi, Dong-Sook; Huang, Shenlin; Huang, Mingsheng; Barnard, Thomas S.; Adams, Richard D.; Seminario, Jorge M.; Tour, James M. [Journal of Organic Chemistry, 1998, vol. 63, # 8, p. 2646 - 2655]
[3]Yuan, Yu-Chao; Kamaraj, Raghu; Bruneau, Christian; Labasque, Thierry; Roisnel, Thierry; Gramage-Doria, Rafael [Organic Letters, 2017, vol. 19, # 23, p. 6404 - 6407]
[4]Yuan, Yu-Chao; Bruneau, Christian; Dorcet, Vincent; Roisnel, Thierry; Gramage-Doria, Rafael [Journal of Organic Chemistry, 2019, vol. 84, # 4, p. 1898 - 1907]
[5]Rowlett, Jarrett R.; Deglmann, Peter; Sprafke, Johannes; Roy, Nabarun; Mülhaupt, Rolf; Bruchmann, Bernd [Journal of Organic Chemistry, 2021, vol. 86, # 13, p. 8933 - 8944]
[6]Location in patent: experimental part Matuszak, Nicolas; Muccioli, Giulio G.; Labar, Geoffray; Lambert, Didier M. [Journal of Medicinal Chemistry, 2009, vol. 52, # 23, p. 7410 - 7420]
[7]Anschuetz; Reuter [Justus Liebigs Annalen der Chemie, 1889, vol. 254, p. 135] Gottlieb [Justus Liebigs Annalen der Chemie, 1851, vol. 77, p. 288]
[8]Corrie, John E. T.; Moore, Madeleine H.; Wilson, Giles D. [Journal of the Chemical Society. Perkin transactions I, 1996, # 8, p. 777 - 781]
[9]Faturaci, Yeliz; Coskun, Necdet [Turkish Journal of Chemistry, 2012, vol. 36, # 5, p. 749 - 758]

4
[ 616-02-4 ]
[ 123-31-9 ]
[ 14554-09-7 ]

Yield	Reaction Conditions	Operation in experiment
20%	Stage #1: citraconic acid anhydride; hydroquinone With aluminum (III) chloride; sodium chloride at 165℃; for 4h; Stage #2: With hydrogenchloride In water at 0℃; for 0.75h; Reflux;	4.2 General method for the preparation of naphthazarins General procedure: To a mixture of anhydrous AlCl3 (10mmol, 1.33g) and NaCl (5mmol, 0.29g) that was heated in an oil bath till molten was added maleic anhydride or 2-methylmaleic anhydride (1mmol) and 1, 4-benzenediol or 4-chlorophenol (1mmol). The temperature was slowly increased and maintained at 165°C for 4h. The reaction mixture was cooled to 0°C, and 10ml of 10% HCl was added, and the mixture was stirred for 15minat 0°C and then refluxed for 30min. The reaction mixture was cooled to room temperature and extracted with ethyl acetate. The resulting product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as the mobile phase. For preparation of substituted naphthazarins, compound 2 (114mg, 0.6mmol) was stirred in EtOH (10mL), and different amines (0.7mmol) were added. The reaction was allowed to stir for several hours at room temperature and the reaction process was monitored by thin layer chromatography. After the reaction completed, the solvent was evaporated under vacuum, and the resulting product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as the mobile phase.
	With aluminium trichloride; sodium chloride at 200 - 220℃;
	With hydrogenchloride; aluminium trichloride; sodium chloride 1) 200 deg C; Yield given. Multistep reaction;

With hydrogenchloride; aluminium trichloride; sodium chloride 1.) 180 deg C, 3 h; 2.) r.t., 2 days; Multistep reaction;

Reference： [1]Zhang, Junmin; Liu, Yaping; Shi, Danfeng; Hu, Guodong; Zhang, Baoxin; Li, Xinming; Liu, Ruijuan; Han, Xiao; Yao, Xiaojun; Fang, Jianguo [European Journal of Medicinal Chemistry, 2017, vol. 140, p. 435 - 447]
[2]Macbeth; Price; Winzor [Journal of the Chemical Society, 1935, p. 325,327]
[3]Tandon; Vaish; Khanna; Anand [Archiv der Pharmazie, 1990, vol. 323, # 7, p. 383 - 385]
[4]Eloeve, Guelnur A.; Schauble, J. Herman [Magnetic Resonance in Chemistry, 1987, vol. 25, p. 194 - 200]

5
[ 616-02-4 ]
[ 5754-18-7 ]

Yield	Reaction Conditions	Operation in experiment
65%	With acetic acid; hydrazine; In ethanol; water; for 24.0h;pH 6.5;Cooling with ice; Reflux;	Citraconic anhydride (24.0 mL, 270 mmol) was added slowly to an ice-cooled mixture of hydrazine (4 M aqueous solution buffered to pH 6.5 by AcOH; 200 mL) and EtOH (250 mL) to give a pale yellow heterogenous mixture. The mixture was heated at gentle reflux for 24 h, allowed to cool to ambient temperature and the EtOH removed in vacuo to give a white heterogenous mixture. The mixture was diluted with water (250 mL). The resulting white precipitate was collected by filtration, washing with water, and dried in vacuo at ambient temperature for 24 h over phosphorus pentoxide to give the title compound as a white powder (21.8 g; 65%). 1H NMR (200 MHz, DMSO-d6): delta 2.00 (3H, s), 6.85 (1H, s), 11.22 (2H, brs).

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1644 - 1658
[2]Journal of the American Chemical Society,1954,vol. 76,p. 4454,4457
[3]Journal of the American Chemical Society,1954,vol. 76,p. 2201
[4]Journal of Organic Chemistry,1954,vol. 19,p. 115,117

6
[ 616-02-4 ]
[ 59107-74-3 ]

Yield	Reaction Conditions	Operation in experiment
73%	With aluminum tri-bromide; bromine; at 120℃; for 16h;Inert atmosphere;	Synthesis of 3-bromo-4-methylfuran-2 ,5-dione3-Methylfuran-2,5-dione (6.24 g, 55.6 mmol, 5.00 mL) was placed in a closed pressure vial. Under N2AIBr3 (0.178 g, 0.668 mmol) was added, followed by Br2 (8.89 g, 55.6 mmol, 2.87 mL). The mixture wasstirred at 120 C for 16 h. The vial was cooled to 0 C. Solids were removed from the vial and recrystallized from toluene/heptane, washed with heptane and dried in vacuo to obtain 3-bromo-4- methylfuran-2,5-dione (7.80 g, 40.8 mmol, 73%) as a brown crystalline solid. LCMS: calc. for [M+H] = 190.93, fd 191.0.
73%	With aluminum tri-bromide; bromine; at 120℃; for 16h;Inert atmosphere;	3-Methylfuran-2,5-dione (6.24 g, 55.6 mmol, 5.00 mL) was placed in a closed pressure vial. Under N2 AIBr3 (0.178 g, 0.668 mmol) was added, followed by Br2 (8.89 g, 55.6 mmol, 2.87 mL). The mixture was stirred at 120C for 16 h. The vial was cooled to 0 C. Solids were removed from the vial and recrystallized from toluene/heptane, washed with heptane and dried in vacuo to obtain 3-bromo-4-methylfuran-2,5-dione (7.80 g, 40.8 mmol, 73%) as a brown crystalline solid. LCMS: cal for [M+H]=1 90.93, fd 191.0.
52.1%	With aluminum (III) chloride; bromine; at 120℃; for 12h;	The D monomer was synthesized according to the previous report with modifications [24]. The synthetic route was illustrated in Fig. S7, containing two steps. (i) Citraconic anhydride (11.2 g, 0.1 mol), aluminium (III) chloride (266 mg, 2.0 mmol) and bromine (10.3 mL, 0.2 mol) were added into a 500 mL flask. The solution was heated to 120 C and stirred for 12 h. After the reaction mixture was cooled to room temperature, ethyl acetate (150 mL) was added into the flask and the solution was then washed with water for three times. The organic layer was dried over anhydrous sodium sulfate and filtered, and the solution was concentrated to yield product (4) as an off-white solid (9.88 g, yield: 52.1%). 1H NMR (300 MHz, DMSO-d6, delta, ppm): 2.11 (s, 3H).

	With aluminum tri-bromide; bromine; at 120℃;	3-bromo-4-methy.-2,5-furandione (P1)A mixture of 3-methyl-2,5-furandione (citraconic anhydride, 1 g), AIBr3 (26 mg) and Br2(0.46 ml.) was heated at 120 0C overnight. Ethyl acetate was then added and the organic phase was washed with HCI 0,1% and then with brine. The organic phase was dried and concentrated in vacuo to give the crude product (1.680 g) that was used without further purification.NMR (1H, CDCI3): delta 2.18 (s, 3H)
	With aluminum tri-bromide; bromine; at 120℃;	A stirred mixture of 3-methyl-2,5-furandione (2.0 g, 17.85 mmol), A1Br3 (0.11 g, 3.18 mmol) and Br2 (1.6 mL, 71.4mmol) was heated overnight at 120C. Upon completion of reaction, the reaction mixture was cooled to RT and diluted with ethyl acetate (100 mL). Theorganic phase was washed with 0.1% HC1 and brine. The organic phase were dried over anhydrous Na2504 and concentrated under reduced pressure to obtain crude compound, which was used in next step without any purification (3.20 g, crude). 1H NMR (300 MHz, CDC13): oe 2.21 (s, 3H).
	With aluminum tri-bromide; bromine; at 120℃;	Step-a Synthesis of 3-bromo-4-methylfuran-2,5-dione A stirred mixture of 3-methyl-2,5-furandione (2.0 g, 17.85 mmol), AlBr3 (0.11 g, 3.18 mmol) and Br2 (1.6 mL, 71.4 mmol) was heated overnight at 120 C. Upon completion of reaction, the reaction mixture was cooled to RT and diluted with ethyl acetate (100 mL). The organic phase was washed with 0.1% HCl and brine. The organic phase were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude compound, which was used in next step without any purification (3.20 g, crude). 1H NMR (300 MHz, CDCl3): delta 2.21 (s, 3H).

Reference： [1]Journal of the American Chemical Society,2014,vol. 136,p. 8729 - 8737
[2]Patent: WO2015/161928,2015,A1 .Location in patent: Page/Page column 75
[3]Patent: WO2015/161924,2015,A1 .Location in patent: Page/Page column 44; 45
[4]Journal of Organic Chemistry,1998,vol. 63,p. 2646 - 2655
[5]Polymer,2019,vol. 172,p. 294 - 304
[6]Justus Liebigs Annalen der Chemie,1861,vol. Suppl.1,p. 351
Justus Liebigs Annalen der Chemie,1862,vol. Suppl.2,p. 103
[7]Journal fur praktische Chemie (Leipzig 1954),1895,vol. <2> 52,p. 292
[8]Patent: WO2007/22936,2007,A1 .Location in patent: Page/Page column 26
[9]Patent: WO2015/104653,2015,A1 .Location in patent: Page/Page column 50
[10]Patent: US2016/368906,2016,A1 .Location in patent: Paragraph 0206

7
[ 616-02-4 ]
[ 2486-70-6 ]
[ 83560-89-8 ]

Reference： [1]Journal of Medicinal Chemistry,1983,vol. 26,p. 85 - 90

8
[ 616-02-4 ]
[ 1779-58-4 ]
[ 71126-39-1 ]
[ 71126-37-9 ]

Reference： [1]Synthetic Communications,1994,vol. 24,p. 1179 - 1186

9
[ 616-02-4 ]
[ 542-92-7 ]
(3aRS,4SR,7RS,7aSR)-3a-methyl-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	In Petroleum ether at 20℃;
92%	In chloroform at 0 - 20℃; Darkness;
90%	With lithium perchlorate In diethyl ether for 3h; Ambient temperature;

99 % Spectr.	With lithium bis((trifluoromethyl)sulfonyl)amide In propan-2-one at 25℃; for 2.5h;
	In diethyl ether at 20℃; for 16h;	1.1 Step 1., Preparation of 2-«iethyi-4-oxa-tricyclo[5.2.1.02,6jdec-8-ene-3,S-dione; A flask (500 mL), equipped with a Vigreux column (20 cm) and a distillation system, was charged with dicyclopentadiene (150 mL) and heated to 210 °C. Cyclopentadiene was recovered in an ice-cold flask. The cyclopentadiene was then added to a solution of 3- methyl-furan~2,5-dionc (40g, 0.36 mol) in ether (100 mL). The reaction mixture was stirred overnight (16 h) at room temperature. The solvent was removed to give a white solid. The solid was treated with hexanes to give the title compound 1 (60.5 g, 95%),
	In chloroform at 20℃; for 24h;

Reference： [1]Lomba; Afarinkia; Vinader [Organic and Biomolecular Chemistry, 2019, vol. 17, # 18, p. 4456 - 4459]
[2]Citron, Christian A.; Wickel, Susanne M.; Schulz, Barbara; Draeger, Siegfried; Dickschat, Jeroen S. [European Journal of Organic Chemistry, 2012, # 33, p. 6636 - 6646]
[3]Grieco, Paul A.; Nunes, Joseph J.; Gaul, Micheal D. [Journal of the American Chemical Society, 1990, vol. 112, # 11, p. 4595 - 4596]
[4]Augé, Jacques; Gil, Richard; Kalsey, Sophie; Lubin-Germain, Nadège [Synlett, 2000, # 6, p. 877 - 879]
[5]Current Patent Assignee: SIRTUIN VALLEY - WO2012/56113, 2012, A1 Location in patent: Page/Page column 51
[6]Coates, Geoffrey W.; Lu, Yiye; Popowski, Yanay; Tolman, William B. [Journal of the American Chemical Society, 2022]

10
[ 616-02-4 ]
[ 40834-42-2 ]
[ 6124-79-4 ]
[ 22122-36-7 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1981,p. 1734 - 1743

11
[ 616-02-4 ]
[ 1072-87-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With 1,1,1,3,3,3-hexamethyl-disilazane; In N,N-dimethyl-formamide; at 100℃; for 1h;	To a solution of citraconic anhydride (25) (12.0 g, 107 mmol) in DMF (100 mL) at 100 C hexamethyldisilazane (34.2 mL, 160 mmol) was added. The mixture was stirred at 100 C for 1 h, then it was cooled to room temperature. The solvent was evaporated under reduced pressure. The crude product was recrystallized from a mixture of hexane and ethyl acetate to give the title compound 26 as a white crystalline solid (8.33 g, 70%), mp 104-105 C (lit.: 104-105 C) [3]; Rf (DCM:MeOH 10:1) 0.71; nmax (KBr) 3271, 3098, 2674, 1844, 1778, 1764, 1712, 1634, 1342, 1284, 1175, 1090 cm_1; 1H NMR (500 MHz; DMSO-d6) d (ppm) 1.94 (3H; d; J 1.8 Hz; C(3)-CH3); 6.50 (1H; q; J 1.8 Hz; H-4); 10.72 (1H; br s; NH-1); 13C NMR (126 MHz; DMSO-d6) d (ppm) 10.2 (C(3)-CH3); 128.0 (C-4); 145.9 (C-3); 172.2 (C-5); 173.1 (C-2); HRMS: M 111.0311 (C5H5O2N; delta _8.1 ppm); HR-EI-MS (rel. int. %): 111(100); 83(8); 68(39).
40%	With 1,1,1,3,3,3-hexamethyl-disilazane; In methanol; N,N-dimethyl-formamide; at 0 - 20℃; for 20.3333h;	Stage 1: 3-methylpyrrole-2,5-dione A solution of hexamethyldisilazane (80.7 g, 104.8 ml, 500 mmol) in methanol was added dropwise to a solution of citraconic anhydride (5.60 g, 4.49 ml, 50 mmol) in N,N-dimethylformamide (170 ml) at 0 C. The reaction solution was stirred at room temperature for 20 h, thereafter methanol (100 ml) was added and the mixture was stirred for a further 20 min. The solvent was concentrated in vacuo and the residue was taken up in a mixture of ethyl acetate/water (150 ml:50 ml). The organic phase was separated off, washed with water (2*50 ml), sodium bicarbonate solution (50 ml) and with water again (50 ml) and then dried with sodium sulfate. The solvent was concentrated and the residue was dried in vacuo. Yield: 2.30 g (40%), white solid Melting point: 100-102 C. [lit. 101-104 C. (K. R. Shah, C. DeWitt Blanton, J. Org. Chem. 1982, 47, 502)].
32%	With urea; In sulfolane; at 180℃; for 1h;Product distribution / selectivity;	25 g (0.219 mol) of 2-methyl succinic anhydride were heated in 37.5 g of sulfolane to a reaction temperature of 180 C. After the reaction temperature was achieved 18.95 g (0.32 mol) of urea were spread in and stirring was continued for 1 h at the reaction temperature under flushing with N2. Following cooling, the reaction mixture was first added with 2-propanol and then with MTBE. 6.5 g of 2-methyl succinic imide (32% of the theoretical yield) were obtained

20%

With urea; In diethyleneglycol diethylether; at 180℃;Product distribution / selectivity;

EXAMPLE 25 In a manner analogous to that of Example 24, diethyleneglycol diethylether was used as the solvent at 180 C. After cooling, first MTBE was added. From the resulting oil 2-methyl succinic imide was obtained in a yield of 20% by recrystallization from ethanol.

Reference： [1]Heterocycles,2004,vol. 63,p. 1013 - 1016
[2]Tetrahedron,2021,vol. 81
[3]Tetrahedron Asymmetry,1999,vol. 10,p. 4469 - 4471
[4]Tetrahedron,1993,vol. 49,p. 4575 - 4580
[5]Patent: US2008/293749,2008,A1 .Location in patent: Page/Page column 22
[6]Angewandte Chemie - International Edition,2016,vol. 55,p. 5582 - 5585
Angew. Chem.,2016,vol. 55,p. 5672 - 5675,4
[7]Patent: US2007/173647,2007,A1 .Location in patent: Page/Page column 3
[8]Advanced Synthesis and Catalysis,2008,vol. 350,p. 411 - 418
[9]European Journal of Organic Chemistry,2008,p. 1511 - 1516
[10]Journal of the Chemical Society. Perkin transactions I,1993,p. 2567 - 2580
[11]Patent: US2007/173647,2007,A1 .Location in patent: Page/Page column 3
[12]Journal of Organic Chemistry,1982,vol. 47,p. 502 - 508
[13]Journal of the Chemical Society,1957,p. 2882,2887

12
[ 616-02-4 ]
[ 100-46-9 ]
[ 73383-82-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	at 20 - 120℃; Inert atmosphere; Neat (no solvent);
92%	With glacial acetic acid for 2h; Heating;
90%	With glacial acetic acid for 12h; Heating;

87%	In glacial acetic acid for 2h; Heating;
80%	With glacial acetic acid at 100℃; for 4h;
73.2%	With glacial acetic acid
53.6%	at 0 - 120℃; for 18h; Inert atmosphere;	Step 1. l-Benzyl-3-methylpyrr ole-2, 5-dione 3-methylfuran-2, 5-dione (2.0 mL; 22.3 mmol) was placed in a 100 mL flask under nitrogen at 0°C and benzylamine (2.43 mL; 22.3 mmol) was added dropwise. The resulting mixture was then heated at 120 °C for 18 h. The reaction mixture was then allowed to cool to ambient temperature and purified by silica gel flash column chromatography eluting with a mixture of EtOAc and heptanes (1:2) to give the desired product as a colorless oil (2.4 g, Yield: 53.6%). LCMS calculated for C12H12NO2 (M+H)+: m/z = 202.1; found: 202.1.
	at 120℃;
	Stage #1: citraconic acid anhydride; benzylamine In chloroform for 1h; Stage #2: With anhydrous Sodium acetate; acetic anhydride for 2h; Reflux;
	With glacial acetic acid Cooling with ice; Reflux;
	In neat (no solvent) at 0 - 120℃; for 16h;	1 Step 1: 1-benzyl-3-methyl-1H-pyrrole-2,5-dione. To 3-methylfuran-2,5-dione (6.0 mL, 55 mmol) at 0 °C, was added benzylamine (6.0 mL, 55 mmol) dropwise and the mixture was heated to 120 °C for 16h. The reaction was cooled to rt and purified by column chromatography (Hexanes :EtO Ac) to afford the title compound.

Reference： [1]Mukherjee, Santanu; Corey [Organic Letters, 2010, vol. 12, # 3, p. 632 - 635]
[2]Shintani, Ryo; Duan, Wei-Liang; Hayashi, Tamio [Journal of the American Chemical Society, 2006, vol. 128, # 17, p. 5628 - 5629]
[3]Nikitin; Andryukhova [Chemistry of Heterocyclic Compounds, 2004, vol. 40, # 5, p. 561 - 569]
[4]Corrie, John E. T.; Moore, Madeleine H.; Wilson, Giles D. [Journal of the Chemical Society. Perkin transactions I, 1996, # 8, p. 777 - 781]
[5]Current Patent Assignee: GUANGZHOU FERMION TECHNOLOGY; GUANGZHOU FERMIZI TECH; GUANGZHOU FERMION TECH - WO2022/12534, 2022, A1 Location in patent: Page/Page column 25
[6]Fan, Yongxian; Lu, Yuele; Chen, Xiaolong; Tekwani, Babu; Li, Xing-Cong; Shen, Yinchu [Molecules, 2018, vol. 23, # 11]
[7]Current Patent Assignee: PRELUDE THERAPEUTICS INCORPORATED - WO2022/99117, 2022, A1 Location in patent: Paragraph 505
[8]Hegazy, Mohamed-Elamir F.; Shishido, Kozo; Hirata, Toshifumi [Tetrahedron Asymmetry, 2006, vol. 17, # 12, p. 1859 - 1862]
[9]Location in patent: experimental part Sortino, Maximiliano; Zacchino, Susana Alicia [Tetrahedron Asymmetry, 2010, vol. 21, # 5, p. 535 - 539]
[10]Location in patent: experimental part Borikar, Sanjay P.; Paul, Vincent; Puranik, Vedavati G.; Sathe, Vilas T.; Lagunas-Rivera, Selene; Ordonez, Mario [Synthesis, 2011, # 10, p. 1595 - 1598]
[11]Current Patent Assignee: UNIVERSITY OF UTAH; CURZA GLOBAL LLC - WO2020/150372, 2020, A1 Location in patent: Paragraph 00704

13
[ 616-02-4 ]
[ 37847-52-2 ]
[ 170950-55-7 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1995,vol. 60,p. 1026 - 1033

14
[ 616-02-4 ]
[ 2393-23-9 ]
[ 215871-89-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With acetic acid at 100℃; for 5h;	15.A Example 15 2-[1-(4-Methoxy-benzyl)-4-methyl-5-oxo-2,5-dihydro-1H-pyrrol-2-ylsulfanyl]-N-pyridin-2-yl-acetamide (Compound 15) A. 1-(4-Methoxy-benzyl)-3-methyl-pyrrole-2,5-dione: 3-Methylmaleic anhydride (10 g, 89.2 mmol) and 4-methoxybenzylamine (11.6 mL, 89.2 mmol) were heated to 100° C. in 35 mL glacial acetic acid for 5 h. Solvent was evaporated. The residue was taken up in EtOAc and washed with sat'd aq NaHCO3, water, and brine. The organic phase was dried (MgSO4), filtered, and evaporated. The title compound was obtained as a solid and used without further purification (18.75 g, quant).
80%	In toluene for 13h; Heating;

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - US2007/99937, 2007, A1 Location in patent: Page/Page column 24
[2]Kakiuchi, Takashi; Kato, Hirohide; Jayasundera, Krishanthi Padmarani; Higashi, Taijiro; Watabe, Kazuhiko; Sawamoto, Daisuke; Kinoshita, Hideki; Inomata, Katsuhiko [Chemistry Letters, 1998, # 10, p. 1001 - 1002]

15
[ 616-02-4 ]
[ 7726-95-6 ]
[ 59107-74-3 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1861,vol. Suppl.1,p. 351
Justus Liebigs Annalen der Chemie,1862,vol. Suppl.2,p. 103
[2]Journal fur praktische Chemie (Leipzig 1954),1895,vol. <2> 52,p. 292

16
[ 616-02-4 ]
[ 135616-40-9 ]
[ 147396-58-5 ]
[ 357418-52-1 ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 2273 - 2282

17
[ 616-02-4 ]
[ 147396-58-5 ]
[ 135616-36-3 ]
cis-(1R,2S)-(+)-1-methyl-1,2,3,6-tetrahydrophthalic anhydride [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2001,p. 2273 - 2282

18
[ 3587-60-8 ]
[ 616-02-4 ]
[ 1738-76-7 ]
[ 562811-77-2 ]

Reference： [1]Tetrahedron,2003,vol. 59,p. 3063 - 3087

19
[ 616-02-4 ]
[ 20605-41-8 ]
(Z)-4-[N'-(2-Methoxy-acetyl)-hydrazino]-2-methyl-4-oxo-but-2-enoic acid [ No CAS ]

Reference： [1]Pharmaceutical Chemistry Journal,2002,vol. 36,p. 174 - 176

20
[ 616-02-4 ]
[ 6124-79-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 2h;
87%	With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 2h; Inert atmosphere;
70%	With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 2h;

68%	With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 6h;	4.2. Synthesis of 4-methyl-2(5H)-furanone (8) To a flame-dried vial was added citraconic anhydride (10 mL,110.22 mmol), THF (250 mL), and NaBH4 (5.24 g, 126.36 mmol). The reaction was stirred at 0 °C for 6 h. The reaction mixture was quenched with H2O (30 mL), and then acidified with aqueous 6M HCl. The reaction mixture was then extracted with Et2O three times, then the combined organic layers were dried over anhydrousNa2SO4, filtered, and concentrated in vacuo. The resulting crude yellow oil was purified by flash chromatography (SiO2) using 4:1 Et2O/hexanes to afford the desired product as a yellow/green oil (7.35 g, 550.75 mmol, 68%). 1H NMR (CDCl3, 400 MHz) d 5.86 (s, 1H),4.72 (s, 2H), 2.14 (s, 3H); 13C NMR (100 MHz, CDCl3) d 174.21,166.44,115.95, 73.83, 13.85. Spectral data matched literature sources [29].
40%	With sodium tetrahydroborate In tetrahydrofuran at 0 - 20℃; for 2.25h;
	With sodium tetrahydroborate

Reference： [1]Gogoi, Sanjib; Argade, Narshinha P. [Tetrahedron, 2006, vol. 62, # 11, p. 2715 - 2720]
[2]Sharma, Vasudha; Kelly, Gilbert T.; Watanabe, Coran M. H. [Organic Letters, 2008, vol. 10, # 21, p. 4815 - 4818]
[3]Paterson, Ian; Xuan, Mengyang; Dalby, Stephen M. [Angewandte Chemie - International Edition, 2014, vol. 53, # 28, p. 7286 - 7289][Angew. Chem., 2014, vol. 126, # 28, p. 7414 - 7417]
[4]Alexander, Taylor S.; Clay, Travis J.; Maldonado, Bryan; Nguyen, Johny M.; Martin, David B.C. [Tetrahedron, 2019, vol. 75, # 14, p. 2229 - 2238]
[5]Von der Ohe; Bruckner [New Journal of Chemistry, 2000, vol. 24, # 9, p. 659 - 669]
[6]Vassilikogiannakis, Georgios; Stratakis, Manolis [Angewandte Chemie - International Edition, 2003, vol. 42, # 44, p. 5465 - 5468]

21
[ 616-02-4 ]
[ 98749-53-2 ]
[ 923025-66-5 ]

Yield	Reaction Conditions	Operation in experiment
73%	In benzene for 6h; Heating;
73%	In benzene Heating;
73%	In benzene for 6h; Heating / reflux;	6 E-4-cinnamoylmethylidene-2-methylbut-2-en-4-olide (5): A solution of 2-methylmaleic anhydride (3) (1.8 g, 16.1 mmol) in benzene (10 mL) is added to a refluxed solution of 4 (5.5 g, 13.5 mmol) in benzene (50 mL) under nitrogen. After refluxing for 6 hrs, TLC indicated complete consumption of 12. The reaction mixture is evaporated to dryness, and the residue is chromatographied on silica gel using hexanes-acetone (4:1) to yield E-4-cinnamoylmethylidene-2-methylbut-2-en-4-olide (5) (2.35 g, 73%) as yellow needles [from chloroform-methanol (1:1)]: mp 160-161 C°, UV (MeOH), ?max, (log e) 208 (4.18), 238 (3.98), 334 (4.50) nm; IR (KBr) ?max, 1770, 1678, 1627, 1588, 1451, 1375, 1209, 1098, 1039, 990, 911, 877, 754, 698, 545; 1H NMR (400 MHz, CDCl3) d 8.10 (1H, s, H-3), 7.64 (1H, d, J=16.0 Hz, H-4'), 7.59 (2H, m, H-6',10'), 7.42 (3H, m, H-7',8',9'), 6.88 (1H, d, J=16.0 Hz, H-3'), 6.48 (1H, s, H-1'), 2.11 (3H, s, Me-2); 3C NMR (100 MHz, CDCl3) d 188.3 (s, C-2'), 169.2 (s, C-1), 159.2 (s, C-4), 144.0 (d, C-4'), 137.0 (d, C-3), 136.4 (s, C-2), 134.3 (s, C-5'), 131.0 (d, C-8'), 129.1 (2C, d, C-6',10'), 128.6 (2C, d, C-7',9'), 127.5 (d, C-3'), 106.0 (d, C-1'), 11.2 (q, Me-2) (NMR assignments were based on 2D HMBC and NOESY experiments); HRESIMS m/z [M+H]+ 241.0841 (calcd for C15H13O3, 241.0859), [M+Na]+263.0659 (calcd for C15H12O3Na, 263.0678), [M+K]+279.0400 (calcd for C15H12O3K, 279.0418).

Reference： [1]Li, Xing-Cong; Ferreira, Daneel; Jacob, Melissa R.; Zhang, Qifeng; Khan, Shabana I.; ElSohly, Hala N.; Nagle, Dale G.; Smillie, Troy J.; Khan, Ikhlas A.; Walker, Larry A.; Clark, Alice M. [Journal of the American Chemical Society, 2004, vol. 126, # 22, p. 6872 - 6873]
[2]Babu, K. Suresh; Li, Xing-Cong; Jacob, Melissa R.; Zhang, Qifeng; Khan, Shabana I.; Ferreira, Daneel; Clark, Alice M. [Journal of Medicinal Chemistry, 2006, vol. 49, # 26, p. 7877 - 7886]
[3]Current Patent Assignee: THE UNIVERSITY OF MISSISSIPPI - US2005/215648, 2005, A1 Location in patent: Page/Page column 13-14

22
[ 616-02-4 ]
[ 80522-42-5 ]
[ 203131-19-5 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: citraconic acid anhydride With sodium tetrahydroborate Stage #2: triisopropylsilyl trifluoromethanesulfonate With triethylamine In dichloromethane at 0 - 25℃; for 6h;
	Stage #1: citraconic acid anhydride With sodium tetrahydroborate Stage #2: triisopropylsilyl trifluoromethanesulfonate With triethylamine In dichloromethane at 0 - 25℃; for 6h;

Reference： [1]Vassilikogiannakis, Georgios; Margaros, Ioannis; Montagnon, Tamsyn [Organic Letters, 2004, vol. 6, # 12, p. 2039 - 2042]
[2]Vassilikogiannakis, Georgios; Margaros, Ioannis; Montagnon, Tamsyn; Stratakis, Manolis [Chemistry - A European Journal, 2005, vol. 11, # 20, p. 5899 - 5907]

23
[ 616-02-4 ]
[ 60-34-4 ]
6-hydroxy-2,5-dimethyl-3-pyridazinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%
73%	With hydrogenchloride In water for 3h; Reflux;	prep of 6-hydroxy-2,5-dimethylpyridazin-3-one (3) To 1.12 g (0.01 mol) of citraconic anhydride in 50 cm3 of 10%HCl 0.46 g (0.01 mol) of methylhydrazine was added dropwise.The mixture was heated under reflux for 3 h. After cooling the mixturewas poured into water and extracted with CH2Cl2. The extractswere washed with water, dried (MgSO4) and evaporated. The residuewas crystallized from EtOH and identified as 3. Yield 73%, mp:265 C (262-263 C [20]); 1H NMR (400 MHz, CDCl3, TMS): d = 2.03(d, J = 1.4 Hz, 3H), 3.44 (s, 3H), 6.74 (q, J = 1.4 Hz, 1H), 11,22 (br s,O H N, 1H); 13C NMR (100 MHz, CDCl3, TMS): d = 22.94, 32.39,129.50, 139.64, 158.97, 163.92.

Reference： [1]Katrusiak, Anna; Katrusiak, Andrzej [Journal of Molecular Structure, 2004, vol. 694, # 1-3, p. 85 - 90]
[2]Katrusiak, Anna; Katrusiak, Andrzej [Journal of Molecular Structure, 2015, vol. 1085, p. 28 - 36]

24
[ 616-02-4 ]
[ 84478-72-8 ]
1-(4-chloro-2-fluoro-5-hydroxy-phenyl)-3-methyl-pyrrole-2,5-dione [ No CAS ]

Reference： [1]Chemistry of Heterocyclic Compounds,2004,vol. 40,p. 561 - 569

25
[ 616-02-4 ]
[ 83247-83-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With bis(norbornadiene)rhodium(l)tetrafluoroborate; C₄₆H₃₈F₆FeN₂P₂S⁽²⁺⁾; hydrogen In ethyl acetate at 20℃; for 1.16667h; Glovebox; Autoclave; enantioselective reaction;
	With 1,4-dihydronicotinamide adenine dinucleotide; sodium phosphate buffer; Marchantia polymorpha p68 reductase at 35℃; for 4h;
93 % ee	With C₃₁H₄₂IrNOP⁽¹⁺⁾*C₃₂H₁₂BF₂₄^(1-); hydrogen In dichloromethane at 20℃; for 18h; Autoclave; High pressure; enantioselective reaction;

Reference： [1]Han, Zhengyu; Wang, Rui; Gu, Guoxian; Dong, Xiu-Qin; Zhang, Xumu [Chemical Communications, 2017, vol. 53, # 30, p. 4226 - 4229]
[2]Shimoda, Kei; Kubota, Naoji [Tetrahedron Asymmetry, 2004, vol. 15, # 24, p. 3827 - 3829]
[3]Bernasconi, Maurizio; Mueller, Marc-Andre; Pfaltz, Andreas [Angewandte Chemie - International Edition, 2014, vol. 53, # 21, p. 5385 - 5388][Angew. Chem., 2014, vol. 126, # 21, p. 5489 - 5492,4]

26
[ 616-02-4 ]
[ 22122-36-7 ]

Yield	Reaction Conditions	Operation in experiment
15%	With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 6h;	4.1. Synthesis of 3-methyl-2(5H)-furanone (6) To a flame-dried vial was added citraconic anhydride (10 mL,110.22 mmol), THF (250 mL), and NaBH4 (5.24 g, 126.36 mmol). The reaction was stirred at 0 °C for 6 h. The reaction mixture was quenched with H2O (30 mL), and then acidified with aqueous 6M HCl. The reaction mixture was then extracted with Et2O three times, then the combined organic layers were dried over anhydrousNa2SO4, filtered, and concentrated in vacuo. The resulting crude yellow oil was purified by flash chromatography (SiO2) using 4:1 Et2O/hexanes to afford the desired product as a yellow/green oil (1.62 g, 16.53 mmol, 15%). 1H NMR (CDCl3, 400 MHz) d 7.14 (m, 1H),4.77 (t, J 2.0 Hz, 2H), 1.94 (m, 3H); 13C NMR (CDCl3, 100 MHz)d 10.6, 70.2, 129.8, 144.6, 174.8. Spectral data matched literature sources [40].
	Stage #1: citraconic acid anhydride With N-cyclohexyl-cyclohexanamine In methanol at -15 - 20℃; for 3.5h; Stage #2: With carbonochloridic acid, butyl ester In dichloromethane at -12℃; for 12h; Stage #3: With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 3h; Further stages.;

Reference： [1]Alexander, Taylor S.; Clay, Travis J.; Maldonado, Bryan; Nguyen, Johny M.; Martin, David B.C. [Tetrahedron, 2019, vol. 75, # 14, p. 2229 - 2238]
[2]Von der Ohe; Bruckner [New Journal of Chemistry, 2000, vol. 24, # 9, p. 659 - 669]

27
[ 108-22-5 ]
[ 616-02-4 ]
[ 865449-14-5 ]

Yield	Reaction Conditions	Operation in experiment
55%	With aluminium trichloride In 1,2-dichloro-ethane for 1.5h; Heating;
55%	In 1,2-dichloro-ethane at 0℃; for 1.75h; Heating / reflux;	7 This example demonstrates a reaction scheme for the synthesis of 2-(1-methoxy-ethylidene)-4-methyl-cyclopent-4-ene-1,3-dione (6). To a solution of 2-methylmaleic anhydride (8.0 g, 71.4 mmol) in dry C2H4Cl2 (200 mL) at room temperature under nitrogen is added anhydrous AlCl3 (32.3 g, 133.4 mmol). The suspension was cooled to 0° C. and α-methylvinyl acetate (10.7 g, 107.1 mmol) was added dropwise in 15 minutes. After finishing the addition, the reaction mixture was heated to reflux for 1.5 hr. After cooling, the reaction mixture was poured into 10% HCl iced water (300 mL). The organic layer was separated. The aqueous layer was extracted with CHCl3 (150 mL×3). The combined organic layers were washed with brine (150 mL) and H2O (200 mL×4) to neutral, dried (Na2SO4), and concentrated to dryness to yield a residue (8.5 g), which was chromatographed on silica gel eluting with hexane-EtOAc (1:2) to afford 2-(1-hydroxy-ethylidene)-4-methyl-cyclopent-4-ene-1,3-dione (5.97 g, 55%) as pale yellow crystals (from Et2O), 1H NMR (400 MHz, CDCl3, two isomers) d 11.8 (br s, OH), 6.50 and 6.42 (br s, H-5), 2.22 (s, vinylic Me), 1.91 (s, Me-4); 13C NMR (100 MHz, CDCl3, two isomers) d 200.4, 199.6, 192.1 and 191.7 (1,3-CO), 176.9 and 176.7 (vinylic C), 157.8 and 153.4 (C-4), 140.5 and 136.2 (C-5), 104.2 and 104.2 (C-2), 17.9 (vinylic Me), 11.2 and 10.2 (Me-4); HRTOFMS m/z [M+H]+ 153.0585 (calcd for C8H9O3, 153.0547).

Reference： [1]Babu, K. Suresh; Li, Xing-Cong; Jacob, Melissa R.; Zhang, Qifeng; Khan, Shabana I.; Ferreira, Daneel; Clark, Alice M. [Journal of Medicinal Chemistry, 2006, vol. 49, # 26, p. 7877 - 7886]
[2]Current Patent Assignee: THE UNIVERSITY OF MISSISSIPPI - US2005/215648, 2005, A1 Location in patent: Page/Page column 15

28
[ 616-02-4 ]
[ 4648-54-8 ]
[ 51440-82-5 ]
[ 51255-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: citraconic acid anhydride; trimethylsilylazide In chloroform at 50 - 60℃; for 5h; Stage #2: With ethanol In chloroform at 0℃; for 0.5h;	2 At room temperature, 50.0 g of trimethylsilylazide was added to a mixture of 44.8 g of citraconic anhydride and 60 ml of chloroform. The mixture was stirred at 50-60° C. for 5 hours. After cooling the reaction mixture with an ice, 25.0 g of ethanol was added, followed by stirring for additional 30 minutes. The resulting solid was collected by filtration, and washed with a mixed solvent of chloroform and ethanol to obtain crude 4-methyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula: Further, the washing solution was concentrated under reduced pressure. T-butyl methyl ether was added to the residue, followed by filtration. The resulting solid was washed with t-butyl methyl ether. The filtrate and the washing solution were combined and concentrated under reduced pressure to obtain crude 5-methyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:
	In chloroform at 50 - 60℃; for 5h;	2 Reference Preparation Example 2 At room temperature, 50.0 g of trimethylsilylazide was added to a mixture of 44.8 g of citraconic anhydride and 60 ml of chloroform. The mixture was stirred at 50-60°C for 5 hours. After cooling the reaction mixture with an ice, 25.0 g of ethanol was added, followed by stirring for additional 30 minutes. The resulting solid was collected by filtration, and washed with a mixed solvent of chloroform and ethanol to obtain crude 4-methyl-2H-1,3-oxazine-2,6(3H)-dione represented by the formula:

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2009/111852, 2009, A1 Location in patent: Page/Page column 15
[2]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP1887002, 2008, A1 Location in patent: Page/Page column 32-33

29
poly(ethylene glycol)-poly[(2-aminoethyl)-L-aspartamide] [ No CAS ]
[ 616-02-4 ]
poly(ethylene glycol)-poly[(N'-citraconyl-2-aminoethyl)-L-aspartamide] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With pyridine at 25℃;

Reference： [1]Lee, Yan; Fukushima, Shigeto; Bae, Younsoo; Hiki, Shigehiro; Ishii, Takehiko; Kataoka, Kazunori [Journal of the American Chemical Society, 2007, vol. 129, # 17, p. 5362 - 5363]

30
[ 616-02-4 ]
[ 1073-62-7 ]
1-benzyl-4-methyl-1,2-dihydropyridazine-3,6-dione [ No CAS ]
[ 489402-46-2 ]

Reference： [1]Tetrahedron Letters,2007,vol. 48,p. 7817 - 7820

31
[ 616-02-4 ]
p-anisidine (2 mol) [ No CAS ]
[ 36725-28-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1998,vol. 46,p. 84 - 96
[2]Chemical and Pharmaceutical Bulletin,1998,vol. 46,p. 84 - 96

32
[ 616-02-4 ]
[ 542-92-7 ]
(1R)-1-methyl-endo,endo-bicyclo<2.2.1>hept-5-ene-2,3-dicarboxylic anhydride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In dichloromethane at -78℃; for 4h;	4.i EXAMPLE 4; Use of Different Dienophiles and bis(imine) Ligands; The general method of Example 2 was repeated using cyclopentadiene as the diene with a range of different dienophiles as depicted in Table 2 below. The reaction times were varied as shown. In each case the copper-exchanged zeolite Y (CuHY) was treated with one of four different bis(oxazoline) compounds as follows

Reference： [1]Current Patent Assignee: JOHNSON MATTHEY PLC - US2005/33100, 2005, A1 Location in patent: Page/Page column 7-8

33
[ 616-02-4 ]
[ 20529-23-1 ]
[ 850804-11-4 ]

Yield	Reaction Conditions	Operation in experiment
87.5%	In toluene for 1 - 4h; Heating / reflux;	1.3 To a solution of 3- [4- (2-Methoxy-phenyl)-piperazin-1-yl]-propylamine (1 gm, 4 mmole) in toluene (10 ml) was added citraconic anhydride (0.44 gm, 4 mmole) under stirring and the reaction mixture was refluxed for 1 to 4 hours with constant removal of azeotropic mixture. After completion of the reaction, the reaction mass was concentrated to yield the title compound in a yield of 1.2 gm (87.5%).

Reference： [1]Current Patent Assignee: SUN PHARMACEUTICAL INDUSTRIES LIMITED - WO2005/37281, 2005, A1 Location in patent: Page/Page column 22

34
[ 616-02-4 ]
[ 86302-43-4 ]
C₁₁H₁₄O₄ [ No CAS ]
[ 74826-53-2 ]

Yield	Reaction Conditions	Operation in experiment
56.6%	In tetrahydrofuran at 12 - 35℃; for 4h;	2 To a cooled (12° C.) solution of the phosphorane (16; 3.008 Kg; 7.99 mol) in THF (12 L) was added citraconic anhydride (1.35 Kg; 12.04 mol) over a 4 h period during which the temperature rose to 35 C. Following the addition, approximately 10 L of THF was removed by distillation and replaced with 4 L of methanol. Addition liquid was removed by distillation and replaced by methanol. A total of 14.6 L was distilled and 7 L of methanol added. To the mixture was added 1 L of water and 6 L of cyclohexane. The cyclohexane layer was separated, and the lower (methanol-water) layer was repeatedly extracted with cyclohexane (a total of 12 extractions each with approximately 6 L of cyclohexane). The cyclohexane fractions were combined and concentrated on a rotary evaporator. After solvent removal, methanol (1 L) was added and the mixture further concentrated on a rotary evaporator. The resulting oil was taken up in methanol (2 L) and cooled to -12° C. for 3 h. After filtration, the solid cake was washed with MeOH (400 mL cooled to 0° C.) and the solid was dried in a vacuum desiccator to afford (4-ethyl-5-oxo-5H-furan-2-ylidene)-acetic acid tert-butyl ester (18, 950 g; 56.6% yield).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2005/234236, 2005, A1 Location in patent: Page/Page column 9; 11

35
[ 4641-57-0 ]
[ 616-02-4 ]
4-((2-Oxo-pyrrolidin-1-yl)-phenyl)-4-oxo-3-methyl-2-butenoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In carbon disulfide	1 4-((2-Oxo-pyrrolidin-1-yl)-phenyl)-4-oxo-3-methyl-2-butenoic acid EXAMPLE 1 4-((2-Oxo-pyrrolidin-1-yl)-phenyl)-4-oxo-3-methyl-2-butenoic acid 66.7 g (0.5 mole) of anhydrous aluminum chloride are suspended in 150 ml of carbon disulphide. 32.2 g (0.2 mole) of N-phenyl-pyrrolidin-2-one and 22.4 g (0.2 mole) of methylmaleic anhydride are added, while stirring and cooling. The mixture is heated under reflux until a viscous mass is formed, and this is left to stand at room temperature for 40 hours, the solvent is decanted off and the mixture is decomposed carefully with icewater and concentrated aqueous hydrochloric acid and extracted with methylene cchloride or ethyl acetate. The organic phase is extracted with dilute sodium hydroxide solution, the aqueous phase is clarified by filtration, acidified with acetic acid and extracted and the extract is concentrated. The resulting oil is further reacted directly. Yield: 37.6 g (69% of theory).

Reference： [1]Current Patent Assignee: SANOFI - US4816454, 1989, A

36
[ 616-02-4 ]
[ 56-12-2 ]
[ 942218-09-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With acetic acid at 150℃; for 6h; Inert atmosphere;	General Procedure A for solventless imide formation General procedure: Substituted maleic anhydride (1.0 eq) was added to 4-aminobutanoic acid (1.0 eq) and heated at150 °C for 6 hours while stirring. The reaction was left to cool to room temperature with theresulting solid mass dissolved in DCM (10 mL). The organic layer was washed using 0.5 N HCl (2x 10 mL) with the combined aqueous layers being back extracted with DCM (20 mL). The organiclayers were then combined and concentrated by reduced pressure to afford the desired maleimide.
68%	In acetic acid for 1.5h; Heating;

Reference： [1]Ibbotson, Lewis T.; Christensen, Kirsten E.; Genov, Miroslav; Pretsch, Alexander; Pretsch, Dagmar; Moloney, Mark G. [Synlett, 2022, vol. 33, # 4, p. 396 - 400]
[2]De Figueiredo, Renata Marcia; Oczipka, Philipp; Froehlich, Roland; Christmann, Mathias [Synthesis, 2008, # 8, p. 1316 - 1318]

37
[ 56281-06-2 ]
[ 616-02-4 ]
C₂₁H₁₆F₂₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.6%	With toluene-4-sulfonic acid In toluene at 112℃; for 46h;	10 Citraconic anhydride (0.75 g, 6.7 mmol), C4F9CH2CF2CH2CH2OH (4.37 g, 13.3 mmol, prepared as described above), /?-toluenesulfonic acid monohydrate (0.13 g), and toluene (50 mL) were refluxed for about 46 h at 112°C, after which only the diester was observed in the LC/MS analysis. The work-up was carried out as in example 1 to give a pale yellow liquid (2.98 g, 59.6% yield, >99% purity) which was analyzed by 1H NMR and LC/MS to confirm the diester structure asC4F9CH2CF2CH2CH2OC(O)C(Cm)=CH2C(O)OCH2CH2CF2CH2C4F9.
59.6%	With toluene-4-sulfonic acid In toluene at 112℃; for 46h;	10 Citraconic anhydride (0.75 g, 6.7 mmol), C4F9CH2CF2CH2CH2OH (4.37 g, 13.3 mmol, prepared as described above), p-toluenesulfonic acid monohydrate (0.13 g), and toluene (50 mL) were refluxed for about 46 h at 112° C., after which only the diester was observed in the LC/MS analysis.The work-up was carried out as in example 1 to give a pale yellow liquid (2.98 g, 59.6% yield, >99% purity) which was analyzed by 1H NMR and LC/MS to confirm the diester structure as C4F9CH2CF2CH2CH2OC(O)C(CH3)=CH2C(O)OCH2CH2CF2CH2C4F9.

Reference： [1]Current Patent Assignee: The Chemours Company - WO2010/2623, 2010, A2 Location in patent: Page/Page column 27
[2]Current Patent Assignee: DUPONT DE NEMOURS INC - US2010/4478, 2010, A1 Location in patent: Page/Page column 11 Current Patent Assignee: DUPONT DE NEMOURS INC - US2010/4482, 2010, A1 Location in patent: Page/Page column 11

38
[ 616-02-4 ]
[ 904055-94-3 ]
C₂₁H₁₄F₂₂N₂O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With toluene-4-sulfonic acid In toluene at 111℃; for 40h;	9 Citraconic anhydride (0.67 g, 6.0 mmol), C3FyOCF(CF3)CONHCH2CH2OH (4.44 g, 12 mmol, prepared as described above), /?-toluenesulfonic acid monohydrate (0.11 g, 0.60 mmol) and toluene (50 mL) were added together and heated to reflux at 111°C, with continual stirring, for 40 h. There were two noticeable solid materials present within the toluene solution. The pinkish solid was removed and the white solid was vacuum filtered. Both materials were analyzed by LC/MS, which confirmed that the pinkish solid was the product and the white solid was unreacted alcohol (1.22g). The product (2.98 g, 59.6% yield, 65% purity) was analyzed by 1H NMR and LC/MS to confirm the structure as C3F7OCF(CF3)C(O)NHCH2CH2OC(O)- C(CH3)=CH2C(O)OCH2CH2NHC(O)CF(CF3)OC3F7.
	With toluene-4-sulfonic acid In toluene at 111℃; for 40h;	9 Citraconic anhydride (0.67 g, 6.0 mmol), C3F7OCF(CF3)CONHCH2CH2OH (4.44 g, 12 mmol, prepared as described above), p-toluenesulfonic acid monohydrate (0.11 g, 0.60 mmol) and toluene (50 mL) were added together and heated to reflux at 111° C., with continual stirring, for 40 h. There were two noticeable solid materials present within the toluene solution. The pinkish solid was removed and the white solid was vacuum filtered. Both materials were analyzed by LC/MS, which confirmed that the pinkish solid was the product and the white solid was unreacted alcohol (1.22 g). The product (2.98 g, 59.6% yield, 65% purity) was analyzed by 1H NMR and LC/MS to confirm the structure as C3F7OCF(CF3)C(O)NHCH2CH2OC(O)-C(CH3)CH2C(O)OCH2CH2NHC(O)CF(CF3)OC3F7.

Reference： [1]Current Patent Assignee: The Chemours Company - WO2010/2623, 2010, A2 Location in patent: Page/Page column 27
[2]Current Patent Assignee: DUPONT DE NEMOURS INC - US2010/4478, 2010, A1 Location in patent: Page/Page column 10-11 Current Patent Assignee: DUPONT DE NEMOURS INC - US2010/4482, 2010, A1 Location in patent: Page/Page column 10-11

39
[ 616-02-4 ]
[ 137820-87-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: citraconic acid anhydride In ethyl acetate for 150h; UV-irradiation; Stage #2: With acetic anhydride at 150℃; for 24h;	6 [Preparation example 6] Preparation of 1, 3-dimethyl-l, 2 , 3 , 4- cyclobutanetetracarboxylic acid dianhydride (DM-CBDA)To a 2L quartz glass photoreactor equipped with sixteen UV lamps (300nm) , a stirrer and a cooler were attached and 250ml of ethyl acetate and lOOg of citraconic anhydride were added thereto followed by stirring for complete mixing. To avoid an excessive temperature increase, an air-cooling type cooler was first run and then UV light was illuminated for a photoreaction for 150 hours with stirring so as not to have the reactants adhered to the reactor walls. As a result, 40 g of white solid was obtained. After the filtration, the white solid was dried for 24 hrs in a vacuum dryer at 60 °C Thus- obtained solid was then added to acetic anhydride, dissolved therein and slowly heated to 150 °C followed by the reaction for 24 hrs. Hot reaction solution was filtered through a filter paper to remove impurities and kept in a freezer at the temperature of 0 °C or less for recrystallization for 24 hours to obtain a yellow solid. Thus-obtained solid was filtered and washed three times with 1,4-dioxane to remove acetic anhydride, and then dried in a vacuum oven at 60°Cfor 48 hours to obtain 35 g of yellow 1 , 3-dimethyl-1 , 2 , 3 , 4-cyclobutane tetracarboxylic acid dianhydride (DM-CBDA) . Figure 6 is a 1H NMR spectrum of said DM-CBDA compound.

Reference： [1]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - WO2008/153286, 2008, A2 Location in patent: Page/Page column 28; 29

40
[ 616-02-4 ]
[ 22259-53-6 ]
[ 1217312-35-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 1124 - 1127

41
4-Chloro-5-(thien-2-yl)thieno[2,3-d]pyrimidine [ No CAS ]
[ 616-02-4 ]
3-methyl-1-(5-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 4-Chloro-5-(thien-2-yl)thieno[2,3-d]pyrimidine With hydrazine In tetrahydrofuran at 80℃; for 4h; Stage #2: citraconic acid anhydride In chloroform at 80℃; for 20h;	1.5 Step 5. Preparation of 3-methyl-l-(5-thiophen-2-yl-thieno[2.3-d1 pyrimidin-4-ylaminos)-pyrrole-2.5-dione; The compound (70mg, 0.28mmol) prepared in the step 4 was dissolved in THF(5ml). Therein, hydrazine monohydrate (27D, 0.56mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 4 hours. After reaction, the solvent was removed under reduced pressure, and dried in vacuum drier. The residue was dissolved in chloroform, therein citraconic anhydride (75D, 0.84mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 20 hours. The reaction mixture was washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:1) to give 51mg (yield: 54%, white solid) of the target compound.[299] 1U NMR(400D, CDCI); δ 8.50(s, IH), 7.43(d, J=4.8Hz, IH), 7.38(s, IH), 7.34(d, J=4.0Hz, IH), 7.14(m, 2H), 6.49(s, IH), 2.16(d, J=1.6Hz, 3H).

Reference： [1]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - WO2007/102679, 2007, A1 Location in patent: Page/Page column 28

42
[ 949526-44-7 ]
[ 616-02-4 ]
1-(2,6-di-thiophen-2-yl-thieno[2,3-d]pyrimidin-4-ylamino)-3-methyl-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	Stage #1: 4-chloro-2,6-di-thiophen-2-yl-thieno[2,3-d]pyrimidine With hydrazine In tetrahydrofuran at 80℃; for 10h; Stage #2: citraconic acid anhydride In chloroform at 80℃; for 20h;	7.5 Step 5. Preparation of l-(2.6-di-thiophen-2-yl-thienor2.3-dl pyrimidin-4-ylaminoV3-methyl-pyrrole-2.5-dione; The compound (55mg, 0. lβmmol) prepared in the step 4 was dissolved in THF(5ml). Therein, hydrazine monohydrate (23D, 0.48mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 10 hours. After reaction, the solvent was removed under reduced pressure, and dried in vacuum drier. The residue was dissolved in chloroform(5ml), therein citraconic anhydride (43D, 0.48mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 20 hours. The reaction mixture was washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 1:1) to give 37mg (yield: 54%, white solid) of the target compound.[343] 1U NMR(400D, CDCI); δ 10.73(s, IH), 7.81(s, IH), 7.70(s, IH), 7.70(d, J=4.0Hz,2H), 7.46(dd, J=LlBz, J=3.6Hz, IH), 7.20(dd, J=4.0Hz, J=5.2Hz, IH), 7.14(t, J =4.4Hz, IH), 7.02(d, J=2.0Hz, IH), 2.07(s, 3H).

Reference： [1]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - WO2007/102679, 2007, A1 Location in patent: Page/Page column 32

43
[ 949526-48-1 ]
[ 616-02-4 ]
1-[2,5-di(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-ylamino]-3-methyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	Stage #1: 4-chloro-2,5-di(thiophen-2-yl)thieno[2,3-d]pyrimidine With hydrazine In tetrahydrofuran at 80℃; for 4h; Stage #2: citraconic acid anhydride In chloroform at 80℃; for 18h;	8.1.5; 8.2.5 Step 5. Preparation of l-(2.5-di-thiophen-2-yl-thieno[2.3-dl pyrimidin-4-ylamino)-3-methyl-pyrrole-2.5-dione; The compound (75mg, 0.22mmol) prepared in the step 4 was dissolved in THF (3ml). Therein, hydrazine monohydrate (33D, 0.67mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 4 hours. After reaction, the solvent was removed under reduced pressure, and dried in vacuum drier. The residue was dissolved in chloroform, therein, citraconic anhydride (65D, 0.67mmol) was slowly added, and the reaction mixture was stirred at 8O0C for 18 hours. The reaction mixture was washed with water and saturated sodium chloride aqueous solution. Combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (n-hexane: ethyl acetate = 2:1) to give 46mg (yield: 48%, yellow solid) of the target compound.[374] 1U NMR(400D, CDCD; δ 7.80(d, J=4.0Hz, IH), 7.45(d, J=4.8Hz, IH), 7.38(m, 2H), 7.30(s, IH), 7.18(m, IH), 7.14(br, 12H), 7.07 (dd, J=4.0Hz, J=5.2Hz, IH), 6.59(d, J=1.6Hz, IH), 2.23(s, IH).; Step 5. Preparation of l-(2.5-di-thiophen-2-yl-thienor2.3-dl pyrimidin-4-ylaminoV3-methyl-pyrrole-2.5-dione hydrochloride; According to the similar procedure in the step 5 and step 6 of example 8 (method 1) by using the compound prepared in the step 4, the target compound was obtained.

Reference： [1]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - WO2007/102679, 2007, A1 Location in patent: Page/Page column 35; 37-38

44
[ 616-02-4 ]
[ 1834-27-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 1644 - 1658

45
[ 616-02-4 ]
[ 756525-95-8 ]
C₁₆H₂₅NO₆ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 4249 - 4253

46
[ 72-18-4 ]
[ 616-02-4 ]
[ 1448189-60-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	With acetic acid at 120℃; for 1h; Microwave irradiation; Sealed tube;	(S)-3-methyl-2-(3-methyl-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butanoic acid -3-methyl-2-(3-methyl-2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)butanoic acid A mixture of 3-methylfuran-2,5-dione (commercially available from for example Aldrich) (0.12 mL, 1.3 mmol) and (S)-2-amino-3-methylbutanoic acid (commercially available from for example Apollo Scientific) (150 mg, 1.3 mmol).in acetic acid (1 mL) was sealed and heated in a Biotage "Initiator" microwave at 120°C for 1 hour. The mixture was evaporated to dryness to afford the title compound (253 mg, 94% yield). LCMS RT= 0.75 min, ES+ve m/z 212 [M+H]+
94%	In acetic acid at 120℃; for 1h; Microwave irradiation;	(S)-3-methyl-2-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butanoic acid A mixture of 3-methylfuran-2,5-dione (commercially available from for example Aldrich) (0.12 mL, 1.3 mmol) and (S)-2-amino-3-methylbutanoic acid (commercially available from for example Apollo Scientific) (150 mg, 1.3 mmol). in acetic acid (1 mL) was sealed and heated in a Biotage "Initiator" microwave at 120° C. for 1 hour. The mixture was evaporated to dryness to afford the title compound (253 mg, 94% yield). LCMS RT=0.75 min, ES+ve m/z 212 [M+H]+.

Reference： [1]Current Patent Assignee: YALE UNIVERSITY; UNIVERSITY OF CAMBRIDGE; GLAXOSMITHKLINE PLC - WO2013/106646, 2013, A2 Location in patent: Page/Page column 199
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC; UNIVERSITY OF CAMBRIDGE; YALE UNIVERSITY - US2014/356322, 2014, A1 Location in patent: Paragraph 0447

47
[ 616-02-4 ]
N-(3-aminopropyl)cinnamamide [ No CAS ]
N-[3-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propyl]cinnamamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With acetic acid for 12h; Reflux;	N-[4-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl]cinnamamide (5b); Typical Procedure General procedure: A stirred soln of N-(4-aminobutyl)cinnamamide (4b, 1.00 g, 4.58 mmol) and citraconic anhydride (565 mg, 5.04 mmol) in glacial AcOH (10 mL) was refluxed for 12 h. AcOH was distilled off under vacuum and sat. NaHCO3 soln was slowly added to the reaction mass. The mixture was extracted with EtOAc (3 × 20 mL) and the combined organic layers were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc-PE, 9:1) to afford pure imide 5b as a white solid; yield: 1.28 g (90%); mp 110-112 °C.

Reference： [1]Batwal, Ramesh U.; Argade, Narshinha P. [Synthesis, 2013, vol. 45, # 20, p. 2888 - 2892]

48
[ 616-02-4 ]
N-(4-aminobutyl)cinnamamide [ No CAS ]
N-[4-(3-methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl]cinnamamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With acetic acid for 12h; Reflux;	N-[4-(3-Methyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)butyl]cinnamamide (5b); Typical Procedure A stirred soln of N-(4-aminobutyl)cinnamamide (4b, 1.00 g, 4.58 mmol) and citraconic anhydride (565 mg, 5.04 mmol) in glacial AcOH (10 mL) was refluxed for 12 h. AcOH was distilled off under vacuum and sat. NaHCO3 soln was slowly added to the reaction mass. The mixture was extracted with EtOAc (3 × 20 mL) and the combined organic layers were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc-PE, 9:1) to afford pure imide 5b as a white solid; yield: 1.28 g (90%); mp 110-112 °C.

Reference： [1]Batwal, Ramesh U.; Argade, Narshinha P. [Synthesis, 2013, vol. 45, # 20, p. 2888 - 2892]

49
[ 616-02-4 ]
[ 1099-45-2 ]
[ 30268-57-6 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: citraconic acid anhydride; ethyl (triphenylphosphoranylidene)acetate In toluene at 20℃; for 0.25h; Stage #2: With sodium methylate In methanol at 20℃; for 20h; Reflux; Stage #3: With hydrogenchloride In ethanol; water	4.12 General procedure for preparation of compounds 7a-7c 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 β-isopropyl-γ-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 50°C, 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]Chen, Yuan-Siao; Yu, Hui-Ming; Shie, Jiun-Jie; Cheng, Ting-Jen Rachel; Wu, Chung-Yi; Fang, Jim-Min; Wong, Chi-Huey [Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 5, p. 1766 - 1772]

50
[ 949561-28-8 ]
[ 616-02-4 ]
1-[2,5-di(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-ylamino]-3-methyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	In chloroform at 80℃; for 18h;	4.2 General procedure for the preparation of title compounds 5a-5d General procedure: To a stirred solution of 3 (0.22 mmol) in THF (3 ml) hydrazine monohydrate (0.67 mmol) was added dropwise, and the mixture was stirred at 80 °C for 4 h. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. The residue 4 was then dissolved in CHCl3 (3 ml), and citraconic anhydride (0.67 mmol) was slowly added. The resulting mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx:EtOAc = 2:1) to afford the title compound 5.
	In chloroform at 80℃;

Reference： [1]Yang, Jee Sun; Park, Chun-Ho; Lee, Chulho; Kim, Hwan; Oh, Changmok; Choi, Yejoo; Kang, Jong Soon; Yun, Jieun; Jeong, Jin-Hyun; Kim, Myung-Hwa; Han, Gyoonhee [European Journal of Medicinal Chemistry, 2014, vol. 85, p. 399 - 407]
[2]Park, Chun-Ho; Lee, Chulho; Yang, Jee Sun; Joe, Bo-Young; Chun, Kwangwoo; Kim, Hyuntae; Kim, Hye Yun; Kang, Jong Soon; Lee, Jangik I.; Kim, Myung-Hwa; Han, Gyoonhee [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2655 - 2660] Park, Chun-Ho; Lee, Chulho; Yang, Jee Sun; Joe, Bo-Young; Chun, Kwangwoo; Kim, Hyuntae; Kim, Hye Yun; Kang, Jong Soon; Lee, Jangik I.; Kim, Myung-Hwa; Han, Gyoonhee [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2655 - 2660]

51
[ 616-02-4 ]
[ 1610505-50-4 ]
3-methyl-1-[2-phenyl-5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-ylamino]-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In chloroform at 80℃; for 18h;	4.2 General procedure for the preparation of title compounds 5a-5d General procedure: To a stirred solution of 3 (0.22 mmol) in THF (3 ml) hydrazine monohydrate (0.67 mmol) was added dropwise, and the mixture was stirred at 80 °C for 4 h. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. The residue 4 was then dissolved in CHCl3 (3 ml), and citraconic anhydride (0.67 mmol) was slowly added. The resulting mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx:EtOAc = 2:1) to afford the title compound 5.
	In chloroform at 80℃;

Reference： [1]Yang, Jee Sun; Park, Chun-Ho; Lee, Chulho; Kim, Hwan; Oh, Changmok; Choi, Yejoo; Kang, Jong Soon; Yun, Jieun; Jeong, Jin-Hyun; Kim, Myung-Hwa; Han, Gyoonhee [European Journal of Medicinal Chemistry, 2014, vol. 85, p. 399 - 407]
[2]Park, Chun-Ho; Lee, Chulho; Yang, Jee Sun; Joe, Bo-Young; Chun, Kwangwoo; Kim, Hyuntae; Kim, Hye Yun; Kang, Jong Soon; Lee, Jangik I.; Kim, Myung-Hwa; Han, Gyoonhee [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2655 - 2660] Park, Chun-Ho; Lee, Chulho; Yang, Jee Sun; Joe, Bo-Young; Chun, Kwangwoo; Kim, Hyuntae; Kim, Hye Yun; Kang, Jong Soon; Lee, Jangik I.; Kim, Myung-Hwa; Han, Gyoonhee [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 12, p. 2655 - 2660]

52
[ 616-02-4 ]
[ 109-73-9 ]
[ 80818-17-3 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: citraconic acid anhydride With pyridine In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: N-butylamine In N,N-dimethyl-formamide at 20℃;	General procedure for the synthesis of maleic acid amide derivatives General procedure: Pyridine (5.0 equiv.) was added to a solution of the prepared maleic anhydride derivative (1.0 equiv.) in DMF at the ambient temperature. After stirring the mixture for 15 min, n-butylamine (1.0 equiv.) was added to it. The resulting mixture was stirred and maintained at the ambient temperature. Reaction completion was monitored by thin-layer chromatography (TLC). Upon completion, the mixture was purified by the methods described in the following sections.

Reference： [1]Kang, Sunyoung; Kim, Youngeun; Song, Youngjun; Choi, Jin Uk; Park, Euddeum; Choi, Wonmin; Park, Jeongseon; Lee, Yan [Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 10, p. 2364 - 2367]

53
[ 616-02-4 ]
[ 1622230-04-9 ]
3-methyl-1-[2-(5-methylthiophen-2-yl)-5-(thiophen-2-yl)thieno[2,3-d]pyrimidin-4-ylamino]-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	In chloroform at 80℃; for 18h;	4.2 General procedure for the preparation of title compounds 5a-5d General procedure: To a stirred solution of 3 (0.22 mmol) in THF (3 ml) hydrazine monohydrate (0.67 mmol) was added dropwise, and the mixture was stirred at 80 °C for 4 h. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. The residue 4 was then dissolved in CHCl3 (3 ml), and citraconic anhydride (0.67 mmol) was slowly added. The resulting mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx:EtOAc = 2:1) to afford the title compound 5.

Reference： [1]Yang, Jee Sun; Park, Chun-Ho; Lee, Chulho; Kim, Hwan; Oh, Changmok; Choi, Yejoo; Kang, Jong Soon; Yun, Jieun; Jeong, Jin-Hyun; Kim, Myung-Hwa; Han, Gyoonhee [European Journal of Medicinal Chemistry, 2014, vol. 85, p. 399 - 407]

54
[ 616-02-4 ]
[ 1622230-05-0 ]
3-methyl-1-[5-(thiophen-2-yl)-2-(thiophen-2-ylmethyl)thieno[2,3-d]pyrimidin-4-ylamino]-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	In chloroform at 80℃; for 18h;	4.2 General procedure for the preparation of title compounds 5a-5d General procedure: To a stirred solution of 3 (0.22 mmol) in THF (3 ml) hydrazine monohydrate (0.67 mmol) was added dropwise, and the mixture was stirred at 80 °C for 4 h. After cooling, the solvent was removed under reduced pressure and concentrated in vacuo. The residue 4 was then dissolved in CHCl3 (3 ml), and citraconic anhydride (0.67 mmol) was slowly added. The resulting mixture was heated to 80 °C and stirred for 18 h. The reaction mixture was cooled to room temperature and washed with water. The organic layer was dried over Na2SO4 and concentrated to dryness. The residue was then purified by flash column chromatography (n-Hx:EtOAc = 2:1) to afford the title compound 5.

Reference： [1]Yang, Jee Sun; Park, Chun-Ho; Lee, Chulho; Kim, Hwan; Oh, Changmok; Choi, Yejoo; Kang, Jong Soon; Yun, Jieun; Jeong, Jin-Hyun; Kim, Myung-Hwa; Han, Gyoonhee [European Journal of Medicinal Chemistry, 2014, vol. 85, p. 399 - 407]

55
[ 616-02-4 ]
[ 1262794-04-6 ]
[ 1262794-05-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: citraconic acid anhydride; tert-butyl N-3,5-diaminophenylcarbamate In chloroform at 25℃; for 3h; Stage #2: With 1,1,1,3,3,3-hexamethyl-disilazane; zinc(II) chloride In N,N-dimethyl-formamide; toluene for 4.33333h; Reflux;	tert-Butyl N-3,5-di-(2-methylmaleimido) phenylcarbamate (3) Citraconic anhydride (1.56 mL, 17.47 mmol) was added to a solution of 2 (1.3 g, 5.82 mmol) in CHCl3 (20 mL) and the resulting mixture was stirred at 25° C. for 3 hours after which volatiles were evaporated under reduced pressure. The crude was triturated with Et2O and filtered under reduced pressure giving the dimaleamic acid as a beige solid (2.59 g, 5.80 mmol, quantitative) that was used in the next step without further purification. (0143) Dimaleamic acid (400 mg, 0.894 mmol) and ZnCl2 (365 mg, 2.68 mmol) were dissolved in toluene/DMF (40:5 mL) after which a dilute solution of HMDS (0.84 mL, 4.02 mmol) in toluene (5 mL) was added over 20 minutes. The resulting mixture was then heated to reflux for 4 hours after which the volatiles were evaporated under reduced pressure. The resulting residue was dissolved in EtOAc and washed successively with 0.1 M HCl and saturated Na2CO3. The crude product was then purified by flash chromatography on silica gel (Toluene/EtOAc 5%) to give 3 as an off-white solid (780 mg, 1.90 mmol, 53%). 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J=2.4 Hz, 2H), 7.12 (t, J=2.4 Hz), 6.59 (bs, 1H), 6.43 (q, J=2.4 Hz, 2H), 2.12 (q, J=2.4 Hz, 6H), 1.47 (bs, 9H); 13C NMR (75 MHz, CDCl3) δ 170.0, 168.9, 152.2, 145.7, 139.5, 132.5, 127.4, 116.5, 114.1, 80.9, 28.1, 11.0; HRMS (ESI) Calculated for C21H21N3O6Na [M+Na]+: 434.1331. Found: 434.1323. m.p.: 179° C.

Reference： [1]Current Patent Assignee: UNIVERSITY OF OTTAWA - US8835641, 2014, B2 Location in patent: Page/Page column 22

56
[ 616-02-4 ]
[ 535-87-5 ]
[ 143659-09-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: citraconic acid anhydride; 3.5-diaminobenzoic acid In acetone at 25℃; for 2h; Stage #2: With 1,1,1,3,3,3-hexamethyl-disilazane; zinc(II) chloride In N,N-dimethyl-formamide; toluene for 5h; Reflux;	3,5-Di-(3-methylmaleimido)benzoic acid (12) To a solution of 3,5-diaminobenzoic acid (1.0 g, 6.58 mmol) in acetone (40 mL) was added citraconic anhydride (1.8 mL, 19.74 mmol) and the resulting mixture was stirred at 25° C. for 2 hours after which solvents were evaporated under reduced pressure. The crude solid was triturated in Et2O, filtered under reduced pressure and used in the next step without further purification. The dimaleamic acid (500 mg, 1.33 mmol) was dissolved in DMF (5 mL) and then toluene (40 mL) was added, followed by ZnCl2 (544 mg, 3.99 mmol) and HMDS (1.13 mL, 5.98 mmol). The resulting mixture was heated to reflux for 5 hours after which the solvents were evaporated. The title compound 12 was obtained as an off-white solid after precipitation with 0.1 M HCl (417 mg, 1.22 mmol, 92%). 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J=1.8 Hz, 2H), 7.62 (t, J=1.8 Hz, 1H), 6.83 (q, J=1.8 Hz, 2H), 2.08 (d, J=1.8 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 170.4, 169.5, 166.2, 146.2, 132.8, 132.2, 128.2, 127.8, 126.0, 11.0; HRMS (ESI) Calculated for C17H13N2O6 [M+H]+: 341.0768. Found: 341.0770. m.p.: 254° C. (dec.).

Reference： [1]Current Patent Assignee: UNIVERSITY OF OTTAWA - US8835641, 2014, B2 Location in patent: Page/Page column 27

57
[ 616-02-4 ]
oleanolic acid [ No CAS ]
(3β)-3-(((E)-3-carboxybut-2-enoyl)oxy)-olean-12-en-28-oic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With dmap In dimethyl sulfoxide at 40℃; for 24h;	2.3.2. General procedure for the synthesis of oleanolic acid esters using cyclic anhydrides General procedure: To a solution of 1 (0.01 g, 0.22 mmol) in 3 mL DMSO is added the appropriate cyclic anhydride (0.88 mmol) in 2 mL DMSO. The solution is thermostatted at 40 °C. N,N-Dimethyl-4-aminopyridine (DMAP) (0.22 mmol) is added to the solution while stirring. The reaction of the mixture is kept at 40 °C for 24 h. The reaction’s product was diluted in distilled water, washed with a solution of HCl (3 M), then extracted with ethyl acetate. The organic layer was dried over sodium sulfate. After the evaporation of the solvent, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) or recrystallization to give the esters 1f-j, in 81-92% yield (Table 2).

Reference： [1]Chouaïb, Karim; Hichri, Fayçal; Nguir, Asma; Daami-Remadi, Majda; Elie, Nicolas; Touboul, David; Ben Jannet, Hichem; Hamza, M'Hamed Ali [Food Chemistry, 2015, vol. 183, p. 8 - 17]

58
[ 616-02-4 ]
2α,3β-dihydroxyolean-12-en-28-oic acid [ No CAS ]
(2α,3β)-2,3-bis(((E)-3-carboxybut-2-enoyl)oxy)olean-12-en-28-oic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap In dimethyl sulfoxide at 40℃; for 24h;	2.3.4. General procedure for the synthesis of maslinic acid esters using cyclic anhydrides General procedure: To a solution of maslinic acid (0.01 g, 0.21 mmol) in 3 mL DMSO is added the appropriate cyclic anhydride (1.7 mmol) in 2 mL DMSO. The solution is thermostatted at 40 °C and N,N-dimethyl-4-aminopyridine (0.44 mmol) is added while stirring. The reaction’s mixture is kept at 40 °C for 24 h. The reaction’s product was isolated and then diluted in distilled water, then extracted with ethyl acetate. After washing it with a solution of hydrochloric acid (3 M), the organic layer was dried over sodium sulfate. After the evaporation of the solvent, the crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate 6:4) to give the esters 2k-o in 81-94% yield (Table 2).

Reference： [1]Chouaïb, Karim; Hichri, Fayçal; Nguir, Asma; Daami-Remadi, Majda; Elie, Nicolas; Touboul, David; Ben Jannet, Hichem; Hamza, M'Hamed Ali [Food Chemistry, 2015, vol. 183, p. 8 - 17]

59
[ 616-02-4 ]
[ 106-50-3 ]
(2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.3%	In tetrahydrofuran at 20℃; for 3.33333h; Inert atmosphere; Cooling with ice;	4 Production Example 4 Production of (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid Production Example 4Production of (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acidUnder a nitrogen atmosphere, into a reaction vessel were charged 10.0 g (92.5 mmol) of 1,4-phenylenediamine and 250 ml of tetrahydrofuran. A solution prepared by dissolving 10.4 g (92.5 mmol) of citraconic anhydride in 20 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 20 minutes, then, the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the deposited crystal was isolated by filtration, and dried to obtain 15 g of coarse (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid. Five grams (5 g) of coarse (2Z)-4-[(4-aminophenyl)amino]-2-methyl4-oxo-2-butenoic acid was repulped with 2-propanol and methanol each at 50° C. for 3 hours, then, repulped with chloroform, to obtain 13.1 g of (2Z)-4-[(4-aminophenyl)amino]-2-methyl-4-oxo-2-butenoic acid as a yellow solid. Yield: 64.3%.

Reference： [1]Current Patent Assignee: SUMITOMO CHEMICAL COMPANY LIMITED; Sumitomo Chemical (w/o Dongwoo Fine-Chem) - US2015/251992, 2015, A1 Location in patent: Paragraph 0191; 0192

60
ferrocenium hexafluorophosphate [ No CAS ]
[ 616-02-4 ]
(±)-(3aS,4R,7S,7aR,8R)-8-hydroxy-3a-methyl-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
9%	With oxygen In water; acetonitrile at 20℃; for 4h;	Cycloaddition Procedure General procedure: The dienophile (1.20 mmol, 2.00 equiv) was dissolved in a mixture of MeCN (5 mL)/H2O (0.05 mL), and Cp2FePF6 (200 mg, 0.60 mmol, 1.00 equiv) was added in one portion at room temperature. The dark blue-black solution was stirred open to air for four hours, becoming dark brown-black over time. The crude reaction mixture was loaded directly onto a short pad of silica gel and eluted with a 50% acetone/hexane mixture (125 mL). The solution was concentrated and the product mixture was further purified by silica gel flash chromatography using 25% ethyl acetate/hexane, then 50% ethyl acetate/hexane, as the eluent. Fractions containing product were concentrated under reduced pressure to afford the cycloadducts.

Reference： [1]Allen, Stacey K.; Lathrop, Thomas E.; Patel, Sweta B.; Harrell Moody, Deanna M.; Sommer, Roger D.; Coombs, Thomas C. [Tetrahedron Letters, 2015, vol. 56, # 44, p. 6038 - 6042]

61
[ 616-02-4 ]
[ 131748-14-6 ]
[ 368-90-1 ]
4-methyl-2-[4-(trifluoromethyl)phenyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]oxy]-3(2H)-pyridazinone [ No CAS ]
5-methyl-2-[4-(trifluoromethyl)phenyl]-6-[[2-(trifluoromethyl)-4-pyridinyl]oxy]-3(2H)-pyridazinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
150 mg; 230 mg		4-Trifluoromethylphenyl hydrazine (4.8 g, 27 mmol) was treated with a mixture of 1 N hydrochloric acid (20 mL) and concentrated hydrochloric acid (2 mL) followed by citraconic anhydride (2.6 mL, 27 mmol). The mixture was heated at 100 C. for 2 h. The reaction mixture produced a thick suspension which, upon cooling, was filtered and washed with water (2×25 mL). The solid was mixed with aqueous sodium hydroxide (1 N, 100 mL) and extracted with dichloromethane (2×100 mL). The aqueous layer was acidified with concentrated hydrochloric acid. The solid produced was filtered and washed with water (3×10 mL). Drying afforded a solid mixture of 4- and 5-methylpyridazinones (1.3 g) which was dissolved in dimethylformamide (5 mL) and treated successively with <strong>[131748-14-6]4-chloro-2-trifluoromethylpyridine</strong> (0.9 g, 5 mmol) and potassium carbonate (2.4 g, 17 mmol). The resulting mixture was heated at 110 C. for 18 h and poured onto ice-water (100 g). After standing the aqueous layer was decanted from an oil which was dissolved in dichloromethane (50 mL) and dried over MgSO4. The residue after filtration and evaporation was subjected to chromatography on silica gel (24 g) eluting with ethyl acetate in hexanes (0-100%). The title compound was eluted first as a thick oil (150 mg).

Reference： [1]Patent: US2016/68509,2016,A1 .Location in patent: Paragraph 0408-0411

62
[ 39222-73-6 ]
[ 616-02-4 ]
1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-methyl-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	In 5,5-dimethyl-1,3-cyclohexadiene; at 20 - 120℃; for 12.6667h;Microwave irradiation;	2-methyl maleic anhydride (0.2 mL, 2.2 mM), 2-amino-5-tert-butyl-1 ,3,4-thiadiazol (230 mg, 1.5 mM) and methyl butyric acid (0.5 mL) were dissolved in xylene (4 mL). The solution was heated - - with stirring in a microwave at 120 C for 40 minutes. 3 mL of the solvent was evaporated, and the mixture was allowed to stand at ambient temperature for 12 hours. The solvent was evaporated to produce a yellow oil which was chromatographed to give a white solid (190 mg, 50%) 1 H NMR (CDCI3): 1.51 (s, 9H), 2.23(s, 3H), 6.62(broad s, 1 H)

Reference： [1]Patent: WO2016/71359,2016,A1 .Location in patent: Page/Page column 40-41

63
[ 616-02-4 ]
[ 150-78-7 ]
[ 14554-09-7 ]

Yield	Reaction Conditions	Operation in experiment
55%	Stage #1: citraconic acid anhydride; 1,4-dimethoxybezene With aluminum (III) chloride; sodium chloride Stage #2: With hydrogenchloride In water at 0℃;
	Stage #1: citraconic acid anhydride; 1,4-dimethoxybezene With aluminum (III) chloride; sodium chloride at 180 - 200℃; Stage #2: With hydrogenchloride at 0℃;	a; b 5,8-dihydroxynaphthoquinone derivatives substituted at the 2, 3, 6 and 7 positions were synthesized. Four different schemes were employed for this purpose. (0122) [0089] Scheme 1 (Figure 1) involved the double Friedel-Crafts acylation reaction using substituted maleic anhydrides and/or substituted l,4-dimethoxybenzene in the presence of aluminum chloride and sodium chloride at high temperatures followed by demethylation with HC1 at 0°C (25-55% yield). With a methyl substitution on both of the reactants 8a and 8b isomeric mixture of products were obtained as inseparable mixture. With the use of visible light initiation (120W flood lamps), free radical halogenation of compound 6 using N- bromosuccinimide gave the brominated side chain compound 9 in 32% yield.
	Stage #1: citraconic acid anhydride; 1,4-dimethoxybezene With aluminum (III) chloride; sodium chloride Stage #2: With hydrogenchloride In methanol at 180 - 200℃;	Figure 6 sets forth the synthesis of the compounds from Figure 5. The first scheme involves the Friedel-Crafts acylation reaction between a substituted maleic anhydride and a substituted 1 ,4-dimeihoxybenzene in the presence of aluminum chloride followed by demethylation of the phenolic methyl ethers with IN hydrochloric acid in methanol to yield substituted 5,8-dihydroxynaphthalene- 1 A-dione compounds 17 to 24. The side chain methyl group of compound 17 was then subjected to free radical brominaiion to obtain the compound 12. Diels-Alder [4+2] cycloaddition reaction of 2-methylthiophene and 1 ,4-benzoquinone, with m-chloroperoxybenzoic acid in chloroform for 48h followed by silica gel chromatography was used for synthesizing compound 13 as illustrated in scheme 2. For the Diels-Alder reaction shown in scheme 3, the diene was initially made in two steps starting with the Wittig reaction of ketone of interest with ethyl (triphenylphosphoranyl idenejacetate in DCM at room temperature to form the α,β-unsaturated ester that is then treated with lithium diisopropylamide followed by trimethylsilyi chloride in foe second step to form foe 3 and/or 4-substituted dienes 1 -ethoxy- 1 - trimethylsiloxy-1, 4-diene. This diene was then reacted with 1 ,4-benzoquinone, the dienone to form the monomer or dimer 5-hydroxynaphihalene- 1 ,4-dione series of products (compounds 15, and 25 to 30). Formation of foe monomer or dimer was dictated by foe stoichiometry of foe 1 ,4- benzoquinone used in the reaction. Use of 1.5 equivalents of 1 ,4-benzoquinone with respect to one equivalent of the diene resulted in the formation of foe dimers 26 to 30. A large excess of 1 ,4-benzoquinone (2.5 equivalents) under similar reaction conditions yielded the monomer 15 and 25.

Reference： [1]Schroeder, Richard L.; Goyal, Navneet; Bratton, Melyssa; Townley, Ian; Pham, Nancy A.; Tram, Phan; Stone, Treasure; Geathers, Jasmine; Nguyen, Kathy; Sridhar, Jayalakshmi [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 13, p. 3187 - 3191]
[2]Current Patent Assignee: XAVIER UNIVERSITY OF LOUISIANA - WO2020/76905, 2020, A1 Location in patent: Paragraph 0020-0024; 0035; 0088-0089
[3]Current Patent Assignee: XAVIER UNIVERSITY OF LOUISIANA - WO2021/81167, 2021, A1 Location in patent: Paragraph 0045; 0092

64
[ 1477-55-0 ]
[ 616-02-4 ]
[ 119462-56-5 ]

Yield	Reaction Conditions	Operation in experiment
97.5%	With acetic acid In toluene at 110℃; for 5h;	1-8 Example 8 60 g of 98% citraconic anhydride and 150 mL of solvent toluene were added to a four-necked flask (with a condensing water separator), and then 3 g of acetic acid was added. The temperature was raised to about 110 ° C and refluxed, and 36 g of m-xylylenediamine was added dropwise. The dropping time is controlled at about 1.0 hour, and the temperature is kept at reflux for 4.0 hours; After the reaction is completed, the toluene is distilled off under normal pressure, and the temperature is lowered to 60 ° C. Add 100g of methanol, stir evenly, and filter after cooling. The filter cake is dried, and the filtrate is collected and recycled. Finished product inspection: appearance of white powder, melting point 78.8 ° C, the yield was 97.5%, and its content was determined by high performance liquid chromatography to be 99.2%.
92%	With acetic acid at 110℃; for 4h;	3 Example 3: Were charged sequentially to a 500 ml three-necked flask112 g (1 mol) of 2-methylmaleic anhydride,224 g acetic acid as solvent,M-xylylenediamine (68 g, 0.5 mol)The oil bath was heated to 110 ° C,Incubation reaction 4 hours,At the end of the reaction,The solvent was distilled off under reduced pressure,Cooling to 70 degrees,To the reaction system, 300 g of a mixed solvent of ethyl acetate and petroleum ether was added,Stirring down to room temperature that there are class of white crystals,Filtered to obtain a white filter cake,Washed with plenty of water,Drying to the desired product1,3-bis (citraconimidemethyl) benzene. The purity was 99.5% by gas chromatography and the yield was 92%.1,3-bis (citraconamidomethyl) benzene

Reference： [1]Current Patent Assignee: SHANDONG STAIR CHEMICAL & TECHNOLOGY CO LTD - CN110003078, 2019, A Location in patent: Paragraph 0015-0022
[2]Current Patent Assignee: LANXI BAIGAO CHEMICAL; ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN106083687, 2016, A Location in patent: Paragraph 0015

65
[ 616-02-4 ]
3,3'-dimethyl-1,1'-bipyrrole-2,2',5,5'-tetraone [ No CAS ]
[ 5754-18-7 ]

Yield	Reaction Conditions	Operation in experiment
1: 65% 2: 20%	With hydrogenchloride; hydrazine hydrate In water Cooling with ice;	prep of 6-hydroxy-5-methylpyridazin-3-one (2) and 3,3'-dimethyl-1,1'-bipyrrole-2,2',5,5'-tetraone (2a) To the stirred and cooled on ice solution of 1.12 g (0.01 mol)of citraconic anhydride in 50 cm3 of 10% HCl 0.49 g (0.01 mol) of99% hydrazine hydrate was added dropwise. The precipitate wasfiltered, crystallized from EtOH and identified as compound 2.Yield 65%, mp: 282-285 C (286.5-287C [8]); 1H NMR(400 MHz; DMSO; TMS): d = 2.02 (d, J = 1.4Hz, 3H), 6.87 (q,J = 1.4Hz, 1H), 10.82 (br s, O H N, 1H), 11.79 (br s, O H N,1H); 13C NMR (100 MHz, DMSO, TMS): d = 129.88, 139.49,158.48, 159.32.The filtrate was extracted with CH2Cl2. The extracts werewashed with water, dried (MgSO4) and evaporated. The residuewas crystallized from H2O and identified as 2a. Yield 20%, mp:139-140 C; 1H NMR (400 MHz, CDCl3, TMS): d = 2.18 (d,J = 1.9 Hz, 6H), 6.55 (q, J = 1.9 Hz, 2H); 13C NMR (100 MHz, CDCl3,TMS): d = 132.32, 150.21, 163.92, 166.28.

Reference： [1]Katrusiak, Anna; Katrusiak, Andrzej [Journal of Molecular Structure, 2015, vol. 1085, p. 28 - 36]

66
[ 616-02-4 ]
[ 100-63-0 ]
[ 91137-94-9 ]
[ 10071-49-5 ]

Yield	Reaction Conditions	Operation in experiment
1: 55% 2: 40%	With hydrogenchloride In water for 3h; Reflux;	prep of 6-Hydroxy-5-methyl-2-phenylpyridazine-3-one (4) and3-methyl-1-(phenylamino)-1H-pyrrole-2,5-dione (4a) To 1.12 g(0.01 mol) of citraconic anhydride in 50 cm3 of 10% HCl 1.09 g(0.01 mol) of phenylhydrazine was added dropwise. The mixturewas heated under reflux for 3 h. After cooling the precipitate wasfiltered and purified by column chromatography. Isolated compoundswere identified as 4 and 4a.Compound 4; Yield 55%, mp: 225 C (220-221 C [8a]); 1H NMRdH (400 MHz, DMSO, TMS): d = 2.11(d, J = 1.3 Hz, 3H), 6.87 (q,J = 1.3 Hz, 1H), 7.32-7.57 (m, 5H), 11.47 (br s, O H N, 1H); 13CNMR (100 MHz, CDCl3, TMS): d = 22.02, 125.15, 126.62, 132.31,141.30, 158.91, 162.95. Compound 4a; Yield 40%, mp: 158-160 C (155-157 C [12]);1H NMR (400 MHz, DMSO, TMS): d = 2.11(d, J = 1.3 Hz, 3H), 7.08(q, J = 1.3 Hz, 1H), 7.33-7.56 (m, 5H), 8.70 (s, 1H); 13C NMR(100 MHz, CDCl3, TMS); d = 11.21, 114.36, 122.84, 125.86, 126.87,142.01, 143.83, 165.43, 168.66.

Reference： [1]Katrusiak, Anna; Katrusiak, Andrzej [Journal of Molecular Structure, 2015, vol. 1085, p. 28 - 36]

67
[ 616-02-4 ]
[ 93102-05-7 ]
cis-5-benzyl-3a-methyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid In dichloromethane at 25℃; for 3h; Inert atmosphere;	5-Benzyltetrahydro-1H-furo[3,4-c]pyrrole-1,3(3aH)-diones 17a-dand 5-Benzylhexahydro-1H-furo[3,4-c]pyrrol-1-one 17e 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.
	With trifluoroacetic acid In dichloromethane at 20℃; for 3h; Inert atmosphere;	61.1 Step 1. Cis-5-benzyl-3a-methyltetrahydro-1H-furo [3, 4-c] pyrrole-1, 3 (3aH) -dione (61b) To a solution of 3-methylfuran-2,5-dione (5.33 g, 47.6 mmol) and N-benzyl-1-methoxy-N- ((trimethylsilyl) methyl) methanamine (14.8 g, 61.9 mmol) in CH 2Cl 2 (170 mL) was added trifluoroacetic acid (543 mg, 4.76 mmol). The mixture was stirred for 3 h and then concentrated to dryness under vacuum to give the title compound 61b (11.62 g). The crude product was used directly in the next step without further purification MS m/z (ESI) : 246 [M+1]

Reference： [1]Sokolenko, Yevhenii M.; Ostapchuk, Eugeniy N.; Artemenko, Artem; Grygorenko, Oleksandr O. [Synthesis, 2017, vol. 49, # 14, p. 3112 - 3117]
[2]Current Patent Assignee: GUANGZHOU INNOCARE PHARMA TECH; GUANGZHOU INNOCARE PHARMA TECH CO LTD; GUANGZHOU NUOCHENG JIANHUA PHARMACEUTICAL TECH - WO2020/259584, 2020, A1 Location in patent: Page/Page column 77

68
[ 616-02-4 ]
[ 1262794-04-6 ]
C₂₁H₂₅N₃O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In chloroform at 25℃; for 3h;	3.i tert-Butyl N-3,5-di-(2-methylmaleimido)phenylcarbamate (12) Citraconic anhydride (617 μL, 6.87 mmol) was added to a solution of 11 (510 mg, 2.29 mmol) in CHCl3 (9 mL) and the resulting mixture was stirred at 25° C. for 3 h, after which volatiles were evaporated under reduced pressure. The crude mixture was suspended in Et2O and filtered under reduced pressure giving the dimaleamic acid as a beige solid (800 mg, 80% yield) that was used in the next step without further purification. The dimaleamic acid (800 mg) and ZnCl2 (748 mg, 5.5 mmol) were dissolved in toluene-DMF (90:10 mL) before a dilute solution of HMDS (1.72 mL, 8.25 mmol) in toluene (5 mL) was added over 20 min. The resulting mixture was then heated to reflux for 3 h after which the volatiles were evaporated under reduced pressure. The resulting residue was dissolved in EtOAc and washed successively with 0.1 M HCl and saturated Na2CO3. The crude product was then purified by flash chromatography on silica gel (hexane/EtOAc 6:4) giving 12 as an off-white solid (660 mg, 70% yield). 1H NMR (400M, CDCl3): δ (ppm) 7.45 (s, 2H), 7.26 (m, 1H), 7.15 (m, 1H), 6.65 (br, 1H), 6.46 (m, 2H), 2.15 (s, 6H), 1.49 (s, 9H).

Reference： [1]Current Patent Assignee: UNIVERSITY OF OTTAWA - US9701667, 2017, B2 Location in patent: Page/Page column 41; 62

69
[ 616-02-4 ]
[ 104-86-9 ]
N-4-chlorobenzyl-2-methylmaleimide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
29.5%	Stage #1: citraconic acid anhydride; 4-chlorobenzylamine In acetone at 20℃; for 1h; Stage #2: With sodium acetate; triethylamine; hydroquinone In toluene at 115℃; for 2.5h;	2 Synthesis of N-4-chlorobenzyl-3-methylmaleimide(1-2) Weighed 0,6 mmo 1 citraconic anhydride to a three-necked round bottom flask, dissolved in 10 ml of acetone, and 0.5 mg of 4-chlorobenzylamine was dissolved in 10 ml of acetone and slowly dropped into a three-necked flask through a constant pressure dropping funnel, After stirring for 1 h at room temperature, the solvent was removed by rotary evaporation to remove the solvent acetone. To the reaction system was added 0.02 g of anhydrous sodium acetate, 0.2 ml of triethylamine, 0.05 g of hydroquinone, To 115 ° C reflux reaction for 2.5 h, the reaction process through the thin layer chromatography silica gel plate tracking. After the completion of the reaction, the mixture was cooled to room temperature and the solvent was removed by rotary evaporation to obtain a concentrated solution. The concentrated solution was subjected to silica gel column chromatography (eluent: Vat: Vzmss = 12: 1), the target solution was collected, Get the target product. Yield 29.5%.

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107162950, 2017, A Location in patent: Paragraph 0035-0037

70
[ 616-02-4 ]
C₇H₁₅NO₄ [ No CAS ]
C₁₂H₁₇NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.5%	Stage #1: C₇H₁₅NO₄ With sodium methylate In methanol at 30℃; for 0.333333h; Stage #2: citraconic acid anhydride In methanol at 30℃; for 1h; Stage #3: With triethylamine In methanol at 60℃; for 2.33333h;	5 Example 5: Preparation of N-quincloram-3-methyl N-substituted maleimide (I-5) Weigh Jinggangmycin 0.176 (1mmol) was added to the round bottom flask, 6ml 0.26mol / L sodium methoxide in methanol was added, the reaction was stirred at 30 for 20min, the amount of 0.1344 (1.2mmol)3-methyl maleic anhydride was added to a round bottom flask, stirred at 30 ° C for 1 h,Then add 150μL 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-quincloram-3-methyl N-substituted maleimide (I-5)

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107033060, 2017, A Location in patent: Paragraph 0048-0051

71
valienamine [ No CAS ]
[ 616-02-4 ]
C₁₂H₁₅NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.3%	Stage #1: valienamine With sodium methylate In methanol at 30℃; for 0.333333h; Stage #2: citraconic acid anhydride In methanol at 30℃; for 1h; Stage #3: With triethylamine In methanol at 60℃; for 2.33333h;	6 Example 6: Preparation of N-Jinggangmycin amine-3-methyl N-substituted maleimide (I-6) Weigh Jinggangmycin 0.175g (1mmol) was added to a round bottom flask, was added 6ml 0.26mol / L sodium methoxide in methanol, the reaction was stirred at 30 ° C for 20min, take 0.1344 (1.2mmol)3-methyl maleic anhydride was added to a round bottom flask, the reaction was stirred at 30 ° C for 1 h,Then add 150μL 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 as N-Jinggangmycin amine 3-methyl N-substituted maleimide (I-6), N-

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107033060, 2017, A Location in patent: Paragraph 0052-0055

72
[ 616-02-4 ]
jinggangmycin amine [ No CAS ]
C₁₂H₁₇NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.2%	Stage #1: jinggangmycin amine With sodium methylate In methanol at 30℃; for 0.333333h; Stage #2: citraconic acid anhydride In methanol at 30℃; for 1h; Stage #3: With triethylamine In methanol at 60℃; for 2.33333h;	7 Example 7: Preparation of N-Wellformamine-3-methyl N-Substituted Maleimide (I-7) Weigh Jinggangmycin amine 0.193g (1mmol) was added to a round bottom flask, was added 16ml 0.26mol / L sodium methoxide in methanol, the reaction was stirred at 30 ° C for 20min, weighed 0.2895 (2.0mmol)3-methyl maleic anhydride was added to a round bottom flask, stirred at 30 ° C for 1 h,Then add 340μL 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-quiamycinamine-3-methyl N-substituted maleimide (I-7)

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107033060, 2017, A Location in patent: Paragraph 0056-0059

73
[ 616-02-4 ]
C₆H₁₃NO₅ [ No CAS ]
C₁₁H₁₅NO₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: C₆H₁₃NO₅ With sodium methylate In methanol at 30℃; for 0.333333h; Stage #2: citraconic acid anhydride In methanol at 30℃; for 1h; Stage #3: With triethylamine In methanol at 60℃; for 2.33333h;	8 Example 8: Preparation of N-glucosamine-3-methyl N-substituted maleimide (I-8) Weigh 0.179g (1mmol) of glucosamine added to a round bottom flask, add 6ml 0.26mol / L sodium methoxide in methanol, stirred at 30 for 20min, weighed 0.1344g (1.2mmol)3 - methyl maleic anhydride was added to a round bottom flask, the reaction was stirred at 30 ° C for 1 h,Then add 150μL triethylamine, the reaction 20min, the system was heated to 60 ° C to continue the reaction 2h, after the reaction was cooled to room temperature, vacuum distillation to give a yellow oily concentrate, the concentrate was separated on a 200 mesh silica gel, the mobile phase forV 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-methyl N-substituted maleimide (I-8), N-

Reference： [1]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN107033060, 2017, A Location in patent: Paragraph 0060-0063

74
[ 616-02-4 ]
[ 454-79-5 ]
1-(2-bromo-5-trifluoromethylphenyl)-3-methyl-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With acetic acid Reflux;	3 The synthesis steps for the synthesis of 1-(2-bromo-5-trifluoromethyl-phenyl)-3-methyl-1H-pyrrole-2,5-dione are as follows: Add 2-bromo-5-trifluoromethyl-aniline (10 mmol) to a reaction vessel containing 25 ml of glacial acetic acid.3-methylfuryl-2,5-dione (11 mmol) was added,The mixture was refluxed overnight and then cooled to <50 °C.The solvent was transferred in vacuo, the residue was dissolved in dichloromethane (50 ml), and the resulting solution was washed with water (50 ml x 2), saturated aqueous NaHCO3 (50 ml x 2) and saturated brine (50 ml x 2), and anhydrous Dry over sodium sulfate. Evaporate the solvent in vacuumThe residue was dissolved in 15 ml of acetone, and then crystallized by dropwise addition of 30 ml of ethanol, filtered, and vacuum dried at 50°C to obtain 2.9 g of white 1-(2-bromo-5-trifluoromethyl-phenyl)-3-methyl- 1H-pyrrole-2,5-dione solid, yield 87%.

Reference： [1]Current Patent Assignee: Tian Yuanqiang - CN107954992, 2018, A Location in patent: Paragraph 0024

75
[ 616-02-4 ]
[ 931-23-7 ]
[ 40834-42-2 ]

Yield	Reaction Conditions	Operation in experiment
7%; 60%	With lithium tri-t-butoxyaluminum hydride; In tetrahydrofuran; at -30 - -15℃; for 3h;Inert atmosphere;	A solution of 5.34 g LiAlH(t-BuO)3 (21.00 mmol) in 40 cm3 anhydrous THF was added dropwise over a 30-min period to a solution of 1.68 g citraconic anhydride (6, 15.00 mmol) in 50 cm3 anhydrous THF under a nitrogen atmosphere at - 30 C. The temperature was maintained at - 15 C for 3 h and then the reaction mixture was warmed to ambient temperature. The reaction was quenched with 50 cm3 1 M HCl, the solution was saturated with NaCl, the crude product was extracted with EtOAc (3 9 50 cm3), and the combined organic fraction was dried over MgSO4. The solvent was removed in vacuo. Purification by column chromatography (SiO2, 20% AcOEt in petroleum ether) afforded 7a (1.023 g,60%) and 7b (116 mg, 7%) as yellow oils. TLC: Rf = 0.16 (for 7a), 0.15 (for 7b) (20% AcOEt in petroleum ether). 7a: 1H NMR (400 MHz, acetone-d6): d = 6.67 (bs, 1H),6.02 (bs, 1H), 5.87 (p, J = 1.5 Hz, 1H), 2.08 (d,J = 1.5 Hz, 3H) ppm; 13C NMR (100 MHz, acetone-d6):d = 171.30 ([C), 166.65 ([C), 118.68 (CH), 100.25(CH), 13.15 (CH3) ppm; MS (EI): m/z (%) = 114.0 ([M?],2), 113.0 (7), 86.0 (61), 85.0 (13), 69.0 (100), 68.0 (82),41.1 (50), 40.1 (65), 39.1 (93).

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

76
[ 616-02-4 ]
[ 84-67-3 ]
C₂₄H₂₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	With acetic acid; In toluene; for 1h;Inert atmosphere; Reflux;	In caseIn a separable flask,50 g (0.234 mol) of <strong>[84-67-3]2,2'-dimethylbiphenyl-4,4'-diamine</strong> (m-TB, manufactured by Wakayama Seika Industry Co., Ltd.)71 g (1.18 mol) of acetic acid and 120 g of toluene were charged and dissolved while heating and stirring at 50 ° C. while introducing nitrogen. 52.8 g (0.472 mol) of citraconic anhydride was added dropwise, and gradually heated while removing generated water outside the system,The reaction was carried out under reflux for 1 hour.After purifying the reaction product by reprecipitation, 90 g of a white crystal bismaleimide compound (e-1) was obtained. Yield 96percent. It was confirmed that the amine equivalent was 100,000 or more and almost all of the amino groups were reacted.

Reference： [1]Patent: JP2015/193628,2015,A .Location in patent: Paragraph 0044

77
[ 15520-10-2 ]
[ 616-02-4 ]
C₁₆H₂₄N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With acetic acid In toluene at 90℃; for 0.133333h;	5.2 2. Add the 86g citraconic anhydride, 400ml toluene, and 70g acetic acid prepared in step 1 to a 1000ml flask connected with a condenser, thermometer and stirrer. Turn on the heating to quickly raise the temperature to 90 ° C, stir, and weigh 44.5g of 2-A. Dipentyl diamine was added dropwise to the flask, and the addition was completed within 8 minutes to prepare a reaction solution containing 2-methyl-1,5-biscitraconamic acid.

Reference： [1]Current Patent Assignee: SHANDONG YANGGU HUATAI CHEMICAL COMPANY LIMITED; SHANDONG DEREK NEW MAT - CN110845387, 2020, A Location in patent: Paragraph 0037-0038

78
[ 17467-41-3 ]
[ 616-02-4 ]
4-methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
15%	With toluene-4-sulfonic acid In toluene at 85℃; for 1h; Microwave irradiation;	No. I.1-558: 5-Hydroxy-4-methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one Citraconic anhydride (400 mg, 3.57 mmol, 1.0 equiv), p-toluenesulfonic acid (92 mg, 0.54 mmol) and 5-amino-3-ethyl-1,2,4-thiadiazole (461 mg, 3.57 mmol, 1.0 equiv) were dissolved in toluene (12 ml) and stirred under microwave conditions at a temperature of 85° C. for 60 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 4-methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione in the form of a colorless solid (120 mg, 15% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.67 (m, 1H), 3.04 (q, 2H), 2.25 (s, 3H), 1.40 (t, 3H). 4-Methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione (100 mg, 0.45 mmol, 1.0 equiv) was dissolved in a mixture of tetrahydrofuran and methanol (10 ml, 1:1) and cooled to a temperature of -30° C., and sodium borohydride (17 mg, 0.45 mmol, 1.0 equiv) was added. The resulting reaction mixture was stirred at -30° C. for 2 h and then slowly warmed to room temperature. After the reaction had ended, acetic acid was added carefully to adjust the pH to 3-4, and water and ethyl acetate were added. The aqueous phase was repeatedly 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 5-hydroxy-4-methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one in the form of a colorless solid (30 mg, 30% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.08 (m, 1H), 6.03 (br. s, 1H), 4.77 (d, 1H), 2.92-2.86 (q, 2H), 2.23 (s, 3H), 1.37 (t, 3H).
15%	With toluene-4-sulfonic acid In toluene at 85℃; for 1h; Microwave irradiation;	4-Methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione 4-Methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione Citraconic anhydride (400 mg, 3.57 mmol, 1.0 equiv), p-toluenesulfonic acid (92 mg, 0.54 mmol) and 5-amino-3-ethyl-1,2,4-thiadiazole (461 mg, 3.57 mmol, 1.0 equiv) were dissolved in toluene (12 ml) and stirred under microwave conditions at a temperature of 85° C. for 60 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 4-methyl-1-(3-ethyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione in the form of a colorless solid (120 mg, 15% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.67 (m, 1H), 3.04 (q, 2H), 2.25 (s, 3H), 1.40 (t, 3H).

Reference： [1]Current Patent Assignee: BAYER AG - US2020/79765, 2020, A1 Location in patent: Paragraph 0194-0195
[2]Current Patent Assignee: BAYER AG - US2020/95241, 2020, A1 Location in patent: Paragraph 0246-0247

79
[ 616-02-4 ]
[ 32039-21-7 ]
4-methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
11%	With toluene-4-sulfonic acid In toluene at 95℃; for 1h; Microwave irradiation;	No. I.1-560: 5-Hydroxy-4-methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one Citraconic anhydride (400 mg, 3.57 mmol, 1.0 equiv), p-toluenesulfonic acid (92 mg, 0.54 mmol) and 5-amino-3-isopropyl-1,2,4-thiadiazole (511 mg, 3.57 mmol, 1.0 equiv) were dissolved in toluene (12 ml) and stirred under microwave conditions at a temperature of 95° C. for 60 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 4-methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione in the form of a colorless solid (90 mg, 11% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.66 (m, 1H), 3.35 (sept, 1H), 2.24 (s, 3H), 1.41 (d, 6H). 4-Methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione (75 mg, 0.32 mmol, 1.0 equiv) was dissolved in a mixture of tetrahydrofuran and methanol (8 ml, 1:1) and cooled to a temperature of -30° C., and sodium borohydride (12 mg, 0.45 mmol, 1.0 equiv) was added. The resulting reaction mixture was stirred at -30° C. for 2 h and then slowly warmed to room temperature. After the reaction had ended, acetic acid was added carefully to adjust the pH to 3-4, and water and ethyl acetate were added. The aqueous phase was repeatedly 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 5-hydroxy-4-methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one in the form of a colorless solid (7 mg, 9% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.08 (m, 1H), 6.05 (d, 1H), 4.81 (d, 1H), 3.23-3.15 (sept, 1H), 2.23 (s, 3H), 1.37 (d, 6H).
11%	With toluene-4-sulfonic acid In toluene at 95℃; for 1h; Microwave irradiation;	4-Methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione 4-Methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione Citraconic anhydride (400 mg, 3.57 mmol, 1.0 equiv), p-toluenesulfonic acid (92 mg, 0.54 mmol) and 5-amino-3-isopropyl-1,2,4-thiadiazole (511 mg, 3.57 mmol, 1.0 equiv) were dissolved in toluene (12 ml) and stirred under microwave conditions at a temperature of 95° C. for 60 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 4-methyl-1-(3-isopropyl-1,2,4-thiadiazol-5-yl)pyrrole-2,5-dione in the form of a colorless solid (90 mg, 11% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.66 (m, 1H), 3.35 (sept, 1H), 2.24 (s, 3H), 1.41 (d, 6H).

Reference： [1]Current Patent Assignee: BAYER AG - US2020/79765, 2020, A1 Location in patent: Paragraph 0196-0197
[2]Current Patent Assignee: BAYER AG - US2020/95241, 2020, A1 Location in patent: Paragraph 0248-0249

80
[ 59669-59-9 ]
[ 616-02-4 ]
4-methyl-1-(3-tert-butyl-1,2-isoxazol-5-yl)pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With acetic acid for 8h; Reflux;	No. I.1-290: 5-Hydroxy-4-methyl-1-(3-tert-butyl-1,2-isoxazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one Citraconic anhydride (2000 mg, 17.84 mmol, 1.0 equiv) and 5-amino-3-tert-butyl-1,2-isoxazole (2752 mg, 19.63 mmol, 1.1 equiv) were dissolved in acetic acid (50 ml) and stirred under reflux conditions for 8 h. 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 4-methyl-1-(3-tert-butyl-1,2-isoxazol-5-yl)pyrrole-2,5-dione in the form of a colorless solid (3620 mg, 78% of theory). 1H-NMR (400 MHz, CDCl3 δ, ppm) 6.56 (m, 1H), 6.22 (s, 1H), 2.19 (s, 3H), 1.35 (s, 9H). 4-Methyl-1-(3-tert-butyl-1,2-isoxazol-5-yl)pyrrole-2,5-dione (3500 mg, 14.94 mmol, 1.0 equiv) was dissolved in methanol (90 ml) and cooled to a temperature -30° C., and sodium borohydride (790 mg, 20.92 mmol, 1.4 equiv) was added a little at a time. The resulting reaction mixture was stirred at -30° C. for 1 h and then slowly warmed to room temperature and stirred at room temperature for another 1 h. After the reaction had ended, acetic acid was added carefully to adjust the pH to 3-4, and water and ethyl acetate were added. The aqueous phase was repeatedly extracted vigorously with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated. By final purification by column chromatography (gradient ethyl acetate/heptane) of the resulting crude product, it was possible to separate 5-hydroxy-4-methyl-1-(3-tert-butyl-1,2-isoxazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one from the isomeric 5-hydroxy-3-methyl-1-(3-tert-butyl-1,2-isoxazol-5-yl)-1,5-dihydro-2H-pyrrol-2-one 1.2-290 and to isolate the compound in the form of a colorless solid (350 mg, 10% of theory). 1H-NMR (400 MHz, d6-DMSO δ, ppm) 7.09 (br. d, 1H), 6.21 (s, 1H), 6.03 (m, 1H), 5.90 (br. d, 1H), 2.04 (s, 3H), 1.27 (s, 9H).

Reference： [1]Current Patent Assignee: BAYER AG - US2020/79765, 2020, A1 Location in patent: Paragraph 0188-0189

81
[ 616-02-4 ]
N-[(2E)-3-(5-propyl-2-thienyl)prop-2-en-1-yl]aniline [ No CAS ]
(3aSR,4RS,4aRS,7aRS)-4-methyl-5-oxo-6-phenyl-2-propyl-4,4a,5,6,7,7a-hexahydro-3aH-thieno[2,3-f]isoindole-4-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	In benzene at 20℃; for 24h; diastereoselective reaction;	Thieno[2,3-f]isoindole-4-carboxylic Acids; General Procedure General procedure: Method ; The Cycloaddition of Monosubstituted Maleic Anhydrides: Ina 25 mL round-bottomed flask equipped with a condenser, amine 3(0.4 mmol) dissolved in PhH (5 mL), Et 2 O, EtOAc (for 7), or PhMe (for8) and the corresponding maleic anhydride (0.4 mmol) were mixedand stirred for 2 days or boiled for 3-10 h (see Table 3). The formedprecipitate was filtered off and washed with PhH (2 × 5 mL) followedby Et 2 O (2 × 10 mL) and dried in air to give the title acids.

Reference： [1]Anokhina, Victoria A.; Horak, Yuriy I.; Khrustalev, Victor N.; Kinzhybalo, Vasyl; Kuznetsov, Maxim L.; Laba, Yevhen-Oleh V.; Lytvyn, Roman Z.; Nadirova, Maryana A.; Obushak, Mykola D.; Pokazeev, Kuzma M.; Siczek, Miłosz; Sokolova, Julya S.; Zaytsev, Vladimir P.; Zubavichus, Yan V.; Zubkov, Fedor I. [Synthesis, 2020, vol. 52, # 15, p. 2196 - 2223]

82
[ 616-02-4 ]
[ 5341-58-2 ]
C₁₆H₁₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With toluene-4-sulfonic acid In chloroform; cyclohexane at 20℃; for 6h;	2 (2) Preparation of intermediate acid Using solvent C (ethyl acetate) as the solvent, raw material A and raw material B react to form intermediate acid F; in terms of specific material dosage and operation:Add 5g of raw material A to 45mL of solvent C, stir at room temperature to form a suspension, and then add dropwise the dissolved solution of raw material B (previously dissolve 2.94 g maleic anhydride with 5mL ethyl acetate), the addition is complete within 1 hour, and stir at room temperature After the reaction for 10 h, the solution was white paste, filtered with suction, the filter cake was washed three times with absolute ethanol, and dried under vacuum. The obtained white solid was intermediate acid F;In terms of molar ratio, raw material A (3-hydroxy-2-naphthoyl hydrazide): raw material B (maleic anhydride) = 1:1.2;(3) Dehydration closed loop to generate target productUsing catalyst D (toluenesulfonic acid) as a catalyst and solvent E (toluene) as a solvent, the intermediate acid F prepared in step (2) undergoes dehydration and ring-closing reaction, and finally prepares the target product; the specific material dosage and operation are as follows:In a three-necked flask with a reflux device, take 5g of the intermediate acid F prepared in step (2), add 100ml of solvent E, 0.5g of catalyst D (p-toluenesulfonic acid), gradually increase the temperature, reflux at 115°C for 10h, and the reaction is complete After cooling to room temperature, add 5-20ml of distilled water dropwise to the solution until the solution becomes turbid, and then let it stand for 24 hours to make a large amount of crystals precipitate, suction filtration, the filter cake is washed three times with distilled water to obtain the crude product, and further vacuum-dried and then reconstituted with ethanol Purified by crystallization, a light yellow solid is obtained, which is the target product after purification (anti-aging agent is not extracted for reactivity).The ethyl acetate and toluene in the reaction process can be recycled and reused by simple distillation.

Reference： [1]Current Patent Assignee: UNIV HUANGHUAI; HENAN HUADING POLYMER - CN112341372, 2021, A Location in patent: Paragraph 0019-0022

83
[ 616-02-4 ]
[ 936-02-7 ]
C₁₂H₁₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With toluene-4-sulfonic acid In ethanol; ethyl acetate at 20℃; for 4h;	3 (2) Preparation of intermediate acid Add 5g of raw material A to 100mL of ethyl acetate C (chloroform), stir at room temperature to form a suspension, and then add dropwise the dissolved solution of raw material B (previously dissolve 5.53g of citraconic anhydride with 20mL of ethyl acetate), and the addition is complete within 1 hour , React for 3 h under stirring at room temperature. After the reaction, the solution is a white suspension, filtered off with suction, the filter cake is washed three times with ethyl acetate, and dried under vacuum. The white solid obtained is intermediate acid F;In terms of molar ratio, raw material A (o-hydroxybenzoyl hydrazide): raw material B (citraconic anhydride) = 1:1.5;In step (three):Take 5g of the intermediate acid F prepared in step (2), add 80ml of solvent E, 0.5g of catalyst D (p-toluenesulfonic acid), gradually increase the temperature, reflux at 80 for 5h, distill out about 50ml of solvent, and add 50ml of absolute ethanol , Continue the reaction for 3h, cool to room temperature after the reaction, add 10~30ml of distilled water until the solution becomes turbid, and then stand for 24h to precipitate a large amount of crystals, filter with suction, and wash the filter cake with distilled water three times to obtain the crude product. After vacuum drying, it is purified by ethanol recrystallization to obtain a light yellow solid, which is the target product after purification (antioxidant is not extracted for reactivity).

Reference： [1]Current Patent Assignee: UNIV HUANGHUAI; HENAN HUADING POLYMER - CN112341372, 2021, A Location in patent: Paragraph 0023-0025

84
[ 616-02-4 ]
[ 10526-07-5 ]
C₂₈H₂₀N₂O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.52 g	With 2,6-di-tert-butyl-4-methyl-phenol; toluene-4-sulfonic acid In N,N-dimethyl-formamide; toluene at 110℃; for 5h; Dean-Stark;	1-2 (Synthetic Working Example 2-1) Synthesis of APB-N Citraconimide A container (internal capacity: 100 ml) equipped with a stirrer, a condenser tube and a burette was prepared. To this container, 2.92 g (10.0 mmol) of 3,3′ (1,3-phenylenebis)oxydianiline (product name: APB-N, manufactured by MITSUI FINE CHEMICALS, Inc.), 4.15 g (40.0 mmol) of citraconic anhydride (manufactured by KANTO CHEMICAL CO., INC.), 30 ml of dimethylformamide, and 60 ml of toluene were charged, and 0.4 g (2.3 mmol) of p-toluenesulfonic acid and 0.1 g of a polymerization inhibitor BHT were added, thereby preparing a reaction solution. The reaction solution was stirred at 110° C. for 5 hours to conduct reaction, and the produced water was recovered with a Dean-and-stark trap through azeotropic dehydration. Next, after cooling the reaction solution to 40° C., it was added dropwise into a beaker in which 300 ml of distilled water was placed, thereby precipitating the product. After filtering the obtained slurry solution, the residue was washed with methanol and subjected to separation and purification with column chromatography to acquire 3.52 g of the target compound (APB-N citraconimide) represented by the following formula: (0260) The following peaks were found by 400 MHz-1H-NMR the compound was confirmed to have a chemical of the above formula. (0261) 1H-NMR: (d-DMSO, internal standard TMS) (0262) δ (ppm) 6.7-7.4 (12H, Ph-H), 6.4 (2H, -CH═C), 2.2 (6H, C-CH3). As a result of measuring the molecular weight of the obtained compound by the above method, it was 480.

Reference： [1]Current Patent Assignee: MITSUBISHI GAS CHEMICAL COMPANY INC - US2021/165327, 2021, A1 Location in patent: Paragraph 0259-0262

85
[ 616-02-4 ]
[ 473-98-3 ]
3-hydroxy(lup-20⁽²⁹⁾-en)-28-yl-4-oxo-3-methylbut-2-enoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38%	With dmap In pyridine; dichloromethane at 20℃; for 24h; Inert atmosphere;	4.1.1. General method of synthesis of ester derivatives 2-4, 6, 8 General procedure: To a solution of 1 mmol of betulin 1 and 1 mmol of DMAP in25 mL of DCM and 5 mL of pyridine, 5 mmol of appropriate acidanhydride solution in 25 mL of DCM was added dropwise. The reactionwas carried out under an argon atmosphere overnight atroom temperature. After completing the reaction, the obtainedmixture was diluted with 50 mL of DCM and washed three timeswith 10 % hydrochloric acid solution and water. The organic layerwas dried using anhydrous Na2SO4 and then concentrated with avacuum evaporator. The crude product was purified by columnchromatography (SiO2, dichloromethane/ethanol 10:1 v/v).

Reference： [1]Pęcak, Paweł; Orzechowska, Beata; Chrobak, Elwira; Boryczka, Stanisław [European Journal of Medicinal Chemistry, 2021, vol. 225]

86
[ 616-02-4 ]
[ 40106-45-4 ]
3-methyl-1-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-1H-pyrrole-2,5-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In chloroform for 18h;	3-Methyl-1-(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-ylamino)-1H-pyrrole-2,5-dione:8 Reaction of 1.0 mmol of 4 with 1.5 mmol of 3-methylfuran-2,5-dione in 15 mL CHCl3for 18 h to give the pyrrolo-dione derivative as yellow powder in Yield: 82%, m.p. <250°C; 1H-NMR (400 MHz, DMSO-d6) ppm: δ 1.72-2.98 (m, 8H, cyclohexane), 2.13 (s, 3H,CH3 at C2-pyrrol), 4.21 (s, NH, D2O exchangeable), 6.98 (s, 4H, 1H, pyrrole ring), 7.24 (s,1H, CH pyrimidine), 13C-NMR (100 MHz, DMSO-d6) ppm: δ 24.54, 24.54, 25.00, 27.03,113.33, 122.68, 127,60, 134.55, 137.50, 143.34, 145.71, 154.65, 164.00, 165.29, 168.21; Anal. forC15H14N4O2S (314.08), Calcd %: C, 57.32; H, 4.49; N, 17.80. Found %: C, 57.44; H, 4.52; N,17.79.

Reference： [1]Alkahtani, Manal Mubarak; Altwaijry, Najla; Attallah, Nashwah G. M.; Elmongy, Elshaymaa I.; Henidi, Hanan Ali [Molecules, 2022, vol. 27, # 1]

87
[ 1708-29-8 ]
[ 616-02-4 ]
(1R*,5S*,6R*,7S*)-6-methyl-3-oxabicyclo[3.2.0]heptane-6,7-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With thio-xanthene-9-one In acetonitrile Inert atmosphere; Irradiation;	General procedure 2: [2+2] cycloadditions with citraconic anhydride General procedure: Thioxanthone (0.1 equiv.) was dissolved in MeCN. Citraconic anhydride (1 equiv., 0.1 M) andalkene (1.5 equiv.) were added and the solution degassed for 30 min under nitrogen. Thesolution was transferred to a syringe and pumped through the chip at 5 mL/h under 375 nmirradiance at 35°C using a Model 11 syringe pump from Harvard Apparatus. 2 mL of thesolution was pumped through the chip to ensure steady state conditions. A 1 mL aliquot wassampled for analysis of the crude reaction mixture by NMR and TLC. The reaction wassampled for 3.5 h

Reference： [1]Bargum, Martin; Krell-Jorgensen, Mikkel; Laraia, Luca; Nielsen, Martin; Qvortrup, Katrine [Synlett, 2022]

88
[ 616-02-4 ]
[ 142-29-0 ]
(1R*,5S*,6R*,7S*)-6-methylbicyclo[3.2.0]heptane-6,7-dicarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With thio-xanthene-9-one In acetonitrile Inert atmosphere; Irradiation;	General procedure 2: [2+2] cycloadditions with citraconic anhydride General procedure: Thioxanthone (0.1 equiv.) was dissolved in MeCN. Citraconic anhydride (1 equiv., 0.1 M) andalkene (1.5 equiv.) were added and the solution degassed for 30 min under nitrogen. Thesolution was transferred to a syringe and pumped through the chip at 5 mL/h under 375 nmirradiance at 35°C using a Model 11 syringe pump from Harvard Apparatus. 2 mL of thesolution was pumped through the chip to ensure steady state conditions. A 1 mL aliquot wassampled for analysis of the crude reaction mixture by NMR and TLC. The reaction wassampled for 3.5 h

Reference： [1]Bargum, Martin; Krell-Jorgensen, Mikkel; Laraia, Luca; Nielsen, Martin; Qvortrup, Katrine [Synlett, 2022]

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]}	{[ getRatePrice(item.pr_usd, 1,1) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]}	{[ item.pr_usastock ]}	Inquiry -	{[ item.pr_chinastock ]}	Inquiry -

CAS No. :	616-02-4	MDL No. :	MFCD00005522
Formula :	C₅H₄O₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	AYKYXWQEBUNJCN-UHFFFAOYSA-N
M.W :	112.08	Pubchem ID :	12012
Synonyms :

Num. heavy atoms :	8
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.2
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	25.05
TPSA :	43.37 Å²

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.81 cm/s

[ CAS No. 616-02-4 ] {[proInfo.proName]}

Quality Control of [ 616-02-4 ]

Related Doc. of [ 616-02-4 ]

Product Details of [ 616-02-4 ]

Calculated chemistry of [ 616-02-4 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 616-02-4 ]

Application In Synthesis of [ 616-02-4 ]

[ 616-02-4 ] Synthesis Path-Upstream 1~7

[ 616-02-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 616-02-4 ]

Acid Anhydrides

Esters

Related Parent Nucleus of
[ 616-02-4 ]

Furans

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

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Inquiry

Log Po/w (iLOGP) :	0.94
Log Po/w (XLOGP3) :	0.25
Log Po/w (WLOGP) :	0.02
Log Po/w (MLOGP) :	0.23
Log Po/w (SILICOS-IT) :	0.98
Consensus Log Po/w :	0.48

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

Log S (ESOL) :	-0.69
Solubility :	22.8 mg/ml ; 0.203 mol/l
Class :	Very soluble
Log S (Ali) :	-0.72
Solubility :	21.3 mg/ml ; 0.19 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.58
Solubility :	29.1 mg/ml ; 0.26 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.96

Signal Word:	Danger	Class:	8,6.1
Precautionary Statements:	P264-P270-P272-P280-P285-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501	UN#:	2922
Hazard Statements:	H303-H311-H314-H317-H334	Packing Group:	Ⅲ
GHS Pictogram:

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P378
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P391	Collect spillage. Hazardous to the aquatic environment
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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.
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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:
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P401
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