Name: 2756-87-8|(E)-4-methoxy-4-oxobut-2-enoic acid|98%
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1
[ 3052-50-4 ]
[ 2756-87-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	at 200℃; for 0.25h; microwave irradiation;
82.5%	With aluminum (III) chloride at 60℃; for 0.5h;	1 General procedure for the synthesis of trans-but-2-enedioic acid monoesters 2a-c General procedure: Anhydrous AlCl3 (0.16 g) was added to the cis-but-2-enedioicacid monoesters (4 g) under stirring. The mixture was heated at 60-70 C for 0.5-2 h. The cooled mixture was diluted with 1 NHCl (30 mL) and the aqueous phase extracted with ethyl acetate(3 40 mL). The organic extracts were collected, washed with brine (2 20 mL), dried over anhydrous Na2SO4, filtrated and evaporated to give crude trans-but-2-enedioic acid monoesters.
	With 2-mercaptothiazoline at 140℃;

	With iodine In toluene for 10h; Heating;
20.9 kg	With acetyl chloride In toluene at 80 - 83℃; for 6.16667h; Large scale;	18.2 Step (ii) Step (ii) The toluene solution from Step (i) was treated with acetyl chloride (367 mL, 406 g, 5.17 mol) and the mixture was heated to 80° C. After stirring the reaction mixture around 80° C. for 14 hr, the mixture was diluted with 16 L of toluene and cooled to 20-25° C. The precipitated product was collected by filtration, rinsed with toluene and dried under vacuum at 40-45° C. for 14 hours to afford the pure monomethyl fumarate as white crystalline solid (5.1 kg). MP 145.4-145.8° C.; MS (ESI): m/z 128.8 (Calcd. 130.1); 1H NMR (DMSO-d6), δ 13.25 (s, 1H), 6.71 (s, 2H), 3.74 (s, 3H).
	With aluminum (III) chloride In methanol; ethyl acetate at 45 - 75℃; Industrial scale;	Preparation of Monomethyl Fumarate 100 g of Maleic anhydride was dissolved in 0.4 V of methanol and the reaction mass was stirred for 3-4 hrs at 45-50° C. To the reaction mass, 150 ml of ethyl acetate was added and 10.0 g of anhydrous aluminum chloride was added at 45-50° C. for 10-20 min and maintained the reaction mass for 4-5 hrs at 70-75° C. After completion of reaction, the reaction mixture was maintained for 60-80 minutes at 5-10° C. and filtered. The solid obtained was washed with chilled ethyl acetate and dried. 80% of the product was isolated after purification.
	With acetyl chloride In toluene at 45℃; for 22h;	6 Example 6: Yield determination Six samples of 13.2 g (0.1 mol) monomethyl maleate were diluted with toluene (50 mL) and 0.1 eq of the isomerization catalyst (trimethylsilylchloride or acetyl chloride) were added, three samples with trimethylsilylchloride and three samples with acetyl chloride.The resulting reaction mixtures were heated to the temperatures of 45°C, 51°C and80°C. After 22 hours the reaction mixtures were cooled to room temperature, the product was filtrated off and dried at 50°C/8-16 mbar overnight. The results are shown in Figure 2 As it can be seen from Figure 2 the isolated yields of the conversion of monomethyl maleate to monomethyl fumarate in the presence of TMS(trimethylsilylchloride) is at any of the reaction temperature higher compared to the one in the presence of AcCl (acetyl chloride).

Reference： [1]Pospíšil, Jiří; Potáček, Milan [Tetrahedron, 2007, vol. 63, # 2, p. 337 - 346]
[2]Ma, Yan-Long; Zhou, Ru-Jin; Zeng, Xing-Ye; An, Ya-Xiong; Qiu, Song-Shan; Nie, Li-Jun [Journal of Molecular Structure, 2014, vol. 1063, # 1, p. 226 - 234]
[3]Current Patent Assignee: RUTH P SCOTT; GOODYEAR TIRE & RUBBER CO - US2414066, 1943, A
[4]Jaroszewski, Jerzy W.; Grossen, Peter; Mohr, Peter; Tamm, Christoph [Helvetica Chimica Acta, 1986, vol. 69, p. 718 - 725]
[5]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2014/364604, 2014, A1 Location in patent: Paragraph 0205
[6]Current Patent Assignee: BIOPHORE INDIA PHARMACEUTICALS PVT LTD - US2017/96384, 2017, A1 Location in patent: Paragraph 0027
[7]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/108960, 2017, A1 Location in patent: Page/Page column 60

2
[ 2756-87-8 ]
[ 17081-97-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 3h; Reflux;	Methyl 3-(chloroformyl)acrylate (2). Monomethyl fumarate (1,5.00 g, 38.4 mmol) was dissolved in CH2Cl2 (125 mL). After DMF (2drops) was added the solution was cooled to 0 °C and thionyl chloride(3.1 mL, 42.3 mmol) was added dropwise. The resulting mixture was refluxed for 3 h. The solvent was distilled off, afford the title compoundas a yellow oil (5.6 g, 37.7 mmol, 99%). 1H NMR (300 MHz, CDCl3) δ:3.86 (s, 3H), 6.96 (d, J = 15.5 Hz, 1H), 7.03 (d, J = 15.5 Hz, 1H).
91%	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h;	Methyl 3-(Chloroformyl)acrylate (3) Monomethyl fumarate (5.00 g, 38.4 mmol) was dissolved in CH2Cl2 (125 mL). After DMF (2 drops) was added, the solution was cooled to 0 °C and oxalyl chloride (3.63 mL, 42.3 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 5 min then at r.t. for 3 h. The solvent was distilled off, affording the title compound as a yellow oil; yield: 5.25 g (35.3 mmol, 91 %). 1H NMR (300 MHz, CDCl3): δ = 7.03 (d, J = 15.5 Hz, 1 H), 6.96 (d, J = 15.5 Hz, 1 H), 3.86 (s, 3 H).
87%	With thionyl chloride at 80℃; for 48h; Inert atmosphere;	1.1 Step 1: (E)-methyl 4-amino-4-oxobut-2-enoate A mixture of (2E)-4-methoxy-4-oxo-2-butenoic acid (20.0 g, 153 mmol) and thionylchloride (25.0 mL, 344 mmol) was stirred at 80°C under a nitrogen atmosphere for 48 hours at which point the reaction mixture was concentrated. The residue was diluted with toluene (100 mL) and concentrated to afford methyl (E)-methyl 4-chloro-4-oxobut-2-enoate (20.0 g, 87%) as a brown oil which was used for the next step directly without further purification

39.63%	With thionyl chloride In dichloromethane at 40 - 65℃;	1 Synthesis of methyl fumaroyl chloride:CHpCLAll glass equipment was dried at HO0C overnight.3.5582 g monomethyl fumarate was suspended in 40ml dichloromethane and placed in a 250 mL two-necked round bottomed flask, equipped with an addition funnel, vigreux distilling column and thermometer. The solution was heated to 40 0C.7.8 ml thionyl chloride was slowly added (~1 hour) through an addition funnel. Gas formation was observed.Dichloromethane was slowly distilled at 40 0C (oil bath ~55°C) EPO The mixture was refluxed at 60-65 0C until gas formation stops and no solids were observed in the round bottle. The mixture was slightly yellow.Excess thionyl chloride was distilled off under reduced pressure (bp: 41°C/ house vacuum)Methyl fumaroyl chloride was distilled off at reduced pressure at about 32 0C/ oil pump.Yield: 1.61gYield%: 61*100/ 4.06 = 39.63%Mp. : 12-13°CCalculations
	With thionyl chloride
	With thionyl chloride for 3h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 3h; Ambient temperature;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 5h;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 0.833333h;
	With oxalyl dichloride In dichloromethane at 20℃; for 1h;	9; 12; 14 Mono methyl fumarate (1.7 g, 13.1 mmol) was taken up in 20 mL of CH2Cl2 along with oxalyl chloride (1.1 mL, 13.1 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). This freshly prepared solution of the acid chloride was added dropwise at 0° C. to a solution containing tert-butyl 2-aminoethylcarbamate (2.1 g, 13.1 mmol) and Et3N (2.8 mL, 19.6 mmol) in 200 mL of CH2Cl2. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. It was then washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 2.2 g of (E)-methyl 442-(tert-butoxycarbonyl)ethylamino)-4-oxobut-2-enoate (62% yield). (E)-Methyl 4-(2-(tert-butoxycarbonyl)ethylamino)-4-oxobut-2-enoate (2.2 g, 8.1 mmol) was taken up in 10 mL of 4 M HCl in dioxane. The resulting reaction mixture was allowed to stand at room temperature for 1 h, then diluted with 50 mL of EtOAc and concentrated under reduced pressure to afford the HCl salt of (E)-methyl 4-(2-aminoethylamino)-4-oxobut-2-enoate.; Separately, mono methyl fumarate (263 mg, 2.02 mmol) was taken up in 10 mL of CH2Cl2 along with oxalyl chloride (170 μL, 2.02 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). This freshly prepared solution of the acid chloride was added dropwise at 0° C. to a solution containing tert-butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg) and Et3N (420 μL, 3 mmol) in 20 mL of CH2Cl2. The resulting reaction mixture was warmed to room temperature and stirred for 2 h. It was then washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 450 mg of (E)-methyl 4-(2-(2-(2-(tert-butoxycarbonyl)ethyl)disulfanyl)ethylamino)-4-oxobut-2-enoate. This material was taken up in 5 mL of a 25% TFA in CH2Cl2 solution and allowed to stand at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure to afford the TFA salt of (E)-methyl 4-(2-(2-(2-aminoethyl)disulfanyl)ethylamino)-4-oxobut-2-enoate. This material was taken up in 10 mL of CH3CN along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 403 mg, 1.23 mmol), HATU (517 mg, 1.35 mmol) and DIEA (0.640 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed successively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (95% CH2Cl2, 5% MeOH) afforded 200 mg of (E)-methyl 4-(2-(2-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)disulfanyl)ethylamino)-4-oxobut-2-enoate. MS (EI) calcd for C31H46N2O4S2: 574.29. found: 575 (M+1).; Mono methyl fumarate (650 mg, 5.0 mmol) was taken up in 10 mL of CH2Cl2 and oxalyl chloride (420 μL, 5.0 mmol) was added. After a few drops of DMF was added, the reaction mixture was stirred at room temperature until all gas evolution had ceased (1 h). This freshly prepared solution of acid chloride was then added dropwise at 0° C. to a solution containing Boc-piperazine (930 mg) and triethylamine (1.0 mL, 7.5 mmol) in 20 mL of CH2Cl2. The resulting reaction mixture was stirred at room temperature for 1 h and washed with brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (CH2Cl2) afforded 310 mg of (E)-tert-butyl 4-(4-methoxy-4-oxobut-2-enoyl)piperazine-1-carboxylate (21% yield).
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;	1.4 [00102] Step-4: Synthesis of compound 7: [00102] Step-4: Synthesis of compound 7: [00103] Mono methyl fumarate 6 (1.7 g, 13.1 mmol) was taken up in 20 mL of CH2C12 along with oxalyl chloride (1.1 mL, 13.1 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). The solvent was evaporated under reduced pressure to get acid chloride 7 was used for next step directly. M.F: C5H5C103, Mol. Wt: 147.99, Elemental Analysis: C, 40.43; H, 3.39; CI, 23.87; O, 32.31.
	With oxalyl dichloride In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 2h;	1 Synthesis of 2-(methoxycarbonyl) phenyl methyl maleate (3) General procedure: Oxalyl chloride (1.7 g, 0.013 mol) was added dropwise to a solution of monomethyl maleate (1.1 g, 0.0085 mol) and two drops ofDMF in 20 mL of anhydrous THF at 0 C. Then the resultant mixture was stirred at room temperature for 2 h. After completion of the reaction, the solvent was evaporated. (Z)-methyl 4-chloro-4-oxobut-2-enoate (3a) was obtained. To a stirred solution of methyl2-hydroxybenzoate (1 g, 0.0066 mol) and NaH (0.32 g, 0.013 mol)in anhydrous THF (15 mL) was added compound 3a at 0 C. The mixture was stirred at room temperature for 1-2 h. After completion of the reaction, the pH of the mixture was adjusted to 4 with 1 N HCl. The solvent was evaporated and the aqueous was extracted with ethyl acetate (3 20 mL). The organic extracts were collected, washed with brine (2 20 mL), dried over anhydrousNa2SO4, filtrated and evaporated to give a colorless oil. The crude material was purified by chromatography on silica gel with ethylacetate-petroleum ether (10:1) to give 1.2 g of a solid (yield69%). mp: 45-46 C; 1H NMR (400 MHz, DMSO-d6): d 7.98 (dd,J = 7.8, 1.6 Hz, 1H), 7.73 (td, J = 7.9, 1.7 Hz, 1H), 7.46 (td, J = 7.7,1.1 Hz, 1H), 7.35 (dd, J = 8.1, 0.8 Hz, 1H), 7.01 (d, J = 0.5 Hz, 2H),3.79 (s, 3H), 3.76 (s, 3H); 13C NMR (101 MHz, DMSO-d6): d164.90, 164.40, 163.27, 149.62, 134.88, 134.72, 132.41, 131.54,127.04, 124.08, 122.84, 52.67, 52.53; MS (ESI) m/z: 248.8[MCH3].
	With thionyl chloride In benzene at 80℃; for 12h; Inert atmosphere;
	With thionyl chloride for 2h; Inert atmosphere; Reflux;	(E)-Methyl 4-(1-methoxy-1-oxoprop-2-en-2-ylamino)-4-oxobut-2-en-oate (6) Under argon, thionyl chloride (0.20 mL, 2.90 mmol) was added to monomethyl fumarate (37.3 mg, 0.29 mmol) in a 10 mL round bottomed flask and then heated to reflux for 2 h. The reaction mixture was then evaporated to remove excessive thionyl chloride to give the acyl chloride, which was used directly for the next step.
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;	4 Step-4: Synthesis of Compound 7 Step-4: Synthesis of Compound 7: Mono methyl fumarate 6 (1.7 g, 13.1 mmol) was taken up in 20 mL of CH2Cl2 along with oxalyl chloride (1.1 mL, 13.1 mmol). After a few drops of DMF were added, the reaction mixture was stirred at room temperature until all the solids had dissolved and all gas evolution had ceased (1 h). The solvent was evaporated under reduced pressure to get acid chloride 7 was used for next step directly. M.F: C5H5ClO3, Mol. Wt.: 147.99, Elemental Analysis: C, 40.43; H, 3.39; Cl, 23.87; O, 32.31.
3 g	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 3.08h; Inert atmosphere;	1 Oxalyl chloride (2.0 M in CH2C12; 15.2 mL, 30.3 mmol) was added dropwise over 2- 3 min to a stirred suspension of monomethylfumarate (2.63 g, 20.2 mmol) in CH2C12 (80 mL) at 0 °C under nitrogen. After complete addition, the mixture was stirred at 0 °C for 5min then allowed to warm to room temperature and stirred for 3 hr (a yellow solution developed). A small aliquot was removed and quenched with MeOH. TLC of the reaction mixture indicated no acid was remaining. The mixture was concentrated under vacuum and CH2C12 (50 mL) was added to the residue and the mixture concentrated under vacuum once more to leave the acid chloride, which was used directly in the tetrazolone-forming step (yield assumed quantitative = 3.0 g). A safety notice for the procedure: Azide compounds are potentially explosive. This reaction was performed behind a blast shield.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h;	1 The mono methyl fumarate (MMF) 1 (10 g, 0.076 mol) was dissolved in DCM (100 ml) and added oxallyl chloride (10 ml, 0.115 mol) at 00 C, followed by 1 drop of DMF. Reaction mixture was allowed to stir for 1 h at room temperature. After completion of the reaction, it was concentrated under N2 atmosphere and the obtained crude acid chloride 2 (10 g) was used in the next step without any further purification.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.5h;
	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;
	With thionyl chloride In dichloromethane at 40 - 65℃; for 1h;	5 Synthesis of compound 9 3.55 g of monomethyl fumarate 8 was suspended in 40 mi of DCM in 250 ml two necked RB flask equipped with addition funnel and condenser. The solution was heated to 40oC, 7.8 ml of thionyl chloride was slowly added through an additional funnel. The mixture was retluxed at 65°C for 1 h excess thionyl chloride was distilled off the product 9 was collected by fractional distillation
	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 3h; Inert atmosphere;	1 Preparation of methyl (E)-3-(5-oxo-4,5-dihydro-1H-tetrazol-1-yl)acrylate 6y Oxalyl chloride (2.0 M in CH2Cl2; 15.2 mL, 30.3 mmol) was added dropwise over 2-3 min to a stirred suspension of monomethyl fumarate (2.63 g, 20.2 mmol) in CH2Cl2 (80 mL) at 0° C. under nitrogen. After complete addition, the mixture was stirred at 0° C. for 5 min then allowed to warm to room temperature and stirred for 3 hr (a yellow solution developed). A small aliquot was removed and quenched with MeOH-TLC indicated no acid remaining. The mixture was concentrated under vacuum and CH2Cl2 (50 mL) was added to the residue and the mixture concentrated under vacuum once more to leave the acid chloride 5w, which was used directly in the tetrazolone-forming step below (yield assumed quantitative=3.0 g).
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;	1; 2; 3; 4; 5 Example 1 -Compound 1 Oxalyl dichloride (97.6 g, 769 mmol) was added to a suspension of monomethyl fumarate (50 g, 384 mmol) in DCM (500 mL). DMF (0.2 mL) was added and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo to remove DCM and excess oxalyl dichloride and the residuedissolved in Et20 (1000 mL). A solution of 1-(2-mercaptoethylamino)-1-propanone (30.7 g, 230 mmol) in Et20 (100 mL) was added and the mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was dissolved in water and EtOAc. The mixture was basified to pH 7-8 by aqueous Na2003 and extracted twice with EtOAc. The combined organic layers were dried over sodiumsulfate then the solvent removed in vacuo and methyl (E)-3-[(2- propionylaminoethylthio)carbonyl]acrylate (1) isolated by column chromatography
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 0℃; for 3h; Reflux;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 15℃; for 12h;	1 Compound 54: O1-methyl 04-[4-[3,5,7-tris[[(E)-4-methoxy-4-oxo-but-2- enoyl]oxy]-4-oxo-chromen-2-yl]phenyl] (E)-but-2-enedioate To a solution of (E)-4-methoxy-4-oxo-but-2-enoic acid (1 g, 7.69 mmol, 1 equiv.) in DCM (5 mL) was added DMF (95.00 mg, 1.30 mmol, 0.1 mL) and (COCI)2 (3.90 g, 30.75 mmol, 2.69 mL, 4 equiv ). The mixture was stirred at 15 °C for 12 h. TLC indicated (E)-4-methoxy-4-oxo-but-2-enoic acid was consumed completely. The reaction mixture was concentrated under reduced pressure to give a residue. The crude product methyl (E)-4-chloro-4-oxo-but-2-enoate (260 mg, crude) as a white solid was used into the next step without further purification.
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 20℃; for 2h;	(E)-methyl 4-(4-(bis(4-chlorophenyl)methyl)piperazin-1-yl)-4-oxobut-2-enoate (21). To asuspension of mono methyl fumarate (20 mg, 0.153 mmol, 1.0 eq.) in DCM (800 μL) was addedoxalyl chloride (26 μL, 306 μmol, 2.0 eq.), followed by DMF (1 drop). The mixture was stirred at rtfor 2 h and then concentrated to give the acid chloride as a yellow solid that was used directly inthe next step. To a solution of 1-(bis(4-chlorophenyl)methyl)piperazine (46 mg, 0.143 mmol, 1.0eq.) in DCM (500 μL), was added triethylamine (30 μL, 0.214 mmol, 1.5 eq.), followed by a 0.5 Msolution of methyl fumaryl chloride (300 μL, 0.150 mmol, 1.05 eq.) in DCM. The mixture was stirred at rt overnight and concentrated. Purification by flash column chromatography on silica gel(0-50% EtOAc/hexanes) afforded the title compound (37 mg, 54% yield) as a yellow solid.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 5 - 27℃;	8-9 Example-8: Preparation of Diroximel fumarate To a mixture of (E)-4-methoxy-4-oxobut-2-enoic acid (4.0 g) and dichloromethane (40 mL) at 5 °C, Oxalyl chloride (5.85 g) was added slowly in 10 minutes, then a drop of DMF was added at the same temperature and allowed the reaction mixture to warm up to 27 °C. After complete evolution of the gas, solvent was evaporated from the reaction mixture. To a mixture of l-(2-hydroxyethyl)pyrrolidine-2,5-dione (5.06 g) and dichloromethane (35 mL), diisopropylethylamine (DIPEA) (9.93 g) was added and cooled the reaction mixture to 5 °C. The former mixture of (E)-4-methoxy-4-oxobut-2-enoic acid chloride in dichloromethane was slowly added to this later mixture at 5 °C for 20 minutes and stirred at the same temperature for 1 hour. The reaction mixture was quenched with saturated ammonium chloride solution and the organic layer was separated. Organic layer was washed with 10% citric acid solution and then with brine solution. The solvent from the separated organic layer was evaporated completely at 30 °C and the resultant solid was combined with acetone (15 mL) at 27 °C and stirred for 8 hours at the same temperature. The solid was filtered and the cake was washed with chilled acetone (3 mL) and then with cyclohexane (4 mL). The wet solid was dried at 40 °C under vacuum to obtain 3.3 g of the title compound with HPLC purity of 99.95 %

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[25]Grandane, Aiga; Longwitz, Lars; Roolf, Catrin; Spannenberg, Anke; Escobar, Hugo Murua; Junghanss, Christian; Suna, Edgars; Werner, Thomas [Journal of Organic Chemistry, 2019, vol. 84, # 3, p. 1320 - 1329]
[26]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2020/118178, 2020, A1 Location in patent: Page/Page column 52; 95; 96
[27]Cai, Luke L.; Eaton, John K.; Furst, Laura; Schreiber, Stuart L.; Viswanathan, Vasanthi S. [Bioorganic and Medicinal Chemistry Letters, 2020, vol. 30, # 23]
[28]Current Patent Assignee: DR REDDY'S LABORATORIES LIMITED - WO2021/74842, 2021, A1 Location in patent: Page/Page column 22-23

3
[ 624-49-7 ]
[ 2756-87-8 ]

Reference： [1]Tetrahedron Letters,2005,vol. 46,p. 5199 - 5201
[2]Journal of Natural Products,2005,vol. 68,p. 769 - 772
[3]Journal of Organic Chemistry,2000,vol. 65,p. 5834 - 5836
[4]Helvetica Chimica Acta,1937,vol. 20,p. 1010
[5]Journal of Heterocyclic Chemistry,1966,vol. 3,p. 129 - 136

4
[ 108-31-6 ]
[ 67-56-1 ]
[ 2756-87-8 ]

Yield	Reaction Conditions	Operation in experiment
92.2%	With thiourea at 40℃; for 0.5h;
56 g	for 5h; Reflux;	1 Example 1 50 g of maleic anhydride (Compound 1) was added to 200 ml of methanol,Heated to reflux,After 5 hours of reaction, the reaction solution was concentrated to give pure 56 g of colorless liquid monomethyl fumarate (Compound 2).
16.5 g	Stage #1: maleic anhydride; methanol In toluene at 42 - 60℃; for 2h; Stage #2: With thionyl chloride In toluene at 20 - 90℃; for 3h;	1 EXAMPLE 1: Preparation of monomethyl fumarate Maleic anhydride (20g) was added in toluene (40mL) and methanol (13.05g) by maintaining temperature at about 42°C to about 55°C. The reaction mixture was maintained at about 50°C to about 60°C for about 2h. The solvent was distilled out and the reaction mixture was stripped out with toluene. To the obtained residue, toluene (80mL) was added, followed by thionyl chloride (2.43g). The reaction mixture was maintained at about 80°C to about 90°C for about 2h. The reaction mixture was cooled to about 20°C to about 30°C, stirred for about 1h and filtered. The solid was washed with toluene and dried under vacuum at about 60°C for about 6h. HPLC Purity: 99.01%; Fumaric acid content in monomethyl fumarate: 0.09% A mixture of the obtained solid in ethyl acetate (60mL) was heated to about 70°C to about 80°C for about 30min and then cooled to about 5°C to about 10°C, stirred for about 2h and filtered. The solid obtained was recrystallized with ethyl acetate and dried. Yield: 16.5g HPLC purity 99.96%; Fumaric acid content in monomethyl fumarate: 0.04%

Reference： [1]Lima, Marcelo T.; Finelli, Fernanda G.; De Oliveira, Alline V. B.; Kartnaller, Vinicius; Cajaiba, Joaõ F.; Leaõ, Raquel A. C.; De Souza, Rodrigo O. M. A. [RSC Advances, 2020, vol. 10, # 5, p. 2490 - 2494]
[2]Hurst,J.K.; Taube,H. [Journal of the American Chemical Society, 1968, vol. 90, # 5, p. 1178 - 1186]
[3]Current Patent Assignee: HENAN NORMAL UNIVERSITY - CN104761557, 2017, B Location in patent: Paragraph 0012; 0013; 0014; 0015
[4]Current Patent Assignee: GLENMARK PHARMACEUTICALS LTD - WO2021/53476, 2021, A1 Location in patent: Paragraph 0143

5
[ 2756-87-8 ]
[ 24316-19-6 ]
[ 61568-73-8 ]

Reference： [1]Journal of Medicinal Chemistry,1977,vol. 20,p. 328 - 332

6
[ 2756-87-8 ]
[ 92050-16-3 ]
[ 104182-38-9 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1986,vol. 34,p. 2275 - 2278

7
[ 6066-82-6 ]
[ 2756-87-8 ]
[ 104302-78-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With dicyclohexyl-carbodiimide In tetrahydrofuran at 0 - 20℃;
40%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20℃; for 24h;
	With dicyclohexyl-carbodiimide In tetrahydrofuran for 0.5h; Ambient temperature;

	With dicyclohexyl-carbodiimide
	With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In water at 25℃; for 0.25h;	2.2. Synthesis of MF-chitosan salt and MF-chitosan amide General procedure: MF-chitosan salt, whose structure will be confirmed by 1H NMR and DOSY later on, is the product from the reaction of MFA with chitosan in the presence of EDC and NHS, while MF-chitosan amideis the product with the mediation of EDC. Typically, 0.2 g of chitosan was dissolved in 10 mL of [BSMIM]CF3SO3 aqueous solution (4 wt%) to obtain the chitosan solution. Predetermined amount of MFA was dissolved in 10 mL of distilled water. After complete dissolution of MFA, predetermined amount of EDC and NHS were added in sequence. Fifteen minutes later, this solution was dripped into the above chitosan solution. The reaction mixture was stirred for 24 h at 25 °C. The resulting polymer of MFA-chitosan salt was dialyzed using dialysis membrane (MWCO: 8-14 kDa) against distilled water for 72 h followed by freeze-drying to remove the EDC, NHS, MFA and side products. For the synthesis of MF-chitosan amide, whose structure wil lbe testified by 1H NMR, DOSY and 13C NMR later on, only EDC was added into the chitosan solution and pH of the reaction system was adjusted to 6.

Reference： [1]Kertmen, Ahmet; Przysiecka, Lucja; Coy, Emerson; Popenda, Lukasz; Andruszkiewicz, Ryszard; Jurga, Stefan; Milewski, Slawomir [Langmuir, 2019, vol. 35, # 15, p. 5281 - 5293]
[2]Davis, Rohan A.; Kotiw, Michael [Tetrahedron Letters, 2005, vol. 46, # 31, p. 5199 - 5201] Davis, Rohan A. [Journal of Natural Products, 2005, vol. 68, # 5, p. 769 - 772]
[3]Oetvoes, Ferenc; Toth, Geza; Lovas, Sandor; Simon, Csaba; Hosztafi, Sandor [Helvetica Chimica Acta, 1996, vol. 79, p. 133 - 136]
[4]Tsujishima, Hidekazu; Shimamoto, Keiko; Shigeri, Yasushi; Yumoto, Noboru; Ohfune, Yasufumi [Heterocycles, 1998, vol. 49, # 1, p. 73 - 78]
[5]Wang, Zhaodong; Zheng, Liuchun; Li, Chuncheng; Zhang, Dong; Xiao, Yaonan; Guan, Guohu; Zhu, Wenxiang [Carbohydrate Polymers, 2015, vol. 117, p. 973 - 979]

8
[ 2756-87-8 ]
[ 27948-61-4 ]
[ 189251-58-9 ]

Yield	Reaction Conditions	Operation in experiment
81%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran for 12h; Ambient temperature;

Reference： [1]Butz, Thomas; Sauer, Juergen [Tetrahedron Asymmetry, 1997, vol. 8, # 5, p. 703 - 714]

9
[ 17102-64-6 ]
[ 2756-87-8 ]
[ 321350-76-9 ]

Yield	Reaction Conditions	Operation in experiment
88%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 3.5h;

Reference： [1]Wu, Jinlong; Sun, Lijie; Dai, Wei-Min [Tetrahedron, 2006, vol. 62, # 35, p. 8360 - 8372]

10
[ 2756-87-8 ]
[ 73670-87-8 ]
[ 907999-88-6 ]

Yield	Reaction Conditions	Operation in experiment
82%	With dmap; dicyclohexyl-carbodiimide In diethyl ether at 20℃; for 3h;
79%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; for 3.5h; Inert atmosphere;	4.7. General procedure C for synthesis of E-substituted 1,3,9-decatrienes (E)-21a-f and 21i General procedure: To a solution of the alcohol (9, 11, 12, 14, or 16) (1.5 mmol), 4-dimethylaminopyridine (DMAP, 0.15 mmol), and fumaric acid monomethyl ester 1711 or monoethyl ester 1811 (2 mmol) in dry CH2Cl2 (20 mL) cooled in an ice-water bath (0 °C) under a nitrogen atmosphere, was added N,N'-dicyclohexylcarbodiimide (DCC, 2.2 mmol) in one portion. After stirring for 30 min at the same temperature, the reaction mixture was allowed to warm up to room temperature followed by stirring for another 3 h. Celite was added to the reaction vessel and the mixture, after stirring for 30 min, was then filtered off with washing by CH2Cl2. The combined filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica gel, eluted with 9% EtOAc in PE) to provide the product (E)-21a-f. The yields are given in Table 1.

Reference： [1]Pearson, Emma L.; Kwan, Laurence C. H.; Turner, Craig I.; Jones, Garth A.; Willis, Anthony C.; Paddon-Row, Michael N.; Sherburn, Michael S. [Journal of Organic Chemistry, 2006, vol. 71, # 16, p. 6099 - 6109]
[2]Location in patent: experimental part Wu, Jinlong; Jiang, Xiuqing; Xu, Jingjing; Dai, Wei-Min [Tetrahedron, 2011, vol. 67, # 1, p. 179 - 192]

11
[ 108-31-6 ]
[ 2756-87-8 ]

Yield	Reaction Conditions	Operation in experiment
86%	In methanol	1.1 1) The maleic anhydride (698.1 g, i.e. 7.12 mol) was introduced into a 2-litre four-necked reactor and then melted by heating the reactor using an oil bath raised to 70° C. Once all the anhydride had melted, the methanol (221.4 g, i.e. 6.92 mol) was introduced, with stirring, via a dropping funnel. Next, the mixture was left, with stirring, for 20 hours at 23° C., then devolatilized by applying a reduced pressure of 10*102 Pa for 1 hour and finally filtered on a filter paper. Thus, 786.9 g of maleic acid monomethylester, of the following formula, was recovered (with a yield of 86%):
	With iodine In methanol	4 Monomethyl fumarate EXAMPLE 4 Monomethyl fumarate 320 g of methanol are added dropwise, at 160° C., to 1000 g of a technical mixture of alkylaromatic compounds, as solvent, 980 g of maleic anhydride and 10 g of iodine. The reaction mixture is filtered while it is hot. On cooling, monomethyl fumarate crystallizes out in colourless crystals. Recrystallization from toluene gives 857 g of pure monomethyl fumarate of melting point 142°-144° C. Analysis: Calculated: C: 46.2; H: 4.6%; Found; C: 46.2; H: 4.6%;

Reference： [1]Current Patent Assignee: SOLVAY - US2003/144393, 2003, A1
[2]Current Patent Assignee: BAYER AG - US4515974, 1985, A

12
[ 72-19-5 ]
[ 2756-87-8 ]
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3-hydroxybutanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water;Heating / reflux;	Example 2; Preparation of 2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3- hydroxybutanoic acid (<strong>[72-19-5]threonin</strong>e monomethylfumarate); Threonine (Fluka, 89180) and MMF (Sigma-Aldrich, 651419, CAS 2756-87-8) in equimolar amounts (0.025 M) were dissolved in 4.0 mL of water. The mixture was stirred and heated until dissolution of all solid material. The solution was transferred to a beaker with 800 mL of acetone, which resulted in formation of a white precipitate. A white powder formed after suction filtration and drying in an electrical oven set at 400C. No specific melting point was EPO <DP n="42"/>observed, which indicates that the product compound was amorphous. The amorphous state was confirmed by x-ray powder crystallography. UV-spectrophotometry was used to check the ratio of <strong>[72-19-5]threonin</strong>e to MMF (208 nm) in the product. A value for the molar mass was estimated by titration.

Reference： [1]Patent: WO2007/6307,2007,A2 .Location in patent: Page/Page column 40-41

13
[ 2756-87-8 ]
[ 7200-25-1 ]
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-5-guanidinopentanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water;Heating / reflux;	Example 8; Preparation of 2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-5- guanidinopentanoic acid (arginine monomethylfumarate); <strong>[7200-25-1]Arg</strong>inine (Fluka, 11010, CAS 74-79-3) and MMF (Sigma-Aldrich, 651419, CAS 2756-87-8) in equimolar amounts (0.025 M) were dissolved in 4.0 mL of water. The mixture was stirred and heated until dissolution of all solid material. The solution was transferred to a beaker with 500 mL of acetone, which resulted in formation of a white sticky material. The white sticky material remained after suction filtration and drying in an electrical oven set at 400C. UV- spectrophotometry was used to check the ratio of arginine to MMF (208 nm) in the product. An approximate value for the molar mass was estimated by titration.

Reference： [1]Patent: WO2007/6307,2007,A2 .Location in patent: Page/Page column 43

14
[ 921-01-7 ]
[ 2756-87-8 ]
2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3-mercaptopropanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; at 60 - 70℃;	Example 9; Preparation of 2-hydro-amino-((E)-methoxy-4-oxobut-2-enoate)-3- mercaptopropanoic acid (cystein monomethylfumarate); Cystein (Fluka, 30089, CAS 52-90-4) and MMF (Sigma-Aldrich, 651419, CAS 2756-87-8) in equimolar amounts (0.025 M) were dissolved in 3.5 mL of water at 60-700C and the solution was stirred until dissolution of all solid material. The solution was transferred to a beaker with 420 mL of acetone, which resulted in the precipitation of a white and sticky material. An amorphous and transparent solid material was formed after suction filtration and drying in an electrical oven at 600C. After drying, the material was hard and transparent. Heating to temperatures above HO0C caused degradation, as observed by a yellow colouring of the product. No specific melting point was observed, which indicates that the product compound was amorphous. The amorphous state was confirmed by x-ray powder crystallography. UV- spectrophotometry was used to check the ratio of cystein to MMF (208 nm) in the product. A value for the molar mass was estimated by titration.

Reference： [1]Patent: WO2007/6307,2007,A2 .Location in patent: Page/Page column 43

15
[ 1016669-60-5 ]
[ 2756-87-8 ]
[ 1016669-53-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With dmap; 1-[3-(dimethylamino)-propyl]-3-ethylcarbodiimide methiodide In dichloromethane at 20℃; for 0.5h;

Reference： [1]Li, Guotao; Zhang, Guozhu; Zhang, Liming [Journal of the American Chemical Society, 2008, vol. 130, # 12, p. 3740 - 3741]

16
[ 2756-87-8 ]
[ 2315-36-8 ]
[ 1208229-58-6 ]

Yield	Reaction Conditions	Operation in experiment
68.8%	With diisopropylamine at 50 - 75℃; for 5h; Inert atmosphere; Large scale;	2 Alternate Synthesis of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (1) Following General Procedure A above, a 5-L, three-neck, round-bottom flask was equipped with a mechanical stirrer, an internal thermometer, a 500 mL addition funnel and a nitrogen inlet and was charged with methyl hydrogen fumarate (MHF) (1.30 kg, 10 mol) and N,N′-diethylchloroacetamide (1.34 kg, 9 mol). The resulting slurry was slowly heated to 50° C. and diisopropylamine (1.75 L; 1.295 kg, 10 mol) was added slowly over a period of two hours with a final internal temperature of 75° C. The reaction mixture was heated to 70° C. for three hours. A sample was taken from the reaction mixture for in process analysis by HPLC. The reaction mixture was then cooled to 50° C. and diluted with ethyl acetate (10 L). The organic phase was transferred into a 20 L separatory funnel and washed with water (3×2 L). The organic phase was separated, dried over sodium sulfate and then evaporated under vacuum to give the product as a viscous oil. This crude product was dissolved in diisopropyl ether (8 L) and warmed to 50° C. The resulting warm milky slurry was filtered through celite. The clear filtrate was slowly cooled to room temperature and then to 0° C. over a period of four hours. During this period the compound crystallized out as a white-solid. It was filtered and dried in a vacuum oven at 40° C. for 48 hrs to afford 1.5 kg of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (68.8% yield).
51%	Stage #1: methyl hydrogen fumarate With cesium bicarbonate In 1-methyl-pyrrolidin-2-one at 20℃; Stage #2: 2-Chloro-N,N-diethylacetamide In 1-methyl-pyrrolidin-2-one	1 General Procedure A: Nucleophilic Substitution of 1-haloacetamides or 1-halo Acetic Acid Derivatives with Monomethyl Fumarate:; (2E)-3-(Methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF), (2E)-3-(tert-butoxycarbonyl)prop-2-enoic acid (tert-butyl hydrogen fumarate), or fumaric acid (FA) (1.0 equivalents) is dissolved in 5-10 mL/3.0 mmol of an inert solvent such as N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA, DMAc), acetonitrile (MeCN), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene, or mixtures thereof. To the solution, 0.8 to 1.2 equivalents of an appropriate inorganic base such as cesium hydrogen carbonate (CsHCO3), cesium carbonate (Cs2CO3), or potassium carbonate (K2CO3) is added. Alternatively, 0.8 b is 1.2 equivalents of a silver salt such silver(I) oxide (Ag2O) or silver(I) carbonate (Ag2CO3); an organic secondary or tertiary base such as dicyclohexylamine (DCHA), triethylamine (TEA), diisopropylethylamine (DIEA), tetrabutylammonium hydroxide (TBAOH), amidine; or a guanidine-based base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,1,3,3-tetramethylguanidine (TMG), can be employed. The corresponding alkali, silver, di-, tri- and tetraalkylammonium, amidine, or guanide salt of monoalkyl fumarate can also be preformed. The solution is stirred for 10-60 min at room temperature followed by addition of 0.8-1.2 equivalents of an appropriately functionalized 1-haloacetamide, 1-halo acetic acid derivative, acyloxyalkyl halide, or alky- or aryloxycarbonyloxyalkyl halide. The reaction mixture is stirred overnight at a temperature between 40 to 100° C. After cooling to room temperature, insolubles can optionally be filtered off and the reaction mixture diluted with one molar (1.0 M) hydrochloric acid (HCl) and an appropriate organic solvent such as methyl tert-butyl ether (MTBE), diethyl ether (Et2O), ethylacetate (EtOAc), or mixtures thereof. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the organic solvents are removed under reduced pressure using a rotary evaporator. If required, the crude reaction products are further purified by well known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass-guided reversed-phase preparative HPLC/lyophilization, precipitation, or crystallization.; Example 1; (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (1); Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at ca. 55° C. with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO3 (0.69 g, 3.60 mmol) to afford 0.37 g (51% yield) of the title compound (1) after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56° C. 1H NMR (CDCl3, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J=7.2 Hz, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)+.
51%	With cesium bicarbonate In 1-methyl-pyrrolidin-2-one at 55℃;	1; A General Procedure A: Nucleophilic substitution of 1-haloacetamides or 1-halo acetic acid derivatives with monomethyl fumarate: General procedure: (2E)-3-(Methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF), (2E)-3-(tert-butoxycarbonyl)prop-2-enoic acid (tert-butyl hydrogen fumarate), or fumaric acid (FA) (1.0 equivalents) is dissolved in 5 - 10 mL/3.0 mmol of an inert solvent such as N-methyl pyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA, DMAc), acetonitrile (MeCN), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene, or mixtures thereof. To the solution, 0.8 to 1.2 equivalents of an appropriate inorganic base such as cesium hydrogen carbonate (CsHCO3), cesium carbonate (Cs2CO3), or potassium carbonate (K2CO3) is added. Alternatively, 0.8 bis 1.2 equivalents of a silver salt such silver(I) oxide (Ag2O) or silver(I) carbonate (Ag2CO3); an organic secondary or tertiary base such as dicyclohexylamine (DCHA), triethylamine (TEA), diisopropylethylamine (DIEA), tetrabutylammonium hydroxide (TBAOH), amidine; or a guanidine-based base such as 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,1,3,3-tetramethylguanidine (TMG), can be employed. The corresponding alkali, silver, di-, tri- and tetraalkylammonium, amidine, or guanide salt of monoalkyl fumarate can also be preformed. The solution is stirred for 10 - 60 min at room temperature followed by addition of 0.8-1.2 equivalents of an appropriately functionalized 1-haloacetamide, 1-halo acetic acid derivative, acyloxyalkyl halide, or alky- or aryloxycarbonyloxyalkyl halide. The reaction mixture is stirred overnight at a temperature between 40 to 100°C. After cooling to room temperature, insolubles can optionally be filtered off and the reaction mixture diluted with one molar (1.0 M) hydrochloric acid (HCl) and an appropriate organic solvent such as methyl tert-butyl ether (MTBE), diethyl ether (Et2O), ethylacetate (EtOAc), or mixtures thereof. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO4). After filtration, the organic solvents are removed under reduced pressure using a rotary evaporator. If required, the crude reaction products are further purified by well known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass-guided reversed-phase preparative HPLC/lyophilization, precipitation, or crystallization. Example 1 (N,N- Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate (1) Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at ca. 55°C with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO3 (0.69 g, 3.60 mnol) to afford 0.37 g (51% yield) of the title compound (1) after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56°C. 1H NMR (CDCl3, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.50 (s, 3H), 3.39 (q, J = 7.2 Hz, 2H), 3.26 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)+.

51%	With cesium bicarbonate In 1-methyl-pyrrolidin-2-one at 55℃;	6 Example 6 (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate Example 6 (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate Following general procedure A, methyl hydrogen fumarate (MHF) (0.39 g, 3.00 mmol) dissolved in NMP was reacted at about 55° C. with 2-chloro-N,N-diethylacetamide (0.44 g, 3.00 mmol) in the presence of CsHCO3 (0.69 g, 3.60 mmol) to afford 0.37 g (51% yield) of the title compound after purification by silica gel column chromatography (Biotage) using a mixture of ethyl acetate (EtOAc) and hexanes (1:1) as eluent. M.p.: 53-56° C. 1H NMR (CDCl3, 400 MHz): δ 6.99-6.90 (m, 2H), 4.83 (s, 2H), 3.80 (s, 3H), 3.39 (q, J=7.2 Hz, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.24 (t, J=7.2 Hz, 3H), 1.14 (t, J=7.2 Hz, 3H). MS (ESI): m/z 244.13 (M+H)+.
	Alkaline conditions;	12 N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate Example 12 Preparation of the MMF Prodrug N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate The diethylamino prodrug of MMF (VI) was prepared by reacting monomethyl fumarate (130 g, 1 mol) with 2-chloro-N,N-diethyl acetamide (157 g, 1.05 mol) in the presence of a base and following the procedure described in Gangakhedkar et al., U.S. Patent Publication No. 2010/0048651. Following concentration under vacuum, the purity by HPLC was 100.00% w/w, with 0.07% dimer.
	With triethylamine In toluene at 85 - 95℃; for 4h; Inert atmosphere;	4 Synthesis, Purification and Analysis of Crystalline Form 4 of (N,N-Diethylcarbamoyl)methyl methyl (2E)but-2-ene-1,4-dioate At a temperature of about 50-70° C., under a nitrogen atmosphere, a slurry of mono-methyl fumarate (130 g), toluene (800 mL) and N,N-diethylchloroacetamide (157 g) is added to triethylamine (1.07 g). The temperature is adjusted to 85-95° C. and maintained there for 4 hours. Then the temperature is then adjusted to 15-25° C. and the mixture is subjected to vigorous agitation. After 30 minutes of vigorous agitation in 200 mL of water, the agitation is stopped and the phases are allowed to separate for 30 minutes. The upper organic phase is washed with additional deionized water (75 mL) with vigorous agitation for 30 minutes. The agitation is then stopped and the phases are allowed to separate for 30 minutes. The organic layer is dried over anhydrous sodium sulfate (25 g) for 2 hours. The reaction is filtered and the solution is cooled to 10-20° C. Heptane (1600 mL), at -5 to -20° C. is added over 5 minutes. The reaction is cooled to -5° C. to -10° C. for 24 to 48 hours. The resulting product is air dried for 12 hours. XRPD analysis confirms product is form 4.

Reference： [1]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2014/56973, 2014, A1 Location in patent: Paragraph 0141; 0145
[2]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2010/48651, 2010, A1 Location in patent: Page/Page column 24-25
[3]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - EP2650279, 2013, A2 Location in patent: Paragraph 0257; 0261-0262
[4]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2013/324539, 2013, A1 Location in patent: Paragraph 0145-0146
[5]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2014/364604, 2014, A1 Location in patent: Paragraph 0192-0193
[6]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2015/73049, 2015, A1 Location in patent: Paragraph 0140

17
[ 2756-87-8 ]
[ 127828-22-2 ]
[ 1314800-97-9 ]

Yield	Reaction Conditions	Operation in experiment
64%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In acetonitrile; at 20℃; for 18h;	tert-Butyl 2-(2-aminoethoxy)ethylcarbamate (1.0 g, 4.90 mmol) was then taken up in 20 mL of CH3CN along with mono methyl fumarate (637 mg, 4.90 mmol) and EDCI (1.7 g. 5.39 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with EtOAc (20 mL), washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (9:1 CH2Cl2/MeOH) to afford 1.0 g of (E)-methyl 4-(2-(2-(tert-butoxycarbonyl)ethoxy)ethylamino)-4-oxobut-2-enoate (64% yield). MS (EI) calcd for C14H24N2O6: 316.16. found: 317 (M+1).

Reference： [1]Patent: US2011/172240,2011,A1 .Location in patent: Page/Page column 36

18
[ 2756-87-8 ]
[ 1314801-11-0 ]
[ 1314801-12-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 0 - 20℃; Inert atmosphere;	23 To a stirring mixture of (S)-tert-butyl 6-amino-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (800 mg, 2.31 mmol), monomethyl fumarate (361 mg, 2.77 mmol), DIEA (1.1 mL, 6.93 mmol) in 10 mL acetonitrile was added HATU (1.14 g, 3.00 mmol) in one portion at 0° C. under an inert atmosphere of argon. The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was diluted with EtOAc (50 mL) and washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S,E)-tert-butyl 6-(4-methoxy-4-oxobut-2-enamido)-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (900 mg, 85%).

Reference： [1]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2011/172240, 2011, A1 Location in patent: Page/Page column 41

19
[ 2756-87-8 ]
[ 1314801-17-6 ]
[ 1314801-18-7 ]

Yield	Reaction Conditions	Operation in experiment
30%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In acetonitrile at 20℃; for 2h;	24 The crude (S)-tert-butyl 2-amino-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)hexanoate, prepared above, was taken up in 40 mL acetonitrile along with monomethyl fumarate (610 mg, 4.69 mmol), DIEA (3.0 mL, 18.8 mmol) and HATU (2.4 g, 6.39 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was taken up in 100 mL of EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S)-tert-butyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (500 mg, 30%).

Reference： [1]Current Patent Assignee: CATABASIS PHARMACEUTICALS, INC. - US2011/172240, 2011, A1 Location in patent: Page/Page column 42; 43

20
[ 2756-87-8 ]
[ 90319-52-1 ]
[ 1428647-00-0 ]

Yield	Reaction Conditions	Operation in experiment
78%		A solution of methyl fumarate (8) (2.66 g, 20.4 mmol) and pivaloyl chloride (2.70 g, 2.76 mL, 22.5 mmol) in THF (40 mL) was cooled to ?20 °C. Triethylamine (4.13 g, 5.68 mL, 40.8 mmol) was added dropwise, and the mixture was stirred 1.5 h at ?20 °C. The cooling bath was removed, and the solution was allowed to warm to room temperature. Solid LiCl (0.953 g, 22.5 mmol) and (R)-phenyl-oxazolidone 9 (5.00 g, 30.6 mmol) were added portionwise, and the reaction was stirred 12 h. H2O (10 mL) and ethyl acetate (50 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with 1 M HCl (1 x 25 mL), saturated Na2CO3 (2 x 50 mL), saturated brine (1 x 50 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with hexanes/ethyl acetate (3:1) to provide 4.38 g (78percent) of the chiral methyl fumarate 7 as a white solid: mp 92-94 °C; 1H NMR (400 MHz) delta 8.17 (d, J = 15.7 Hz, 1 H), 7.43 (comp, 5 H), 6.87 (d, J = 15.7, 1 H), 5.50 (dd, J = 4.0, 8.9 Hz, 1 H), 4.76 (t, J = 8.9 Hz, 1 H), 4.36 (dd, J = 4.0, 8.9 Hz, 1 H), 3.81 (s, 3 H); 13C NMR (100 MHz) delta 165.1, 163.1, 153.2, 138.2, 133.8, 132.2, 129.1, 128.8, 125.9, 70.2, 57.7, 52.2; IR (neat) 1780, 1727, 1690, 1387, 1341, 1306, 1279, 1196 cm-1; mass spectrum (CI) m/z 275.0869 [C14H13NO5 (M+1) requires 275.0794].
78%		A solution of methyl fumarate (29) (2.66 g, 20.4 mmol) and pivaloyl chloride (2.70 g, 2.76 mL, 22.5 mmol) in THF (40 mL) was cooled to -20 °C. Triethylamine (4.13 g, 5.68 mL, 40.8 mmol) was added dropwise, and the mixture was stirred 1.5 h at -20 °C. The cooling bath was removed, and the solution was allowed to warm to room temperature. Solid LiCl (0.953 g, 22.5 mmol) and (R)-phenyl-oxazolidone 13 (5.00 g, 30.6 mmol) were added portionwise, and the reaction was stirred 12 h H2O (10 mL) and ethyl acetate (50 mL) were added. The layers were separated, and the aqueous layer was extracted with ethyl acetate (210 mL). The combined organic layers were washed with 1 M HCl (125 mL), saturated Na2CO3 (250 mL), saturated brine (150 mL), dried (Na2SO4), and concentrated under reduced pressure. The crude product was purified by flash chromatography, eluting with hexanes/ethyl acetate (3:1) to provide 4.38 g (78percent) of the chiral methyl fumarate 30 as a white solid: mp 92-94 °C; 1H NMR (400 MHz) delta 8.17 (d, J=15.7 Hz, 1H), 7.43 (comp, 5H), 6.87 (d, J=15.7, 1H), 5.50 (dd, J=4.0, 8.9 Hz, 1H), 4.76 (t, J=8.9 Hz, 1H), 4.36 (dd, J=4.0, 8.9 Hz, 1H), 3.81 (s, 3H); 13C NMR (100 MHz) delta 165.1, 163.1, 153.2, 138.2, 133.8, 132.2, 129.1, 128.8, 125.9, 70.2, 57.7, 52.2; IR (neat) 1780, 1727, 1690, 1387, 1341, 1306, 1279, 1196 cm-1; mass spectrum (CI) m/z 275.0869 [C14H13NO5 (M+1) requires 275.0794].

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 2074 - 2076
[2]Tetrahedron,2015,vol. 71,p. 6361 - 6368

21
[ 2756-87-8 ]
C₁₈H₂₈N₂O₄ [ No CAS ]
[ 1439852-40-0 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: methyl hydrogen fumarate With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 25℃; for 1.5h; Stage #2: C₁₈H₂₈N₂O₄ With dmap; triethylamine In dichloromethane at 0 - 25℃; for 2h;	II General Procedure II: General Procedure II: [0173] To methyl hydrogen fumarate (0.398 g, 3.06 mmol) in 4 ml CH2Cl2 at 0° C. was added oxalyl chloride (0.262 ml, 3.06 mmol) and one drop of DMF. The solution was stirred at 25° C. for 1.5 h before concentration in vacuum. To oxidized amine (1.53 mmol) and 4-(dimethylamino)pyridine (0.093 g, 0.764 mmol) in 4 ml CH2Cl2 at 0° C. were added fresh prepared acyl chloride in 3 ml CH2Cl2 followed by triethylamine (1.06 ml, 7.64 mmol). The reaction mixture was stirred at 25° C. for 2 h before addition of saturated NH4Cl. Aqueous layer was extracted with ethyl acetate 3 times, then the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography.

Reference： [1]Current Patent Assignee: UNIVERSITY OF COLORADO (SYSTEM) - US2013/137720, 2013, A1 Location in patent: Paragraph 0172; 0173

22
[ 2756-87-8 ]
[ 1310809-19-8 ]
[ 1310809-22-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: methyl hydrogen fumarate With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 0.833333h; Stage #2: tert-butyl (4-((benzoyloxy)amino)butyl)carbamate With dmap; triethylamine In dichloromethane at 0 - 20℃; for 2h;	(E)-Methyl 4-(benzoyloxy(4-(tert-butoxycarbonylamino)butyl)amino)-4-oxobut-2-enoate (4) (E)-Methyl 4-(benzoyloxy(4-(tert-butoxycarbonylamino)butyl)amino)-4-oxobut-2-enoate (4) Oxalyl chloride (0.39 mL, 4.5 mmol) was added dropwise to a solution of mono-methyl fumarate (0.64 g, 4.9 mmol) in distilled CH2Cl2 (7 mL) at 0° C., then a drop of anhydrous DMF was added. The resulting mixture was stirred at this temperature for 20 minutes before it was warmed to room temperature and stirred for another 30 minutes. A solution of 3 (1.16 g, 3.75 mmol) in distilled CH2Cl2 (3 mL) was added at 0° C., followed by the addition of freshly distilled triethylamine (1.05 mL, 7.5 mmol) and DMAP (0.049 g, 0.40 mmol). The reaction was stirred at room temperature for 2 h. A saturated aqueous solution of NH4Cl was added and the aqueous layer was extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude oil, which was purified by column chromatography on silica gel (hexanes/ethyl acetate=10:1) to afford 4 (1.14 g, 2.7 mmol) as a colorless oil in 72% yield: IR (thin film): 3368, 2976, 1768, 1713, 1520, 1240, 1170, 1006 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.15-8.03 (m, 2H), 7.68 (t, J=7.5 Hz, 1H), 7.52 (t, J=7.7 Hz, 2H), 7.13 (d, J=15.7 Hz, 1H), 6.92 (d, J=15.4 Hz, 1H), 4.65-4.56 (br, 1H), 3.89 (t, J=6.9 Hz, 2H), 3.73 (s, 3H), 3.18-3.13 (m, 2H), 1.75-1.70 (m, 2H), 1.61-1.52 (m, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3): δ 165.80, 164.62, 156.15, 135.03, 133.03, 131.28, 130.37, 129.20, 126.24, 79.31, 52.43, 52.39, 48.38, 40.20, 28.54, 27.48, 24.50 ppm. HRMS (m/z): [M+Na]+ calcd. for C21H28N2NaO7, 443.1788; found, 443.1792.

Reference： [1]Current Patent Assignee: UNIVERSITY OF COLORADO (SYSTEM) - US2013/137720, 2013, A1 Location in patent: Paragraph 0160; 0161

23
[ 622-40-2 ]
[ 2756-87-8 ]
[ 1448896-48-7 ]

Yield	Reaction Conditions	Operation in experiment
81%	Stage #1: methyl hydrogen fumarate With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; Stage #2: 2-(morpholin-4-yl)ethanol With dmap In dichloromethane at 0 - 20℃;	1 General Procedure B1 Activation of Carboxylic Acid Derivatives with Dehydration Agents for Aminolysis or Alcoholysis General procedure: General Procedure B1 Activation of Carboxylic Acid Derivatives with Dehydration Agents for Aminolysis or Alcoholysis [0427] A monoalkyl fumarate (1.0 equivalents) is reacted at temperature from ca. 0° C. (ice bath) to room temperature with 1.0-1.5 equivalents of a carbodiimide dehydration agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAC, EDC), N,N′-diisopropylcarbodiimide (DIC), N,N′-dicyclohexylcarbodiimide (DCC) in an inert solvent such as dichloromethane (DCM), N,N-dimethylformamide, N-methylpyrrolidone (NMP), or N,N-dimethylacetamide (DMA, DMAc) (ca. 3 mL/mmol). 1.0-1.5 equivalents of 1-hydroxyalkyl morpholine dissolved in the same solvent and, optionally, in the presence of a catalytic or stoichiometric amount of 4-(N,N-dimethylaminopyridine) (DMAP) is added at a temperature from ca. 0° C. to room temperature. When the amine is a salt form, an equimolar amount of an organic tertiary base, such as triethylamine (TEA), or diisopropylethylamine (DIEA) may be added to free the amine base prior to the coupling step. The reaction mixture is stirred for 4 to 12 hours at room temperature. Optionally, the organic solvents are removed under reduced pressure using a rotary evaporator and the residue diluted with an appropriate extraction solvent such as diethyl ether (Et2O), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), or others. The procedures described in Procedure A for product isolation and purification may be employed. Example 1 Methyl (2-morpholinoethyl)fumarate (Methyl 2-morpholin-4ylethyl(2E)but-2-ene-1,4-dioate) (1) [0433] dichloromethane (DCM) at ca. 0° C. 2-Morpholin-4-ylethyl-1-ol (26.2 g, 0.2 mol) and 4-N,N-dimethylaminopyridine (DMAP) (1 g, 0.008 mol) were added to the activated carboxylic acid. After synthesis, 38 g (81% yield) of the title compound was isolated as a viscous-oil. [0435] 1H NMR (CDCl3, 400 MHz): δ 6.88 (m, 2H), 4.35-4.33 (m, 2H), 3.82 (s, 3H), 3.72-3.70 (m, 4H), 2.699-2.68 (m, 2H), 2.67-2.51 (m, 4H), MS (ESI): m/z 245.11 (M+H)+
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃;	14 Methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1,4-dioate Example 14 Preparation of the MMF Prodrug Methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1,4-dioate Methyl 2-morpholin-4-ylethyl (2E)but-2-ene-1,4-dioate Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0° C. 2-Morpholin-4-yl-ethyl-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous oil.

Reference： [1]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2013/203753, 2013, A1 Location in patent: Paragraph 0426-0427; 0432-0435
[2]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2014/364604, 2014, A1 Location in patent: Paragraph 0196-0197

24
[ 2756-87-8 ]
2-chloro-N-cyclopropyl-N-ethylacetamide [ No CAS ]
(N-cyclopropyl-N-ethylcarbamoyl)methyl methyl 2-(E)-but-2-ene-1,4-dioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.3%	With N-ethyl-N,N-diisopropylamine In toluene at 80℃;	13 Example 13 (N-cyclopropyl-N-ethylcarbamoyl)methyl methyl 2(E)but-2-ene-1,4-dioate Example 13 (N-cyclopropyl-N-ethylcarbamoyl)methyl methyl 2(E)but-2-ene-1,4-dioate Following the general procedure A, methyl hydrogen fumarate (MHF) (38.7 g, 0.297 mol) suspended in toluene (100 mL) was reacted at about 80° C. with 2-chloro-N-cyclopropyl-N-ethylacetamide (48 g, 0.297 mol) in the presence of N,N-diisopropylethylamine (DIEA; 42.3 g, 57 mL, 0.327 mol) to afford 50 g (63.3%) of the title compound after recrystallization using methyl tert-butyl ether. The crystalline compound had a melting point of 92.1° C. 1H NMR (CDCl3, 400 MHz): δ 7.01-6.92 (m, 2H), 4.99 (s, 2H), 3.81 (s, 3H), 3.44 (q, J=7.2 Hz, 2H), 2.69-2.66 (m, 1H), 1.14 (t, J=7.2 Hz, 3H), 0.94-0.91 (m, 2H), 0.83-0.81 (m, 2H). MS (ESI): m/z 256.2 (M+H)+

Reference： [1]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - US2013/324539, 2013, A1 Location in patent: Paragraph 0159-0160

25
[ 2756-87-8 ]
[ 136917-95-8 ]
[ 1613403-91-0 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: methyl hydrogen fumarate With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: (±)-1-[(tert-butyldimethylsilyl)oxy]-3-chloropropan-2-ol In N,N-dimethyl-formamide for 2h;	Synthesis of compound 3 To a stirred solution of monomethyl fumerate (1.0 eq) in DMF (10.0 vol) , DIPEA (3.0 eq) and HOBt (1.5 eq) were added at room temperature. EDC.HC1 was added to the reaction mass and stirred for 30.0 minutes, then Compound-2 (1.2 eq) was added slowly to it and stirred for 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extracted twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure (yield: 75%).

Reference： [1]Current Patent Assignee: KANDULA, Mahesh - WO2014/87323, 2014, A2 Location in patent: Paragraph 00144-00145

26
[ 2756-87-8 ]
[ 1613403-99-8 ]
[ 1613404-00-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: methyl hydrogen fumarate With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: C₅₂H₁₀₀O₇Si₄ In N,N-dimethyl-formamide for 2h;	To a stirred solution of monomethylfumerate (1.0 eq) in DMF (10.0 vol), DIPEA (3.0 eq) and HOBt (1.5 eq) were added at room temperature. EDC.HC1 was added to the reaction mass and stirred for 30.0 minutes, then Compound-6 (1.2 eq) was added slowly to it and stirred for 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extracted twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure to obtain compound 7 (yield: 75%).

Reference： [1]Current Patent Assignee: KANDULA, Mahesh - WO2014/87323, 2014, A2 Location in patent: Paragraph 00161

27
[ 2756-87-8 ]
[ 1621698-51-8 ]
[ 1613403-77-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: methyl hydrogen fumarate With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: C₁₉H₃₉NO₅Si In N,N-dimethyl-d<SUB>6</SUB>-formamide for 2h;	Synthesis of compound 4 To a stirred solution of monomethylfumarate (1.0 eq) in DMF (10.0 vol), DIPEA (3.0 eq) and HOBt (1.5 eq) were added at room temperature. EDC.HCl was added to the reaction mass and stirred for 30 minutes, then compound-3 (1.2 eq) was added slowly to it and stirred for another 2.0 hrs. Reaction was monitored by TLC. On completion of the reaction, the solvent was removed in vacuo and the crude was diluted with water and extracted twice with DCM. The organic layer was washed with water followed by brine and dried over anhydrous Na2S04 and evaporated under reduced pressure to yield compound 4 (yield 75%).

Reference： [1]Current Patent Assignee: KANDULA, Mahesh - WO2014/87323, 2014, A2 Location in patent: Paragraph 00110-00111

28
[ 5835-79-0 ]
[ 2756-87-8 ]
[ 1448896-52-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃;	Example 16 Preparation of the MMF Prodrug Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate Methyl 4-morpholin-4-ylbutyl (2E)but-2-ene-1,4-dioate Monomethyl fumarate (MMF) was reacted with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC) (1.2 eq) in dichloromethane (DCM) at ca. 0 C. 4-Morpholin-4-yl-butan-1-ol (1 eq) and 4-N,N-dimethylaminopyridine (DMAP) (catalytic amount) were added to the activated carboxylic acid. After the completion of the reaction, followed by the work-up of the reaction mixture, the title compound was isolated as a viscous-oil.

Reference： [1]Patent: US2014/364604,2014,A1 .Location in patent: Paragraph 0200-0201

29
[ 2756-87-8 ]
[ 82745-20-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sodium hydride In tetrahydrofuran for 3h; Reflux;	2 Synthesis of Methyl ((trimethoxysilyl)methyl) fumarate (Compound 12) To a stirred solution of monomethyl fumarate (3.5 g, 27 mmol, 1.0 equiv.) in anhydrous THF (35 mL) at room temperature was added sodium hydride (1.08 g, 27 mmol, 1.0 equiv.) in small portions. After addition, the mixture was heated to reflux for 3 hours, and then cooled to room temperature. The solid was collected by filtration and washed twice with diethyl ether, and further dried in vacuo to give 3.8 g of 12B (93%).
93%	With sodium hydride In tetrahydrofuran for 3h; Reflux;	8 Example 8: Synthesis of methyl ((trimethoxysilyl)methyl) fumarate (Compound 12) Example 8: Synthesis of methyl ((trimethoxysilyl)methyl) fumarate (Compound 12) To a stirred solution of monomethyl fumarate (3.5 g, 27 mmol, 1.0 equiv.) in anhydrous THF (35 mL) at room temperature was added sodium hydride (1.08 g, 27 mmol, 1.0 equiv.) in small portions. After addition, the mixture was heated to reflux for 3 hours, and then cooled to room temperature. The solid was collected by filtration and washed twice with diethyl ether, and further dried in vacuo to give 3.8 g of 12B (93%).
93%	With sodium hydride In tetrahydrofuran for 3h; Reflux;	12 To a stirred solution of monomethyl fumarate (3.5 g, 27 mmol, 1.0 equiv.) in anhydrous THF (35 mL) at room temperature was added sodium hydride (1.08 g, 27 mmol, 1.0 equiv.) in small portions. After addition, the mixture was heated to reflux for 3 hours, and then cooled to room temperature. The solid was collected by filtration and washed twice with diethyl ether, and further dried in vacuo to give 3.8 g of 12B (93%).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - US2014/336151, 2014, A1 Location in patent: Paragraph 0127-0128
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/190056, 2014, A2 Location in patent: Page/Page column 116
[3]Current Patent Assignee: BIOGEN IDEC INC. - WO2015/172083, 2015, A1 Location in patent: Page/Page column 202

30
[ 2756-87-8 ]
[ 2182-66-3 ]
(E)-O,O'-(dimethylsilanediyl)dimethyl difumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	at 170℃; for 1h; Microwave irradiation;	1.2 Preparation of (E)-O,O′-(dimethylsilanediyl)dimethyl difumarate 11 A mixture of 11B (2.0 mL, 12 mmol, 1.5 equiv.) and 11C (1.04 g, 8.0 mmol, 1.0 equiv.) in a sealed tube was heated at 170° C. with stirring under microwave condition for 1 hour. After cooling to 50° C., the mixture was transferred to a round bottom flask and the excess silica reactant 11B was removed under vacuum at 100° C. to afford compound 11 as brown oil (1.47 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm: 6.82-6.80 (m, 4H), 3.79 (s, 6H), 0.57 (s, 6H).
60%	at 170℃; for 1h; Sealed tube; Microwave irradiation;	7.2 Step 2: Preparation of (E)-O, 0 ‘-(dimethylsilanediyl)dimethyl difumarate 11 Step 2: Preparation of (E)-O, 0 ‘-(dimethylsilanediyl)dimethyl difumarate 11 A mixture of 11B (2.0 mL, 12 mmol, 1.5 equiv.) and 11C (1.04 g, 8.0 mmol, 1.0 equiv.) in a sealed tube was heated at 170 °C with stirring under microwave condition for 1 hour. After cooling to 50 °C, the mixture was transferred to a round bottom flask and the excess silica reactant 11B was removed under vacuum at 100 °C to afford compound 11 as brown oil (1.47 g, 60%). 1H NMR (400 MHz, CDC13) ö ppm: 6.82-6.80 (m, 4H), 3.79 (s, 6H), 0.57 (s, 6H).
60%	at 170℃; for 1h; Sealed tube; Microwave irradiation;	11.2 Step 2: Preparation of (E)-O, 0 ‘-(dimethylsilanediyl)dimethyl difumarate 11 A mixture of 11B (2.0 mL, 12 mmol, 1.5 equiv.) and 11C (1.04 g, 8.0 mmol, 1.0 equiv.) in a sealed tube was heated at 170 °C with stirring under microwave condition for 1 hour. After cooling to 50 °C, the mixture was transferred to a round bottom flask and the excess silica reactant 11B was removed under vacuum at 100 °C to afford compound 11 as brown oil (1.47 g, 60%). ‘H NMR (400 MHz, CDC13) (5ppm: 6.82-6.80 (m, 4H), 3.79 (s, 6H), 0.57 (s, 6H).

Reference： [1]Current Patent Assignee: BIOGEN IDEC INC. - US2014/336151, 2014, A1 Location in patent: Paragraph 0125-0126
[2]Current Patent Assignee: BIOGEN IDEC INC. - WO2014/190056, 2014, A2 Location in patent: Page/Page column 116
[3]Current Patent Assignee: BIOGEN IDEC INC. - WO2015/172083, 2015, A1 Location in patent: Page/Page column 201; 202

31
[ 2756-87-8 ]
chitosan, degree of deacetylation 85%; M_w = 52 kDa [ No CAS ]
2-aminium monomethyl fumarate chitosan, degree of deacetylation 85%; degree of complex = 0.17 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl hydrogen fumarate With 1-hydroxy-pyrrolidine-2,5-dione; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In water at 25℃; for 0.25h; Green chemistry; Stage #2: chitosan, degree of deacetylation 85%; M_w = 52 kDa With 1-methyl-3-(4-sulfonylbutyl)-1H-imidazol-3-ium trifluoromethanesulfonate In water at 25℃; for 24h; Green chemistry;	2.2. Synthesis of MF-chitosan salt and MF-chitosan amide General procedure: MF-chitosan salt, whose structure will be confirmed by 1H NMR and DOSY later on, is the product from the reaction of MFA with chitosan in the presence of EDC and NHS, while MF-chitosan amideis the product with the mediation of EDC. Typically, 0.2 g of chitosan was dissolved in 10 mL of [BSMIM]CF3SO3 aqueous solution (4 wt%) to obtain the chitosan solution. Predetermined amount of MFA was dissolved in 10 mL of distilled water. After complete dissolution of MFA, predetermined amount of EDC and NHS were added in sequence. Fifteen minutes later, this solution was dripped into the above chitosan solution. The reaction mixture was stirred for 24 h at 25 °C. The resulting polymer of MFA-chitosan salt was dialyzed using dialysis membrane (MWCO: 8-14 kDa) against distilled water for 72 h followed by freeze-drying to remove the EDC, NHS, MFA and side products. For the synthesis of MF-chitosan amide, whose structure wil lbe testified by 1H NMR, DOSY and 13C NMR later on, only EDC was added into the chitosan solution and pH of the reaction system was adjusted to 6.

Reference： [1]Wang, Zhaodong; Zheng, Liuchun; Li, Chuncheng; Zhang, Dong; Xiao, Yaonan; Guan, Guohu; Zhu, Wenxiang [Carbohydrate Polymers, 2015, vol. 117, p. 973 - 979]

32
[ 2756-87-8 ]
chitosan, degree of deacetylation 85%; M_w = 52 kDa [ No CAS ]
2-fumarmonoamide methyl ester chitosan, degree of deacetylation 85%; degree of substitution = 0.34 [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: methyl hydrogen fumarate With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In water at 25℃; for 0.25h; Green chemistry; Stage #2: chitosan, degree of deacetylation 85%; M_w = 52 kDa With 1-methyl-3-(4-sulfonylbutyl)-1H-imidazol-3-ium trifluoromethanesulfonate In water at 25℃; for 24h; Green chemistry;	2.2. Synthesis of MF-chitosan salt and MF-chitosan amide General procedure: MF-chitosan salt, whose structure will be confirmed by 1H NMR and DOSY later on, is the product from the reaction of MFA with chitosan in the presence of EDC and NHS, while MF-chitosan amideis the product with the mediation of EDC. Typically, 0.2 g of chitosan was dissolved in 10 mL of [BSMIM]CF3SO3 aqueous solution (4 wt%) to obtain the chitosan solution. Predetermined amount of MFA was dissolved in 10 mL of distilled water. After complete dissolution of MFA, predetermined amount of EDC and NHS were added in sequence. Fifteen minutes later, this solution was dripped into the above chitosan solution. The reaction mixture was stirred for 24 h at 25 °C. The resulting polymer of MFA-chitosan salt was dialyzed using dialysis membrane (MWCO: 8-14 kDa) against distilled water for 72 h followed by freeze-drying to remove the EDC, NHS, MFA and side products. For the synthesis of MF-chitosan amide, whose structure wil lbe testified by 1H NMR, DOSY and 13C NMR later on, only EDC was added into the chitosan solution and pH of the reaction system was adjusted to 6.

Reference： [1]Wang, Zhaodong; Zheng, Liuchun; Li, Chuncheng; Zhang, Dong; Xiao, Yaonan; Guan, Guohu; Zhu, Wenxiang [Carbohydrate Polymers, 2015, vol. 117, p. 973 - 979]

33
[ 2756-87-8 ]
[ 1892-57-5 ]
C₁₃H₂₃N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In water; at 25℃; for 0.25h;	General procedure: MF-chitosan salt, whose structure will be confirmed by 1H NMR and DOSY later on, is the product from the reaction of MFA with chitosan in the presence of EDC and NHS, while MF-chitosan amideis the product with the mediation of EDC. Typically, 0.2 g of chitosan was dissolved in 10 mL of [BSMIM]CF3SO3 aqueous solution (4 wt%) to obtain the chitosan solution. Predetermined amount of MFA was dissolved in 10 mL of distilled water. After complete dissolution of MFA, predetermined amount of EDC and NHS were added in sequence. Fifteen minutes later, this solution was dripped into the above chitosan solution. The reaction mixture was stirred for 24 h at 25 C. The resulting polymer of MFA-chitosan salt was dialyzed using dialysis membrane (MWCO: 8-14 kDa) against distilled water for 72 h followed by freeze-drying to remove the EDC, NHS, MFA and side products. For the synthesis of MF-chitosan amide, whose structure wil lbe testified by 1H NMR, DOSY and 13C NMR later on, only EDC was added into the chitosan solution and pH of the reaction system was adjusted to 6.

Reference： [1]Carbohydrate Polymers,2015,vol. 117,p. 973 - 979

34
[ 2756-87-8 ]
4-(3-aminophenyl)-1H-indole-7-carboxamide [ No CAS ]
(E)-methyl 4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	Stage #1: methyl hydrogen fumarate With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 20℃; for 0.0833333h; Stage #2: 4-(3-aminophenyl)-1H-indole-7-carboxamide In dichloromethane at 20℃; for 3h;	D.1 Example D.1: (E)-Methyl 4-((3-(7-carbamoyl-1H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoate To a solution of (E)-4-methoxy-4-oxobut-2-enoic acid (0.43 g, 3.28 mmol) in DCM (40 mL) and DIEA (0.59 mL, 3.58 mmol) was added HATU (1.362 g, 3.58 mmol). The mixture was stirred at rt for 5 mm then 4-(3-aminophenyl)-1H-indole-7-carboxamide (0.75 g, 2.98 mmol, Preparation A.1) was added. The mixture was strired at rt for about 3 h. The mixture was concentrated and the residue was suspended between water and EtOAc. The mixture was stirred at rt for about 30 mm, filtered to collect the solid, which was washed with water and EtOAc, and dried under vacumm to provided (E)methyl 4-((3-(7-carbamoyl-]H-indol-4-yl)phenyl)amino)-4-oxobut-2-enoate (0.64 g, 59%): LC/MS (Table 1, Method R = 1.45 mm; MS m/z: 364 (M+H) (Btk IC50 = A)

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2014/210255, 2014, A1 Location in patent: Page/Page column 191

35
[ 6007-64-3 ]
[ 2756-87-8 ]
[ 1577221-95-4 ]

Yield	Reaction Conditions	Operation in experiment
700 mg		Step 2: To a suspension of monomethyl fumarate (1.5 g; 11.5 mmol) in dichloromethane (30 mL) were added at 0C were addedl-Ethyl-3-(3-dimethylaminopropyl) carbodiimid hydrochloride (EDC; 2.65 g, 13.8 mmol), 2-thiomorpholin-4-yl ethanol (as obtained from step 1; 2.43 g) and DMAP (0.1 g; 1.2 mmol) and the mixture was stirred overnight at room temperature. It was diluted with dichloromethane (50 ml), washed with water (2 x 70 mL), dried over sodium sulfate and concentrated under reduced pressure. The brown residue was taken up in diethylether (40 mL), filtered and to the yellow filtrate was added HC1 (3 M in n-butanol; 6 mL). The immediately formed precipitate was filtered off, washed with diethylether and tetrahydrofuran and finally recrystallized from chloroform. Yield: 700 mg Chemical purity (HPLC, area- at lambda=226 nm): 99.3%

Reference： [1]Patent: WO2015/43688,2015,A1 .Location in patent: Page/Page column 14-15

36
[ 2756-87-8 ]
[ 87-91-2 ]
(E)-but-2-enedioic acid (1R,2R)-1,2-bisethoxycarbonyl-2-((E)-3-methoxy carbonylacryloyloxy)ethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 22.5h;	1 Example 1: Synthesis of (E)-But-2-enedioic acid (lR,2R)-l,2-bis- ethoxy-carbonyl- 2-((E)-3-methoxy carbonyl-acryloyloxy)-ethyl ester methyl ester Monomethyl fumarate (1.5 g; 11.5 mmol), diethyl tartrate (0.71 g, 3.5 mmol), N-ethyl- N'-(3-methylaminopropyl)carbodiimide hydrochloride (EDC) (2.21 g, 11.5 mmol) and 4-(dimethylamino)pyridine (DMAP) (70 mg, 0.6 mmol) were dissolved in dry dichloromethane (30 ml). The reaction mixture was kept under continuous stirring at room temperature for 22.5 h. The organic layer was washed 2 times with water (2x50 ml), the aqueous layer was washed with dichloromethane (50 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo at 41°C. The black oily product was subjected to column chromatography (eluent: EtOAc/n-hexane 1/1). A colorless oil resulted which solidified to a white solid. Yield: 305 mg (0.7 mmol); 20% of theory 1H NMR (400 MHz, CDC13) δ ppm 1.24 (t, J=7.04 Hz, 6 H) 3.83 (s, 6 H) 4.24 (t, J=6.84 Hz, 4 H) 5.84 (s, 2 H) 6.95 (s, 3 H) IR (ATR) [cm"1] 3091, 2997, 2951, 2912, 2850, 1765, 1741, 1716, 1659, 1479, 1439, 1373, 1350, 1321, 1292, 1265, 1240, 1209, 1132, 1059, 1032, 1022, 1009, 976, 924, 872, 771, 712, 671

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2015/82588, 2015, A1 Location in patent: Page/Page column 21-22

37
[ 2756-87-8 ]
[ 2217-15-4 ]
(E)-but-2-enedioic acid (1R,2R)-1,2-bisisopropoxycarbonyl-2-((E)-3-methoxycarbonylacryloyloxy)ethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 22.5h;	2 Example 2: ((E)-But-2-enedioic acid (lR,2R)-l,2-bis-isopropoxycarbonyl-2-((E)-3- methoxycarbonyl-acryloyloxy)-ethyl ester methyl ester) Monomethyl fumarate (3 g; 23.06 mmol), diisopropyl tartrate (1.62 g, 6.9mmol), N- ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (EDC) (4.42g, 23.1 mmol) and 4-(dimethylamino)pyridine (DMAP) (140 mg, 1.2 mmol) were dissolved in dry dichloromethane (60 ml). The reaction mixture was kept under continuous stirring at room temperature for 22.5 h. The organic layer was washed 2 times with water (3x20 ml), the aqueous layer was washed with dichloromethane (100 ml) and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo at 41°C. The black oily product was subjected to column chromatography (eluent: EtOAc/n-hexane 1/1). A colorless oil resulted which solidified to a white solid. Yield: 1.92 g (14.1 mmol); 61% of theory 1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.15 (d, J=6.26 Hz, 6 H) 1.25 (d, J=6.26 Hz, 7 H) 3.81 (s, 6 H) 5.07 (dt, J=12.51, 6.26 Hz, 2 H) 5.81 (s, 2 H) 6.93 (s, 4 H) 13C-NMR (100 MHz, CHLOROFORM-d) d ppm 21.6, 52.4, 70.7, 71.4, 131.7, 135.1, 163.4, 164.5, 164.9 IR (ATR) [cm-1] 2993, 2955, 1755, 1747, 1722, 1470, 1441, 1333, 1309, 1282, 1248, 1225, 1165, 1142, 1134, 1101, 1038, 1007, 980, 955, 945, 926, 914, 897, 820, 775, 671

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2015/82588, 2015, A1 Location in patent: Page/Page column 23-24

38
[ 2756-87-8 ]
2,4-dimethylhex-2,4-dienol [ No CAS ]
(2E,4E)-2,4-dimethylhexa-2,4-dienyl methyl fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0℃; for 2h;	3 4.2.3 (2E,4E)-2,4-Dimethylhexa-2,4-dien-1-yl methyl fumarate (18) 4.2.3 (2E,4E)-2,4-Dimethylhexa-2,4-dien-1-yl methyl fumarate (18) 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.82 g, 9.52 mmol), 4-dimethylaminopyridine (0.1 g, 0.79 mmol) and monomethyl fumarate (1.24 g, 9.52 mmol) was added to the alcohol 14 (1 g, 7.9 mmol) in CH2Cl2 (26 mL) at 0 °C and the reaction mixture was stirred for 2 h. Saturated aqueous sodium hydrogen carbonate (26 mL) was added and the mixture extracted with ethyl acetate (3*30 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure. Chromatography of the residue using light petroleum:ether, 30:1→20:1, as eluent gave the title compound 18 as a white solid (1.6 g, 85%), mp 42-50 °C, Rf 0.72 (light petroleum:ether, 1:1) (Found: M++Na, 261.1106. C13H18O4Na requires M, 261.1098); vmax/cm-1 2960, 1715, 1435, 1370, 1294, 1148, 991, 863 and 773; δH (400 MHz, CDCl3) 1.70 (3H, d, J 7, 6'-H3), 1.76 (3H, s, 4'-CH3), 1.83 (3H, s, 2'-CH3), 3.82 (3H, s, CO2CH3), 4.63 (2H, s, 1-H2), 5.46 (1H, q, J 7, 5'-H), 5.95 (1H, s, 3'-H) and 6.89 (2H, s, 2-H and 3-H); δC (100 MHz, CDCl3) 13.7, 15.6, 16.3, 52.3, 71.9, 125.9, 128.2, 132.6, 133.3, 133.6, 133.9, 164.8 and 165.5; m/z (ES+) 261 (M++23, 100%).

Reference： [1]Hoather, Hugh A.; Raftery, James; Yalavac, Irem; Thomas, Eric J. [Tetrahedron, 2015, vol. 71, # 24, p. 4124 - 4131]

39
[ 2756-87-8 ]
all-(E)-2,4,6,8-tetramethyldeca-2,4,6,8-tetraen-1-ol [ No CAS ]
all-(E)-2,4,6,8-tetramethyldeca-2,4,6,8-tetraenyl methyl fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 0.166667h;	9 4.2.9 Methyl (2E,4E,6E,8E)-2,4,6,8-tetramethyldeca-2,4,6,8-tetraen-1-yl fumarate (29) 4.2.9 Methyl (2E,4E,6E,8E)-2,4,6,8-tetramethyldeca-2,4,6,8-tetraen-1-yl fumarate (29) EDCI (0.11 g, 0.58 mmol), monomethyl fumarate 17 (75 mg, 0.58 mmol) and DMAP (6 mg, 0.05 mmol) were added to tetraenol 27 (0.10 g, 0.49 mmol) in DCM (1.6 mL) at 0 °C and the mixture was warmed to rt then stirred for 10 min. Saturated aqueous sodium hydrogen carbonate (3 mL) was added and the mixture extracted with ethyl acetate (3*3 mL). The organic extracts were dried (Na2SO4) and concentrated under reduced pressure. Chromatography of the residue using light petroleum:ethyl acetate, 20:1 to 10:1, as eluent gave the title compound 29 (0.075 g, 50%) as a green oil, Rf 0.74 (light petroleum:ethyl acetate, 1:1) (Found: M++Na, 341.1729. C19H26O4Na requires M, 341.1724); vmax/cm-1 2916, 2858, 1721, 1645, 1437, 1373, 1293, 1257, 1150, 1008, 978, 904 and 734; δH (400 MHz, C6D6) 1.60 (3H, d, J 6.8, 10'-H3), 1.71 (3H, s, 8'-CH3), 1.72 (3H, s, 6'-CH3), 1.89 (3H, s, 4'-CH3), 1.91 (3H, s, 2'-CH3), 3.24 (3H, s, OCH3), 4.51 (2H, s, 1'-H2), 5.49 (1H, q, J 6.8, 9'-H), 5.95 (2H, s, 3'-H and 5'-H), 5.97 (1H, s, 7'-H) and 6.95 (2H, s, 2-H and 3-H); δC (125 MHz, C6D6) 13.8, 15.8, 16.8, 18.9, 19.2, 51.6, 71.6, 125.2, 129.8, 132.0, 132.1, 133.5, 133.8, 133.8, 134.6, 135.0, 136.4, 164.6 and 165.0; m/z (ES+) 341 (M++Na, 15%) and 189 (100).

Reference： [1]Hoather, Hugh A.; Raftery, James; Yalavac, Irem; Thomas, Eric J. [Tetrahedron, 2015, vol. 71, # 24, p. 4124 - 4131]

40
[ 2756-87-8 ]
[ 14347-78-5 ]
S-(E)-but-2-enedioic acid 2,2-dimethyl[1,3]dioxolan-4-ylmethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.89%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 2h;	1 Compound 18: (S)-2,3-bis(propionyloxy)propyl methyl fumarate To a solution of (R)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methanol (5 g, 37.83 mmol, 186.92 mI_, 1 equiv.) in DCM (50 ml) was added (E)~4-methoxy-4-oxo-but-2-enoic acid (7.38 g, 56.75 mmol, 1.5 equiv.), DCC (1 1.71 g, 56.75 mmol, 1 1.48 mL, 1.5 equiv.) and DMAP (2.31 g, 18.92 mmol, 0.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 2 h. Spots on a thin layer chromatogram (TLC) indicated formation of a new compound. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 10/1 ). (S)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl methyl fumarate (7.29 g, 29.85 mmol, 78.89% yield) was obtained as a white solid.
	With dmap; 1-ethyl-3-(3-methylaminopropyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; Inert atmosphere;	2.1 Step 1 : S-(E)-But-2-enedioic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester methyl Step 1 : S-(E)-But-2-enedioic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester methyl (0209) Monomethylfumarate (1.65 g; 12.7 mmol), R-(2,2-Dimethyl-[l,3]dioxolan-4-yl)- methanol (1 g; 8 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (1.62 g, 8.5 mmol) and 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) are dissolved in dry dichloromethane (22 ml). The reaction mixture is kept under continuous stirring at room temperature under nitrogen for 5 h. The organic layer is washed with water (20 ml), the aqueous layer is washed with dichloromethane (3x50 ml) and the combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The black oily product is subjected to column chromatography (flash chromatography; eluent: ethylacetate/n-heptane 1/1). The obtained product is subjected once more to column chromatography (eluent: ethylacetate/n-heptane 1/2) to yield the product as colourless oil. After drying the oil on the rotary evaporator at 50°C for 3 hours, the colourless oil is slowly solidifying to a white solid at room temperature.

Reference： [1]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2020/118178, 2020, A1 Location in patent: Page/Page column 52; 64; 65
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2015/128488, 2015, A1 Location in patent: Page/Page column 33

41
[ 2756-87-8 ]
[ 22323-82-6 ]
R-(E)-but-2-enedioic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.58%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 2h;	1 Compound 17: (R)-2,3-bis(propionyloxy)propy methyl fumarate To a solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (5 g, 37.83 mmol, 4.67 mL, 1 equiv.) in DCM (50 mL) was added (E)-4-methoxy-4-oxo-but-2-enoic acid (7.38 g, 56.75 mmol, 1.5 equiv.), DCC (11.71 g, 56.75 mmol, 1 1.48 mL, 1.5 equiv.) and DMAP (2.31 g, 18.92 mmol, 0.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 2 h. Spots on a thin layer chromatogram (TLC) indicated formation of a new compound. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 10/1 ). Compound (R)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl methyl fumarate (8 g, 32.75 mmol, 86.58% yield) was obtained as a white solid.
	With dmap; 1-ethyl-3-(3-methylaminopropyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; Inert atmosphere;	3.1 Step 1 : R-(E)-But-2-enedioic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester methyl ester Step 1 : R-(E)-But-2-enedioic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester methyl ester : Monomethylfumarate (1.65 g; 12.7 mmol), S-(2,2-Dimethyl-[l,3]dioxolan-4-yl)- methanol (1 g; 8 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (1.62 g, 8.5 mmol) and 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) are dissolved in dry dichloromethane (22 ml). The reaction mixture is kept under continuous stirring at room temperature under nitrogen for 5 h. The organic layer is washed with water (20 ml), the aqueous layer is washed with dichloromethane (3x50 ml) and the combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The black oily product is subjected to column chromatography (flash chromatographie; eluent: EtOAc/n-heptane 1/1). The obtained product is subjected once more to column chromatography (EE/n-heptane 1/2) to yield the product as colourless oil. After drying the oil on the rotary evaporator at 50°C for 3 hours, the colourless oil is slowly solidifying to a white solid at room temperature.

Reference： [1]Current Patent Assignee: FLAGSHIP PIONEERING INC - WO2020/118178, 2020, A1 Location in patent: Page/Page column 52; 64
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2015/128488, 2015, A1 Location in patent: Page/Page column 34

42
[ 2756-87-8 ]
[ 6601-38-3 ]
O₄-[2-(methanesulfonamido)ethyl] O₁-methyl (E)-but-2-enedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	Stage #1: methyl hydrogen fumarate With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 0.166667h; Stage #2: N-(2-hydroxyethyl)methanesulfonamide In N,N-dimethyl-formamide at 20℃; for 18h;	1 Compound 2: Methyl (2-(methylsulfonamido)ethyl)fumarate General procedure: General Procedure 1: To a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5 equivalents) in dimethylformamide (25 ml per g of MMF) was added Hüinigs base (2.0 equivalents). The dark brown solution was stirred for 10 minutes and turned into a brown suspension, before addition of the alcohol (1.0-1.5 equivalents). The reaction was stirred for 18 hours at room temperature. Water was added and the product extracted into ethyl acetate three times. The combined organic layers were washed with water three times, dried with magnesium sulphate, filtered and concentrated in vacuo at 45° C. to give the crude product. The crude product was purified by silica chromatography and in some cases further purified by trituration with diethyl ether to give the clean desired ester product. All alcohols were either commercially available or made following known literature procedures; Methyl (2-(methylsulfonamido)ethyl) fumaratewas synthesised from N-(2-hydroxyethyl)methanesulfona-mide following general procedure 1(319mg, 3 9%). ‘H NMR(300 MHz, CDC13): ö 6.88 (2H, d), 4.69 (1H, brt), 4.34 (2H,t), 3.82 (3H, s), 3.47 (2H, q), 2.99 (3H, s). mlz [M+H]=258.11.
	With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	1 O4-[2-(methanesulfonamido)ethyl] O1-methyl (E)-but-2-enedioate(1) Monomethyl fumarate (MHF) (0.30 g, 1.0 eq) was added to a mixture of compound (1a) (2.0 eq), HBTU (or EDAC or PyBOP) (3.0 eq), DIEA (3.0 eq), and DMAP (ca. 1.0 eq) in DCM (25 mL). The mixture was stirred at 0° C. for 1 h and then at 20° C. overnight. The reaction was concentrated in vacuo to a residue and then purified by reverse-phase (C-18) liquid chromatography using water and acetonitrile as eluents to yield compound (1). MS (ESI): m/z 252.0 (M+H)+.

Reference： [1]Current Patent Assignee: ALKERMES PLC - US2015/239829, 2015, A1 Location in patent: Paragraph 0147; 0153; 0154
[2]Current Patent Assignee: Nguyen, Mark Quang - US2017/20837, 2017, A1 Location in patent: Page/Page column 0479; 0481

43
[ 90666-21-0 ]
[ 2756-87-8 ]
methyl (2-(N-methylmethylsulfonamido)ethyl)fumarate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With potassium carbonate In acetonitrile Reflux;	1 Compound 2: General Procedure 2: A mixture of monomethyl fumarate (MMF) (1.3 equivalent), the alkyl mesylate (1 equivalent), and potassium carbonate (1.5 equivalent) in acetonitrile (50 ml per g of MMF) was heated at reflux overnight. The mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic phase dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave the crude product which was purified in each case by silica chromatography; Methyl (2-(N-methylmethylsulfonamido)ethyl) fumarate was synthesised from 2-(N-methylmethylsulfonamido)ethyl methanesulfonate following general procedure 2 (557 mg, 59%). ‘HNMR (300 MHz, CDC13); 6.87 (2H, d), 4.37 (2H, t),3.80 (3H, s), 3.48 (2H, t), 2.95 (3H, s), 2.83 (3H, s). mlz [M+H]=266.13.

Reference： [1]Current Patent Assignee: ALKERMES PLC - US2015/239829, 2015, A1 Location in patent: Paragraph 0150; 0152

44
[ 2756-87-8 ]
C₆₉H₉₀O₄ [ No CAS ]
C₇₉H₉₈O₁₀ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0℃; Inert atmosphere;	Compound 34 DCC (0.24 g, 1.16 mmol) was added portionwise to a cooled (0 °C) solution of compound 32 (0.20 g, 0.20 mmol), mono-methyl fumarate (0.26 g, 2.03 mmol) and DMAP (0.10 g, 0.82 mmol) in dry DCM (6 ml) under a nitrogen atmosphere. The reaction mixture was stirred overnight and the formed DCU was filtered and DCM was removed under reduced pressure. The resulting residue was purified by column chromatography gradient elution (silica gel, 10% ethylacetate in hexanes to 20% ethylacetate in hexanes) to yield a viscous oil that slowly crystallised over a few days. Then the product was triturated with hexane and filtered to yield 34 as a white powder (0.15 g, 60%). 1 H NMR (400 MHz, CDCb): δ (ppm) 0.72-0.84 (m, 10H), 1.06-1.56 (m, 36H), 1.72 (quint., 4H), 1.85 (quint., 4H), 2.08 (m, 4H), 3.84 (s, 6H), 4.05 (t, 4H), 4.24 (t, 4H), 6.89 (s, 4H) 7.03 (d, 4H), 7.59-7.83 (m, 18H). Mass (MALDI)= 1206.7 (M+). Liquid crystalline transitions (°C): [Cr 76 N 107 1].

Reference： [1]Current Patent Assignee: LOMOX LIMITED - WO2015/159098, 2015, A1 Location in patent: Page/Page column 52

45
[ 2756-87-8 ]
[ 4730-54-5 ]
4-methoxy-4-oxo-3-(1,4,7-triazonan-1-yl)butanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With N-ethyl-N,N-diisopropylamine; In dichloromethane; for 2h;	<strong>[4730-54-5]1,4,7-triazacyclononane</strong> (991.5 mg, 2.0 equiv.) and DIPEA (1.33 ml, 2.0 equiv.) weredissolved in 10 ml DCM. To this solution, 500 mg (1.0 equiv.) of Mono-methyl fumarate predissolved in 1.0 ml DCM was added drop-wise over a period of 10-15 min. After 2 hr of agitation, the DCM was removed in vacuo. The product was further dissolved in 4.0 ml DMF and kept overnight at -20 C for the precipitation of the (1). The DMF was decanted and theresidual DMF was co-evaporated with toluene in vacuo which gave a yield of 94%. 1HNMR(400 MHz, MeOD): delta 3.36 (1H, t), 2.93 (2H, m), 2.74 (2H, m), 2.61-2.70 (2H, m), 2.58 (2H,m), 2.56 (3H, s), 2.36-2.51 (5H, m), 2.24 (1H, m) ; 13C NMR (100 MHz, MeOD): delta 179.4,175.3, 64.4, 52.2 (2), 50.3, 46.8 (2), 45.8 (2), 35.1. HRMS (ESI+): calcd. for C11H22N3O4[M+H] 260.1605; found 260.1612.

Reference： [1]Synlett,2016,vol. 27,p. 1685 - 1688

46
[ 2756-87-8 ]
[ 6807-44-9 ]
C₉H₁₃NO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36.2%	With triethylamine In tetrahydrofuran at 0 - 50℃; for 18h;	45 Example 45 (Methoxy-N-methylcarbonylamino)methyl methyl (2E)but-2-ene- 1 ,4-dioate (47) General procedure: General Procedure C: Nucleophilic Substitution of iV-alkyl-iV- alkyloxycarbonylaminomethyl chloride derivatives with Monomethyl Fumarate (2E)-3-(Methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF), (2E)-3- (/er/-butoxycarbonyl)prop-2-enoic acid (/er/-butyl hydrogen fumarate), or fumaric acid (FA) (1.0 equivalents) is dissolved in 5-10 mL/3.0 mmol of an inert solvent such as N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA, DMAc), acetonitrile (MeCN), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), toluene, or mixtures thereof. To the solution, 0.8 to 1.2 equivalents of an appropriate inorganic base such as cesium hydrogen carbonate (CsHC03), cesium carbonate (CS2CO3), or potassium carbonate (K2CO3) is added. Alternatively, 0.8 b is 1.2 equivalents of a silver salt such silver(I) oxide (Ag20) or silver(I) carbonate (Ag2C03); an organic secondary or tertiary base such as dicyclohexylamine (DCHA), triethylamine (TEA), diisopropylethylamine (DIEA), tetrabutylammonium hydroxide (TBAOH), amidine; or a guanidine-based base such as l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), or 1,1 ,3,3-tetramethylguanidine (TMG), can be employed. The corresponding alkali, silver, di-, tri- and tetraalkylammonium, amidine, or guanide salt of monoalkyl fumarate can also be preformed. The solution is stirred for 10-60 min at room temperature followed by addition of 0.8- 1.2 equivalents of an appropriately functionalized N-alkyl-N-alkyloxycarbonylaminomethyl chloride derivative. The reaction mixture is stirred overnight at a temperature between 40 to 100° C. After cooling to room temperature, insolubles can optionally be filtered off and the reaction mixture diluted with one molar (1.0 M) hydrochloric acid (HQ) and an appropriate organic solvent such as methyl tert- butyl ether (MTBE), diethyl ether (Et20), ethylacetate (EtOAc), or mixtures thereof. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO/t). After filtration, the organic solvents are removed under reduced pressure using a rotary evaporator. If required, the crude reaction products are further purified by well known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass- guided reversed-phase preparative HPLC/lyophilization, precipitation, or crystallization Following general Procedure C, methyl hydrogen fumarate (MHF) (3.9 g, 30 mmol) and triethylamine (3.5 g, 34.6 mmol) were added in 10 mL of tetrahydrofuran (THF) at ca. 0°C. N- methyl-N-methyloxycarbonylaminomethyl chloride (4.11 g, 30 mmol) was added to the carboxylic acid salt. Then the reaction mixture was warmed to 50°C for 18 h. After synthesis, 2.5 g (36.2% yield) of the title compound was isolated as a viscous-oil. 1H NMR (CDCI3, 400 MHz): 6.96-6.94 (m, 2H), 5.50 (br s, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.03 (s, 3H). MS (ESI): m/z 232.07 (M+H)+.

Reference： [1]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - WO2016/61393, 2016, A1 Location in patent: Page/Page column 77; 99

47
[ 108-01-0 ]
[ 2756-87-8 ]
[ 1577222-37-7 ]

Yield	Reaction Conditions	Operation in experiment
62.2%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃;	1 Example 1 2-(dimethylamino)ethyl methyl (2E)but-2-ene-l,4-dioate (3) General procedure: General Procedure A: Activation of Carboxylic Acid Derivatives with Dehydration Agents for Alcoholysis or aminolysis. (2E)-3-(Methoxycarbonyl)prop-2-enoic acid (methyl hydrogen fumarate, MHF), 2-[(2E)- 3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) or 2-[(2E)-3-(methoxycarbonyl)prop-2- enoyloxy]propanoic acid (24), (1.0 equivalents) are reacted at temperature from ca. 0° C. (ice bath) to room temperature with 1.0-1.5 equivalents of a carbodiimide dehydration agent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (ED AC, EDC), N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexylcarbodiimide (DCC) in an inert solvent such as dichloromethane (DCM), N,N-dimethylformamide (DMF), N-methylpyrrolidone ( MP), or N,N- dimethylacetamide (DMA, DMAc) (ca. 3 mL/mmol). 1.0-1.5 Equivalents of an appropriately functionalized hydroxyl compound dissolved in the same solvent and, optionally, in the presence of a catalytic or stoichiometric amount of 4-(N,N-dimethylaminopyridine (DMAP) is added at a temperature from ca. 0° C. to room temperature. When the amine is a salt form, an equimolar amount of an organic tertiary base, such as triethylamine (TEA), or diisopropylethylamine (DIEA) may be added to free the amine base prior to the coupling step. The reaction mixture is stirred for 4 to 12 hours at room temperature. Optionally the organic solvents are removed under reduced pressure using a rotary evaporator and the residue diluted with an appropriate extraction solvent such as diethyl ether (Et20), methyl tert-butyl ether (MTBE), ethyl acetate (EtOAc), or others. After phase separation, the aqueous phase is extracted several times with the same solvent. The combined organic extracts are washed with water, brine, and dried over anhydrous magnesium sulfate (MgSO/t). After filtration, the organic solvents are removed under reduced pressure using a rotary evaporator. If required, the crude reaction products are further purified by well-known purification techniques such as silica gel flash column chromatography (i.e., Biotage), mass-guided reversed-phase preparative HPLC/lyophilization, precipitation, or crystallization. Following general Procedure A, methyl hydrogen fumarate (MHF) (13g, 0.1 mol) was activated with l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (ED AC) (20 g, 0.1 mol) in 100 mL of dichloromethane (DCM) at ca. 0°C. 2-(dimethylamino) ethanol (8.9 g, 0.1 mol) and 4-N,N-dimethylaminopyridine (DMAP) (1 g, 0.008 mol) were added to the activated carboxylic acid. After synthesis, 12.5 g (62.2 % yield) of the title compound was isolated as a viscous-oil.

Reference： [1]Current Patent Assignee: AZURITY PHARMACEUTICALS INC - WO2016/61393, 2016, A1 Location in patent: Page/Page column 75-76; 78

48
[ 67337-74-0 ]
[ 2756-87-8 ]
O₄-[(2,5-dioxoimidazolidin-4-yl)methyl]O₁-methyl (E)-but-2-enedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine at 0 - 20℃;	1 O4-[(2,5-Dioxoimidazolidin-4-yl)methyl]O1-methyl (E)-but-2-enedioate (1) 5-(Hydroxymethyl)imidazolidine-2,4-dione (1.5 eq) was added to a mixture of methyl hydrogen fumarate (MHF) (1.0 g, 1.0 eq), EDAC (or HBTU) (2.0 eq) and triethylamine (2.0 eq) in dichloromethane (or DMF) (20 mL). The mixture was stirred at 0° C. for 1 h and then at 20° C. overnight. The reaction was concentrated in vacuo to a residue and then purified by reverse-phase (C-18) liquid chromatography using water and acetonitrile as eluents to yield compound (1). MS (ESI): m/z 243.1 (M+H)+.

Reference： [1]Current Patent Assignee: Nguyen, Mark Quang - US2016/229819, 2016, A1 Location in patent: Paragraph 0279; 0280

49
[ 18190-44-8 ]
[ 2756-87-8 ]
[ 1577222-14-0 ]

Yield	Reaction Conditions	Operation in experiment
78%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	Procedure B Monomethylfumarate (1.5 g; 11.5 mmol) was suspended in dry DCM (30 mL) at 0C. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimid hydrochloride (2.47 g; 12.8 mmol), N- <strong>[18190-44-8](2-hydroxyethyl)succinimide</strong> (1.62 g; 11.3 mmol) and DMAP (0.07 g; 0.6 mmol) were added. The solution was stirred overnight at RT. The formed yellow solution was diluted with DCM (50 mL) and washed with water twice (2x35 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (n-heptane:ethyl acetate 1: 1->1:2). The final product showed polymorphic form A. The form A according to alternative Procedure B showed a prismatic habitus as depicted in Figure 7d Yield: 2.3 g (78%) Purity: 99.5 area-% at 200 nm
35%		General procedure: To a mixture of monomethyl fumarate (MMF) (1.0 equivalent) and HBTU (1.5 equivalents) in dimethylformamide (25 ml per g of MMF) was added Huenigs base (2.0 equivalents). The dark brown solution was stirred for 10 minutes, where turned into a brown suspension, before addition of the alcohol (1.0-1.5 equivalents). The reaction was stirred for 18 hours at room temperature. Water was added and the product extracted into ethyl acetate three times. The combined organic layers were washed with water three times, dried with magnesium sulphate, filtered and concentrated in vacuo at 45 C. to give the crude product. The crude product was purified by silica chromatography and in some cases further purified by trituration with diethyl ether to give the clean desired ester product. All alcohols were either commercially available or made following known literature procedures.

Reference： [1]Patent: WO2017/108960,2017,A1 .Location in patent: Page/Page column 59; 60
[2]Patent: US2016/228376,2016,A1 .Location in patent: Paragraph 0182; 0189-0191

50
[ 2756-87-8 ]
[ 6971-10-4 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: methyl hydrogen fumarate With thionyl chloride In toluene for 4h; Reflux; Stage #2: With ammonia In tetrahydrofuran at 20℃; for 1h; Cooling with ice;	11.a Synthesis of (E) -4-amino-4-oxo-2-butenoic acid methyl ester Monomethyl fumarate (15 g, 115 mmol) was dissolved in 20 ml of toluene, and thionyl chloride (20 ml) was added,Heated to reflux for 4 hours,concentrate.The THF solution (80 ml) of NH3 was added dropwise to the acid chloride prepared as described above under ice-cooling,After completion of the drop, the reaction was carried out at room temperature for 1 h.Washed with aqueous citric acid solution to pH 6,Ethyl acetate, the organic phase was washed with saturated NaHCO3, dried,Concentration gave (E) -4-amino-4-oxo-2-butenoic acid methyl ester (8.9 g, yield 60%).
	Multi-step reaction with 2 steps 1: oxalyl dichloride; N,N-dimethyl-formamide / dichloromethane / 0.5 h 2: ammonia / tetrahydrofuran; water / 0.5 h / 0 °C
	Multi-step reaction with 2 steps 1: thionyl chloride / 48 h / 80 °C / Inert atmosphere 2: ammonia / tetrahydrofuran / 16 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: ARROMAX PHARMATECH SUZHOU CO LTD - CN106146511, 2016, A Location in patent: Paragraph 0192; 0193; 0194
[2]Yang, Zhantao; Ma, Meiyan; Yang, Chun-Hua; Gao, Yuan; Zhang, Quan; Chen, Yue [Journal of Natural Products, 2016, vol. 79, # 9, p. 2408 - 2412]
[3]Current Patent Assignee: ROCHE HOLDING AG - WO2021/97110, 2021, A1

51
[ 2756-87-8 ]
[ 142-26-7 ]
O-4-(2-acetamidoethyl)-O-1-methyl (E)-but-2-en-edioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine; In dichloromethane; at 0 - 20℃;	Monomethyl thmarate (MHF) (0.50 g, 1.0 eq) was added to a mixture of compound (la) (2.0 eq), EDAC (or HETU or PyBOP) (2.0 eq), triethylamine (3.0 eq), and DMAP (ca. 1.0 eq) in dichloromethane (20 mE). The mixture was stirred at 0 C. for 1 h and then at 20 C. overnight. The reaction was concentrated in vacuo to a residue and then purified by reverse-phase (C-i 8) liquid chromatography using water and acetonitrile as eluents to yield compound (1). MS (ESI): mlz 216.1 (M+H)+.

Reference： [1]Patent: US2017/22149,2017,A1 .Location in patent: Paragraph 0453; 0455

52
[ 2756-87-8 ]
[ 112-27-6 ]
(E)-but-2-enedioic acid 2-{2-[2-((E)-3-methoxycarbonylacryloyloxy)ethoxy]ethoxy}ethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 23℃; for 2h;	2 Example 2 (E)-l3ut-2-enedioic acid 2-{2-[2-((E)-3-methoxycar- bonyl-acryloyl-oxy)-ethoxy] -ethoxy}-ethyl estermethyl ester Triethylene glycol (3 g, 20.0 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (11.49 g, 59.9 mmol), and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmol) were suspended in dry THF (55 ml). Monomethylfumarate (6.24 g, 47.9 mmol) was dissolved in THF (70 ml) and added dropwise into the triethyleneglycol suspension. The reaction mixture was kept under continuous stirring at 23° C. for 2 h. The organic layer was evaporated at 40° C. to yield a syrupy slightly pink/brown product. The crude product was subjected to flash chromatography (eluent: ethylacetate/n-hexane 4/1 (Rf-value 0.7) to yield the product (5.44 g; 73%) as colorless solid, which was dried under vacuum. 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (s, 4H) 3.71-3.76 (m, 4H) 3.77-3.83 (m, 7H) 4.29-4.40 (m, 4H) 6.86 (s, 3H) 13C NMR (100 MHz, CDCl3) δ ppm 52.3, 64.4, 68.9, 70.6, 133.4, 133.5, 164.8, 165.3

Reference： [1]Current Patent Assignee: ALBRECHT (inventors) - US2017/29357, 2017, A1 Location in patent: Paragraph 0190; 0191; 0192; 0193

53
[ 2756-87-8 ]
[ 111-46-6 ]
[ 64374-37-4 ]

Yield	Reaction Conditions	Operation in experiment
63%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 23℃; for 2h;	3 Example 3 (E)-l3ut-2-enedioic acid 2-[2-((E)-3-methoxycarbo- nyl-acryloyloxy)-ethoxy]-ethyl ester methyl ester Diethyleneglycol (3 g, 28.3 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (16.3 g, 84.8 mmol), and 4-(dimethylamino)pyridine (0.17 g, 1.4 mmol) were suspended in dry THF (70 ml). Monomethylfumarate (8.83 g, 67.8 mmol) was dissolved in THF (100 ml) and added dropwise into the diethyleneglycol suspension. The reaction mixture was kept under continuous stirring at 23° C. for 2 h. The organic layer was evaporated at 41° C. to yield a syrupy slightly pink/brown product. The crude product was subjected to flash chromatography (eluent: ethylacetate/n-hexane 4/1 to yield the product (5.9 g; 63%) as colourless solid, which was dried under vacuum. 1H NMR (400 MHz, CDCl3) δ ppm 3.72-3.75 (m, 4H) 3.79 (s, 6H) 4.28-4.40 (m, 4H) 6.86 (s, 4H) 13C NMR (100 MHz, CDCl3) δ ppm 52.3, 64.2, 68.8, 133.3, 133.6, 164.8, 165.2

Reference： [1]Current Patent Assignee: ALBRECHT (inventors) - US2017/29357, 2017, A1 Location in patent: Paragraph 0194; 0195; 0196; 0197

54
[ 2756-87-8 ]
[ 111-46-6 ]
(E)-but-2-enedioic acid 2-(2-hydroxyethoxy)ethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 23℃; for 1.83333h;	6 Example 6 (E)-But-2-enedioic acid 2-(2-hydroxy-ethoxy)-ethylester methyl ester Diethyleneglycol (4.89 g, 46.1 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (3.54 g, 18.4 mmol) and 4-(dimethylamino)pyridine (0.09 g, 0.8 mmol) were dissolved in THF (20 ml). Monomethylfumarate (2 g, 15.4 mmol) was dissolved in THF (30 ml) and added dropwise into the diethyleneglycol solution at 23° C. within 20 minutes. The reaction mixture was kept under continuous stirring at 23° C. for 1.5 h. Stirring was stopped and a biphasic layer was obtained, the lower layer was discarded and the upper layer evaporated. The obtained crude product was subjected to flash chromatography with 100% ethylacetate or ethylacetate/n-hexane (4/1) to yield the product as colourless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.46 (s, 1H) 3.53-3.59 (m, 2H) 3.69 (s, 4H) 3.75 (s, 3H) 4.31 (m, J=4.70, 4.70 Hz, 2H) 6.82 (s, 2H)
2.7 g	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 2.08333h;	1 Example 1: (E)-But-2-enedioic acid 2-(2-hydroxy-ethoxy)-ethyl ester methyl ester 16.31 g (0.15 mol) diethylenglycol (DEG), 7.07 g (36.9 mmol) N-ethyl-N’-(3- dimethyl-aminopropyl)carbodiimide hydrochloride (EDCxHC1), and 0.19 g (1.5 mmol) 4-(dimethylamino)pyridine (DMAP) were dissolved in 40 mltetrahydrofuran (THF). 4 g (30.8 mmol) monomethylfumarate dissolved in 66 mlTHF were dropped into the DEG-solution at room temperature (RT) within35 minutes. The reaction mixture was kept under continuous stirring at RT for1.5 h. Stirring was stopped and a biphasic system was obtained; the lower layerwas discarded and the upper layer was evaporated. The obtained crude product(colorless oil) was subjected to flash chromatography (100% ethyl acetate) twice.The product was dried under high vacuum at RT for 5 hours to yield the product as colorless oil (2.7 g; 12.3 mmol).
2.7 g	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 2.08333h;	1 Example 1: (E)-But-2-enedioic acid 2-(2-hydroxy-ethoxy)-ethyl ester methyl ester Example 1: (E)-But-2-enedioic acid 2-(2-hydroxy-ethoxy)-ethyl ester methyl ester (0129) (0130) 16.31 g (0.15 mol) diethylenglycol (DEG), 7.07 g (36.9 mmol) N-ethyl-N'-(3- dimethyl-aminopropyl)carbodiimide hydrochloride (EDCxHCl) and 0.19 g (1.5 mmol) 4-(dimethylamino)pyridine (DMAP) were dissolved in 40 ml tetrahydrofuran (THF). 4 g (30.8 mmol) monomethyl fumarate dissolved in 66 ml THF were dropped into the DEG solution at room temperature (RT) within 35 minutes. The reaction mixture was kept under continuous stirring at RT for 1.5 h. Stirring was stopped and a biphasic system was obtained; the lower layer was discarded and the upper layer was evaporated. The obtained crude product (colorless oil) was subjected to flash chromatography (100% ethyl acetate) twice. The product was dried under high vacuum at RT for 5 hours to yield the product as colorless oil (2.7 g; 12.3 mmol). 1H NMR (400 MHz, CDC13) δ [ppm] : 2.44 - 2.49 (s, 1 H) 3.53 - 3.59 (m, 2 H) 3.69 (s, 4 H) 3.75 (s, 3 H) 4.31 (m, J=4.70, 4.70 Hz, 2 H) 6.82 (s, 2H)

Reference： [1]Current Patent Assignee: ALBRECHT (inventors) - US2017/29357, 2017, A1 Location in patent: Paragraph 0203; 0204; 0205
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/68052, 2017, A1 Location in patent: Page/Page column 21
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/68053, 2017, A1 Location in patent: Page/Page column 20

55
[ 112-60-7 ]
[ 2756-87-8 ]
(E)-but-2-enedioic acid 2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl ester methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 23℃; for 1.83333h;	4 Example 4 (E)-But-2-enedioic acid 2-{2-[2-(2-hydroxy- ethoxy)-ethoxy] -ethoxy}-ethyl ester methyl ester Tetraethyleneglycol (8.96 g, 46.1 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (3.54 g, 18.4 mmol), and 4-(dimethylamino)pyridine (0.09 g, 0.8 mmol) were dissolved in THF (20 ml). Monomethylfumarate (2 g, 15.4 mmol) was dissolved in THF (30 ml) and added dropwise into the tetraethyleneglycol solution at 23° C. within 20 minutes. The reaction mixture was kept under continuous stirring 23° C. for 1.5 h. Stirring was stopped and a biphasic layer was obtained, the lower layer was discarded and the upper layer evaporated. The obtained crude product was subjected to flash chromatography with 100% ethylacetate or ethylacetate/n-hexane (4/1) to yield the product as colourless oil (2.47 g; 53%). 1H NMR (400 MHz, CDCl3) δ ppm 2.73 (s, 1H) 3.52-3.57 (m, 2H) 3.61 (s, 8H) 3.63-3.73 (m, 4H) 3.75 (s, 3H) 4.26-4.35 (m, 2H) 6.76-6.92 (m, 2H)
3.14 g	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 3h;	2 Example 2: (E)-But-2-enedioic acid 2-{2- [2-(2-hydroxy-ethoxy)-ethoxy] - ethoxy}-ethyl ester methyl ester 13.4 g (69.2 mmol) tetraethylenglycol (TEG), 5.3 g (27.7 mmol) EDCxHC1, 0.14 g (1.2 mmol) DMAP were dissolved in 50 ml THF. 3 g (23 mmol) monomethyl fumarate, dissolved in 50 ml THF, were added into the TEG-solution at RT. The reaction mixture was kept under continuous stirring at RT for 3 h. Stirring was stopped and a biphasic layer was obtained, the lower layer was discarded and the upper layer evaporated. The obtained crude product was subjected to flash chromatography (100% ethyl acetate) twice. The product was dried under highvacuum at RT for 5 hours to yield the product as colorless oil (3.14 g; 10.3 mmol)‘H NMR (400 MHz, CDC13) ö [ppm]: 2.53 (s, 1 H) 3.55 - 3.60 (m, 2 H) 3.64 (s, 8 H) 3.67 - 3.74 (m, 4 H) 3.78 (s, 3 H) 4.32 - 4.35 (m, 2 H) 6.86 (s, 2 H)
3.14 g	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃; for 3h;	2 Example 2: (E)-But-2-enedioic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]- ethoxy}-ethyl ester methyl ester Example 2: (E)-But-2-enedioic acid 2-{2-[2-(2-hydroxy-ethoxy)-ethoxy]- ethoxy}-ethyl ester methyl ester (0132) (0133) 13.4 g (69.2 mmol) Tetraethylenglycol (TEG), 5.3 g (27.7 mmol) EDCxHCl, 0.14 g (1.2 mmol) DMAP were dissolved in 50 ml THF. 3 g (23 mmol) monomethyl fumarate, dissolved in 50 ml THF, were added into the TEG solution at RT. The reaction mixture was kept under continuous stirring at RT for 3 h. Stirring was stopped and a biphasic layer was obtained, the lower layer was discarded and the upper layer evaporated. The obtained crude product was subjected to flash chromatography ( 100% ethyl acetate) twice. The product was dried under high vacuum at RT for 5 hours to yield the product as colorless oil (3.14 g; 10.3 mmol) 1H NMR (400 MHz, CDC13) δ [ppm] : 2.53 (s, 1 H) 3.55 - 3.60 (m, 2 H) 3.64 (s, 8 H) 3.67 - 3.74 (m, 4 H) 3.78 (s, 3 H) 4.32 - 4.35 (m, 2 H) 6.86 (s, 2 H)

Reference： [1]Current Patent Assignee: ALBRECHT (inventors) - US2017/29357, 2017, A1 Location in patent: Paragraph 0198; 0199; 0200
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/68052, 2017, A1 Location in patent: Page/Page column 21; 22
[3]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/68053, 2017, A1 Location in patent: Page/Page column 20; 21

56
[ 112-60-7 ]
[ 2756-87-8 ]
(E)-but-2-enedioic acid mono[2-(2-{2-[2-((E)-3-methoxycarbonylacryloyloxy)ethoxy]ethoxy}ethoxy)ethyl ester] methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 23℃; for 2.5h;	1.A Example 1 (E)-But-2-enedioic acid 2-(2-{2-[2-((E)-3-methoxy- carbonyl-acryloyl-oxy)-ethoxy]-ethoxy}-ethoxy)ethyl ester methyl ester Tetraethyleneglycol (TEG, 3 g, 15.4 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (EDC, 8.83 g, 46.3 mmol), and 4-(dimethylamino)pyridine (DMAP, 0.09 g, 0.8 mmol) were suspended in dry THF (30 ml). Monomethylfumarate (4.82 g, 37.1 mmol) was dissolved in THF (50 ml) and added dropwise into the tetraethyleneglycol suspension. The reaction mixture was kept under continuous stirring at 23° C. for 2.5 h. The organic layer was evaporated at 43° C. to yield a syrupy slightly brown product. The crude product was subjected to flash chromatography (eluent: ethyl acetate/n-hexane 4/1 (Rf-value 0.75) to yield the product (4.16 g; 64%) as colourless oil, which was dried under vacuum. 1H NMR (400 MHz, CDCl3) δ ppm 3.65 (s, 8H) 3.74 (t, J=4.69 Hz, 5H) 3.80 (s, 6H) 4.35 (t, J=4.70 Hz, 4H) 6.87 (s, 3H) 13C NMR (100 MHz, CDCl3) δ ppm 52.3, 64.4, 68.9, 70.7, 133.5, 164.8, 165.3

Reference： [1]Current Patent Assignee: ALBRECHT (inventors) - US2017/29357, 2017, A1 Location in patent: Paragraph 0184; 0185; 0186; 0187; 0188; 0189

57
[ 61-90-5 ]
[ 2756-87-8 ]
(S,E)-2-(4-methoxy-4-oxobut-2-enamido)-4-methylpentanoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	Stage #1: methyl hydrogen fumarate With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 4h; Stage #2: L-leucine With sodium carbonate In dichloromethane; water; acetone for 1h; Cooling with ice;	45.1 Step 1: (S,E)-2-(4-Methoxy-4-oxobut-2-enamido)-4-methylpentanoic acid [I-45] Step 1: (S,E)-2-(4-Methoxy-4-oxobut-2-enamido)-4-methylpentanoic acid [I-45] To a solution of (E)-4-methoxy-4-oxobut-2-enoic acid (1.0 g, 7.69 mmol) in DCM (30 mL) was added SOCl2 (1.83 g, 15.38 mmol), and then DMF (0.1 mL). The solution was heated to 40° C. for 4 h. The solution was concentrated to dryness to afford an oil. The oil was diluted with DCM (10 mL). The solution of (S)-2-amino-4-methylpentanoic acid (1.0 g, 7.62 mmol) in acetone (20 mL) and sat. Na2CO3 (20 mL) solution cooled with an ice-bath was added dropwise. After 1 h, the solution was adjusted pH 2 with 6 M HCl solution, extracted with EtOAc (402), washed with resulting solution was filtered (80 mL3) and brine (80 mL), dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by chromatography (silica, MeOH/DCM=1/20) to afford (S,E)-2-(4-methoxy-4-oxobut-2-enamido)-4-methylpentanoic acid (I-45), (1.0 g, 4.11 mmol, 53%) as a yellow oil. ESI-MS (EI+, m/z): 244.2 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 7.32 (d, J=15.2 Hz, 1H), 7.05 (d, J=15.2 Hz, 1H), 6.85-6.89 (m, 2H), 7.30-7.46 (m, 1H), 3.82 (s, 1H), 1.63-1.78 (m, 3H), 0.97 (d, J=4.8 Hz, 6H).
53%	Stage #1: methyl hydrogen fumarate With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 40℃; for 4h; Stage #2: L-leucine With sodium carbonate In dichloromethane; water; acetone at 20℃; for 1h; Cooling with ice;

Reference： [1]Current Patent Assignee: NAVITOR PHARM; NAVITOR PHARMACEUTICALS - US2017/114080, 2017, A1 Location in patent: Paragraph 0402
[2]Current Patent Assignee: NAVITOR PHARM; NAVITOR PHARMACEUTICALS - WO2018/200625, 2018, A1 Location in patent: Paragraph 00293; 00294; 00295

58
[ 2756-87-8 ]
2-hydroxyethyl 2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetate [ No CAS ]
O₄-[2-[2-[2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-5,7-dihydropyrrolizin-3-yl]acetyl]oxyethyl] O₁-methyl (E)-but-2-enedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃;	6 Example 6: 04- [2- [2- [2-(4-chlorophenyl)-6,6-dimethyl-1 -phenyl-5,7-dihydro- pyrrolizin-3-yl]acetyl]oxyethyl] 01-methyl (E)-but-2-enedioate 1.5 g (3.5 mmol) 2-hydroxyethyl 2- [2- (4-chlorophenyl)-6,6-dimethyl- 1 -phenyl5,7-dihydropyrrolizin-3-yl]acetate, 1 g (5.2 mmol) EDCxHC1, 20 mg (0.2 mmol) DMAP and 0.55 g (4.2 mmol) monomethylfumarate were dissolved in 20 ml THF.The reaction mixture was stirred 0/N at RT. Stirring was stopped (solution with a syrupy brown precipitate) and the solvent was evaporated yielding a brown syrup. After addition of 100 ml water the mixture was extracted with 3x100 ml ethyl acetate. The solvent was evaporated and the crude product subjected to flash chromatography (80 g silica gel, ethyl acetate/n-heptane 50:50 (v/v), flow30 mL/min.) to yield the product as yellow oil, which was dried at 4x10-2 mbar at RT for 1 hour. To the oily product, 30 ml n-pentane was added and the mixture was stirred 0/N at RT which resulted in the formation of a precipitate. The solid was filtered off and dried under vacuum at 30°C for 30 minutes.‘H-NMR (400 MHz, DMSO-d6) ö [ppm]: 1.20 (s, 6 H) 2.76 (s, 2 H) 3.55 (s, 2 H)3.70 (s, 5 H) 4.30 - 4.39 (m, 4 H) 6.73 (s, 2 H) 6.94 (d, 1=7.43 Hz, 2 H) 7.00 - 7.07(m, 3 H) 7.12 - 7.18 (m, 2 H) 7.29 (d, 1=7.82 Hz, 2 H).LC-MS (ESIj: m/z 536 [M+H]
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In tetrahydrofuran at 20℃;	6 Example 6: 04-[2-[2-[2-(4-chlorophenyl)-6,6-dimethyl-l-phenyl-5,7-dihydro- pyrrolizin-3-yl]acetyl]oxyethyl] Ol-methyl (E)-but-2-enedioate Example 6: 04-[2-[2-[2-(4-chlorophenyl)-6,6-dimethyl-l-phenyl-5,7-dihydro- pyrrolizin-3-yl]acetyl]oxyethyl] Ol-methyl (E)-but-2-enedioate (0159) (0160) 1.5 g (3.5 mmol) 2-hydroxyethyl 2-[2-(4-chlorophenyl)-6,6-dimethyl- l -phenyl - 5,7-dihydropyrrolizin-3-yl]acetate, 1 g (5.2 mmol) EDCxHCl, 20 mg (0.2 mmol) DMAP and 0.55 g (4.2 mmol) monomethyl fumarate were dissolved in 20 ml THF. The reaction mixture was stirred O/N at RT. Stirring was stopped (solution with a syrupy brown precipitate) and the solvent was evaporated yielding a brown syrup. After addition of 100 ml water the mixture was extracted with 3x 100 ml ethyl acetate. The solvent was evaporated and the crude product subjected to flash chromatography (80 g silica gel, ethyl acetate/n-heptane 50:50 (v/v), flow 30 mL/min.) to yield the product as yellow oil, which was dried at 4x 10" mbar at RT for 1 hour. To the oily product, 30 ml n-pentane were added and the mixture was stirred O/N at RT which resulted in the formation of a precipitate. The solid was filtered off and dried under vacuum at 30°C for 30 minutes. (0161) 1H-NMR (400 MHz, DMSO- 6) δ [ppm] : 1.20 (s, 6 H) 2.76 (s, 2 H) 3.55 (s, 2 H) 3.70 (s, 5 H) 4.30 - 4.39 (m, 4 H) 6.73 (s, 2 H) 6.94 (d, J=7.43 Hz, 2 H) 7.00 - 7.07 (m, 3 H) 7.12 - 7.18 (m, 2 H) 7.29 (d, J=7.82 Hz, 2 H). LC-MS (ESI+): m/z 536 [M+H]+

Reference： [1]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/68052, 2017, A1 Location in patent: Page/Page column 24; 25
[2]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - WO2017/68053, 2017, A1 Location in patent: Page/Page column 24; 25

59
[ 2756-87-8 ]
[ 23408-05-1 ]
C₁₆H₁₈O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.9%	Stage #1: methyl hydrogen fumarate With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In dichloromethane for 0.5h; Stage #2: 2-Hydroxy-benzoic acid tert-butyl ester In dichloromethane at 20℃; for 16h;	1 2. Esterification of monomethyl fumarate with compound A3 Monomethyl fumarate (10.4 g) was added to dimethylformamide (DCM) (100 ml) was added a mixed solution of HATU (45.6 g) and DIEA (31 g). The reaction mixture was stirred for 30 minutes, compound A3 (10 g) was then added to the above reaction mixture at room temperature for 16 h at room temperature, LC-MS showed the reaction was complete. The reaction mixture was quenched with water (200 ml) extracted with DCM (2 * 200 ml). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated Remove the organic solvent. The product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to give the product (12.6 g, yield 79.9%) as a pale yellow oil (given compound A4).

Reference： [1]Current Patent Assignee: CHONGQING NEUROPARK BIOSCIENCE - CN106946701, 2017, A Location in patent: Paragraph 0047; 0051-0053

60
[ 96-50-4 ]
[ 2756-87-8 ]
(E)-3-(thiazol-2-ylcarbamoyl)acrylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7%	Stage #1: methyl hydrogen fumarate With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In dichloromethane; N,N-dimethyl-formamide at 20℃; for 0.833333h; Stage #2: 2-thiazolylamine In dichloromethane; N,N-dimethyl-formamide at 20℃;	1.1.2.1 Step 1: Amide Coupling. General procedure: To the acid (1-1.2 equiv.) and TBTU (1-1.2 equiv.) in anhydrous DCM/DMF (2:1, 0.3M) was added DIPEA/anhydrous DCM, (1-1.2 equiv., 0.3 M). The reaction mixture was stirred at ambient temperature for 50 mi After this time, the amine/anhydrous DCM, (1 equiv., 0.14 M) was added and the reaction mixture stirred at ambient temperature overnight. To the reaction vessel wasadded tetrafluorophthalic anhydride (0.8 - 1 equiv.) in anhydrous DMF (0.48 M) and allowed to stir for 2-3 h to scavenge unreacted acid and TBTU. After this time, 2-3 equiv. MP-Carbonate was added and the reaction mixture stirred 6-12 h. The reaction mixture was applied to a preconditioned Si-NH2 cartridge (1 or 2 g) and eluted with DMF (1 x column volume) and MeOH (1 x column volume). Evaporation of the eluents yielded the desired amide. In some instances,preparative LC-MS was required for purification.

Reference： [1]Current Patent Assignee: HSF PHARMACEUTICALS; HSF PHATMACEUTICALS - WO2018/50656, 2018, A2 Location in patent: Page/Page column 63; 65; 67

61
[ 2756-87-8 ]
[ 1202759-91-8 ]
C₂₄H₂₄FN₅O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%		Weigh 29mgMonomethyl fumarate,84mg HATU, 30mg HOAT in a 25ml round bottom flask, add 1.6mlDCM, 0.4 ml DMF and 66 mul DIEA were used as solvents. After stirring at room temperature for about 10 minutes, 74 mg of the A1 intermediate was added to the reaction system. After stirring for about 1 hour at room temperature, 100 ml of saturated aqueous sodium bicarbonate solution was added, followed by 15 ml of DCM. The mixture was extracted 3 times and the organic phase was evaporated to dryness under reduced pressure. The residue was applied to a silica gel column with DCM:MeOH=70:1 (volume ratio) to obtain 60 mg of the compound represented by Formula I-2 in a yield of 62%

Reference： [1]Patent: CN107973754,2018,A .Location in patent: Paragraph 0101-0103; 0108; 0109

62
[ 2756-87-8 ]
C₆₈H₉₀O₄Si [ No CAS ]
C₇₈H₉₈O₁₀Si [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
16.4%	With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 20h; Inert atmosphere;	J8-8FU M DOO (0.52 g, 2.50 mmol) was added portion wise to a solution of compound 13 (0.50 g, 0.50mmol), mono-methyl fumarate (0.33 g, 2.50 mmol) and DMAP (61 mg, 0.50 mmol) in dryOH2OI2 (20 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 20 h and the formed DOU was filtered and OH2OI2 was removed using a rotary evaporator. The resulting residue was purified by column chromatography (dry loaded, silica gel, 20% ethylacetate in hexanes) to yield a white solid, which was further purified byrecrystallisation from DOM/ethanol layering to yield a white crystalline solid (0.10 g, 16.4%).1H NMR (400 MHz, ODOI3): O (ppm) 0.83 (6 H, t, J = 7.0 Hz, OH3), 1.00-1.04 (4 H, m, OH2),1.20-1.55 (40 H, m, OH2), 1.70(4 H, quint., OH2), 1.82(4 H, quint., OH2), 3.81 (6 H, 5, OH3),4.02 (4 H, t, J = 6.6 Hz, OH2), 4.21 (4 H, t, J = 6.6 Hz, OH2), 6.87 (4 H, 5, OH=OH), 7.00 (4 H,d, J = 8.8 Hz, Ar-H), 7.58 (4 H, d, J = 8.8 Hz, Ar-H), 7.65 (4 H, d, J = 8.4 Hz, Ar-H), 7.72 (6H, d, J = 8.0 Hz, Ar-H), 7.89 (2 H, d, J = 1.6 Hz, Ar-H), 7.92 (2 H, d, J = 8.0 Hz, Ar-H). 13CNMR (100 MHz, 0D013): O (ppm) 12.5 (CH2), 14.2 (CH3), 22.8 (CH2), 24.1 (CH2), 26.0 (CH2),26.1 (CH2), 28.6 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (x2) (CH2), 32.0 (CH2), 33.6 (CH2), 52.5(CH3), 65.6 (CH3), 68.2 (CH2), 115.0 (CH), 121.4 (CH), 125.3 (CH), 127.2 (CH), 127.5 (CH),128.2 (CH), 129.0 (CH), 131.9 (CH), 133.2 (CH), 133.3 (CH), 134.1 (CH), 139.0 (CH), 139.5 (C), 139.6 (C), 139.8 (C), 147.3 (C), 158.9 (CO), 165.2 (C=O), 165.6 (C=O). MALDI-MS: 1222.6 (M+) Elemental analysis: expected C = 76.56, H = 8.07, measured C = 76.11, H =7.99.

Reference： [1]Current Patent Assignee: LOMOX LIMITED - WO2018/65786, 2018, A1 Location in patent: Page/Page column 68; 69; 70

63
[ 72418-40-7 ]
[ 2756-87-8 ]
[ 7188-38-7 ]
[ 106-49-0 ]
methyl 2-(2-(tert-butylcarbamoyl)-4-oxo-2-(3-phenylisoxazol-5-yl)-1-(p-tolyl)azetidin-3-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	In methanol at 55℃; for 10h;

Reference： [1]Gao, Xing; Shan, Chunhui; Chen, Zhihao; Liu, Yan; Zhao, Xia; Zhang, Ao; Yu, Peng; Galons, Hervé; Lan, Yu; Lu, Kui [Organic and Biomolecular Chemistry, 2018, vol. 16, # 33, p. 6096 - 6105]

64
[ 2756-87-8 ]
[ 119072-55-8 ]
[ 106-47-8 ]
[ 10111-08-7 ]
methyl 2-(2-(tert-butylcarbamoyl)-1-(4-chlorophenyl)-2-(1H-imidazol-2-yl)-4-oxoazetidin-3-yl)acetate [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2018,vol. 16,p. 6096 - 6105

65
[ 2756-87-8 ]
(2S)-isopropyl-2-[((3-fluoro-4-(hydroxymethyl)phenoxy)(methoxymethyl)phosphoryl)amino]propanoate [ No CAS ]
4-[[2-fluoro-4-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino](methoxymethyl)phosphoryl]oxyphenyl]methyl] 1-methyl (E)-but-2-enedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
8.6%	Stage #1: methyl hydrogen fumarate With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1h; Stage #2: (2S)-isopropyl-2-[((3-fluoro-4-(hydroxymethyl)phenoxy)(methoxymethyl)phosphoryl)amino]propanoate With triethylamine In dichloromethane at 20℃; for 4h;	23.2 4-[[2-fluoro-4-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino](methoxymethyl)phosphoryl]oxyphenyl]methyl] 1-methyl (E)-but-2-enedioate Monomethyl fumarate 22A (0.65 g, 5 mmol) was dissolved in dichloromethane (30 mL). Two drops of N,N-dimethylformamide and oxalyl chloride (1.5 mL) were added and stirred for 1 h. Concentrated under reduced pressure to remove excess oxalyl chloride; The residue was dissolved in dry dichloromethane (20 mL) and triethylamine (1.01 g, 10 mmol), a solution of 23B (1.82 g, 5 mmol) in dichloromethane (10 mL)Stir at room temperature for 4 h. Dilute with water (20 mL) and separate the organic phase.The aqueous phase was extracted with dichloromethane (20 mL×2).The combined organic layers were washed with brine (40 mL×1) and dried over anhydrous sodium sulfate.After concentration under reduced pressure, and then purified by column chromatography ( petroleum ether / ethyl acetate = 1:1) to give a colorless liquid compound 23 (0.205g, 8.6% yield).

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN109305989, 2019, A Location in patent: Paragraph 0663-0666; 0671-0675

66
[ 2756-87-8 ]
isopropyl (2S)-2-[[[4-(hydroxymethyl)-2-methoxyphenoxy](methoxymethyl)phosphoryl]amino]propanoate [ No CAS ]
4-[[3-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino](methoxymethyl)phosphoryl]oxy-4-methoxyphenyl]methyl] 1-methyl (E)-but-2-enedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
22%	Stage #1: methyl hydrogen fumarate With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 1h; Stage #2: isopropyl (2S)-2-[[[4-(hydroxymethyl)-2-methoxyphenoxy](methoxymethyl)phosphoryl]amino]propanoate With triethylamine In dichloromethane at 20℃; for 4h;	22 4-[[3-[[[(1S)-2-isopropoxy-1-methyl-2-oxoethyl]amino](methoxymethyl)phosphoryl]oxy-4-methoxyphenyl]methyl] 1-methyl (E)-but-2-enedioate Monomethyl fumarate 22A (0.39 g, 3.00 mmol) was dissolved in 10 mL dichloromethane. Two drops of N,N-dimethylformamide and oxalyl chloride (1 mL) were added and stirred for 1 h. The excess oxalyl chloride was removed by concentration under reduced pressure; the residue was dissolved in dry dichloromethane (10 mL). add a solution of triethylamine and intermediate 3 in dichloromethane (5 mL) and stir at room temperature for 4 h. dilute with water (20 mL) and separate the organic phase. the aqueous phase was extracted with dichloromethane (20 mL x 2) and the organic phases were combined. washed with saturated brine (40 mL), dry over anhydrous sodium sulfate for 0.5 h, After concentration under reduced pressure and column chromatography (petroleum ether / ethyl acetate = 1: 1) to give a yellow oil was prepared to give isolated compound 22 (0.32g, yield 22.0%)

Reference： [1]Current Patent Assignee: HAISCO PHARMACEUTICAL GROUP CO., LTD. - CN109305989, 2019, A Location in patent: Paragraph 0648-0662

67
[ 2756-87-8 ]
[ 121-79-9 ]
C₁₅H₁₆O₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; In toluene; for 5h;Reflux;	In a three-necked flask equipped with a water separator, 135 g of monomethyl fumarate was charged.212 g of propyl gallate, 1000 g of toluene, 20 g of sulfuric acid (98%), and refluxed at elevated temperature.The reflux time is 5 hours, during which the water produced by the reaction is continuously separated by a water separator.After the reaction is completed, the toluene is distilled off.The substrate was washed with 200 ml of a 5% NaOH (w/w) solution, and the precipitate was filtered.The precipitate is refined with a solution of ethanol: water (w/w) = 1:1.285 g of white crystals were obtained with a yield of 86%. HPLC detection content 98%

Reference： [1]Patent: CN109503384,2019,A .Location in patent: Paragraph 0026-0028

68
[ 2756-87-8 ]
C₃₇H₅₃NO₃ [ No CAS ]
benzyl (2S,4aS,6aS,6bR,8aR,10S,12aS,12bR,14bR)-10-((E)-4-methoxy-4-oxobut-2-enamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,11,12,12a,12b,13,14b-icosahydropicene-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;	41 Example 41 (2S,4aS,6aS,6bR, 8aR, lOS, 1 2a5, 1 2bR, 1 4bR)- 1 0-((E)-4-Methoxy-4-oxobut-2- enamido)-2,4a,6a,6b,9,9, 12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9, 10, 11, 12, 12a, 1 2b, 13,1 4b-icosahydropicene-2-carboxylic acid (66-2) Synthesis of benzyl (25,4a5,6a5,6bR,8aR, 105, 12a5, 1 2bR, 1 4bR)- 1 0-((E)-4-methoxy-4-oxobut-2-enamido)-2,4a,6a,6b,9,9,12a-heptamethyl-13-oxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9, 10,11, 12,12a,2b, 13,1 4b-icosahydropicene-2-carboxylate (66-1). Into a 8-mL round-bottom flask, was placed (2E)-4-methoxy-4-oxobut-2-enoic acid (66.48 mg, 0.51 mmol, 1.20 equiv.), 54-1 (200 mg, 0.36 mmol, 1.00 equiv.), DIEA (220.13 mg, 1.70 mmol, 4.00 equiv.), DMF (2 mL), HATU (343 mg,0.90 mmol, 1.50 equiv.). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with EtOAc/petroleum ether (100:1). This resulted in 200mg (83%) of 66-1 as a yellow solid.

Reference： [1]Current Patent Assignee: PHONEOPTIKA - WO2019/60051, 2019, A1 Location in patent: Page/Page column 138

69
[ 19005-93-7 ]
[ 931-53-3 ]
[ 2756-87-8 ]
[ 106-49-0 ]
C₂₈H₃₁N₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
96%	In methanol at 20℃; for 24h;	General procedure for the synthesis of Ugi-adduct 3a-j General procedure: To a stirred solution of 2-formylindole (1 mmol) and amine(1 mmol) in MeOH (5 mL), carboxylic acid (1 mmol) and then isocyanide (1 mmol) at reflux were added. The reaction process was monitored by TLC. After 24 h, the residue was filtered and washed with methanol and Et2O. The solid was dried collected as pure product and used for further reactions.

Reference： [1]Shiri, Morteza; Heravi, Majid M.; Zadsirjan, Vahideh; Ghiasi, Mina; Shintre, Suhas A.; Koorbanally, Neil A.; Singh, Thishana [Journal of the Iranian Chemical Society, 2019, vol. 16, # 7, p. 1517 - 1526]

70
[ 19005-93-7 ]
[ 931-53-3 ]
[ 2756-87-8 ]
[ 536-90-3 ]
C₂₈H₃₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	In methanol at 20℃; for 24h;	General procedure for the synthesis of Ugi-adduct 3a-j General procedure: To a stirred solution of 2-formylindole (1 mmol) and amine(1 mmol) in MeOH (5 mL), carboxylic acid (1 mmol) and then isocyanide (1 mmol) at reflux were added. The reaction process was monitored by TLC. After 24 h, the residue was filtered and washed with methanol and Et2O. The solid was dried collected as pure product and used for further reactions.

Reference： [1]Shiri, Morteza; Heravi, Majid M.; Zadsirjan, Vahideh; Ghiasi, Mina; Shintre, Suhas A.; Koorbanally, Neil A.; Singh, Thishana [Journal of the Iranian Chemical Society, 2019, vol. 16, # 7, p. 1517 - 1526]

71
[ 19005-93-7 ]
[ 931-53-3 ]
[ 2756-87-8 ]
[ 104-94-9 ]
C₂₈H₃₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	In methanol at 20℃; for 24h;	General procedure for the synthesis of Ugi-adduct 3a-j General procedure: To a stirred solution of 2-formylindole (1 mmol) and amine(1 mmol) in MeOH (5 mL), carboxylic acid (1 mmol) and then isocyanide (1 mmol) at reflux were added. The reaction process was monitored by TLC. After 24 h, the residue was filtered and washed with methanol and Et2O. The solid was dried collected as pure product and used for further reactions.

Reference： [1]Shiri, Morteza; Heravi, Majid M.; Zadsirjan, Vahideh; Ghiasi, Mina; Shintre, Suhas A.; Koorbanally, Neil A.; Singh, Thishana [Journal of the Iranian Chemical Society, 2019, vol. 16, # 7, p. 1517 - 1526]

72
[ 19005-93-7 ]
[ 931-53-3 ]
[ 2756-87-8 ]
[ 106-47-8 ]
C₂₇H₂₈ClN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	In methanol at 20℃; for 24h;	General procedure for the synthesis of Ugi-adduct 3a-j General procedure: To a stirred solution of 2-formylindole (1 mmol) and amine(1 mmol) in MeOH (5 mL), carboxylic acid (1 mmol) and then isocyanide (1 mmol) at reflux were added. The reaction process was monitored by TLC. After 24 h, the residue was filtered and washed with methanol and Et2O. The solid was dried collected as pure product and used for further reactions.

Reference： [1]Shiri, Morteza; Heravi, Majid M.; Zadsirjan, Vahideh; Ghiasi, Mina; Shintre, Suhas A.; Koorbanally, Neil A.; Singh, Thishana [Journal of the Iranian Chemical Society, 2019, vol. 16, # 7, p. 1517 - 1526]

73
[ 2756-87-8 ]
[ 67630-01-7 ]
[ 693-13-0 ]
C₂₈H₄₄N₄O₈ [ No CAS ]