[ CAS No. 61-68-7 ] {[proInfo.proName]}

Name: 61-68-7|2-((2,3-Dimethylphenyl)amino)benzoic acid|95%
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Quality Control of [ 61-68-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 61-68-7 ]

Product Details of [ 61-68-7 ]

CAS No. :	61-68-7	MDL No. :	MFCD00051721
Formula :	C₁₅H₁₅NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	HYYBABOKPJLUIN-UHFFFAOYSA-N
M.W :	241.29	Pubchem ID :	4044
Synonyms :	C.I. 473;CN-35355;Apo Mefenamic;Antigen Brand of Mefenamic Acid;Acid, Mefenaminic;Acid, Mefenamic;Mefacit;Clonmel Brand of Mefenamic Acid;Coslan;Parkemed;Ponstel;NSC 94437;CI 473	Chemical Name :	2-((2,3-Dimethylphenyl)amino)benzoic acid

Calculated chemistry of [ 61-68-7 ]

Physicochemical Properties

Num. heavy atoms :	18
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.13
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	72.88
TPSA :	49.33 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	Yes
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.14 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.34
Log Po/w (XLOGP3) :	5.12
Log Po/w (WLOGP) :	3.75
Log Po/w (MLOGP) :	2.22
Log Po/w (SILICOS-IT) :	3.1
Consensus Log Po/w :	3.3

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.85

Water Solubility

Log S (ESOL) :	-4.86
Solubility :	0.00335 mg/ml ; 0.0000139 mol/l
Class :	Moderately soluble
Log S (Ali) :	-5.9
Solubility :	0.000304 mg/ml ; 0.00000126 mol/l
Class :	Moderately soluble
Log S (SILICOS-IT) :	-5.12
Solubility :	0.00183 mg/ml ; 0.00000757 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	2.01

Safety of [ 61-68-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 61-68-7 ]

* 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 [ 61-68-7 ]
Downstream synthetic route of [ 61-68-7 ]

[ 61-68-7 ] Synthesis Path-Upstream 1~15

1
[ 87-59-2 ]
[ 118-91-2 ]
[ 61-68-7 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	Stage #1: With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 0.5 h; Stage #2: With manganese(II) acetate In water; N,N-dimethyl-formamide; toluene at 120 - 130℃;	In a 250 mL four-necked flask, 10 g of DMF was charged and heated to 80 ° C., Into 27 g of o-chlorobenzoic acid, Until o-chlorobenzoate is completely dissolved, 25g of sodium carbonate is added for salt formation and incubated at 80 ° C for half an hour. Then water trap, add 25g of toluene for water division, until no water out. After 0.5 g of catalyst manganese acetate and 22.5 g of 2,3-dimethylaniline were put, the temperature was maintained at 120 to 130 ° C. Sample HPLC control, when o-chlorobenzoic acid Suction filtration, drying, About 39.5 g of an off-white solid was obtained, Moore yield 94.8percent NMR data and reaction are as follows.

Reference： [1] Patent: CN105949075, 2016, A, . Location in patent: Page/Page column 0029; 0030; 0032; 0034
[2] Bulletin de la Societe Chimique de France, 1982, vol. 2, # 5-6, p. 139 - 143
[3] Tetrahedron Letters, 1997, vol. 38, # 29, p. 5107 - 5110
[4] Synthetic Communications, 2013, vol. 43, # 9, p. 1270 - 1279
[5] Synthetic Communications, 1989, vol. 19, # 11-12, p. 2077 - 2080
[6] Patent: CN106380414, 2017, A, . Location in patent: Paragraph 0054; 0055; 0056

2
[ 13481-67-9 ]
[ 61-68-7 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 1, p. 314 - 317
[2] Chemical Communications, 2011, vol. 47, # 45, p. 12358 - 12360

3
[ 1488-42-2 ]
[ 87-59-2 ]
[ 61-68-7 ]

Reference： [1] Journal of the American Chemical Society, 2003, vol. 125, # 14, p. 4087 - 4096
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 11, p. 2093 - 2103
[3] Journal of Organic Chemistry, 1980, vol. 45, # 11, p. 2127 - 2131

4
[ 88-67-5 ]
[ 87-59-2 ]
[ 61-68-7 ]

Reference： [1] Journal of Chemical Research, 2006, # 5, p. 342 - 344

5
[ 16497-87-3 ]
[ 87-59-2 ]
[ 61-68-7 ]

Reference： [1] Arzneimittel-Forschung/Drug Research, 1983, vol. 33, # 4 A, p. 621 - 627
[2] Journal of Inorganic Biochemistry, 2011, vol. 105, # 2, p. 195 - 201

6
[ 87-59-2 ]
[ 61-68-7 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 1, p. 314 - 317

7
[ 55591-34-9 ]
[ 61-68-7 ]

Reference： [1] Organic Letters, 2014, vol. 16, # 1, p. 314 - 317

8
[ 88-67-5 ]
[ 61-68-7 ]

Reference： [1] Journal of Organic Chemistry, 1980, vol. 45, # 11, p. 2127 - 2131

9
[ 873-32-5 ]
[ 87-59-2 ]
[ 61-68-7 ]

Reference： [1] Chemical Communications, 2011, vol. 47, # 45, p. 12358 - 12360

10
[ 1804-54-2 ]
[ 61-68-7 ]

Reference： [1] Archiv der Pharmazie, 1991, vol. 324, # 11, p. 887 - 890

11
[ 137488-33-6 ]
[ 61-68-7 ]

Reference： [1] Archiv der Pharmazie, 1991, vol. 324, # 11, p. 887 - 890

12
[ 137488-43-8 ]
[ 61-68-7 ]

Reference： [1] Archiv der Pharmazie, 1991, vol. 324, # 11, p. 887 - 890

13
[ 137488-42-7 ]
[ 61-68-7 ]

Reference： [1] Archiv der Pharmazie, 1991, vol. 324, # 11, p. 887 - 890

14
[ 137488-44-9 ]
[ 61-68-7 ]

Reference： [1] Archiv der Pharmazie, 1991, vol. 324, # 11, p. 887 - 890

15
[ 137488-45-0 ]
[ 61-68-7 ]

Reference： [1] Archiv der Pharmazie, 1991, vol. 324, # 11, p. 887 - 890

[ 61-68-7 ] Synthesis Path-Downstream 1~84

1
[ 67-56-1 ]
[ 61-68-7 ]
[ 1222-42-0 ]

Yield	Reaction Conditions	Operation in experiment
82%	With sulfuric acid; In methanol;Reflux;	A solution of the appropriate mefenamic acid (10 mmol), absolute methanol (10 ml) and concentrated sulfuric acid (1 ml) was heated under reflux for the appropriate time 35-42 h. The solvent was evaporated under reduced pressure, the remaining contents cooled to room temperature and neutralized with a concentrated solution of sodium carbonate, and then the aqueous solution extracted with ether. The combined ether extracts were dried, and the solvent is removed under reduced pressure to yield the corresponding ester. Yield, 82 %; mp 176-180 C; IR(KBr) numax 3,260 (-OH), 1,692 (C=O) 1,589 (C=C) cm-1; 1H NMR (DMSO-d6, 400 MHz,): d = 8.89 (s, 1H, NH), 6.89-7.44 (m, 7H, Ar-H), 3.86 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.19 (s, 3H, CH3); 13C NMR (DMSO-d6, 100 MHz,): d = 169.7 (C=O), 148.3 (C1-Ar2), 148.2 (C2-Ar1), 139.9 (C3-Ar2), 134.7 (C4-Ar1), 133.8 (C6-Ar1), 127.5 (C2-Ar2), 124.8 (C5-Ar2), 124.4 (C4-Ar2), 121.7 (C5-Ar1), 121.2 (C3-Ar1), 120.1 (C1-Ar1), 119.5 (C6-Ar2), 54.8 (-OCH3), 18.5 (-3-CH3), 15.7(-2-CH3); LCMS m/z [M]+ 255.1; Anal. Calcd. for C16H17NO2 (255.31): C,75.27; H, 6.71; N, 5.49. Found: C, 75.36; H, 6.61; N, 5.44.

Reference： [1]Medicinal Chemistry Research,2015,vol. 24,p. 2580 - 2590
[2]Journal of the Brazilian Chemical Society,2010,vol. 21,p. 98 - 104
[3]Farmaco, Edizione Scientifica,1975,vol. 30,p. 276 - 286
[4]Molecules,2011,vol. 16,p. 3544 - 3551

2
[ 61-68-7 ]
[ 24332-20-5 ]
[ 137488-44-9 ]

Reference： [1]Archiv der Pharmazie,1991,vol. 324,p. 821 - 825

3
[ 1488-42-2 ]
[ 87-59-2 ]
[ 61-68-7 ]

Reference： [1]Journal of the American Chemical Society,2003,vol. 125,p. 4087 - 4096
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 2093 - 2103
[3]Journal of Organic Chemistry,1980,vol. 45,p. 2127 - 2131

4
[ 87-59-2 ]
[ 118-91-2 ]
[ 61-68-7 ]

Yield	Reaction Conditions	Operation in experiment
94.8%		In a 250 mL four-necked flask, 10 g of DMF was charged and heated to 80 C., Into 27 g of o-chlorobenzoic acid, Until o-chlorobenzoate is completely dissolved, 25g of sodium carbonate is added for salt formation and incubated at 80 C for half an hour. Then water trap, add 25g of toluene for water division, until no water out. After 0.5 g of catalyst manganese acetate and 22.5 g of 2,3-dimethylaniline were put, the temperature was maintained at 120 to 130 C. Sample HPLC control, when o-chlorobenzoic acid Suction filtration, drying, About 39.5 g of an off-white solid was obtained, Moore yield 94.8% NMR data and reaction are as follows.
91.3%		(1) To a reactor equipped with a rectification column with a sita ring as a packing, 57g of N, N-dimethylformamide, 150g of o-chlorobenzoic acid, and 105g of sodium carbonate were sequentially added. After stirring for 10 minutes, heating and temperature increase were started, and when the internal temperature rose to 80 C, the reaction was maintained for 1 hour.(2) Then, 230g of toluene (toluene recovery) is added and heated to reflux, the height of the packing in the packing tower is 20cm, the inner diameter of the packing is 3cm, and the heat preservation thickness is 0.5cm. Continue heating. When the internal temperature reaches 112 , start draining and keep the internal temperature at 100-120 . When the displacement is 9ml, toluene is charged with water for 1 hour, 120g of 2,3-dimethylaniline is added and 1.1g of copper powder is added at an internal temperature of 104 C, without heating. After about 20 minutes, the reaction is intense and the liquid level Increase, wait for the reaction to slow down, then continue to heat up, control the internal temperature at 110-123 , continue to react for 4-5 hours, sampling and testing prove that the reaction is complete.(3) Continue to add 194g of toluene (toluene recovery), acidify the product to pH 3-5 with dilute hydrochloric acid solution, and then start to add water and wash, the temperature of each wash should be controlled above 65 , after washing three times, start cooling and freezing. Filtration starts when the internal temperature is 5 C. After filtration, 245 g of wet products are obtained. Finally, the wet products are placed in a drying oven to dry, and finally 210 g of dry products are obtained with a yield of 91.3%.
	With sodium acetate; copper 8-hydroxyquinolinate; sodium phenylsulfonate; sodium hydrogencarbonate; at 104 - 110℃; for 3h;pH 6.5 - 7.5;Large scale;	, open the condensation reaction tank condenser cooling valve, the tank by adding 2,3_ dimethylaniline 130 kg, strong acid cationSub-exchange resin 15 kg, adding o-chlorobenzoic acid 100 kg, 50 kg of sodium bicarbonate, copper catalyst 10 kg, sodium acetate 10kg,Sodium benzenesulfonate 1 kg,Cover the lid,When the temperature to 104 C when the start time,Press the 10 kg / 10 min drop solutionAlkali evenly dropping for half an hour,And then by 5 kg / 10 minutes dropping 1 hour,The control reaction pH was 6.5-7.5, The reaction temperature 104-Ll C for a total of 1.5 hours;

Reference： [1]Patent: CN105949075,2016,A .Location in patent: Page/Page column 0029; 0030; 0032; 0034
[2]Patent: CN107602400,2020,B .Location in patent: Paragraph 0021-0028
[3]Bulletin de la Societe Chimique de France,1982,vol. 2,p. 139 - 143
[4]Tetrahedron Letters,1997,vol. 38,p. 5107 - 5110
[5]Synthetic Communications,2013,vol. 43,p. 1270 - 1279
[6]Synthetic Communications,1989,vol. 19,p. 2077 - 2080
[7]Patent: CN106380414,2017,A .Location in patent: Paragraph 0054; 0055; 0056

5
[ 61-68-7 ]
[ 64-19-7 ]
N-(2-(diethylamino)ethyl)-2-[(2,3-dimethylphenyl)amino]benzamide acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.5%		Preparation of N-diethylaminoethyl 2-[(2,3-dimethylphenyl)amino] benzoamide.AcOH.; <n="16"/>[33] 24.1 g (0.1 mol) of <strong>[61-68-7]2-[(2,3-dimethylphenyl)amino]benzoic acid</strong> was dissolved in100 ml of acetonitrile. 32.1 g of O-(Benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate and 30 ml of triethylamine were added into the reaction mixture. 11.6 g of dimethylaminoethylamine was added into the reaction mixture. The mixture was stirred for 3 hours at RT. The solvents were evaporated off. 250 ml of ethyl acetate was added into the reaction mixture and the mixture was washed with water (3 x 100 ml). The organic solution was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration. 6 g of acetic acid was added into the reaction mixture with stirring. Hexane (200 ml) was added. The solid product was collected by filtration. After drying, it yielded 37 g of the desired product (92.5%). Hygroscopic product; Solubility in water: 400 mg/ml; Elementary analysis: C H N O ; MW: 399.53. Calculated % C: 69.14; H: 8.33; N: 10.52; O: 12.01; Found % C: 69.11; H: 8.35; N: 10.51; O: 12.03. 1H-NMR (400 MHz, D2O): delta: 1.41 (t, 6H), 2.10 (s, 3H), 2.30 (s, 3H), 2.31 (s, 3H), 3.22 (m, 4H), 3.54 (m, 2H), 3.60 (m, 2H), 6.15 (m, IH), 6.30 (m, IH), 6.57 (m, IH), 6.72 (m, IH), 7.20 (m, 2H), 7.70 (m, IH), 7.80 (b, IH).

Reference： [1]Patent: WO2008/29199,2008,A1 .Location in patent: Page/Page column 13-14

6
[ 2629-72-3 ]
[ 61-68-7 ]
[ 106724-32-7 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; triethylamine In tetrahydrofuran; water; benzene	S.2 Synthetic Example 2 Synthetic Example 2 A 2.41 g amount of N-(2,3-xylyl)anthranilic acid and 3.6 g of thionyl chloride were mixed in 20 ml of benzene and the mixture was reacted under reflux for 3 hours. The solvent and the extra thionyl chloride were distilled off. The residue was then charged with 50 ml of tetrahydrofuran and 1.37 g of 3-(4-pyridyl) propanol, followed by a gradual addition of 1.5 g of triethylamine while stirring at room temperature. The mixture was stirred for 30 minutes and was then allowed to react under reflux for one hour. After the reaction, the solvent was distilled off in vacuo and the residue was charged with water. The mixture was then extracted with ether. The oily residue thus obtained was recrystallized from methanol, and as a result, the desired pale yellow 3-(4-pyridyl)propyl-N-(2,3-xylyl) anthranilate having the following physical properties was obtained. m.p.: 56°-57° C. Elemental analysis: C23 H24 O2 N2: Calc (%) C 76.64; H 6.71; N 7.77. Found (%) C 76.51; H 6.43; N 7.58. Mass spectrum parent ion (m/e)=360.

Reference： [1]Current Patent Assignee: SHISEIDO COMPANY LIMITED - US4666929, 1987, A

7
[ 61-68-7 ]
[ 99218-62-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium hydroxide; In ethanol; at 20℃; for 1h;	10 mL of KOH (1 mmol) solution were added dropwise upon stirring to the solution of mefenamic acid (1 mmol) in ethanol (100 mL). The mixture was stirred for 1 h at room temperature. The solvent was removed in a rotary evaporator under reduced pressure. The solid product was recrystallized in chloroform : n-hexane(1 : 1).

Reference： [1]Journal of Molecular Structure,2010,vol. 970,p. 79 - 89
[2]Medicinal Chemistry Research,2013,vol. 22,p. 5120 - 5128
[3]Russian Journal of General Chemistry,2015,vol. 85,p. 1745 - 1751
Zh. Obshch. Khim.,2015,vol. 85,p. 1745 - 1751,7

8
[ 92594-46-2 ]
[ 61-68-7 ]
9a-(3-[(2-[(2,3-dimethylphenyl)amino]phenyl)carbonyl]amino}propyl)-9a-aza-9-deoxo-9-dihydro-9a-homoerythromycin A [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		General procedure: A dry reaction vessel equipped with a stir bar was charged with PS-CDI (1.3 equiv, 1.24 mmol/g). A solution of carboxylic acid (1 equiv) and HOBt (0.7 equiv), in a mixture of CH2Cl2 (2 mL) and DMF (0.15 mL) was added onto the dry resin followed by additional CH2Cl2 (1 mL). The mixture was stirred at room temperature for 5 min, upon which the macrolide amine 1 (40 mg, 0.05 mmol) dissolved in CH2Cl2 (2 mL) was added. The reaction vessel was sealed and heated under microwave irradiation at 70 C for 5 min in a CEM Explorer. After completion of the reaction, PS-trisamine (3 equiv, 4.11 mmol/g) was added and the mixture was stirred for 3 h at room temperature. The product was separated from the resin by filtration and the resin was washed with CH2Cl2 (3 × 1 mL), and the solvent evaporated under reduced pressure to afford the desired amide.

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 1745 - 1748

9
[ 61-68-7 ]
[ 22121-60-4 ]

Reference： [1]Molecules,2011,vol. 16,p. 3544 - 3551
[2]Molecules,2011,vol. 16,p. 3544 - 3551
[3]Medicinal Chemistry Research,2015,vol. 24,p. 2580 - 2590
[4]Research on Chemical Intermediates,2019,vol. 45,p. 2269 - 2286
[5]Egyptian Journal of Chemistry,2020,vol. 63,p. 155 - 169

10
[ 13481-67-9 ]
[ 61-68-7 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 314 - 317
[2]Chemical Communications,2011,vol. 47,p. 12358 - 12360
[3]Journal of the American Chemical Society,2018,vol. 140,p. 15200 - 15205

11
[ 61-68-7 ]
2-((2,3-dimethylphenyl)amino)benzoyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In benzene;Reflux;	General procedure: A solution of NSAIDs having carboxylic acid group (1a-h) (1 mmol) in dry benzene (5-8 mL) was refluxed with freshly distilled thionyl chloride (1.2 mmol) for 2-3 h. After the completion of reaction, excess of thionyl chloride was removed under reduce pressure to afford the acid chlorides (2a-h) which were dissolved in anhydrous acetone for further use. The acid chlorides (2a-h) were then treated with a solution of (+)-6-aminopenicillanic acid (6-APA, 1 mmol) in 2% NaHCO3 (40 mL) diluted with acetone (30 mL). The reaction mixture was stirred for 2-4 h at room temperature and then concentrated under reduced pressure and washed with ethyl acetate (25 mL). The aqueous layer was then acidified with HCl (0.1 M), extracted with ethyl acetate and then washed with distilled water dried over anhydrous Na2SO4. The ethyl acetate was rotary evaporated and triturated with n-hexane to afford the title compounds (4a-h).
	With thionyl chloride; In tetrahydrofuran;Microwave irradiation;	A mixture of aceclofenac (6 mmol, 2.12 g) and thionyl chloride(7 mmol, 3.5 mL) was taken in a reaction vessel mixed thoroughlyin THF and then irradiated in a microwave oven at 420Wfor 90 minafforded 2-chloro-2-oxoethyl 2-(2-((2,6-dichlorophenyl)amino)phenyl)acetate, 2. Similarly a mixture of mefenamic acid (6 mmol,1.45 g) and thionyl chloride (7 mmol, 3.14 mL) was taken in a reactionvessel mixed thoroughly in THF and then irradiated in amicrowave oven at 340W for 45 min afforded 2-((2,3-dimethylphenyl)amino)benzoyl chloride, 6. Completion of the reactionwas determined by the stoppage of SO2 gas. Removal ofexcess of thionyl chloride was carried out by distillation underreduced pressure. Further a base trap was connected in order toneutralize the excess vapour evolved. To the compounds 2 and 6(in-situ) 2-(benzo [d] oxazol-2-yl)aniline 3 (6 mmol, 1.26 g) andamberlite-IRA-402 (OH) ion exchange resin (20 mg) was added andsubjected to microwave oven at a power of 340W for 2 h. Thecompletion of the reaction was monitored by thin layer chromatography(TLC) using Petroleum ether: EtOAc (3:1). After completion,the catalyst was filtered off and the mixture was diluted withEtOAc, washed with water followed by brine and dried overanhydrous Na2SO4. The solvent was removed under vacuum andthe resulting solid was filtered, dried and purified using columnchromatography to afford compounds 4 and 7.

Reference： [1]Asian Journal of Chemistry,2012,vol. 24,p. 1237 - 1241
[2]RSC Advances,2014,vol. 4,p. 53842 - 53853
[3]PLoS ONE,2015,vol. 10
[4]Journal of Molecular Structure,2020,vol. 1200
[5]ChemMedChem,2020,vol. 15,p. 1187 - 1199

12
[ 61-68-7 ]
[ 633-03-4 ]
Brilliant Green mefenamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	for 2h;	An ion-pair of Brilliant Green mefenamate (Fig. 1) was prepared by mixing equal quantities of 1 × 10-2 mol/L mefenamic acid and 1 × 10-2 mol/L of basic dye BG. The solution was settled for 2 h and the ion-pair sediment was filtered (quantitative rapid filter paper). This residue was treated with 50 mL of cold distilled water. The precipitate was dried for 24 h at room temperature. This ion-pair was used as an electrode active substance for preparing the mefenamate-sensitive sensor.

Reference： [1]Kormosh, Zholt; Matviychuk, Oksana [Chinese Chemical Letters, 2013, vol. 24, # 4, p. 315 - 317]

13
[ 95-14-7 ]
[ 61-68-7 ]
[ 1567789-54-1 ]

Yield	Reaction Conditions	Operation in experiment
78%		General procedure: SOCl2 (2.64 mmol) was added to a solution of 1H-benzotriazole (8;1.03 g, 8.7 mmol) in anhydrous CH2Cl2 (60 mL) at r.t. and the reaction mixture was stirred for 20 min. Ibuprofen (1 + 1?; 453 mg, 2.2 mmol), mefenamic acid (2; 530 mg, 2.2 mmol), naproxen (4; 506 mg, 2.2 mmol), or indomethacin (5; 787 mg, 2.2 mmol) was added and the mixture was stirred for 3 h at r.t. The white precipitate formed was filtered off and the filtrate was concentrated under reduced pressure. Each residue was diluted with EtOAc (50 mL) and each solution was washed with aq 4 M HCl (3 × 15 mL) and dried (MgSO4). Removal of the solvent under reduced pressure gave the desired products 9a + 9a?, 9b, 9d, and 9e. For the preparation of compound 9c, diclofenac (3; 651 mg, 2.2 mmol) was treated with 1H-benzotriazole (8; 1.03 g, 8.7 mmol) in the presence of DCC (453 mmol, 2.2 mmol) in anhydrous CH2Cl2 (60 mL) at r.t. and the reaction mixture was stirred for 3 h. The white precipitate formed was filtered off through Celite and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (50 mL) andthe solution was washed with aq 10% Na2CO3 (3 × 15 mL) and dried (MgSO4). Removal of the solvent under reduced pressure gave the desired product.

Reference： [1]Synthesis,2013,vol. 45,p. 3369 - 3374

14
[ 107-35-7 ]
[ 61-68-7 ]
[ 1191073-68-3 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In pyridine; water; at 4℃; for 7h;	The synthesis of MFA-AMP, MFA-Gly, MFA-NAC, and MFA-Tau wascarried out with a solution consisting of 110 mg N,N9-dicyclohexylcarbodiimidein 0.4 ml pyridine (Ikegawa et al., 1999; Horng and Benet, 2013). Briefly, an N,N9-dicyclohexylcarbodiimide solution was added to a solution containing MFA(0.49 mmol), and either AMP, Gly, Tau, or NAC (0.49 mmol) separately in 75%pyridine/25% water. The reaction mixture was stirred at 4C for 7 hours and thencentrifuged at 3000g for 5 minutes to remove any N-acylurea derivatives. Thesupernatant was transferred to another culture tube for precipitation by theaddition of acetone (10 ml). The resulting precipitate was isolated by centrifugationat 3000g for 5 minutes followed by further washes with acetone (10 10 ml) and acidified water (pH 4-5) (10 10 ml). For MFA-AMP, theprecipitate was dissolved in 0.1 M potassium phosphate buffer (pH 6) andunderwent continued liquid-liquid washes with ethyl acetate (10 10 ml).Following precipitation via 1 M HCl, the MFA-AMP was further washed withacetone (10 10 ml). The MFA-AMP precipitate was -down to dryness usingN2 gas and weighed out for preparation of a 1 mM MFA-AMP solution inDMSO. For MFA-Gly, MFA-NAC, and MFA-Tau, the initial acetone-derivedprecipitate was dissolved in DMSO and subjected to purification via HPLC/UVmassspectrometry. The correct HPLC eluent fractions, as determined byUV-MS, of each acyl-linked metabolite were collected, blown down to dryness,weighed, and then prepared as 1-mM solutions in DMSO. MFA-AMP eluted ata retention time of 7.6 minutes and showed no impurities when analyzed byHPLC/UV (wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reversephasegradient elution (as described above), and 1H-NMR (Horng and Benet,2013). LC-MS/MS analysis of MFA-AMP revealed collision-induced dissociation(CID) of MH+ ion at m/z 571, m/z (%) yielded: m/z 224 ([M + H - AMP]+,100%), m/z 207 ([M + H - 364]+, 25%), and m/z 136 ([M + H - adenine]+, 28%).MFA-Gly eluted at a retention time of 8.7 minutes (Fig. 2C) and showed noimpurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262, and 280nm) and LC-MS via reverse-phase gradient elution (as described above). LC-MS/MS analysis of MFA-Gly (CID of MH+ ion at m/z 299), m/z (%): m/z 224 ([M +H - Gly]+, 99%), m/z 209 ([M + H - 90]+, 20%), m/z 180 ([M + H - 119]+,18%), m/z 152 ([M + H - 147]+, 4%), m/z 127 ([M + H - 172]+, 2%), m/z 77([Gly + H]+, 1%) (Fig. 2, A and B). MFA-Tau eluted at a retention time of 9.1minutes (Fig. 3C) and showed no impurities when analyzed by HPLC/UV(wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reverse-phasegradient elution (as described above). LC-MS/MS analysis of MFA-Tau (CID ofMH+ ion at m/z 349), m/z (%): m/z 332 ([M + H - H2O]+, 10%), m/z 224 ([M +H - Tau]+, 99%), m/z 209 ([M + H - 140]+, 25%), m/z 180 ([M + H - 169]+,16%), m/z 152 ([M + H - 197]+, 4%), and m/z 126 ([Tau + H+]+, 2%) (Fig. 3, Aand B). MFA-NAC eluted at a retention time of 9.3 minutes (Fig. 4C) andshowed no impurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262,and 280 nm) and LC-MS via reverse-phase gradient elution (as described above).LC-MS/MS analysis of MFA-NAC (CID of MH+ ion at m/z 387), m/z (%): m/z309 ([M + H - 78]+, 30%), m/z 224 ([M + H - NAC]+, 99%), m/z 209 ([M + H -178]+, 18%), m/z 180 ([M + H - 207]+, 13%), and m/z 165 ([NAC + H]+, 3%)(Fig. 4, A and B).

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1923 - 1933

15
[ 7218-04-4 ]
[ 61-68-7 ]
C₂₀H₂₂N₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In pyridine; water; at 4℃; for 7h;	The synthesis of MFA-AMP, MFA-Gly, MFA-NAC, and MFA-Tau wascarried out with a solution consisting of 110 mg N,N9-dicyclohexylcarbodiimidein 0.4 ml pyridine (Ikegawa et al., 1999; Horng and Benet, 2013). Briefly, an N,N9-dicyclohexylcarbodiimide solution was added to a solution containing MFA(0.49 mmol), and either AMP, Gly, Tau, or NAC (0.49 mmol) separately in 75%pyridine/25% water. The reaction mixture was stirred at 4C for 7 hours and thencentrifuged at 3000g for 5 minutes to remove any N-acylurea derivatives. Thesupernatant was transferred to another culture tube for precipitation by theaddition of acetone (10 ml). The resulting precipitate was isolated by centrifugationat 3000g for 5 minutes followed by further washes with acetone (10 10 ml) and acidified water (pH 4-5) (10 10 ml). For MFA-AMP, theprecipitate was dissolved in 0.1 M potassium phosphate buffer (pH 6) andunderwent continued liquid-liquid washes with ethyl acetate (10 10 ml).Following precipitation via 1 M HCl, the MFA-AMP was further washed withacetone (10 10 ml). The MFA-AMP precipitate was -down to dryness usingN2 gas and weighed out for preparation of a 1 mM MFA-AMP solution inDMSO. For MFA-Gly, MFA-NAC, and MFA-Tau, the initial acetone-derivedprecipitate was dissolved in DMSO and subjected to purification via HPLC/UVmassspectrometry. The correct HPLC eluent fractions, as determined byUV-MS, of each acyl-linked metabolite were collected, blown down to dryness,weighed, and then prepared as 1-mM solutions in DMSO. MFA-AMP eluted ata retention time of 7.6 minutes and showed no impurities when analyzed byHPLC/UV (wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reversephasegradient elution (as described above), and 1H-NMR (Horng and Benet,2013). LC-MS/MS analysis of MFA-AMP revealed collision-induced dissociation(CID) of MH+ ion at m/z 571, m/z (%) yielded: m/z 224 ([M + H - AMP]+,100%), m/z 207 ([M + H - 364]+, 25%), and m/z 136 ([M + H - adenine]+, 28%).MFA-Gly eluted at a retention time of 8.7 minutes (Fig. 2C) and showed noimpurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262, and 280nm) and LC-MS via reverse-phase gradient elution (as described above). LC-MS/MS analysis of MFA-Gly (CID of MH+ ion at m/z 299), m/z (%): m/z 224 ([M +H - Gly]+, 99%), m/z 209 ([M + H - 90]+, 20%), m/z 180 ([M + H - 119]+,18%), m/z 152 ([M + H - 147]+, 4%), m/z 127 ([M + H - 172]+, 2%), m/z 77([Gly + H]+, 1%) (Fig. 2, A and B). MFA-Tau eluted at a retention time of 9.1minutes (Fig. 3C) and showed no impurities when analyzed by HPLC/UV(wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reverse-phasegradient elution (as described above). LC-MS/MS analysis of MFA-Tau (CID ofMH+ ion at m/z 349), m/z (%): m/z 332 ([M + H - H2O]+, 10%), m/z 224 ([M +H - Tau]+, 99%), m/z 209 ([M + H - 140]+, 25%), m/z 180 ([M + H - 169]+,16%), m/z 152 ([M + H - 197]+, 4%), and m/z 126 ([Tau + H+]+, 2%) (Fig. 3, Aand B). MFA-NAC eluted at a retention time of 9.3 minutes (Fig. 4C) andshowed no impurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262,and 280 nm) and LC-MS via reverse-phase gradient elution (as described above).LC-MS/MS analysis of MFA-NAC (CID of MH+ ion at m/z 387), m/z (%): m/z309 ([M + H - 78]+, 30%), m/z 224 ([M + H - NAC]+, 99%), m/z 209 ([M + H -178]+, 18%), m/z 180 ([M + H - 207]+, 13%), and m/z 165 ([NAC + H]+, 3%)(Fig. 4, A and B).

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1923 - 1933

16
[ 70-18-8 ]
[ 61-68-7 ]
[ 1197207-22-9 ]

Yield	Reaction Conditions	Operation in experiment
		The synthesis of MFA-CoA and MFA-GSH thioesters was accomplished bya method employing ECF as described previously (Stadtman and Elliott, 1957;Grillo and Benet, 2002; Horng and Benet, 2013). Briefly, MFA (1.6 mmol) wasdissolved in anhydrous THF (25 ml). While stirring at room temperature,triethylamine (1.6 mmol) was added to the solution followed by the addition ofECF (1.6 mmol). After 30 minutes, the resulting triethylamine hydrochloridewas removed by passing the reaction mixture through a glass funnel fitted witha glass wool plug. The filtered solution was then added to a solution containingCoA (0.13 mmol, 100 mg) or GSH (1 g) and KHCO3 (1.6 mmol) in nanopurewater (10 ml) and THF (15 ml). The solution was stirred continuously at roomtemperature for 2 hours, after which the reaction was terminated by acidification(pH 4-5) through the addition of 1 M HCl. THF was then removed byevaporation under N2 gas, followed by further solvent washes: acidified water(pH 5) (3 10 ml) and ethyl acetate (3 10 ml) for MFA-CoA or acetone (3 10 ml) for MFA-GSH. MFA-CoA and MFA-GSH precipitate was blown down todryness using N2 gas and then weighed out for preparation of a 1-mM MFA-CoAor 1-mM MFA-GSH solution in DMSO. HPLC analysis of MFA-CoA thioesterresulted in an elution time of 7.3 minutes and showed no impurities whenanalyzed by HPLC/UV (wavelengths: 220, 254, 262, and 280 nm) and LC-MSvia reverse-phase gradient elution (as described above). LC-MS/MS analysis ofMFA-CoA standard yielded (CID of MH+ ion at m/z 991), m/z (%): m/z 582 ([M+ H - adenosine diphosphate - H2O]+, 20%), m/z 484 ([M + H - adenosinetriphosphate]+, 94%), m/z 428 ([adenosine diphosphate + H+]+, 40%), m/z 382([M + H - 609]+, 25%), m/z 330 ([adenosine monophosphate + H - H2O]+, 3%),m/z 224 ([M + H - CoA]+, 99%). Synthetic MFA-GSH eluted at a retention timeof 7.7 minutes and showed no detectable impurities when analyzed by HPLC/UV(wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reverse-phase gradientelution (as described above). LC-MS/MS analysis of MFA-GSH standard yieldedproduct in mass spectrum under CID of the protonated molecular ion at MH+ m/z531, m/z (%): m/z 456 ([M + H - GSH]+, 10%), m/z 384 ([M + H - pyroglutamicacid - water]+, 82%), m/z 224 ([MFA + H - H2O]+, 73%).

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1923 - 1933

17
[ 61-68-7 ]
[ 61-19-8 ]
[ 1425793-56-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In pyridine; water; at 4℃; for 7h;	The synthesis of MFA-AMP, MFA-Gly, MFA-NAC, and MFA-Tau wascarried out with a solution consisting of 110 mg N,N9-dicyclohexylcarbodiimidein 0.4 ml pyridine (Ikegawa et al., 1999; Horng and Benet, 2013). Briefly, an N,N9-dicyclohexylcarbodiimide solution was added to a solution containing MFA(0.49 mmol), and either AMP, Gly, Tau, or NAC (0.49 mmol) separately in 75%pyridine/25% water. The reaction mixture was stirred at 4C for 7 hours and thencentrifuged at 3000g for 5 minutes to remove any N-acylurea derivatives. Thesupernatant was transferred to another culture tube for precipitation by theaddition of acetone (10 ml). The resulting precipitate was isolated by centrifugationat 3000g for 5 minutes followed by further washes with acetone (10 10 ml) and acidified water (pH 4-5) (10 10 ml). For MFA-AMP, theprecipitate was dissolved in 0.1 M potassium phosphate buffer (pH 6) andunderwent continued liquid-liquid washes with ethyl acetate (10 10 ml).Following precipitation via 1 M HCl, the MFA-AMP was further washed withacetone (10 10 ml). The MFA-AMP precipitate was -down to dryness usingN2 gas and weighed out for preparation of a 1 mM MFA-AMP solution inDMSO. For MFA-Gly, MFA-NAC, and MFA-Tau, the initial acetone-derivedprecipitate was dissolved in DMSO and subjected to purification via HPLC/UVmassspectrometry. The correct HPLC eluent fractions, as determined byUV-MS, of each acyl-linked metabolite were collected, blown down to dryness,weighed, and then prepared as 1-mM solutions in DMSO. MFA-AMP eluted ata retention time of 7.6 minutes and showed no impurities when analyzed byHPLC/UV (wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reversephasegradient elution (as described above), and 1H-NMR (Horng and Benet,2013). LC-MS/MS analysis of MFA-AMP revealed collision-induced dissociation(CID) of MH+ ion at m/z 571, m/z (%) yielded: m/z 224 ([M + H - AMP]+,100%), m/z 207 ([M + H - 364]+, 25%), and m/z 136 ([M + H - adenine]+, 28%).MFA-Gly eluted at a retention time of 8.7 minutes (Fig. 2C) and showed noimpurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262, and 280nm) and LC-MS via reverse-phase gradient elution (as described above). LC-MS/MS analysis of MFA-Gly (CID of MH+ ion at m/z 299), m/z (%): m/z 224 ([M +H - Gly]+, 99%), m/z 209 ([M + H - 90]+, 20%), m/z 180 ([M + H - 119]+,18%), m/z 152 ([M + H - 147]+, 4%), m/z 127 ([M + H - 172]+, 2%), m/z 77([Gly + H]+, 1%) (Fig. 2, A and B). MFA-Tau eluted at a retention time of 9.1minutes (Fig. 3C) and showed no impurities when analyzed by HPLC/UV(wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reverse-phasegradient elution (as described above). LC-MS/MS analysis of MFA-Tau (CID ofMH+ ion at m/z 349), m/z (%): m/z 332 ([M + H - H2O]+, 10%), m/z 224 ([M +H - Tau]+, 99%), m/z 209 ([M + H - 140]+, 25%), m/z 180 ([M + H - 169]+,16%), m/z 152 ([M + H - 197]+, 4%), and m/z 126 ([Tau + H+]+, 2%) (Fig. 3, Aand B). MFA-NAC eluted at a retention time of 9.3 minutes (Fig. 4C) andshowed no impurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262,and 280 nm) and LC-MS via reverse-phase gradient elution (as described above).LC-MS/MS analysis of MFA-NAC (CID of MH+ ion at m/z 387), m/z (%): m/z309 ([M + H - 78]+, 30%), m/z 224 ([M + H - NAC]+, 99%), m/z 209 ([M + H -178]+, 18%), m/z 180 ([M + H - 207]+, 13%), and m/z 165 ([NAC + H]+, 3%)(Fig. 4, A and B).

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1923 - 1933

18
[ 61-68-7 ]
[ 85-61-0 ]
[ 1425793-57-2 ]

Yield	Reaction Conditions	Operation in experiment
		The synthesis of MFA-<strong>[85-61-0]CoA</strong> and MFA-GSH thioesters was accomplished bya method employing ECF as described previously (Stadtman and Elliott, 1957;Grillo and Benet, 2002; Horng and Benet, 2013). Briefly, MFA (1.6 mmol) wasdissolved in anhydrous THF (25 ml). While stirring at room temperature,triethylamine (1.6 mmol) was added to the solution followed by the addition ofECF (1.6 mmol). After 30 minutes, the resulting triethylamine hydrochloridewas removed by passing the reaction mixture through a glass funnel fitted witha glass wool plug. The filtered solution was then added to a solution containing<strong>[85-61-0]CoA</strong> (0.13 mmol, 100 mg) or GSH (1 g) and KHCO3 (1.6 mmol) in nanopurewater (10 ml) and THF (15 ml). The solution was stirred continuously at roomtemperature for 2 hours, after which the reaction was terminated by acidification(pH 4-5) through the addition of 1 M HCl. THF was then removed byevaporation under N2 gas, followed by further solvent washes: acidified water(pH 5) (3 10 ml) and ethyl acetate (3 10 ml) for MFA-<strong>[85-61-0]CoA</strong> or acetone (3 10 ml) for MFA-GSH. MFA-<strong>[85-61-0]CoA</strong> and MFA-GSH precipitate was blown down todryness using N2 gas and then weighed out for preparation of a 1-mM MFA-<strong>[85-61-0]CoA</strong>or 1-mM MFA-GSH solution in DMSO. HPLC analysis of MFA-<strong>[85-61-0]CoA</strong> thioesterresulted in an elution time of 7.3 minutes and showed no impurities whenanalyzed by HPLC/UV (wavelengths: 220, 254, 262, and 280 nm) and LC-MSvia reverse-phase gradient elution (as described above). LC-MS/MS analysis ofMFA-<strong>[85-61-0]CoA</strong> standard yielded (CID of MH+ ion at m/z 991), m/z (%): m/z 582 ([M+ H - adenosine diphosphate - H2O]+, 20%), m/z 484 ([M + H - adenosinetriphosphate]+, 94%), m/z 428 ([adenosine diphosphate + H+]+, 40%), m/z 382([M + H - 609]+, 25%), m/z 330 ([adenosine monophosphate + H - H2O]+, 3%),m/z 224 ([M + H - <strong>[85-61-0]CoA</strong>]+, 99%). Synthetic MFA-GSH eluted at a retention timeof 7.7 minutes and showed no detectable impurities when analyzed by HPLC/UV(wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reverse-phase gradientelution (as described above). LC-MS/MS analysis of MFA-GSH standard yieldedproduct in mass spectrum under CID of the protonated molecular ion at MH+ m/z531, m/z (%): m/z 456 ([M + H - GSH]+, 10%), m/z 384 ([M + H - pyroglutamicacid - water]+, 82%), m/z 224 ([MFA + H - H2O]+, 73%).

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1923 - 1933

19
[ 61-68-7 ]
[ 56-40-6 ]
[ 1346110-39-1 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl-carbodiimide; In pyridine; water; at 4℃; for 7h;	The synthesis of MFA-AMP, MFA-Gly, MFA-NAC, and MFA-Tau wascarried out with a solution consisting of 110 mg N,N9-dicyclohexylcarbodiimidein 0.4 ml pyridine (Ikegawa et al., 1999; Horng and Benet, 2013). Briefly, an N,N9-dicyclohexylcarbodiimide solution was added to a solution containing MFA(0.49 mmol), and either AMP, Gly, Tau, or NAC (0.49 mmol) separately in 75%pyridine/25% water. The reaction mixture was stirred at 4C for 7 hours and thencentrifuged at 3000g for 5 minutes to remove any N-acylurea derivatives. Thesupernatant was transferred to another culture tube for precipitation by theaddition of acetone (10 ml). The resulting precipitate was isolated by centrifugationat 3000g for 5 minutes followed by further washes with acetone (10 10 ml) and acidified water (pH 4-5) (10 10 ml). For MFA-AMP, theprecipitate was dissolved in 0.1 M potassium phosphate buffer (pH 6) andunderwent continued liquid-liquid washes with ethyl acetate (10 10 ml).Following precipitation via 1 M HCl, the MFA-AMP was further washed withacetone (10 10 ml). The MFA-AMP precipitate was -down to dryness usingN2 gas and weighed out for preparation of a 1 mM MFA-AMP solution inDMSO. For MFA-Gly, MFA-NAC, and MFA-Tau, the initial acetone-derivedprecipitate was dissolved in DMSO and subjected to purification via HPLC/UVmassspectrometry. The correct HPLC eluent fractions, as determined byUV-MS, of each acyl-linked metabolite were collected, blown down to dryness,weighed, and then prepared as 1-mM solutions in DMSO. MFA-AMP eluted ata retention time of 7.6 minutes and showed no impurities when analyzed byHPLC/UV (wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reversephasegradient elution (as described above), and 1H-NMR (Horng and Benet,2013). LC-MS/MS analysis of MFA-AMP revealed collision-induced dissociation(CID) of MH+ ion at m/z 571, m/z (%) yielded: m/z 224 ([M + H - AMP]+,100%), m/z 207 ([M + H - 364]+, 25%), and m/z 136 ([M + H - adenine]+, 28%).MFA-Gly eluted at a retention time of 8.7 minutes (Fig. 2C) and showed noimpurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262, and 280nm) and LC-MS via reverse-phase gradient elution (as described above). LC-MS/MS analysis of MFA-Gly (CID of MH+ ion at m/z 299), m/z (%): m/z 224 ([M +H - Gly]+, 99%), m/z 209 ([M + H - 90]+, 20%), m/z 180 ([M + H - 119]+,18%), m/z 152 ([M + H - 147]+, 4%), m/z 127 ([M + H - 172]+, 2%), m/z 77([Gly + H]+, 1%) (Fig. 2, A and B). MFA-Tau eluted at a retention time of 9.1minutes (Fig. 3C) and showed no impurities when analyzed by HPLC/UV(wavelengths: 220, 254, 262, and 280 nm) and LC-MS via reverse-phasegradient elution (as described above). LC-MS/MS analysis of MFA-Tau (CID ofMH+ ion at m/z 349), m/z (%): m/z 332 ([M + H - H2O]+, 10%), m/z 224 ([M +H - Tau]+, 99%), m/z 209 ([M + H - 140]+, 25%), m/z 180 ([M + H - 169]+,16%), m/z 152 ([M + H - 197]+, 4%), and m/z 126 ([Tau + H+]+, 2%) (Fig. 3, Aand B). MFA-NAC eluted at a retention time of 9.3 minutes (Fig. 4C) andshowed no impurities when analyzed by HPLC/UV (wavelengths: 220, 254, 262,and 280 nm) and LC-MS via reverse-phase gradient elution (as described above).LC-MS/MS analysis of MFA-NAC (CID of MH+ ion at m/z 387), m/z (%): m/z309 ([M + H - 78]+, 30%), m/z 224 ([M + H - NAC]+, 99%), m/z 209 ([M + H -178]+, 18%), m/z 180 ([M + H - 207]+, 13%), and m/z 165 ([NAC + H]+, 3%)(Fig. 4, A and B).

Reference： [1]Drug Metabolism and Disposition,2013,vol. 41,p. 1923 - 1933

20
[ 366-18-7 ]
[ 61-68-7 ]
[ 7646-85-7 ]
C₄₀H₃₆N₄O₄Zn [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%		A methanolic solution (10 mL) of mefenamic acid (0.4 mmol, 97 mg) and KOH (0.4 mmol, 22 mg) after 1 h stirring was added dropwise slowly and simultaneously with a methanolic solution (10 mL) of bipy (0.2 mmol, 31 mg) to a methanolic solution (10 mL) of ZnCl2 (0.2 mmol, 27 mg). The resultant solution was left for slow evaporation. Colorless crystals of [Zn(mef)2(bipy)], 2 (100 mg, 71 %) suitable for X-ray structure determination, were collected after a few days (found C, 68.15; H, 5.25; N, 8.24; C40H36N4O4Zn (MW=702.10) requires C, 68.43; H, 5.17; N, 7.98%). IR: numax/cm-1; nuasym(CO2): 1581 (vs); nusym(CO2): 1393 (vs); Delta=188cm-1 (KBr disk); UV-vis: lambda/nm (epsilon/M-1cm-1) as nujol mull: 353, 286; in dmso: 351 (10,400), 284 (20,500). 1H NMR in dmso-d6 (delta/ppm): 2.03 (6H, s, H11-mef), 2.21 (6H, s, H10-mef), 6.60 (2H, m(J=7.5Hz), H3-mef), 6.75 (2H, d(J=8.0Hz), H5-mef), 6.88 (2H, m(J=7.2Hz), H9-mef), 7.03 (2H, m(J=7.6Hz), H8-mef), 7.08 (2H, d(J=8.2Hz), H7-mef), 7.16 (2H, m(J=7.7Hz), H4-mef), 7.65 (2H, m(J=6.5Hz), H4- and H4?-bipy), 7.92 (2H, d (J=7.8Hz), H2-mef), 8.15 (2H, d(J=6.5Hz), H6- and H6?-bipy), 8.56 (2H, d(J=7.3Hz), H5- and H5?-bipy), 8.82 (2H, d(J=3.1Hz), H3- and H3?-bipy), 10.11 (2H, s, H6-mef). The complex is soluble in dmso (LambdaM=12mhocm2mol-1, 1 mM in dmso).

Reference： [1]Journal of Inorganic Biochemistry,2013,vol. 128,p. 85 - 96

21
[ 1202-34-2 ]
[ 61-68-7 ]
[ 7646-85-7 ]
C₄₀H₃₈N₅O₄Zn [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		General procedure: A methanolic solution (10 mL) of mefenamic acid (0.4 mmol, 97 mg) and KOH (0.4 mmol, 22 mg) after 1 h stirring was added dropwise slowly and simultaneously with a methanolic solution (10 mL) of bipy (0.2 mmol, 31 mg) to a methanolic solution (10 mL) of ZnCl2 (0.2 mmol, 27 mg). The resultant solution was left for slow evaporation. Colorless crystals of [Zn(mef)2(bipy)], 2 (100 mg, 71 %) suitable for X-ray structure determination, were collected after a few days

Reference： [1]Journal of Inorganic Biochemistry,2013,vol. 128,p. 85 - 96

22
[ 61-68-7 ]
[ 458-37-7 ]
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-((2,3-dimethylphenyl)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	General procedure: A solution of Curcumin (1.2mmol), NSAID (1.0 mmol), EDCI (1.0 mmol) and DMAP (0.1mmol) in CH2Cl2 (30 mL), the mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with satd. aqueous NaHCO3, extracted with CH2Cl2 (3 x 30 mL), dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3044 - 3051

23
[ 61-68-7 ]
[ 458-37-7 ]
((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2-methoxy-4,1-phenylene) bis(2-((2,3-dimethylphenyl)amino)benzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 1h;	General procedure: Curcumin (1.2 mmol), NSAID (2.0 mmol), EDCI (1.0 mmol) and DMAP (0.1 mmol) were dissolved in CH2Cl2 (30 mL), and the mixture was stirred for 1 h at room temperature. The reaction mixture was quenched with satd. aqueous NaHCO3, extracted with CH2Cl2 (3 x 30 mL), dried over Na2SO4, concentrated under reduced pressure and purified by silica gel chromatography. All crude products were recrystallized in petroleumether/diethyl ether (v/v 1:1) to give the pure products.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3044 - 3051

24
[ 14871-92-2 ]
[ 61-68-7 ]
Pd(mefenamic acid)<SUB>2</SUB>(2,2'-bipyridine) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63%		Mefenamic acid (0.40 mmol) was dissolved in methanol (15 mL) followed by the addition of KOH (0.40 mmol). After 60 min of stirring, the resulting solution was slowly added to an aqueous solution of [PdCl2(bipy)] (0.20 mmol). After 40 min of constant stirring, the yellow solid obtained was collected by filtration, washed with ethanol and dried in a desiccator with P4O10. The yield was 63%. Anal. Calc. for [Pd(C15H14NO2)2(bipy)] (%): C 64.6; H 4.88;N 7.54. Found: C 63.3; H 4.74; N 7.62. The complex is soluble inchloroform and insoluble in water and DMSO. As already observed for the Pd-tra complex, no single crystals were obtained to perform an X ray structural characterization. The [PdCl2(bipy)] complexused as a precursor in the synthesis of Pd-mef was synthesized as described in the literature [21].

Reference： [1]Journal of Molecular Structure,2015,vol. 1100,p. 6 - 13

25
[ 61-68-7 ]
[ 4407-36-7 ]
cinnamyl 2-(2,3-dimethylphenylamino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With dmap; dicyclohexyl-carbodiimide; at 20℃; for 4h;	General procedure: The corresponding acid was dissolved in chloroform of dichloromethane, N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) were added successively under stirring, followed by the addition of cinnamyl alcohol ((2E)-3-phenylprop-2-en-1-ol), dissolved in the same solvent. The mixture was left at room temperature for 4 h, then the precipitated dicyclohexylurea was filtered off and the final product was purified by flash chromatography, using ethyl acetate/petroleum ether as eluents.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 5028 - 5031

26
[ 61-68-7 ]
[ 121148-01-4 ]
C₂₅H₃₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: To a solution of compound 3 (0.72 g, 2.0 mmol) and 4-Methylmorpholine (0.61 g, 6. 0 mmol) in dichloromethane (50 mL), HOBt (0.32 g, 2.4 mmol) and EDCI (0.49 g, 2.4 mmol) was added, and the mixture was stirred at room temperature for 0.5 h. After compound 4a was added, the solution was stirred overnight. The solvent was evaporated, and the obtained residue was extracted with ethyl acetate. The combined extracts were washed with saturated NaHCO3, 1 M aqueous HCl, brine, dried over anhydrous MgSO4, and concentrated to yield the crude product which was purified by column chromatography eluting with PE/EA (1:1 v/v) to give compound 5a as white solid (0.58 g, yield: 46.2%);

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5539 - 5545

27
[ 528-43-8 ]
[ 61-68-7 ]
5,5'-diallyl-2'-hydroxy-[1,1'-biphenyl]-2-yl-2-((2,3-dimethylphenyl)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap; In dichloromethane; at 25 - 30℃;	General procedure: 1.2 mmol of magnolol and 1.0 mmol to 2.0 mmol of mefenamic acid were placed in a round bottom flask,Plus 50 mL of dichloromethane and a catalytic amount of DMAP (N, N-4-dimethylaminopyridine)A solution of 2 to 4 mmol of EDCI (1-ethyl- (3-dimethylaminopropyl) phthalimide hydrochloride) or DCC (dicyclohexylcarbodiimide) in methylene chloride was slowly added dropwise The reaction was stirred at room temperature (25 ~ 30 ) for 1 ~ 4h,The product was isolated by column chromatography.The elution of the column by column chromatography was ethyl acetate: petroleum ether = 1: 1 to 1: 2,Spin dry solvent,Dried in vacuo to give the desired product,I.e., compound 9 and compound 10.The yields were 92% and 71%, respectively

Reference： [1]MedChemComm,2015,vol. 6,p. 2129 - 2139
[2]Patent: CN105884614,2016,A .Location in patent: Paragraph 0045-0047

28
[ 528-43-8 ]
[ 61-68-7 ]
5,5'-diallyl-[1,1'-biphenyl]-2,2'-diyl-bis(2-((2,3-dimethylphenyl)amino)benzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With dmap; In dichloromethane; at 25 - 30℃;	General procedure: 1.2 mmol of magnolol and 1.0 mmol to 2.0 mmol of mefenamic acid were placed in a round bottom flask,Plus 50 mL of dichloromethane and a catalytic amount of DMAP (N, N-4-dimethylaminopyridine)A solution of 2 to 4 mmol of EDCI (1-ethyl- (3-dimethylaminopropyl) phthalimide hydrochloride) or DCC (dicyclohexylcarbodiimide) in methylene chloride was slowly added dropwise The reaction was stirred at room temperature (25 ~ 30 ) for 1 ~ 4h,The product was isolated by column chromatography.The elution of the column by column chromatography was ethyl acetate: petroleum ether = 1: 1 to 1: 2,Spin dry solvent,Dried in vacuo to give the desired product,I.e., compound 9 and compound 10.The yields were 92% and 71%, respectively

Reference： [1]MedChemComm,2015,vol. 6,p. 2129 - 2139
[2]Patent: CN105884614,2016,A .Location in patent: Paragraph 0045-0047

29
[ 501-36-0 ]
[ 61-68-7 ]
(E)-5-(4-((2-((2,3-dimethylphenyl)amino)benzoyl)oxy)-styryl)-1,3-phenylene bis(2-((2,3-dimethylphenyl)amino)benzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 8h;Inert atmosphere;	General procedure: To a solution of resveratrol in dry dichloromethane at room temperature, NSAIDs, EDCI and DMAP were added. After 8 h, aqueous NaHCO3 solution was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the target compounds.

Reference： [1]Chemical and Pharmaceutical Bulletin,2016,vol. 64,p. 609 - 615

30
[ 61-68-7 ]
[ 1622988-44-6 ]
(E)-4-(3,5-bis((triisopropylsilyl)oxy)styryl)phenyl2-((2,3-dimethylphenyl)amino)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 8h;Inert atmosphere;	General procedure: To a solution of resveratrol in dry dichloromethane at room temperature, NSAIDs, EDCI and DMAP were added. After 8 h, aqueous NaHCO3 solution was added and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the target compounds.

Reference： [1]Chemical and Pharmaceutical Bulletin,2016,vol. 64,p. 609 - 615

31
[ 61-68-7 ]
tert-butyl (2,2-difluoro-3-hydroxypropyl)carbamate [ No CAS ]
C₂₃H₂₈F₂N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	302 mg (1.0 eq., 1.43 mmol) of the compound 1 was dissolved in 15 mL of DCM, and added with 346 mg (1.0 eq., 1.43 mmol) of mefenamic acid and 17 mg (0.1 eq., 0.14 mmol) of DMAP. Then, under ice cooling, 550 mg (2.0 eq., 2.87 mmol) of WSC was added followed by stirring overnight at room temperature. After confirming by TLC the disappearance of the reacting materials, liquid fractionation extraction was performed 3 times by using ethyl acetate and water. The collected organic layer was washed in order with 5% aqueous solution of citric acid, 5% aqueous solution of NaHCO3, and a saturated aqueous solution of NaCl. After drying over magnesium sulfate, the obtained solution was concentrated under reduced pressure by using an evaporator in water bath at 40 C. It was then purified by silica gel column chromatography (toluene:ethyl acetate=15:1) to obtain the desired compound 20 in an amount of 252 mg (yield of 41%). 1H-NMR signal assignment is given in the following. 1H-NMR (500 MHz, CDCl3) delta1.45 (9H, s), 2.16 (3H, s), 2.33 (3H, s), 3.70 (2H, m), 4.55 (2H, t), 4.91 (1H, br), 6.66 (2H, m), 7.03-7.28 (3H, m), 7.97 (1H, d), 9.02 (1H, s).

Reference： [1]Patent: US2016/151506,2016,A1 .Location in patent: Paragraph 0407-0411

32
[ 123-90-0 ]
[ 61-68-7 ]
(2-((2,3-dimethylphenyl)amino)phenyl)(thiomorpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 4h;	General procedure: To the corresponding acid (1 mmol) dissolved in CH2Cl2, thiomorpholine(1.2 mmol) was added followed by the addition of N,N?-dicyclohexylcarbodiimide(DCC, 1.3 mmol) in the same solvent. The mixture was stirred for 4 hours at room temperature. After the removal of N,N?-dicyclohexylurea (DCU) byfiltration, the final compounds were isolated with flash chromatography using asuitable mixture of petroleum ether and ethyl acetate as eluent.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 910 - 913

33
[ 1202-34-2 ]
cobalt(II) chloride hexahydrate [ No CAS ]
[ 61-68-7 ]
[Co(mefenamic acid)₂(2,2′-bipyridylamine)] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: A methanolic solution (15mL) of the NSAID (HL=Hfluf, Hmef) (0.8mmol) and KOH (0.8mmol, 44mg) was stirred for 1h and afterwards was added simultaneously with a methanolic solution (10mL) of bipyam (0.4mmol, 68mg) into a methanolic solution (10mL) of CoCl2·6H2O (0.4mmol, 96mg). The resultant mixture was further stirred for 30min and left for slow evaporation.

Reference： [1]Journal of Inorganic Biochemistry,2016,vol. 160,p. 125 - 139

34
[ 5146-68-9 ]
[ 61-68-7 ]
C₂₀H₂₀N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With pyridine; trichlorophosphate; at 5℃; for 8h;	appropriately weighed quantities of mefenamic acid(0.965 g, 4 mmol) and N-hydroxymethylsuccinimide(0.516g; 5mmol) were separately dissolved in a minimum quantity of dry pyridine (5mL) and then mixed together underice cold conditions. To this resulting mixture phosphorousoxychloride (0.5mL) was added slowly over a period of 10 min. The content of the mixture was mechanically shaken for 8 h and throughout the period the temperature was maintained below 5C. Finally the reaction mixture was decomposedby pouring on to the crushed ice to get a solid mass.The product was separated by filtration and purified by recrystallization in methanol. The purity of pure cream crystalline powder of MA-NH was further assessed by TLC. Yield:88%, M.P.(C): 211. Rf: 0.78, Log P (chloroform/phosphatebuffer at 28 C) 2.89. IR (KBr/max) cm-1: 3069 (Ar C-H),1684 (C=O, ketone), 1514 (N-H, aromatic amine), 1305 (CN,aromatic amine), 1274 (C-O, ester). 1H NMR (DMSOd6):( ppm) 2.11 (s, 3H, CH3 meta to NH), 2.30 (s, 3H,CH3), 2.51 (s, 4H, 2xCH2), 5.47 (s, 1H, NH), 5.68 (s, 2H,CH2N), 7.06-7.14 (m, 3H, ring A), 7.29-7.34 (m, 4H, ringB); 13C-NMR (DMSO-d6: ( ppm) 7.1, 15.2, 26.5, 65.60,114.60, 118.60, 125.30,126.90, 134.20, 138.21, 115.6,118.9, 115.8, 126.3, 131.2, 139.4, 165.8, 172.2; MS: m/z352 (M+); C20H20N2O4; Calc. C 68.18, H 5.68, N 7.95;Found C 68.26, H 5.81, N 7.88.

Reference： [1]Medicinal Chemistry,2016,vol. 12,p. 585 - 591

35
[ 61-68-7 ]
[ 66356-53-4 ]
N-(2-((5-((dimethylamino)methyl)furan-2-yl)methylthio)ethyl)-2-(2,3-dimethylphenylamino)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In acetonitrile; at 20℃; for 15h;	To a solution of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium (HBTU) (195mg,0.46mmol), mefenamic acid (152mg, 0.63mmol), and triethylamine(47mg, 0.7mmol) inacetonitrile (35mL), a solution of (2) (110mg, 0.51mmol) in acetonitrile(5mL) was added. Afterbeing stirred for a period of 15 hours at room temperature, the reaction suspension was filteredand the filtration was evaporated under reduced pressure. The resulting residue was purified bycolumn chromatography. The silica gel was first conditioned ethyl acetate, and then the productwas eluted with 8:1 ethyl acetate/methanol. Evaporation of the solvent yielded N-(2-((5-((dimethylamino)methyl)furan-2-yl)methylthio)ethyl)-2-(2,3-dimethylphenylamino)benzamide(25) as a pale yellow oil (200mg, 89.0%)

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 5573 - 5579

36
[ 67-56-1 ]
[ 366-18-7 ]
nickel(II) chloride hexahydrate [ No CAS ]
[ 61-68-7 ]
C₄₂H₄₄N₄NiO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		A methanolic solution (10 mL) containing Hmef (0.4 mmol, 97 mg)and KOH (0.4 mmol, 22 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolicsolution (5 mL) of bipy (0.2 mmol, 61 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(mef)2(bipy)(MeOH)2], 1 (80 mg, 70%), suitable for X-ray structuredetermination, were collected after a week. Anal. Calcd. for[Ni(mef)2(bipy)(MeOH)2] (C42H44N4NiO6) (MW = 759.54): C 66.42,H 5.84, N 7.36%; found C 66.12, H 5.77, N 7.36%. IR (KBr disk):numax, cm-1; nuasym(CO2): 1575 (vs (very strong)); nusym(CO2): 1382(vs); Delta = nuasym(CO2) - nusym(CO2): 193 cm-1; rho(C-H)bipy: 766(s (strong)); UV-vis: lambda, nm as nujol mull: 990, 625 (sh (shoulder)),402 (sh), 341 (sh), 301; lambda, nm (epsilon, M-1 cm-1) in DMSO: 995 (10), 620(20), 397 (sh) (120), 342 (sh) (5800), 298 (19,500); 10 Dq =10,050 cm-1, B = 745 cm-1, 10 Dq/B = 13.5. mueff = 3.17 BM, at roomtemperature. The complex is soluble in DMSO, DMF, CHCl3, CH2Cl2and acetone and is non-electrolyte (LambdaM=20 muS/cm, 1 mM in DMSO).

Reference： [1]Journal of Inorganic Biochemistry,2015,vol. 145,p. 79 - 93

37
[ 1202-34-2 ]
nickel(II) chloride hexahydrate [ No CAS ]
[ 61-68-7 ]
C₄₀H₃₇N₅NiO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: A methanolic solution (10 mL) containing Hmef (0.4 mmol, 97 mg)and KOH (0.4 mmol, 22 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolicsolution (5 mL) of bipy (0.2 mmol, 61 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(mef)2(bipy)(MeOH)2], 1 (80 mg, 70%),

Reference： [1]Journal of Inorganic Biochemistry,2015,vol. 145,p. 79 - 93

38
[ 67-56-1 ]
[ 66-71-7 ]
nickel(II) chloride hexahydrate [ No CAS ]
[ 61-68-7 ]
C₄₄H₄₄N₄NiO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: A methanolic solution (10 mL) containing Hmef (0.4 mmol, 97 mg)and KOH (0.4 mmol, 22 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolicsolution (5 mL) of bipy (0.2 mmol, 61 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(mef)2(bipy)(MeOH)2], 1 (80 mg, 70%),

Reference： [1]Journal of Inorganic Biochemistry,2015,vol. 145,p. 79 - 93

39
[ 67-56-1 ]
[ 1562-95-4 ]
nickel(II) chloride hexahydrate [ No CAS ]
[ 61-68-7 ]
C₅₂H₄₆N₈NiO₆*CH₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		General procedure: A methanolic solution (10 mL) containing Hmef (0.4 mmol, 97 mg)and KOH (0.4 mmol, 22 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolicsolution (5 mL) of bipy (0.2 mmol, 61 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(mef)2(bipy)(MeOH)2], 1 (80 mg, 70%),

Reference： [1]Journal of Inorganic Biochemistry,2015,vol. 145,p. 79 - 93

40
[ 110-86-1 ]
nickel(II) chloride hexahydrate [ No CAS ]
[ 61-68-7 ]
C₄₀H₄₂N₄NiO₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%		General procedure: A methanolic solution (10 mL) containing Hmef (0.4 mmol, 97 mg)and KOH (0.4 mmol, 22 mg) was stirred for 1 h at room temperature.The resultant solution was added simultaneously with a methanolicsolution (5 mL) of bipy (0.2 mmol, 61 mg) to a methanolic solution(5 mL) of NiCl2·6H2O (0.2 mmol, 48 mg). The solution was stirred for30 min and left for slowevaporation at roomtemperature. Blue crystalsof [Ni(mef)2(bipy)(MeOH)2], 1 (80 mg, 70%),

Reference： [1]Journal of Inorganic Biochemistry,2015,vol. 145,p. 79 - 93

41
[ 61-68-7 ]
[ 458-37-7 ]
4-((1E,6E)-7-(4-hydroxy-3-methoxyphenyl)-3,5-dioxohepta-1,6-dien-1-yl)-2-methoxyphenyl 2-((2,3-dimethylphenyl)amino)benzoate [ No CAS ]
((1E,6E)-3,5-dioxohepta-1,6-diene-1,7-diyl)bis(2-methoxy-4,1-phenylene) bis(2-((2,3-dimethylphenyl)amino)benzoate) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%; 86%	With dmap; In dichloromethane; at 25 - 30℃;	1. 2 mmol of curcumin and 1 0 mmol-2 mmol of mefenamic acid were placed in a round bottom flask,0.01 mL of DMAP (N, N-4-dimethylaminopyridine) was added to 50 mL of dichloromethane and the amount of catalyst,A solution containing 2 to 3 mmol of EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride)Or DCC (dicyclohexylcarbodiimide) in dichloromethane at room temperature (25 to 30 C) for 1 to 4 hours. The product was purified by column chromatography.The eluate was isolated and purified by column chromatography as ethyl acetate: cyclohexane = 1: 10 ~ 1: 2. The solvent was dried and dried in vacuo to give the title compound, compound 11 and compound 12. The yields were 55% and 86%, respectively.

Reference： [1]Patent: CN105884615,2016,A .Location in patent: Paragraph 0057-0060

42
[ 61-68-7 ]
[ 62-53-3 ]
[ 21122-53-2 ]

Yield	Reaction Conditions	Operation in experiment
75%		To a mixture of 0.002 mol of 2-(2,3-dimethylphenylamino)benzoic acid and 0.0022 mol of aniline in DCM (dichloromethane) and DMAP (dimethyl amino pyridine) was added with continuous stirring. After 30 min of stirring at 0 C, the cooled solution of DCC (N,N`-dicyclohexylcarbodiimide) (1.1 equiv) was added in to the above reaction mixture and allowed to stir at room temperature under the N2 environment for 15 h. The reaction was monitored using TLC using ethyl acetate: hexane (0.5: 4.5) as the solvent system. After completion of the reaction the pale yellow product was extracted using DCM after repeated washing with brine and sodium bicarbonate.