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[ CAS No. 5222-73-1 ]

{[proInfo.proName]} ,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Chemical Structure| 5222-73-1

Chemical Structure| 5222-73-1

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Quality Control of [ 5222-73-1 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 5222-73-1 ]

SDS Specification

Alternatived Products of [ 5222-73-1 ]

Product Details of [ 5222-73-1 ]

CAS No. :	5222-73-1	MDL No. :	MFCD00101316
Formula :	C₆H₆O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	SZBNZTGCAMLMJY-UHFFFAOYSA-N
M.W :	142.11	Pubchem ID :	123227
Synonyms :

Calculated chemistry of [ 5222-73-1 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	0
Fraction Csp3 :	0.33
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	30.94
TPSA :	52.6 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	No
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.22 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.26
Log Po/w (XLOGP3) :	-0.07
Log Po/w (WLOGP) :	-0.36
Log Po/w (MLOGP) :	-1.87
Log Po/w (SILICOS-IT) :	0.73
Consensus Log Po/w :	-0.06

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-0.54
Solubility :	40.5 mg/ml ; 0.285 mol/l
Class :	Very soluble
Log S (Ali) :	-0.58
Solubility :	37.1 mg/ml ; 0.261 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-0.97
Solubility :	15.3 mg/ml ; 0.108 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.63

Safety of [ 5222-73-1 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P302+P352-P333+P313-P337+P313-P304+P340-P312-P280-P332+P313	UN#:	2811
Hazard Statements:	H315-H317-H319-H334-H335	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 5222-73-1 ]

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

Upstream synthesis route of [ 5222-73-1 ]
Downstream synthetic route of [ 5222-73-1 ]

[ 5222-73-1 ] Synthesis Path-Upstream 1~12

1
[ 2892-51-5 ]
[ 149-73-5 ]
[ 5222-73-1 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	at 56℃; for 24 h;	Compound 30 was synthesized using a modification of the procedure reported by Liu et al. [7]. 3,4-Dihydroxy-3-cyclobutene-1,2-dione (squaric acid, 2.053 g, 18 mmol) was dissolved in anhydrous methanol (18 ml), and trimethyl orthoformate (4 ml, 36.5 mmol) was added to the solution. The reaction mixture was refluxed at 56 °C for 24 h. The crude product was then concentrated under reduced pressure. The pale yellow solid was dissolved in methylene chloride and purified on a silica gel column (EtOAc: Hexanes 1:2) to give 3,4-dimethoxycyclobut-3-ene-1,2-dione (2.29 g, 89.4percent) as a white solid. mp 55-57 °C (lit. 56-58 °C) [7, 8]¹H NMR (300 MHz, CD₂Cl₂) δ 4.34 (6H, s, OCH₃) ¹³C NMR (75 MHz, CD₃OD) δ 189.35 (C2, C=O), 189.35 (C1, C=O), 184.35 (C3), 184.35 (C4), 60.29 (OCH₃), 60.29 (OCH₃) LRMS (EI): 142.03 (100), 114.03 (18), 99.01 (16), 86.01 (54), 67.99 (8), 56.25 (7)

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 2, p. 282 - 287
[2] Organic Syntheses, 1999, vol. 76, p. 189 - 189
[3] Chemistry - A European Journal, 2011, vol. 17, # 49, p. 13698 - 13705
[4] Chemistry - A European Journal, 2017, vol. 23, # 47, p. 11234 - 11238
[5] Chemical Communications, 2018, vol. 54, # 26, p. 3231 - 3234
[6] Organic and Biomolecular Chemistry, 2015, vol. 13, # 22, p. 6225 - 6241
[7] Journal of Organic Chemistry, 2018, vol. 83, # 17, p. 10627 - 10635
[8] RSC Advances, 2018, vol. 8, # 54, p. 30761 - 30776
[9] Patent: WO2008/5570, 2008, A1, . Location in patent: Page/Page column 74-75
[10] Patent: WO2009/5802, 2009, A1, . Location in patent: Page/Page column 20-21

2
[ 122-51-0 ]
[ 2892-51-5 ]
[ 5222-73-1 ]

Reference： [1] Patent: WO2009/5801, 2009, A1, . Location in patent: Page/Page column 30-31

3
[ 2892-51-5 ]
[ 74-88-4 ]
[ 5222-73-1 ]

Reference： [1] Organic Letters, 2015, vol. 17, # 9, p. 2150 - 2153

4
[ 80-11-5 ]
[ 2892-51-5 ]
[ 5222-73-1 ]

Reference： [1] Tetrahedron, 2001, vol. 57, # 27, p. 5769 - 5772

5
[ 67-56-1 ]
[ 2892-51-5 ]
[ 5222-73-1 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 49, p. 13076 - 13079[2] Angew. Chem., 2013, vol. 125, # 49, p. 13314 - 13317,4
[3] Angewandte Chemie - International Edition, 2014, vol. 53, # 10, p. 2628 - 2632[4] Angew. Chem., 2014, vol. 126, # 10, p. 2666 - 2670,5

6
[ 1027429-37-3 ]
[ 5222-73-1 ]

Reference： [1] Journal of Organic Chemistry, 1995, vol. 60, # 3, p. 735 - 738

7
[ 67-56-1 ]
[ 2892-51-5 ]
[ 149-73-5 ]
[ 5222-73-1 ]

Reference： [1] Synthetic Communications, 1997, vol. 27, # 12, p. 2177 - 2180
[2] Organic and Biomolecular Chemistry, 2016, vol. 14, # 39, p. 9322 - 9330

8
[ 67-56-1 ]
[ 61699-62-5 ]
[ 5222-73-1 ]

Reference： [1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1768 - 1773

9
[ 67-56-1 ]
[ 5231-87-8 ]
[ 5222-73-1 ]

Reference： [1] Journal of Organic Chemistry, 1988, vol. 53, # 11, p. 2477 - 2482

10
[ 2892-51-5 ]
[ 5222-73-1 ]

Reference： [1] Australian Journal of Chemistry, 2010, vol. 63, # 12, p. 1656 - 1664

11
[ 1007834-23-2 ]
[ 5222-73-1 ]

Reference： [1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1768 - 1773

12
[ 2892-51-5 ]
[ 149-73-5 ]
[ 67543-98-0 ]
[ 5222-73-1 ]

Reference： [1] Organic Syntheses, 1999, vol. 76, p. 189 - 189

[ 5222-73-1 ] Synthesis Path-Downstream 1~62

1
[ 50632-53-6 ]
[ 5222-73-1 ]
[ 100749-01-7 ]

Reference： [1]Archiv der Pharmazie,1985,vol. 318,p. 977 - 983
[2]Journal of Organic Chemistry,2005,vol. 70,p. 10792 - 10802

2
[ 505-23-7 ]
[ 5222-73-1 ]
[ 161033-73-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	Stage #1: 1,3 dithiane With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.333333h; Stage #2: 3,4-dimethoxy-3-cyclobutene-1,2-dione In tetrahydrofuran; hexane at -40℃; for 0.5h;
	With n-butyllithium In tetrahydrofuran; hexane 1.) -78 deg C, 20 min, 2.) 20 min;

Reference： [1]Tan, Haibo; Zheng, Chao; Liu, Zheng; Wang, David Zhigang [Organic Letters, 2011, vol. 13, # 9, p. 2192 - 2195]
[2]Lee, Kwan Hee; Moore, Harold W. [Journal of Organic Chemistry, 1995, vol. 60, # 3, p. 735 - 738]

3
[ 4282-77-3 ]
[ 5222-73-1 ]
2,3-dimethoxy-4-hydroxy-4-(3-carbazolyl-1-propynyl)-2-cyclobuten-1-one [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1996,vol. 61,p. 9168 - 9177

4
[ 6386-71-6 ]
[ 73286-71-2 ]
[ 5222-73-1 ]
(4aR,7aS)-4a,7a-Dihydroxy-6,7-dimethoxy-5-oxo-2,3,3a,4,4a,5,7a,7b-octahydro-pentaleno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 3151 - 3154

5
[ 67788-09-4 ]
[ 73286-71-2 ]
[ 5222-73-1 ]
C₂₀H₂₉NO₆ [ No CAS ]
C₂₀H₂₉NO₆ [ No CAS ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 3151 - 3154
[2]Canadian Journal of Chemistry,2000,vol. 78,p. 689 - 696

6
[ 52794-97-5 ]
[ 5222-73-1 ]
(8S,10S)-8-Acetyl-1,6,8,11-tetrahydroxy-10-[(2R,4S,5S,6S)-5-hydroxy-4-(2-methoxy-3,4-dioxo-cyclobut-1-enylamino)-6-methyl-tetrahydro-pyran-2-yloxy]-7,8,9,10-tetrahydro-naphthacene-5,12-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With triethylamine In ethanol at 20℃;

Reference： [1]Tevyashova, Anna; Sztaricskai, Ferenc; Batta, Gyula; Herczegh, Pál; Jeney, András [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 18, p. 4783 - 4789]

7
[ 25100-12-3 ]
[ 5222-73-1 ]
[ 100749-02-8 ]

Reference： [1]Journal of Organic Chemistry,2005,vol. 70,p. 10792 - 10802

8
[ 464913-11-9 ]
[ 5222-73-1 ]
[ 473732-10-4 ]

Yield	Reaction Conditions	Operation in experiment
78%	In methanol;	The amine from Prepartive Example 3 (5 g) and dimethylsquarate (3.95 g) in MeOH were stirred overnight. The precipitated product was filtered to give 6.32 g of solid (78%, MH+=291.1)

Reference： [1]Patent: US2004/147559,2004,A1 .Location in patent: Page 106
[2]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4107 - 4110

9
[ 195314-59-1 ]
[ 5222-73-1 ]
C₂₆H₄₂N₄O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol; at 120℃; for 1h;Microwave;	(4-Amino-cyclohexyl)-carbamic acid tert-butyl ester (2 eq.) and 3,4-dimethoxy-3- cyclobutene-l,2-dione (1 eq.) are dissolved in EtOH and heated at 120C for 1 hour in the microwave. The solvent is removed in vacuo. The resulting material is dissolved in DCM. TFA is added and the reaction mixture is stirred at RT for 2 hours. The solvent is removed in vacuo the material is then dissolved in minimal volume of ethanol/saturated aqueous sodium carbonate solution until the pH of the solution is adjusted to pH 9 (ensuring the compound remains in solution). The solution is loaded onto an Isolute C 18 column and washed through firstly with water and then MeOH. The fractions are combined and concentrated in vacuo to yield the title product.

Reference： [1]Patent: WO2007/121924,2007,A2 .Location in patent: Page/Page column 68

10
[ 2892-51-5 ]
[ 149-73-5 ]
[ 5222-73-1 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	In methanol; at 56℃; for 24h;	Compound 30 was synthesized using a modification of the procedure reported by Liu et al. [7]. 3,4-Dihydroxy-3-cyclobutene-1,2-dione (<strong>[2892-51-5]squaric acid</strong>, 2.053 g, 18 mmol) was dissolved in anhydrous methanol (18 ml), and trimethyl orthoformate (4 ml, 36.5 mmol) was added to the solution. The reaction mixture was refluxed at 56 C for 24 h. The crude product was then concentrated under reduced pressure. The pale yellow solid was dissolved in methylene chloride and purified on a silica gel column (EtOAc: Hexanes 1:2) to give 3,4-dimethoxycyclobut-3-ene-1,2-dione (2.29 g, 89.4%) as a white solid. mp 55-57 C (lit. 56-58 C) [7, 8]1H NMR (300 MHz, CD2Cl2) delta 4.34 (6H, s, OCH3) 13C NMR (75 MHz, CD3OD) delta 189.35 (C2, C=O), 189.35 (C1, C=O), 184.35 (C3), 184.35 (C4), 60.29 (OCH3), 60.29 (OCH3) LRMS (EI): 142.03 (100), 114.03 (18), 99.01 (16), 86.01 (54), 67.99 (8), 56.25 (7)
	With trifluoroacetic acid; In methanol;Heating / reflux;	Preparative Example 5; Preparation of Compound 209A; Charged 9.5 kg of the compound of formula 214 to 50 gallon glass reactor equipped with a thermocouple, N2 inlet and feed tank. Charged 65 liters dry methanol (KF < 0.1 %) followed by 20 liters trimethylorthoformate and 0.2 kg trifluroracetic acid. Heated the batch to reflux and maintained for about one hour. Concentrated the batch at one atmosphere until the internal temperature exceeded 7O0C. Maintained the batch at reflux for about four hours. Adjusted the batch to a temperature between 40 and 500C and charged 26 liters dry methanol. Adjusted the temperature to about 20 to 30C. Charged 78 liters of dry methanol and adjusted the batch to a temperature between -5 and 5C. Charged 13.0 kg of the compound of formula V. Over about 4 hours, charged 11.1 kg triethylamine (TEA) to the batch while maintaining the batch at a temperature between -5 and 50C. About one and a half hours after the start of the <n="76"/>TEA charge, seeded the batch with 130 grams of compound (209A) added as a solid. After the addition of TEA was completed, agitated the batch for about 30 minutes at a temperature between -5 and 5C. Charged 12 liters acetic acid while maintaining the batch at a temperature between -5 and 50C. Heated the batch to a temperature between 60 and 700C and maintained this temperature for about 1 hour. Adjusted the temperature to about 25 to 350C over about 1 hour. Adjusted the temperature to about -5 to 50C over about 1 hour. Filtered the batch and washed the filter cake with 65 liters (5 x) methanol. Dried the batch in a vacuum oven for at least 24 hours at 60 to 700C. Yield 14.5 kg , 81%. 1HNMR (CD3CN) 8.07 (1 H, s); 7.56 (1 H, d); 7.28 (1H, d); 6.99 (1 H, t); 4.35 (3H, s); 3.10 (6H1 s)
	With trifluoroacetic acid; In methanol; for 5h;Heating / reflux;	Example Ia - In Situ Preparation of Dimethyl Squarate (2A2) and Reaction With Compound (2B) to Form Compound (2Ca). Into a 50 gallon glass reactor equipped with a thermocouple, N2 inlet and feed tank was charged 9.5 kg of the compound of Formula 2A. The reactor was then charged with 65 liters dry methanol (Karl Fischer titration "KF" indicates water present at < 0.1 %) followed by 20 liters trimethylorthoformate and 0.2 kg trifluroracetic acid. The reaction mixture was heated to reflux and maintained for about one hour. The reaction mixture was concentrated at one atmosphere until the internal temperature exceeded 700C. The reaction mixture was maintained at reflux for about four hours then the temperature was adjusted to a temperature between 40 0C and 50 0C. The reactor was charged with 26 liters dry methanol and the reaction mixture temperature was adjusted to about 20 0C to 30 C. The reactor was charged with 78 liters of dry methanol and the reaction mixture temperature was adjusted to a temperature between -5 0C and 50C. The reactor was charged with 13.0 kg of the compound of Formula 2B. Triethylamine (TEA), 11.1 kg, was charged into the reactor over 4 hours while maintaining the batch at a temperature between -5 and 50C. About one and a half hours after the start of the TEA charge, the reaction mixture was seeded with 130 grams of the compound 2C. After the addition of TEA was completed the reaction mixture was agitated for about 30 minutes maintaining the batch temperature between -5 and 50C. Acetic acid, 12 liters was charged into the reactor while maintaining the batch at a temperature between -5 and 50C. The reaction mixture was heated to a temperature between 60 and 7O0C and maintained in this temperature range for about 1 hour. After about 1 hour the temperature was adjusted to a temperature in the range of 25 0C to 35 0C and maintained at that temperature range for about 1 hour, then the temperature was readjusted to a temperature in the range of [-5 0C] to [+50C] over about 1 hour. The reaction mixture was filtered and the filter cake washed with 65 liters methanol. The solids collected were dried in a vacuum oven for about 24 hours with the oven temperature maintained at 600C to 7O0C. Yield was 14.5 kg , about 81% based on the amount of the compound of Formula 2C employed. 1HNMR (CD3CN) 8.07 (1H, s); 7.56 (1H1 d); 7.28 (1H, d); 6.99 (1H, t); 4.35 (3H, s); 3.10 (6H, s)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 282 - 287
[2]Organic Syntheses,1999,vol. 76,p. 189 - 189
[3]Chemistry - A European Journal,2011,vol. 17,p. 13698 - 13705
[4]Chemistry - A European Journal,2017,vol. 23,p. 11234 - 11238
[5]Chemical Communications,2018,vol. 54,p. 3231 - 3234
[6]Chemical Communications,2019,vol. 55,p. 11283 - 11286
[7]Organic and Biomolecular Chemistry,2015,vol. 13,p. 6225 - 6241
[8]Journal of Organic Chemistry,2018,vol. 83,p. 10627 - 10635
[9]RSC Advances,2018,vol. 8,p. 30761 - 30776
[10]Patent: WO2008/5570,2008,A1 .Location in patent: Page/Page column 74-75
[11]Patent: WO2009/5802,2009,A1 .Location in patent: Page/Page column 20-21

11
[ 7284-37-9 ]
[ 5222-73-1 ]
C₁₁H₁₅NO₈ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37%	With triethylamine In methanol at 20℃; for 24h;

Reference： [1]Sztaricskai, Ferenc; Roth, Erzsebet; Andrei, Maria; Pelyvas, Istvan F.; Herczegh, Pal [Chemistry Letters, 2007, vol. 36, # 8, p. 1012 - 1013]

12
[ 869-19-2 ]
[ 5222-73-1 ]
[ 952418-83-6 ]

Reference： [1]Chemistry Letters,2007,vol. 36,p. 1012 - 1013

13
[ 5222-73-1 ]
[ 85068-29-7 ]
[ 1073917-05-1 ]

Yield	Reaction Conditions	Operation in experiment
85%	In dichloromethane; at 20℃; for 24h;Inert atmosphere;	To a solution of dimethyl squarate (710 mg, 5 mmol) in CH2Cl2 (10 mL) was added a solution of 3,5-Bis(trifluoromethyl)benzylamine (1.27 g, 5.25 mmol) in CH2Cl2 (5 mL) under N2 atmosphere. After 24 h, the reaction was completed (monitored by TLC), then the reaction mixture was concentrated and purified by flash chromatography (1:9 = Hexane:EtOAc) to afford 1n as a colourless solid; yield: 1.5 g (85%). To a solution of 1n (1.4 mmol) in MeOH (5 mL) was added a solution of cinchona alkaloid derived amine2 (1.5 mmol) in MeOH under an N2 atmosphere. After 48 h, the reaction mixture was filtered. The precipitate was washed with cold MeOH (3×5 mL) to afford the corresponding pure squaramide catalysts 1f-i as colourless solids.
	In methanol; at 20℃; for 48h;	General procedure: Step 1. 3,4-Dimethoxycyclobut-3-ene-1,2-dione (16) (1.0 equiv.) was dissolved in MeOH (0.07 M) and the amine 17a - 17f or 19a (1.1 equiv.) was added. The resulting mixture was stirred at ambient temperature for 48 hours. The mixture was then filtered and the collected solid residue was washed with ice-cold MeOH and dried in vacuo to afford the corresponding squaramate 18a - 18f and catalyst 7.

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 3786 - 3796
[2]Journal of the American Chemical Society,2017,vol. 139,p. 15308 - 15311
[3]Journal of the American Chemical Society,2008,vol. 130,p. 14416 - 14417
[4]Tetrahedron Letters,2016,vol. 57,p. 1227 - 1231
[5]Organic and Biomolecular Chemistry,2014,vol. 12,p. 8656 - 8670
[6]Chemistry - A European Journal,2018,vol. 24,p. 6854 - 6860
[7]Organic Letters,2012,vol. 14,p. 5884 - 5887
[8]Advanced Synthesis and Catalysis,2012,vol. 354,p. 3523 - 3532
[9]Tetrahedron Letters,2016,vol. 57,p. 5232 - 5236
[10]Chemistry - A European Journal,2017,vol. 23,p. 11234 - 11238
[11]Organic Letters,2019,vol. 21,p. 9166 - 9170

14
[ 455-14-1 ]
[ 5222-73-1 ]
[ 1132827-67-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	In methanol at 20℃; for 48h; Inert atmosphere;
86%	In methanol at 20℃; for 48h;
78%	In methanol at 20℃; for 48h;	4.2.1 Synthesis of organocatalysts II In a 25mL round-bottomed flask, 4-(trifluoromethyl)aniline (0.805g, 5.0mmol) was added to dimethyl squarate (0.71g, 5.0mmol) which was dissolved in 10mL of methanol. The mixture was then stirred at room temperature for 48h, after which the precipitate was filtered to afford the mono-squaramide as a white solid (1.06g, 78% yield). To a solution of hydroquinine derivatives (325mg, 1.0mmol) in CH2Cl2 (10mL) was added mono-squaramide (272mg, 1mmol). After stirring for 48h at room temperature, squaramide catalyst II was obtained by filtration as a white solid (480mg, 85% yield). Mp 203-205°C (decomp.), [α]28D=-72.7[α]D28=-72.7 (c 0.30, DMSO). 1H NMR (400MHz, DMSO-d6): δ 10.07 (br s, 1H), 8.88 (d, J=4.4Hz, 1H), 8.41 (br s, 1H), 8.03 (d, J=9.2Hz, 1H), 7.83 (br s, 1H), 7.74 (d, J=4.4Hz, 1H), 7.68 (d, J=8.4Hz, 2H), 7.62 (d, J=8.4Hz, 2H), 7.48 (dd, J1=9.2Hz, J2=2.4Hz, 1H), 6.09 (br s, 1H), 4.01 (s, 3H), 3.53-3.35 (m, 4H), 3.21-3.16 (m, 1H), 2.66 (br s, 1H), 2.50 (d, J=12.8Hz, 1H), 1.57-1.36 (m, 7H), 0.81 (t, J=7.2Hz, 1H), 0.66 (br s, 1H) ppm; 13C NMR (100MHz, DMSO-d6): δ 184.6, 179.7, 168.4, 163.1, 157.8, 147.7, 144.3, 143.0, 142.3, 131.5, 127.4, 126.50, 126.46, 124.3 (q, 1JC-F=-270.2Hz), 122.5 (q, 2JC-F=32.0Hz), 121.8, 118.0, 101.3, 57.1, 55.6, 40.2, 36.6, 27.8, 26.8, 25.7, 24.9, 11.8ppm; IR (KBr): ν 3226, 3184, 3002, 2962, 2940, 2869, 1800, 1675, 1655, 1621, 1606, 1575, 1542, 1513, 1475, 1460, 1443, 1420, 1377, 1329, 1322, 1269, 1241, 1192, 1172, 1162, 1119, 1070, 1042, 1016, 840, 826, 767, 728, 715, 681, 637cm-1; HRMS (ESI): m/z calcd for C31H32F3N4O3 [M+H]+ 565.24210, found 565.24180.

	In methanol at 20℃;
	at 20℃; for 48h;
	In methanol
	In methanol at 20℃; for 48h;	Preparation of squaramide catalysts 1 - 8 General procedure: Step 1. 3,4-Dimethoxycyclobut-3-ene-1,2-dione (16) (1.0 equiv.) was dissolved in MeOH (0.07 M) and the amine 17a - 17f or 19a (1.1 equiv.) was added. The resulting mixture was stirred at ambient temperature for 48 hours. The mixture was then filtered and the collected solid residue was washed with ice-cold MeOH and dried in vacuo to afford the corresponding squaramate 18a - 18f and catalyst 7.
	In dichloromethane at 20℃; for 72h; Sealed tube;
	In ethanol at 20℃;	4.2.10. General procedure for the synthesis of the target compound 6 General procedure: To a solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione 16(1.0 mmol, 1.0 equiv.) in ethanol (10 mL) was added substitutedamine (1.0 mmol, 1.0 equiv.). The reaction mixture was stirred atroom temperature overnight. The precipitate was filtered, washedwith cooled ethanol and dried to afford the intermediate 17. To suspended solution of 17 in ethanol (10 mL) was added the corresponding amine (1.2 mmol, 1.2 equiv.). The reaction mixture wasstirred at room temperature overnight. The precipitate was filtered,wash with cooled ethanol and dried to afford the target compound 6.

Reference： [1]Zhu, Ye; Malerich, Jeremiah P.; Rawal, Viresh H. [Angewandte Chemie - International Edition, 2010, vol. 49, # 1, p. 153 - 156]
[2]Yang, Wen; Du, Da-Ming [Organic Letters, 2010, vol. 12, # 23, p. 5450 - 5453]
[3]Zhao, Bo-Liang; Du, Da-Ming [Tetrahedron Asymmetry, 2014, vol. 25, # 4, p. 310 - 317]
[4]Dai, Le; Wang, Su-Xi; Chen, Fen-Er [Advanced Synthesis and Catalysis, 2010, vol. 352, # 13, p. 2137 - 2141]
[5]Tungen, Jorn E.; Nolsoe, Jens M. J.; Hansen, Trond V. [Organic Letters, 2012, vol. 14, # 23, p. 5884 - 5887]
[6]Qiu, Lin; Wang, Dongwei; Lv, Fengping; Guo, Xin; Hu, Wenhao; Yang, Liping; Liu, Shunying [Tetrahedron, 2014, vol. 70, # 7, p. 1471 - 1477]
[7]Kristianslund, Renate; Aursnes, Marius; Tungen, Jørn Eivind; Hansen, Trond Vidar [Tetrahedron Letters, 2016, vol. 57, # 47, p. 5232 - 5236]
[8]Majee, Debashis; Jakkampudi, Satish; Arman, Hadi D.; Zhao, John C.-G. [Organic Letters, 2019, vol. 21, # 22, p. 9166 - 9170]
[9]Fu, Lei; Huang, Haihong; Li, Gang; Li, Peng; Lin, Ziyun; Lu, Yu; Wang, Bin; Zhang, Dongfeng [European Journal of Medicinal Chemistry, 2020, vol. 206]

15
9-amino-9-deoxy-epi-cinchonidine [ No CAS ]
[ 5222-73-1 ]
[ 1204591-50-3 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol at 20℃;

Reference： [1]Woong Lee, Ji; Hi Ryu, Tae; Suk Oh, Joong; Yong Bae, Han; Bin Jang, Hyeong; Eui Song, Choong [Chemical Communications, 2009, # 46, p. 7224 - 7226]

16
[ 79606-46-5 ]
[ 5222-73-1 ]
[ 1360898-76-5 ]

Reference： [1]Chemistry - A European Journal,2011,vol. 17,p. 13698 - 13705

17
[ 5222-73-1 ]
[ 168828-90-8 ]
[ 1308299-21-9 ]

Reference： [1]Medicinal Chemistry,2011,vol. 7,p. 45 - 55

18
[ 146476-38-2 ]
[ 5222-73-1 ]
[ 1395055-59-0 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 20℃; for 48h; Inert atmosphere;	General procedure for the preparation of catalysts Compound I and catalysts TP1, TP2, TP3, TP4 and TP5 were synthesized according to the previous literature.[1]Compound II was synthesized according to the following procedure: Into a 25 mL oven-dried reaction flask under Ar gas protection were added compound I (319 mg, 1.0 mmol), 3,4-dimethoxycyclobut-3-ene-1,2-dione (142 mg, 1.0 mmol) and DCM (5 mL), the reaction mixture was stirred at room temperature for 48 h, then the solvent was removed under reduced pressure and the residue was purified by flash column chromatography to give white solid.

Reference： [1]Hu, Fangle; Wei, Yin; Shi, Min [Tetrahedron, 2012, vol. 68, # 38, p. 7911 - 7919]

19
[ 5222-73-1 ]
[ 328-74-5 ]
[ 167316-27-0 ]
C₃₃H₂₅F₆N₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To a solution of 3,4-dimethoxy-3-cyclobutane-1,2-dione (2.0 g,14.1 mmol) in MeOH (30 mL) was added 3,5-bis(trifluoromethyl)aniline or 9-amino(9-deoxy)epiquinine (15.5 mmol,1.1 equiv) at room temperature. The mixture was stirred at roomtemperature for 2 days. The reaction mixture was filtered andwashed with MeOH to give a yellow solid. The yellow solid(1.0 mmol) was then dissolved in MeOH (5 mL) and the correspondingsubstituted amine (1.1 mmol) was added. The solutionwas stirred at room temperature for 2 days. The reaction mixturewas filtered and the precipitate was washed with MeOH (5 mL).The crude product obtained was purified by recrystallization fromMeOH to give pure desired products V-VII.

Reference： [1]Tetrahedron Asymmetry,2013,vol. 24,p. 1312 - 1317

20
[ 67-56-1 ]
[ 2892-51-5 ]
[ 5222-73-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With sulfuric acid; for 24h;Reflux;	A solution of 0.30 g (2.6 mmol) of <strong>[2892-51-5]squaric acid</strong> (1) and 0.80 g(4.1 mmol) of concentrated sulfuric acid in 25 mL of anhydrous methanolin a round-bottomed flask equipped with a reflux condenser washeated until reflux for 24 h. After the reaction was complete, the solutionwas cooled, neutralized with saturated sodium bicarbonate solutionand extracted with 3 × 50 mL of dichloromethane. The organicphase was then dried with anhydrous magnesium sulfate, filtered andevaporated to afford 0.32 g (87%) of a yellow oil. IR (ATR, cm-1): 2996(nuc-H), 1809 (nuC=O), 1638 (nuC=C), 1266 (nuC-O), 735 (deltaC-H)·1H NMR(400 MHz, CDCl3-d1) delta 4.37. 13C NMR (400 MHz, CDCl3-d1) delta 61.22,184.67, 189.39.

Reference： [1]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2019,vol. 223
[2]Angewandte Chemie - International Edition,2013,vol. 52,p. 13076 - 13079
Angew. Chem.,2013,vol. 125,p. 13314 - 13317,4
[3]Angewandte Chemie - International Edition,2014,vol. 53,p. 2628 - 2632
Angew. Chem.,2014,vol. 126,p. 2666 - 2670,5
[4]ACS Medicinal Chemistry Letters,2020,vol. 11,p. 414 - 418

21
[ CAS Unavailable ]
[ 5222-73-1 ]
[ 1073917-05-1 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane

Reference： [1]Du, Haiying; Rodriguez, Jean; Bugaut, Xavier; Constantieux, Thierry [Chemistry - A European Journal, 2014, vol. 20, # 27, p. 8458 - 8466]

22
[ 947-73-9 ]
[ 5222-73-1 ]
3-methoxy-4-(phenanthren-9-ylamino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	In methanol at 20℃; for 64h;

Reference： [1]Fernández-Moreira, Vanesa; Alegre-Requena, Juan V.; Herrera, Raquel P.; Marzo, Isabel; Gimeno, M. Concepción [RSC Advances, 2016, vol. 6, # 17, p. 14171 - 14177]

23
[ 2693-46-1 ]
[ 5222-73-1 ]
3-(fluoranthen-3-ylamino)-4-methoxycyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	In methanol at 20℃; for 93h;

Reference： [1]Fernández-Moreira, Vanesa; Alegre-Requena, Juan V.; Herrera, Raquel P.; Marzo, Isabel; Gimeno, M. Concepción [RSC Advances, 2016, vol. 6, # 17, p. 14171 - 14177]

24
[ 137848-28-3 ]
[ 5222-73-1 ]
3-([(R)-2'-hydroxy-{1,1'-binaphthalen}-2-yl]amino)-4-methoxycyclobut-3-ene-1,2-dione [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 14171 - 14177

25
[ 153-78-6 ]
[ 5222-73-1 ]
3-([9H-fluoren-2-yl]amino)-4-methoxycyclobut-3-ene-1,2-dione [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 14171 - 14177

26
[ 153-78-6 ]
[ 5222-73-1 ]
3,4-bis([9H-fluoren-2-yl]amino)cyclobut-3-ene-1,2-dione [ No CAS ]

Reference： [1]RSC Advances,2016,vol. 6,p. 14171 - 14177

27
[ 885677-91-8 ]
[ 5222-73-1 ]
[ 328-74-5 ]
[ 1211565-11-5 ]

Yield	Reaction Conditions	Operation in experiment
80%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 12; 41
[2]Soft Matter,2016,vol. 12,p. 4361 - 4374

28
[ 320778-92-5 ]
[ 5222-73-1 ]
[ 328-74-5 ]
[ 1211565-07-9 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 14; 41

29
[ 5222-73-1 ]
[ 328-74-5 ]
[ 174291-96-4 ]
N-((1R,2R)-2-(2-(3,5-bis(trifluoromethyl)phenylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 41; 42; 43
[2]Soft Matter,2016,vol. 12,p. 4361 - 4374

30
[ 10420-89-0 ]
[ 372-39-4 ]
[ 5222-73-1 ]
(S)-3-(3,5-difluorophenylamino)-4-(1-(naphthalen-1-yl)ethylamino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	Stage #1: 3,5-difluoroaniline; 3,4-dimethoxy-3-cyclobutene-1,2-dione In methanol at 20℃; for 30h; Stage #2: (S)-1-(1-Naphthyl)ethylamine In methanol for 3h;	2; 18 General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Current Patent Assignee: GOVERNMENT OF SPAIN; UNIVERSITY OF ZARAGOZA - WO2016/5407, 2016, A1 Location in patent: Page/Page column 10; 12; 41; 49; 50

31
[ 372-39-4 ]
[ 5222-73-1 ]
[ 174291-96-4 ]
N-((1R,2R)-2-(2-(3,5-difluorophenylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 41; 43; 44
[2]Soft Matter,2016,vol. 12,p. 4361 - 4374

32
[ 104-94-9 ]
[ 5222-73-1 ]
[ 174291-96-4 ]
N-((1R,2R)-2-(2-(4-methoxyphenylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 11; 41; 44; 45
[2]Soft Matter,2016,vol. 12,p. 4361 - 4374

33
[ 885677-91-8 ]
[ 5222-73-1 ]
[ 85068-29-7 ]
3-[3,5-bis(trifluoromethyl)benzyl]amino}-4-[(R,R)-2-( piperidine-1-yl)cyclohexyl]amino}cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 13; 41

34
[ 5222-73-1 ]
[ 85068-29-7 ]
[ 174291-96-4 ]
N-((1R,2R)-2-(2-(3,5-bis(trifluoromethyl)benzylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 11; 41; 45; 46

35
[ 885677-91-8 ]
[ 163733-96-8 ]
[ 5222-73-1 ]
3-((1R,2R)-2-(piperidin-1-yl)cyclohexylamino)-4-(3,4,5-trifluorophenylamino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 12; 41; 50

36
[ 885677-91-8 ]
[ 137848-28-3 ]
[ 5222-73-1 ]
3-((R)-2'-hydroxy-1,1'-binaphthyl-2-ylamino)-4-((1R,2R)-2-(piperidin-1-yl)cyclohexylamino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 12; 41; 50; 51

37
[ 885677-91-8 ]
[ 455-14-1 ]
[ 5222-73-1 ]
[ 1211565-08-0 ]

Yield	Reaction Conditions	Operation in experiment
77%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.4 mmol) in MeOH (1 mL), 0.4 mmol of 4-(trifluoromethyl)aniline (2c) was firstly added at room temperature. After 48 h a precipitate was observed and 0.4 mmol of <strong>[885677-91-8](1R,2R)-trans-2-(1-piperidinyl)cyclohexylamine</strong> (4g) was solved in MeOH (3 mL) and added to the reaction mixture. After 3 h the test tube was placed in a freezer (-22C) for 30 minutes to facilitate the overall precipitation of final product Scg. The product was filtered under vacuum and washed with cold MeOH (2 mL). Final squaramide Scg was obtained as a white solid in 77% yield.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 12; 41

38
[ 885677-91-8 ]
[ 768-94-5 ]
[ 5222-73-1 ]
C₂₅H₃₇N₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 14; 41

39
[ 885677-91-8 ]
[ 5222-73-1 ]
(R)-2'-methoxy-[1,1'-binaphthalen]-2-amine [ No CAS ]
3-(((R)-2’-methoxy-[1,1'-binaphthalen]-2-yl)amino)-4-(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
31%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 14; 15; 41; 55; 56

40
[ 885677-91-8 ]
[ 137848-29-4 ]
[ 5222-73-1 ]
3-(((S)-2'-hydroxy-[1,1'-binaphthalen]-2-yl)amino)-4-(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 14; 15; 41; 54

41
[ 885677-91-8 ]
[ 91-59-8 ]
[ 5222-73-1 ]
3-(naphthalen-2-ylamino)-4-(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 14; 16; 41; 56

42
[ 885677-92-9 ]
[ 137848-28-3 ]
[ 5222-73-1 ]
3-((R)-2'-hydroxy-1,1'-binaphthyl-2-ylamino)-4-((1R,2R)-2-(pyrrolidin-1-yl)cyclohexylamino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 12; 41; 51

43
[ 111-26-2 ]
[ 5222-73-1 ]
[ 174291-96-4 ]
N-((1R,2R)-2-((2-(hexylamino)-3,4-dioxocyclobut-1-en-1-yl)amino)-cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 14; 15; 41; 53
[2]Soft Matter,2016,vol. 12,p. 4361 - 4374

44
[ 109-73-9 ]
[ 5222-73-1 ]
[ 4543-96-8 ]
[ 1541171-10-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 3,4-dimethoxy-3-cyclobutene-1,2-dione; N,N,N'-trimethylpropane-1,3-diamine In methanol at 20℃; for 2.5h; Stage #2: N-butylamine In methanol for 12.5h;	4 Example 4. One-pot synthesis of antiparasitic agent 11 To a mixture of 3,4-dimethoxy-3-cyclobutene-1,2-dione (Ia) (0.2 mmol) in MeOH (0.25 mL), 0.2 mmol of N,N,M-trimethyl-1 ,3-propanediamine (8) was firstly added at roomtemperature. After 2.5 h n-butylamine (10) (0.2 mmol) was solved in MeOH (1.75 mL) and added to the reaction mixture. After 12.5 h the solvent was evaporated in vacuo and the product was purified by column chromatography (Si02, AcOEt:MeOH 1:1 to AcOEt:MeOH:Et3N 5:5:0.1). Final anti-Chagasic drug II was obtained as a white solid in 78% yield.

Reference： [1]Current Patent Assignee: UNIVERSITY OF ZARAGOZA; GOVERNMENT OF SPAIN - WO2016/5407, 2016, A1 Location in patent: Page/Page column 42

45
[ 594-39-8 ]
[ 5222-73-1 ]
[ 150517-76-3 ]
[ 202520-55-6 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 2-methyl-2-butylamine; 3,4-dimethoxy-3-cyclobutene-1,2-dione In methanol at 20℃; for 20h; Stage #2: 2,4-dichloro-6-methylbenzylamine In methanol for 72h;	6 Example 6. One-pot synthesis of WAY-151616 (20) To a mixture of 3,4-dimethoxy-3-cyclobutene-1,2-dione (Ia) (0.4 mmol) in MeOH (0.5 mL), 0.4 mmol of 1,1-dimethylpropylamine (17) were firstly added at room temperature.After 20 h, 0.4 mmol of 2,4-dichloro-6-methylbenzylamine (19) were solved in MeOH (3.5 mL) and added to the reaction mixture. After 3 days, the test tube was placed in a freezer (-22°C) for 30 minutes to facilitate the overall precipitation of final drug 20. The product was purified by column chromatography (Si02, hexane/EtOAc 6:4 to 0:1 and EtOAc/MeOH 9:1. Final bladder-selective agonist KATP channel 20 was obtained as awhite solid in 72% yield.

Reference： [1]Current Patent Assignee: GOVERNMENT OF SPAIN; UNIVERSITY OF ZARAGOZA - WO2016/5407, 2016, A1 Location in patent: Page/Page column 42

46
[ 769-92-6 ]
[ 5222-73-1 ]
[ 174291-96-4 ]
N-((1R,2R)-2-(2-(4-tert-butylphenylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%		General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.

Reference： [1]Patent: WO2016/5407,2016,A1 .Location in patent: Page/Page column 10; 11; 41; 44
[2]Soft Matter,2016,vol. 12,p. 4361 - 4374

47
[ 63-45-6 ]
[ 5222-73-1 ]
3-methoxy-4-({4-[(6-methoxyquinolin-8-yl)amino]pentyl}amino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		General procedure: A reaction mixture of <strong>[63-45-6]primaquine diphosphate</strong> (1.2 equiv), andNEt3 (2.4 equiv) in dry solvent (1 mL/3-cyclobutene-1,2-dionederivative 8) was stirred for 30 min at room temperature undernitrogen atmosphere, before addition of 3-cyclobutene-1,2-dionederivative 8 (1.0 equiv). After heating at reflux for 12-48 h, the solventwas removed under reduced pressure and the residueobtained dissolved in EtOAc. The mixture was then washed withwater (2) and dried over anhydrous Na2SO4. The crude productwas purified by flash chromatography on silica gel using as eluenta gradient from n-hexane (100%) to n-hexane/EtOAc (1:2), followedby preparative TLC (n-Hexane/EtOAC 2:1). Following the general procedure, starting with primaquinediphosphate (192.2 mg, 0.422, 1.2 equiv), NEt3 (118 lL,0.845 mmol, 2.4 equiv) in 3.5 mL of dry methanol, and then 3,4-dimethoxy-3-cyclobutene-1,2-dione (8b, 50 mg, 0,352 mmol,1.0 equiv) (reaction time: 12 h), compound 5f was obtained as alight yellow solid (102.7 mg, 0.278 mmol, 79% yield). Mp: 139-141 C; IR (KBr, selected peaks): 3272, 2971, 1802, 1696, 1614,1521, 1382 cm1, 1H NMR (300 MHz, CDCl3) d (ppm): 8.52 (dd,J = 4.2, 1.6 Hz, 1H, HAr), 7.92 (dd, J = 8.3, 1.6 Hz, 1H, HAr), 7.31 (dd,J = 8.3, 4.2 Hz, 1H, HAr), 6.71 (br s, 1H, NH), 6.34 (d, J = 2.4 Hz, 1H,HAr), 6.26 (d, J = 2.4 Hz, 1H, HAr), 5.96 (d, J = 8.3 Hz, 1H, NH), 4.30(s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.73-3.56 (m, 1H, CH), 3.49-3.35 (m, 1H, NCH2), 1.84-1.62 (m, 4H, 2CH2), 1.30 (d, J = 6.4 Hz,3H, CH3); 13C NMR (75 MHz, CDCl3) d (ppm): 189.60 (CO),183.01 (CO), 177.69 (Cq), 172.26 (Cq), 159.48 (CqAr), 144.88(CqAr), 144.53 (CHAr), 135.39 (CqAr), 135.03 (CHAr), 130.04 (CqAr),122.07 (CHAr), 97.03 (CHAr), 91.96 (CHAr), 60.52 (OCH3), 55.36(OCH3), 47.71 (CH), 44.87 (CH2), 33.27 (CH2), 27.27 (CH2),20.82 (CH3). MS (ESI) m/z calcd for C20H23N3O4: 369, found 370[M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 1786 - 1792

48
[ 137848-29-4 ]
[ 5222-73-1 ]
C₂₅H₁₇NO₄ [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2016,vol. 358,p. 1801 - 1809

49
[ 313342-22-2 ]
(S)-((1S,2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine [ No CAS ]
[ 5222-73-1 ]
C₄₆H₄₃F₆N₅O₅S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: N-((1S,2S)-2-amino-1,2-diphenylethyl)-3,5-bis(trifluoromethyl)benzenesulfonamide; 3,4-dimethoxy-3-cyclobutene-1,2-dione In methanol at 20℃; for 23h; Stage #2: (S)-((1S,2S,4S,5R)-5-ethylquinuclidin-2-yl)(6-methoxyquinolin-4-yl)methanamine In methanol at 20℃; for 24h;

Reference： [1]Sakai, Takaaki; Hirashima, Shin-ichi; Yamashita, Yoshifumi; Arai, Ryoga; Nakashima, Kosuke; Yoshida, Akihiro; Koseki, Yuji; Miura, Tsuyoshi [Journal of Organic Chemistry, 2017, vol. 82, # 9, p. 4661 - 4667]

50
[ 1329061-17-7 ]
[ 894493-95-9 ]
[ 5222-73-1 ]
C₂₅H₂₉F₉N₄O₄S [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 4661 - 4667

51
[ 328-68-7 ]
[ 5222-73-1 ]
3-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-5-(trifluoromethyl)benzoic acid [ No CAS ]

Reference： [1]Chemistry - A European Journal,2017,vol. 23,p. 8185 - 8195
[2]Journal of the American Chemical Society,2017,vol. 139,p. 15308 - 15311

52
[ 22235-25-2 ]
[ 5222-73-1 ]
C₁₄H₁₀F₃NO₅ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2017,vol. 139,p. 15308 - 15311

53
[ 5222-73-1 ]
[ 34213-86-0 ]
N-[4-(α-D-mannopyranosyloxy)phenyl]amido}squaric acidmethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	In methanol at 20℃; for 16h;	N-[4-(α-D-Mannopyranosyloxy)phenyl]amido}squaric acidmethyl ester (10) To a solution of the aminophenyl mannoside6 [26,27] (200 mg, 737 μmol) in dry methanol (15 mL),squaric acid dimethyl ester (9, 314 mg, 2.21 mmol) was added.The solution was stirred at room temperature for 16 h. Subsequently,the solvent was removed under reduced pressure andthe crude product was purified by flash column chromatography(ethyl acetate/methanol 3:1). The product was isolated as acolorless solid (166 mg, 436 μmol, 59%)

Reference： [1]Beiroth, Femke; Koudelka, Tomas; Overath, Thorsten; Knight, Stefan D.; Tholey, Andreas; Lindhorst, Thisbe K. [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 1890 - 1900]

54
[ 1118-89-4 ]
[ 5222-73-1 ]
(S)-diethyl 2-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)amino)pentanedioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With triethylamine; In methanol; at 20℃; for 24h;	L-Glutamic acid diethyl ester hydrochloride (6, 3.6 g, 15 mmol) was dissolved in MeOH (30 mL) and Et3N (2.1 mL, 15 mmol) was added dropwise. The resulting solution was added dropwise to a mixture of 3,4-dimethoxy-3-cyclobutene-1,2-dione (5, 2.4 g, 16.5 mmol) in MeOH (30 mL) at room temperature. After 24 h, the solvent was removed under vacuum and the product was purified by column chromatography (SiO2, hexane/EtOAc 7:3 to hexane/EtOAc1:1). Product 7 was obtained as a brown oil in 95% yield (4.5 g,14.25 mmol); [alpha]D22+11.6 (c 0.56, CHCl3); 1H NMR (300 MHz, DMSO-d6) delta 9.10 (d, J= 7.6 Hz, 0.5H, NH), 8.88 (d, J= 7.9 Hz, 0.5H, NH), 4.70-4.58 (m, 0.5H, NH-CH), 4.40-3.98 (m, 7.5H, O-CH3, NH-C Hand O=C-O-CH2), 2.48-2.33 (m, 2H, NH-CH-CH2-CH2), 2.25-2.05 (m, 1H, NH-CH-CH2), 2.02-1.85 (m, 1H, NH-CH-C H2), 1.18 (t, J= 7.1 Hz, 6H, O=C-O-CH2-CH3); 13C APT-NMR (75 MHz, DMSO-d6) delta 189.1 and 188.7 (2 s, 1C, O=C-C=C-C=O or O=C-C=C-C=O), 183.1 and 182.8 (2 s, 1C, O=C-C=C-C=O or O=C-C=C-C=O), 177.9 and 177.8 (2 s, 1C, O=C-C=C-C=O or O=C-C=C-C=O), 172.8 and 172.3 (2 s, 1C, O=C-C=C-C=O), 171.9 (s, 1C, O=C-O), 170.6 and 170.3 (2 s, 1C, O=C-O), 61.3 (s, 1C, O=C-O-CH2), 60.3 and 60.1 (2 s, 1C, O-CH3), 60.0 (s,1C, O=C-O-CH2), 55.8 and 55.2 (2 s, 1C, NH-CH), 29.7 (s, 1C,NH-CH-CH2-CH2), 26.8 and 26.5 (s, 1C, NH-CH-CH2), 14.0 (s, 1C, O=C-O-CH2-CH3), 14.0 (s, 1C, O=C-O-CH2-CH3); FTIR (oil, cm-1) nu: 3269, 2983, 1806, 1736, 1653, 1618, 1610, 1500, 1464, 1378, 1345, 1299, 1263, 1201, 1102, 1024; HRMS(ESI+) m/z: [M + Na]+calcd for C14H19NNaO7, 336.1054; found, 336.1094.

Reference： [1]Beilstein Journal of Organic Chemistry,2018,vol. 14,p. 2065 - 2073

55
[ 35132-20-8 ]
[ 5222-73-1 ]
4,4'-(((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-methoxycyclobut-3-ene-1,2-dione) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	In methanol at 20℃;	4.2 Synthesis of 4-6 (General procedure) General procedure: Dimethyl squarate (0.70g, 4.91mmol) was added to a solution of corresponding diamine 1, 2 or 3 (2.33mmol) in MeOH (2mL) in one portion. After 20h of stirring at room temperature the precipitate was filtered, washed with EtOAc (3×10mL) and dried under reduced pressure (10Torr) to afford corresponding compound 4, 5 or 6.
66%	In methanol for 12h;

Reference： [1]Kostenko, Alexey A.; Kucherenko, Alexander S.; Zlotin, Sergei G. [Tetrahedron, 2018, vol. 74, # 36, p. 4769 - 4776]
[2]Kochetkov, Sergei V.; Kucherenko, Alexander S.; Zlotin, Sergei G. [Organic and Biomolecular Chemistry, 2018, vol. 16, # 35, p. 6423 - 6429]

56
[ 29841-69-8 ]
[ 5222-73-1 ]
4,4'-(((1S,2S)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-methoxycyclobut-3-ene-1,2-dione) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In methanol at 20℃;	4.2 Synthesis of 4-6 (General procedure) General procedure: Dimethyl squarate (0.70g, 4.91mmol) was added to a solution of corresponding diamine 1, 2 or 3 (2.33mmol) in MeOH (2mL) in one portion. After 20h of stirring at room temperature the precipitate was filtered, washed with EtOAc (3×10mL) and dried under reduced pressure (10Torr) to afford corresponding compound 4, 5 or 6.
62%	In methanol for 12h;

Reference： [1]Kostenko, Alexey A.; Kucherenko, Alexander S.; Zlotin, Sergei G. [Tetrahedron, 2018, vol. 74, # 36, p. 4769 - 4776]
[2]Kochetkov, Sergei V.; Kucherenko, Alexander S.; Zlotin, Sergei G. [Organic and Biomolecular Chemistry, 2018, vol. 16, # 35, p. 6423 - 6429]

57
[ 885677-91-8 ]
[ 5222-73-1 ]
3,4-bis(((1R,2R)-2-(piperidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2019,vol. 84,p. 4304 - 4311

58
[ 122734-32-1 ]
[ 5222-73-1 ]
tert-butyl (2-((2-methoxy-3,4-dioxocyclobut-1-en-1-yl)(methyl)amino)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	In methanol; at 20℃;	To the solution of 3, 4-Dimethoxy-cyclobut-3-ene-1,2-dione (4.26 g, 3 mmol, 1.0 equiv.) in methanol (30 mL) was added tert-butyl (2- (methylamino) ethyl) carbamate (5.21 g, 3 mmol, 1.0 equiv.) at room temperature. The reaction was stirred overnight, and then was concentrated under vacuum. The residues were purified through silica gel chromatography (PE: EA = 5: 1 to 1: 1) to afford 6.3 g of the title product as pale green. Yield: 80%. MS (ES+) : 229 [M + 1 -56] +.

Reference： [1]Patent: WO2019/120296,2019,A1 .Location in patent: Page/Page column 59; 60

59
[ 3470-53-9 ]
[ 5222-73-1 ]
C₁₅H₁₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In ethanol at 20℃;	4.2.10. General procedure for the synthesis of the target compound 6 General procedure: To a solution of 3,4-dimethoxy-3-cyclobutene-1,2-dione 16(1.0 mmol, 1.0 equiv.) in ethanol (10 mL) was added substitutedamine (1.0 mmol, 1.0 equiv.). The reaction mixture was stirred atroom temperature overnight. The precipitate was filtered, washedwith cooled ethanol and dried to afford the intermediate 17. To suspended solution of 17 in ethanol (10 mL) was added the corresponding amine (1.2 mmol, 1.2 equiv.). The reaction mixture wasstirred at room temperature overnight. The precipitate was filtered,wash with cooled ethanol and dried to afford the target compound 6.

Reference： [1]Fu, Lei; Huang, Haihong; Li, Gang; Li, Peng; Lin, Ziyun; Lu, Yu; Wang, Bin; Zhang, Dongfeng [European Journal of Medicinal Chemistry, 2020, vol. 206]

60
[ 771580-86-0 ]
[ 5222-73-1 ]
C₁₂H₉Br₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane at 35℃; for 24h;

Reference： [1]Chhanda, Sadia Afrin; Itsuno, Shinichi [Reactive and functional polymers, 2021, vol. 164]

61
[ 68941-06-0 ]
[ 5222-73-1 ]
C₂₁H₂₇NO₉ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.48 g	In methanol at 20℃; for 24h;	Compound M2. To a degassed solution of 4-nitrobenzo-18-crown-6 ether (1.5 g, 4.20mmol) in 40 mL of a THF/MeOH mixture (1:4) 20 mg of 10% Pd/C was added. The reactionmixture was kept under an H2 atmosphere (balloon pressure) at room temperature overnight.The catalyst was removed by filtration through a pad of Celite and washed withMeOH. The filtrate was concentrated under reduced pressure to give the crude productin near quantitative yield (1.35 g). The obtained 4-aminobenzo-15-crown-5 ether was usedin the next step without further purification. To the solution of 4-aminobenzo-18-crown-6ether (1.35 g 4.12 mmol) in methanol (20 mL), 3,4-dimethoxy-3-cyclobutene-1,2-dione (0.59g, 4.15 mmol) was added. The reaction mixture was stirred at room temperature overnight.The resulting precipitate was isolated by filtration and the obtained solid materialwas washed several times with methanol. The obtained white solid was dried in vacuo togive the desired product (1.48 g, 3.38 mmol, 82% yield).HRMS (ESI): calcd for C21H27NO9Na [M + Na]+: 460.1584, found: 460.1591. 1H NMR(300 MHz, DMSO-d6) δ 10.64 (s, 1H), 7.15-6.95 (m, 1H), 6.94-6.86 (m, 1H), 6.84-6.74 (m,1H) 4.37 (s, 3H), 4.07-3.99 (m, 4H), 3.83-3.72 (m, 4H), 3.65-3.58 (m, 8H). 13C NMR (75 MHz, DMSO-d6) δ 188.7, 183.8, 178.5, 169.1, 148.8, 145.5, 131.9, 113.9, 112.1, 106.3, 70.4, 70.3, 70.3,69.2, 69.1, 68.9, 68.5.

Reference： [1]Jagleniec, Damian; Romański, Jan; Wilczek, Marcin [Molecules, 2021, vol. 26, # 9]

62
[ 611-34-7 ]
[ 5222-73-1 ]
3-methoxy-4-(quinolin-5-ylamino)cyclobut-3-ene-1,2-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In methanol at 20℃; for 72h;	4.9.29. 3-Methoxy-4-(quinolin-5-ylamino)cyclobut-3-ene-1,2-dione (5b) 3,4-Dimethoxycyclobut-3-ene-1,2-dione (296 mg, 2.08 mmol, 1eq) was dissolved in MeOH (14 mL) and 5-aminoquinoline (300 mg,2.08 mmol, 1 eq) was added. The mixture was stirred at roomtemperature for 3 d. The mixture was cooled to 0 C and filteredthrough paper filter. The residue was washed with cooled MeOH(0 C, 10 mL) and the solvent was removed in vacuo. The obtainedsolid was dried at 75 C at atmospheric pressure to provide 5b as ared solid, 404 mg, 1.59 mmol, 76%, C14H10N2O3 (254.25 g/mol). TLC(Silica): Rf 0.51 (CH2Cl2 8% MeOH). mp: 150 C (dec.). Exactmass (APCI): m/z calcd. for C14H11N2O3 [M H] 255.0764, found255.0774. Purity (HPLC, method D): 89%, Rt 8.9 min 1H NMR(600 MHz, DMSO-d6): d 11.07 (s, 1H, NH), 8.94 (dd, J 4.1, 1.6 Hz,1H, 2-CHquinolinyl), 8.54 (ddd, J 8.6, 1.7, 0.9 Hz, 1H, 4-CHquinolinyl),7.91 (dt, J 8.3,1.0 Hz, 1H, 8-CHquinolinyl), 7.76 (dd, J 8.5, 7.5 Hz, 1H,7-CHquinolinyl), 7.60 (dd, J 8.6, 4.1 Hz, 1H, 3-CHquinolinyl), 7.43 (dd,J 7.5, 1.1 Hz, 1H, 6-CHquinolinyl), 4.31 (s, 3H, CH3), 3.17 (s, CH3,methanol). 13C NMR (101 MHz, DMSO-d6): d 188.4 (1C, C-1cyclobutenyl),184.8 (1C, C-2cyclobutenyl), 178.9 (1C, C-3cyclobutenyl), 170.8 (1C,C-4cyclobutenyl), 150.9 (1C, C-2quinolinyl), 147.9 (1C, C-8aquinolinyl), 133.1(1C, C-5quinolinyl), 131.6 (1C, C-4quinolinyl), 129.0 (1C, C-7quinolinyl),126.8 (1C, C-8quinolinyl), 122.5 (1C, C-4aquinolinyl), 121.4 (1C, C-3quinolinyl),121.0 (1C, C-6quinolinyl), 60.4 (1C, CH3), 48.6 (CH3, methanol).FTIR (neat): (cm1) 2978 (NeH), 2345, 2326, 2307 (CeH), 1798,1712 (C]O), 1627, 1608, 1589, 1558 (C-Carom).

Reference： [1]Patberg, Marius; Isaak, Andreas; Füsser, Friederike; Ortiz Zacarías, Natalia V.; Vinnenberg, Laura; Schulte, Janine; Michetti, Lucia; Grey, Lucie; van der Horst, Cas; Hundehege, Petra; Koch, Oliver; Heitman, Laura H.; Budde, Thomas; Junker, Anna [European Journal of Medicinal Chemistry, 2021, vol. 226]

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P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
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P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

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