[ CAS No. 303-38-8 ] {[proInfo.proName]}

Name: 303-38-8|2,3-Dihydroxybenzoic acid|98%
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Quality Control of [ 303-38-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 303-38-8 ]

CAS No. :	303-38-8	MDL No. :	MFCD00002446
Formula :	C₇H₆O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GLDQAMYCGOIJDV-UHFFFAOYSA-N
M.W :	154.12	Pubchem ID :	19
Synonyms :	Catecholcarboxylic acid;NSC 27435;Hypogallic acid;3-Hydroxysalicylic acid;2-Pyrocatechuic acid;O-Pyrocatechuic acid;2,3-Dihydroxybenzoic acid	Chemical Name :	2,3-Dihydroxybenzoic acid

Calculated chemistry of [ 303-38-8 ] Expand+

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	3.0
Molar Refractivity :	37.45
TPSA :	77.76 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 :	Yes
Log Kp (skin permeation) :	-6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.09
Log Po/w (XLOGP3) :	1.2
Log Po/w (WLOGP) :	0.8
Log Po/w (MLOGP) :	0.4
Log Po/w (SILICOS-IT) :	0.26
Consensus Log Po/w :	0.75

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.89
Solubility :	1.99 mg/ml ; 0.0129 mol/l
Class :	Very soluble
Log S (Ali) :	-2.43
Solubility :	0.573 mg/ml ; 0.00372 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-0.6
Solubility :	38.3 mg/ml ; 0.248 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	1.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.09

Safety of [ 303-38-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Applications of [ 303-38-8 ]

2,3-Dihydroxybenzoic acid (CAS: 303-38-8) is an antioxidant commonly found in various plants, known for its protective effects against oxidative damage. It has been utilized as a model compound in the study of infectious diseases and its impact on biological systems.

Application In Synthesis of [ 303-38-8 ]

* 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 [ 303-38-8 ]
Downstream synthetic route of [ 303-38-8 ]

[ 303-38-8 ] Synthesis Path-Upstream 1~17

1
[ 303-38-8 ]
[ 1668-84-4 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887

2
[ 303-38-8 ]
[ 769-30-2 ]

Reference： [1] Patent: CN103804341, 2018, B,

3
[ 303-38-8 ]
[ 101417-40-7 ]

Reference： [1] Patent: CN103804341, 2018, B,

4
[ 303-38-8 ]
[ 66411-55-0 ]

Reference： [1] Journal of the Chemical Society, 1926, p. 2932
[2] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644

5
[ 303-38-8 ]
[ 5768-39-8 ]

Reference： [1] Journal of Medicinal Chemistry, 2004, vol. 47, # 4, p. 871 - 887
[2] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644
[3] Patent: WO2016/131098, 2016, A1,
[4] Patent: CN104016960, 2018, B,

6
[ 75-11-6 ]
[ 303-38-8 ]
[ 5768-39-8 ]

Reference： [1] Journal of the Chemical Society, 1926, p. 2932

7
[ 303-38-8 ]
[ 33842-16-9 ]

8
[ 303-38-8 ]
[ 106-93-4 ]
[ 4442-53-9 ]

Reference： [1] Journal of Organic Chemistry, 1948, vol. 13, p. 489,493
[2] Patent: US5919814, 1999, A,

9
[ 303-38-8 ]
[ 4442-53-9 ]

Reference： [1] Journal of Agricultural and Food Chemistry, 2011, vol. 59, # 2, p. 635 - 644
[2] Bioorganic and Medicinal Chemistry, 2014, vol. 22, # 11, p. 2947 - 2954
[3] Patent: CN106905335, 2017, A,

10
[ 303-38-8 ]
[ 74-88-4 ]
[ 2150-42-7 ]

Reference： [1] Journal of the Chemical Society, 1955, p. 4206,4213

11
[ 186581-53-3 ]
[ 303-38-8 ]
[ 2150-42-7 ]

Reference： [1] Gazzetta Chimica Italiana, 1982, vol. 112, # 11/12, p. 443 - 446

12
[ 99-50-3 ]
[ 89-86-1 ]
[ 149-91-7 ]
[ 99-10-5 ]
[ 303-38-8 ]
[ 490-79-9 ]
[ 99-06-9 ]
[ 69-72-7 ]
[ 74-88-4 ]
[ 99-96-7 ]
[ 2150-41-6 ]
[ 606-45-1 ]
[ 5368-81-0 ]
[ 121-98-2 ]
[ 2150-38-1 ]
[ 1916-07-0 ]
[ 2150-42-7 ]
[ 2150-40-5 ]
[ 2150-37-0 ]

Reference： [1] Chemical Communications, 2014, vol. 50, # 14, p. 1694 - 1697

13
[ 303-38-8 ]
[ 20734-66-1 ]

Reference： [1] Archiv der Pharmazie, 2011, vol. 344, # 9, p. 557 - 563

14
[ 303-38-8 ]
[ 3943-73-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid In ethanol; water	PREPARATION 1 2,3-Dihydrobenzo[1,4]dioxin-5-carboxylic acid ethyl ester The following is the preparation of a compound of formula 1a wherein R¹and R² are each independently hydrogen, and R is ethyl. A mixture of 2,3-dihydroxybenzoic acid(994 g), ethanol (3.8 L) and sulfuric acid (320 g) was refluxed for 44 hours. A portion of the solvent distilled out of the solution, and the solution was cooled and stirred overnight, and then further cooled in an ice/water bath. To the solution was added water (5.6 L). The solution was aged, and the crystals were filtered, washed with water, and dried to give ethyl 2,3-dihydroxybenzoate (1002 g, 85percent); m.p. 66.0-67.2° C.

Reference： [1] Patent: US6172062, 2001, B2,
[2] Journal fuer Praktische Chemie (Leipzig), 1891, vol. 44, p. 1,2
[3] Journal of the American Chemical Society, 2017, vol. 139, # 46, p. 16959 - 16966

15
[ 64-17-5 ]
[ 303-38-8 ]
[ 3943-73-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	for 24 h; Reflux	To a solution of 2,3-dihydroxybenzoic acid (25 g) in ethanol (320 ml) was added concentrated sulfuric acid (1.8 ml), and the mixture was heated under reflux for one day. The reaction mixture was concentrated, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent ethyl acetate) to give the title compound (30 g, 100percent). NMR(300MHz, CDCl₃)δ:1.42(3H, t, J=7.2Hz), 4.42(2H, q, J=7.2Hz), 6.80(1H, dd, J=8.1, 7.8Hz), 7.11(1H, dd, J=7.8, 1.5Hz), 7.38(1H, dd, J=8.1, 1.5Hz),10.99(1H, s).

Reference： [1] Patent: EP2116538, 2009, A1, . Location in patent: Page/Page column 49
[2] Monatshefte fuer Chemie, 1906, vol. 27, p. 1200
[3] ChemMedChem, 2011, vol. 6, # 11, p. 1986 - 1989

16
[ 303-38-8 ]
[ 105603-49-4 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 19, p. 2279 - 2280
[2] Chemistry - A European Journal, 2011, vol. 17, # 23, p. 6369 - 6381
[3] Patent: EP3404033, 2018, A1,

17
[ 303-38-8 ]
[ 154447-36-6 ]

Reference： [1] Australian Journal of Chemistry, 2003, vol. 56, # 11, p. 1099 - 1106

[ 303-38-8 ] Synthesis Path-Downstream 1~109

1
[ 108-73-6 ]
[ 303-38-8 ]
[ 6732-85-0 ]

Yield	Reaction Conditions	Operation in experiment
83%	With tin(ll) chloride at 140℃; for 0.0138889h; Microwave irradiation; regioselective reaction;	4.1. General procedures for the synthesis of hydroxyxanth General procedure: To an equimolar mixture of phenolic acids and phenol derivatives, anhydrous AlCl3, ZnCl2, TiCl4 or SnCl2 was added. The reaction mixture was heated at 140 °C for 50 s in CEM microwave. The contents were poured into ice and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The product thus obtained was purified by silica gel column chromatography.
45%	With zinc(II) chloride; trichlorophosphate at 65℃; for 3h; Inert atmosphere;
10%	With trichlorophosphate at 80℃; for 2h;	1 Freshly fused ZnCl2 (35 g, 224 mmol) was added with benzoic acid (175 mmol), phloroglucinol (32 g, 253 mmol), and phosphorus oxychloride (200 mL). The mixture was stirred at 800C for 2 hours. After cooled to room temperature, the red oil was slowly poured onto the crushed ice (1500 g), the precipitated red solid was allowed to settle overnight, collected by filtration, air-dried, and further dried at 1000C in vacuo for 12 hours. The crude product was dissolved in acetone (4000 mL) and refluxed for 2 hours. After cooled to room temperature, the mixture was passed through a short column packed with silica gel (6 inches thick), washed with ethyl acetate. The combined filtrate and washings were concentrated in vacuo to give a light yellow powder. When X = O and Y = OH, the yield was 10 - 30%. H NMR (acetone-d6) δ 12.95 (s, 1 H, OH), 9.62-9.49 (br, 2 H, OH), 7.66 (dd, J= 7.31, 2.05 Hz, 1 H), 7.33 (dd, J= 8.24, 2.05 Hz, 1 H), 7.26 (dd, J= 7.31, 8.24 Hz, 1 H), 6.46 (d, J= 2.0 Hz, I H), 6.26 (d, J= 2.03 Hz, 1 H). MS m/e 245 (M + H+).

With acetic anhydride at 280℃; zuletzt unter vermindertem Druck_.;

Reference： [1]Location in patent: experimental part Verbanac, Donatella; Jain, Subhash C.; Jain, Nidhi; Chand, Mahesh; Čipčić Paljetak, Hana; Matijašić, Mario; Perić, Mihaela; Stepanić, Višnja; Saso, Luciano [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 10, p. 3180 - 3185]
[2]Zhang, Xiaojin; Li, Xiang; Tao, Lei; Gao, Yuan; Gong, Dandan; Xi, Meiyang; Xu, Xiaoli; Guo, Qinglong; You, Qidong; Ye, Suofu; Zhang, Yu; Meng, Huyan; Zhang, Mingqian; Gao, Wenlei [Medicinal Chemistry, 2012, vol. 8, # 6, p. 1012 - 1025,14]
[3]Current Patent Assignee: CYLENE PHARMACEUTICALS, INC. - WO2006/23445, 2006, A2 Location in patent: Page/Page column 10-11
[4]Lund et al. [Journal of the Chemical Society, 1953, p. 2434,2439]

2
[ 75-11-6 ]
[ 303-38-8 ]
[ 5768-39-8 ]

Reference： [1]Journal of the Chemical Society,1926,p. 2932

3
[ 64-17-5 ]
[ 303-38-8 ]
[ 3943-73-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	sulfuric acid; for 24.0h;Reflux;	To a solution of 2,3-dihydroxybenzoic acid (25 g) in ethanol (320 ml) was added concentrated sulfuric acid (1.8 ml), and the mixture was heated under reflux for one day. The reaction mixture was concentrated, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent ethyl acetate) to give the title compound (30 g, 100%). NMR(300MHz, CDCl3)delta:1.42(3H, t, J=7.2Hz), 4.42(2H, q, J=7.2Hz), 6.80(1H, dd, J=8.1, 7.8Hz), 7.11(1H, dd, J=7.8, 1.5Hz), 7.38(1H, dd, J=8.1, 1.5Hz),10.99(1H, s).

Reference： [1]Patent: EP2116538,2009,A1 .Location in patent: Page/Page column 49
[2]Monatshefte fur Chemie,1906,vol. 27,p. 1200
[3]ChemMedChem,2011,vol. 6,p. 1986 - 1989

4
[ 303-38-8 ]
[ 72517-15-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With bromine; acetic acid at 20℃; for 24h;
99%	With bromine In acetic acid at 20℃; for 16h; Inert atmosphere; regioselective reaction;
88%	With bromine In acetic acid at 20℃;

88%	With bromine In acetic acid at 20℃;
73%	With bromine; acetic acid at 20℃; for 20h; Inert atmosphere;
71%	With bromine; acetic acid for 20h; Ambient temperature;
	With bromine; acetic acid
	With bromine; acetic acid In methanol
	With bromine; acetic acid at 20℃; for 12h;	17.1 Step 1. Synthesis of 102 5-bromo-2,3-dihydro benzoic acid (17-1) Br2 (3.32 mL, 64.9 mmol) was added dropwise into 103 2,3-dihydrobenzoic acid (10.0 g, 64.9 mmol, Aldrich reagent) in 22 AcOH (120 mL), after which a resulting mixture was stirred at room temperature for 12 hours. A reaction was completed with a saturated Na2S2O3 aqueous solution, after which a resulting mixture was dried under reduced pressure, so as to remove a volatile substance. A resulting residue was distributed between EtOAc and water. A water layer was extracted with EtOAc, after which a combined organic layer was dried over anhydrous MgSO4, filtered and concentrated under vacuum. The title compound (17-1) (14.1 g, 60.3 mmol, 93%) was used in a following step without an additional purification. 1H NMR (400 MHz, CDCl3); δ 7.47 (s, 1H), 7.37 (s, 1H)
	With bromine; acetic acid at 20℃; for 12h;	3 5-Bromo-2,3-dihydroxybenzoic acid (v). To a suspension of 2,3-dihydroxybenzoic acid (10.0 g, 64.88 mmol, 1.0 eq.; CAS 303-38-8) in acetic acid (120 mL) was added bromine (3.32 mL, 64.88 mmol, 1.0 eq.). After 12 h at rt, the reaction mixture was quenched with sat. aq. Na2S2Ch solution then concentrated under reduced pressure. The residue was diluted with EtOAc and H2O and the layers separated. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were dried over Mg2S04, filtered and concentrated to provide the crude product as an off white solid (containing about 25% unreacted starting material), which was used in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6,) d 11.25 (broad s, 1H), 9.9 (broad s, 2H), 7.31 (d, J= 2.5 Hz, 1H), 7.12 (d, J= 2.5 Hz, 1H).

Reference： [1]Abbiati, Giorgio; Doda, Arjana; Dell'Acqua, Monica; Pirovano, Valentina; Facoetti, Diego; Rizzato, Silvia; Rossi, Elisabetta [Journal of Organic Chemistry, 2012, vol. 77, # 22, p. 10461 - 10467]
[2]Hierold, Judith; Baek, Sohee; Rieger, Rene; Lim, Tae-Gyu; Zakpur, Saman; Arciniega, Marcelino; Lee, Ki Won; Huber, Robert; Tietze, Lutz F. [Chemistry - A European Journal, 2015, vol. 21, # 47, p. 16887 - 16894]
[3]Huang, Yunsheng; Luedtke, Robert R.; Freeman, Rebekah A.; Wu, Li; Mach, Robert H. [Bioorganic and Medicinal Chemistry, 2001, vol. 9, # 12, p. 3113 - 3122] Mach, Robert H.; Hammond, Philip S.; Huang, Yunsheng; Yang, Biao; Xu, Yueping; Cheney, Jason T.; Freeman, Rebekah; Luedtke, Robert R. [Medicinal Chemistry Research, 1999, vol. 9, # 6, p. 355 - 373]
[4]Tiwari, Shashi B.; Kohli [Medicinal Chemistry Research, 2008, vol. 17, # 2-7, p. 386 - 398]
[5]Ellermann, Manuel; Paulini, Ralph; Jakob-Roetne, Roland; Lerner, Christian; Borroni, Edilio; Roth, Doris; Ehler, Andreas; Schweizer, W. Bernd; Schlatter, Daniel; Rudolph, Markus G.; Diederich, Francois [Chemistry - A European Journal, 2011, vol. 17, # 23, p. 6369 - 6381]
[6]Yee, Nathan K.; Nummy, Larry J.; Roth, Gregory P. [Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 19, p. 2279 - 2280]
[7]v. Hemmelmayr [Monatshefte fur Chemie, 1912, vol. 33, p. 972][Monatshefte fuer Chemie, 1913, vol. 34, p. 374]
[8]Current Patent Assignee: ROCHE HOLDING AG - US2005/137162, 2005, A1 Location in patent: Page/Page column 6
[9]Current Patent Assignee: JEIL PHARMA HOLDINGS INC - EP3404033, 2018, A1 Location in patent: Paragraph 0141
[10]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2020/86864, 2020, A1 Location in patent: Paragraph 00234-00235

5
[ 303-38-8 ]
[ 3943-73-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sulfuric acid; In ethanol; water;	PREPARATION 1 2,3-Dihydrobenzo[1,4]dioxin-5-carboxylic acid ethyl ester The following is the preparation of a compound of formula 1a wherein R1and R2 are each independently hydrogen, and R is ethyl. A mixture of 2,3-dihydroxybenzoic acid(994 g), ethanol (3.8 L) and sulfuric acid (320 g) was refluxed for 44 hours. A portion of the solvent distilled out of the solution, and the solution was cooled and stirred overnight, and then further cooled in an ice/water bath. To the solution was added water (5.6 L). The solution was aged, and the crystals were filtered, washed with water, and dried to give ethyl 2,3-dihydroxybenzoate (1002 g, 85%); m.p. 66.0-67.2 C.

Reference： [1]Patent: US6172062,2001,B2
[2]Journal fur praktische Chemie (Leipzig 1954),1891,vol. 44,p. 1,2
[3]Journal of the American Chemical Society,2017,vol. 139,p. 16959 - 16966

6
[ 303-38-8 ]
[ 108-24-7 ]
[ 486-79-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	In diethyl ether for 12h;
91%	With sulfuric acid In diethyl ether at 20℃; for 12h;
85%	With dmap; triethylamine for 3h; Reflux;

74%	With sulfuric acid for 0.416667h; Heating;
	With pyridine
	With sulfuric acid
	With dmap; triethylamine In tetrahydrofuran
	at 100 - 110℃;
	With dmap; triethylamine In tetrahydrofuran at 29℃;

Reference： [1]Bergeron; McGovern; Channing; Burton [Journal of Organic Chemistry, 1980, vol. 45, # 9, p. 1589 - 1592]
[2]Poras, Herve; Kunesch, Gerhard; Barriere, Jean-Claude; Berthaud, Nadine; Andremont, Antoine [Journal of Antibiotics, 1998, vol. 51, # 8, p. 786 - 794]
[3]Brönstrup, Mark; Grunenberg, Jörg; Hotop, Sven-Kevin; Karge, Bianka; Lai, Yi-Hui; Peukert, Carsten; Pinkert, Lukas; Schulze, Lara Marie [Journal of Medicinal Chemistry, 2021, vol. 64, # 20, p. 15440 - 15460]
[4]Obaseki, Andrew O.; Steffen, James E.; Porter, William R. [Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 529 - 533]
[5]Simokoriyama [Bulletin of the Chemical Society of Japan, 1941, vol. 16, p. 284,288]
[6]Yu, Kuo-Long; Ruediger, Edward; Luo, Guangxiang; Cianci, Christopher; Danetz, Stephanie; Tiley, Laurence; Trehan, Ashok K.; Monkovic, Ivo; Pearce, Bradley; Martel, Alain; Krystal, Mark; Meanwell, Nicholas A. [Bioorganic and Medicinal Chemistry Letters, 1999, vol. 9, # 15, p. 2177 - 2180]
[7]Location in patent: scheme or table Rho, Ho Sik; Baek, Heung Soo; Ahn, Soo Mi; Yoo, Jae Won; Kim, Duck Hee; Kim, Han Gon [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1532 - 1533]
[8]Current Patent Assignee: Bayer & Co. - DE287960, 1800, C [Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 12, p. 684][Fortschr. Teerfarbenfabr. Verw. Industriezweige, vol. 12, p. 684]
[9]Peukert, Carsten; Langer, Laura N. B.; Wegener, Sophie M.; Tutov, Anna; Bankstahl, Jens P.; Karge, Bianka; Bengel, Frank M.; Ross, Tobias L.; Brönstrup, Mark [Journal of Medicinal Chemistry, 2021, vol. 64, # 16, p. 12359 - 12378]

7
[ 303-38-8 ]
[ 106-93-4 ]
[ 4442-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide;	Step A 5-Carboxy-2,3-dihydro-1,4-benzodioxin A mixture of 10.8 g (70 mmol) of 2,3-dihydroxybenzoic acid, 38.6 g (280 mmol) of dry potassium carbonate and 24 ml (278 mmol) of 1,2-dibromoethane in 40 ml of N,N-dimethylformamide is heated at 65° C. for 24 hours under an inert atmosphere. After cooling, the reaction mixture is diluted with water and then extracted with ether. The aqueous phase is then acidified with a 3N hydrochloric acid solution and subsequently extracted with dichloromethane. After removal of the solvent by evaporation in vacuo, the residue obtained is recrystallized from toluene to yield the title acid in the form of a white solid. Melting point 193-194° C.

Reference： [1]Journal of Organic Chemistry,1948,vol. 13,p. 489,493
[2]Patent: US5919814,1999,A

8
[ 303-38-8 ]
[ 74-88-4 ]
[ 2411-83-8 ]

Reference： [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 3576 - 3585
[2]Journal of the Chemical Society,1955,p. 4206,4213
[3]Journal of the Chemical Society,1955,p. 4206,4213

9
[ 303-38-8 ]
[ 74-88-4 ]
[ 2150-42-7 ]

Reference： [1]Journal of the Chemical Society,1955,p. 4206,4213

10
[ 186581-53-3 ]
[ 303-38-8 ]
[ 2150-42-7 ]

Reference： [1]Gazzetta Chimica Italiana,1982,vol. 112,p. 443 - 446

11
[ 67-56-1 ]
[ 303-38-8 ]
[ 2411-83-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sulfuric acid; at 0℃; for 12h;Heating / reflux;	(aj 2, 3-Dihydroxy-benzoic acid methyl ester (1)This method is disclosed in Coleman, R.S. & Grant, E.B.; J.Am.Chem.Soc, 117(44), 10889 (1995), which is incorporate herein by reference. 2,3 Dihydroxy-benzoic acid (15 g, 97.3 mmol) was dissolved in methanol (150 ml_) and cooled to 00C with stirring. Concentrated sulfuric acid (9 ml_) was added dropwise to the solution. The reaction mixture was heated to reflux for 12 hours and turned brown. The solvent was evaporated, yielding pale brown oil. Ethyl acetate and saturated NaHCO3 solution were added until effervescence ceased. The aqueous phase was extracted with ethyl acetate (3 x 150 ml_) and the organic layer dried using Na2SO4. The resulting solution was concentrated under reduced pressure to give pale brown solid (16.47 g, 99%).1H NMR (300 MHz, CDCI3): delta 3.97 (3H, s), 5.70 (1H, s), 6.82 (1 H1 1, J= 8.0 Hz), 7.10 (1H, d, J = 7.9 Hz), 7.32 (1 H, d, J = 8.0 Hz), 10.9 (1H, s). 13C NMR (75 MHz, CDCI3): delta 52.9, 112.8, 119.6, 120.3, 121.0, 145.4, 149.2, 171.2. m.p.: 83-850C. I.R.: 3455, 2363, 2222, 2163, 1987, 1668, 1607, 1458, 1340 cm"1. HRMS: [M+NH4] + calc. 186.0761 , meas. 186.0762.
95%	With sulfuric acid; for 8h;Reflux;	A mixture of 2,3-dihydroxy-benzoic acid (15 g, 97.3 mmol)Was dissolved in methanol (150 mL) and stirredCooled to 0 C.Concentrated sulfuric acid (9 mL) was added dropwise to the solution.The reaction mixture was heated to reflux for 8 hours,TLC monitoring reaction is completed,Brownish brown.Evaporation of methanol solvent,To give a light brown oil.Ethyl acetate and saturated NaHCO3 solution were added,Until the stop effervescence.The aqueous phase was extracted with ethyl acetate (3 x 150 mL)Dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure,A gray solid.Yield 95%.
93.1%	With sulfuric acid;Reflux;	Dissolve 7.7g (0.05mol) of 2,3-dihydroxybenzoic acid in 50ml of methanol.0.5 ml of concentrated sulfuric acid was added dropwise at room temperature and the mixture was stirred under reflux overnight. After stopping the reaction to room temperature,The solvent was evaporated under reduced pressure to give a red solid. Add ethyl acetate and saturated sodium bicarbonate solution to dissolveThe liquid was separated, and the aqueous phase was extracted twice with ethyl acetate. The organic phases were combined and washed with saturated brine.Anhydrous sodium sulfate was dried for 8 h. The desiccant was filtered off, the solvent was evaporated under reduced pressure, and the residue was separated by silica gel column chromatography.The desired fractions were collected by eluting with petroleum ether:ethyl acetate (8:1) and evaporated to dryness under reduced pressure to give 7.8 g of a white solid II.Yield 93.1%.

89%	With sulfuric acid; at 20℃; for 17h;Heating / reflux;	EXAMPLE 345 2,3-Bis[(3,5-Dichlorophenyl)Methoxy]Benzoic Acid A solution of 2,3-dihydroxybenzoic acid (3.00 g, 19.46 mmol) and 96% sulfuric acid (3 ML, 55 mmol) in methanol (60 ML) at room temperature under argon was stirred for 1 h.The reaction mixture was heated to reflux for 16 h, then cooled, concentrated to half the volume and poured into water (150 ML) and ethyl acetate (150 ML).The organic fraction was washed with water, aqueous NaHCO3 solution, dried (MgSO4) and concentrated to give the title compound as a white solid (2.90 g, 89%).mp 77-78 C. LC/MS gave the correct molecular ion [(M-H)-=167] for the desired compound.
88%	With sulfuric acid; at 65℃;	A stirred suspension of 1 (8.06 g, 52.3 mmol) in 100 mL of MeOH was treated with 2.00 ml of concentrated sulfuric acid. The suspension warmed and clarified 2 minutes after the addition. The reaction was equipped with a reflux condenser and was heated to 65C overnight. The next morning the conversion was verified by LC-MS and the volatiles were removed under reduced pressure. The crude was partitioned between H2O (100 mL) and ethyl acetate (100 mL) and the aqueous layer was extracted with ethyl acetate (3x50 mL). The organic extracts were combined, dried over MgS04, and concentrated under reduced pressure. The crude was passed through a plug of silica using 10% ethyl acetate in hexanes as eluent. The eluent was concentrated under reduced pressure and dried under high vacuum for 2 hours to yield 2 (7.66 g, 45.6 mmol, 88%) as a white solid, the spectral properties of which matched previous reports (Weitl, et al. , J. Am. Chem. Soc, 1980, 102 (7): 2289-2293).
81%	With hydrogenchloride; for 72h;Heating / reflux;	2,3-Dihydroxybenzoic acid (5.029 g, 32.63 mmol) was heated under reflux in a solution (80 ml) of 10% hydrogen chloride in methanol for 3 days. The solvent of the reaction solution was evaporated under reduced pressure, diluted with water and extracted with ethyl acetate. The obtained ethyl acetate solution was dried over anhydrous magnesium sulfate and passed through silica gel. The solvent was evaporated under reduced pressure. The obtained residue was crystallized from cold diisopropyl ether-hexane to give the objective substance. brown crystal yield 4.439 g, 81% mp 77-78C; 1H-NMR (CDCl3, 200MHz) delta 3.96 (3H, s), 5.65 (1H, s), 6.80 (1H, t, J = 8.1 Hz), 7.11 (1H, dd, J = 1.5 Hz, 7.7 Hz), 7.37 (1H, dd, J = 1.1 Hz, 8.1 Hz), 10.89 (1H, s); IR (KBr) 3465, 3100 2850, 1674, 1468, 1437, 1321, 1269, 1194, 1152, 1076, 1009, 837, 758 cm-1; Anal. Calcd for C8H8O4: C, 57.14; H, 4.80. Found: C, 56.93; H, 4.94.
79%	With sulfuric acid;Reflux;	Weigh the compound 2,3-dihydroxybenzoic acid (1.5 g, 9.7 mmol) In a 100mL round bottom flask, Add 30mL of anhydrous methanol to dissolve, Concentrated H2SO4 (200 mg, 2 mmol) was added dropwise with stirring. After the addition was complete, it was heated to reflux overnight. After cooling overnight to room temperature, The solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate/petroleum ether to give 1.3 g of pink D-1 crystals. Yield 79%.
54%	With sulfuric acid;Reflux;	2,3-Dihydroxybenzoic acid (5.0 g, 32.4 mmol) in anhydrous methanol (50 mL) was treated with concentrated sulfuric acid (10 drops) and heated at reflux overnight. The reaction mixture was concentrated in vacuo, diluted using EtOAc (100 mL) washed using sat. aqueous NaHC03(2 x 50 mL), brine (50 mL) then dried (MgS04) and concentrated in vacuoio give methyl 2,3-dihydroxybenzoate (2.92 g; 54%).1H NMR (400 MHz, CDCI3): delta = 10.9 (s, 1 H), 7.32 (dd, J = 8.0, 1 .2 Hz, 1 H), 7.09 (m, 1 H), 6.78 (t, .7 = 8.0 Hz, 1 H), 5.65 (s, 3H).13C NMR (100 Hz, CDCIs) 170.7, 148.8, 145.0, 120.5, 1 19.8, 1 19.2, 1 12.4, 52.4.
	With sulfuric acid; at 60℃; for 24h;	A mixture of 2,3-dihydroxybenzoic acid (5 g), methanol (50 ml) and concentrated sulphuric acid (10 drops) was stirred and heated to 60C for 24 hours. The mixture was evaporated and the residue was taken up in ethyl acetate. The organic solution was washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to give methyl 2,3-dihydroxybenzoate (2.19 g); NMR Spectrum: (CDC13) 3.95 (s, 3H), 5.7 (s, 1H), 6.8 (t, 1H), 7.15 (d, H), 7.35 (d, H).
	sulfuric acid; at 60℃; for 24h;	A mixture [OF 2,] 3-dihydroxybenzoic acid (5 g), methanol (50 [ML)] and concentrated sulphuric acid (10 drops) was stirred and heated to [60C] for 24 hours. The mixture was evaporated and the residue was taken up in ethyl acetate. The organic solution was washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate and evaporated to give methyl 2, 3-dihydroxybenzoate (2.19 g); NMR Spectrum : (CDC13) 3.95 (s, 3H), 5.7 (s, 1H), 6.8 (t, 1H), 7.15 (d, H), 7.35 (d, H).
	With sulfuric acid; at 90℃; for 8h;	General procedure: Protocatechuic acid (1mmol) in methanol (30mL) was treated with concentrated sulfuric acid (0.5mL) under 90C overnight. The solvent was removed leaving oil which was dissovled in ethyl acetate (20mL) and extracted with water (40mL). After drying the organic layer with anhydrous Na2SO4 and evaporating the solvent under reduced pressure a solid appeared. The solid was recyrstallized from ethanol to obtain the compound 1. In the three-necked flask under a nitrogen atmosphere, compound 1 (1mmol) was dissolved in dry acetone (10mL), and then added anhydrous potassium carbonate (2mmol). After that, the acetone solution containing dibromomethane (1mmol) was added dropwise then refluxed for 24h. The reaction solution was evaporated reduced pressure distillation. The appropriate amount of water was added in the residue and extracted with ethyl acetate (3×40mL). Combined organic layer and dried with anhydrous magnesium sulfate. The solvent was removed by reduced pressure steam to give compound 2. Compound 2 was then saponified (NaOH (aq)/MeOH/THF=1:1:1) at 75C for two hours. Filtered and recrystallization led to 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid (compound 3).
	With sulfuric acid; for 4h;Reflux;	2,3-Dihydroxybenzoic acid 7 (10 g, 65 mmol) was dissolved in MeOH (200 mL) in the presence of concentrated H2SO4 (10 mL).After 4 h of refluxing, the solvent was evaporated under reduced pressure. The resulting solid was dissolved in water and K2CO3 was added until pH 7. The aqueous layer was extracted three times with EtOAc. The combined organic phases were dried over Na2SO4,filtered and concentrated in vacuo. The residue was dissolved with acetone (300 mL). K2CO3 (40.3 g, 290 mmol) and benzyl bromide(18.5 mL, 150 mmol) were added and the mixture was stirred at reflux for 12 h. The volatiles were removed and the resulting oil was purified by silica gel column chromatography with gradient elution (cyclohexane to cyclohexane/EtOAc 8:2) to provide the desired product 11 as a white solid (22 g, quantitative). Characterization of 11 matches a previous description of the same compound prepared by another method.

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12
[ 303-38-8 ]
[ 100-39-0 ]
[ 74272-78-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 2,3-Dihydroxybenzoic acid With sulfuric acid In methanol Stage #2: benzyl bromide With potassium carbonate In methanol; chloroform Stage #3: With barium(II) hydroxide In tetrahydrofuran; water at 50℃;
93%	With methanol; sodium hydroxide for 48h; Heating;
91%	Stage #1: 2,3-Dihydroxybenzoic acid; benzyl bromide With potassium carbonate In acetone for 24h; Reflux; Stage #2: With lithium hydroxide In methanol; water for 3h; Reflux; Stage #3: With hydrogenchloride In methanol; water at 0℃;	4.2.2. 2,3-Bis(benzyloxy)benzoic acid (6) A mixture of 10.15 g of 2,3-bis(hydroxy)benzoic acid acid (4, 65.86 mmol), 1.2 mL benzylbromide (100 mmol), 41 g anhydrous K2CO3 (100 mmol) in 220 mL acetone was refluxed for 24 h, then evaporated. The residue was dissolved in 150 mL methanol; 15 g of LiOH-H2O were carefully added. The mixture was then refluxed for 3 h. After cooling, the mixture was concentrated, 3 N HCl was carefully added at 0 °C until pH=2. After 24 h, white crystals were filtered, washed subsequently with 5×50 mL of water, dried under vacuum to give pure compound 6 (20 g, 91%) as white powder.1H NMR (DMSO-d6, 300 MHz, 25 °C) δ=7.76 (dd, J=7.7 Hz, 1.7 Hz, 1H, Ar-H), 7.38-7.52 (m, 10H, Ar-H), 7.20-7.36 (m, 2H, Ar-H), 5.26 (s, 2H, O-CH2), 5.22 (s, 2H, O-CH2).13C NMR (CDCl3, 75 MHz, 25 °C) δ=166.0 (ArC), 151.8 (ArC), 147.6 (ArC), 136.3 (ArC), 135.2 (ArC), 129.7 (ArCH), 129.6 (ArCH), 129.2 (ArCH), 129.0 (ArCH), 128.2 (ArCH), 125.4 (ArCH), 124.8 (ArCH), 123.5 (ArC), 119.4 (ArCH), 77.5 (CH2), 71.9 (CH2).

89%	With potassium hydroxide In dimethyl sulfoxide for 4h;
85%	Stage #1: 2,3-Dihydroxybenzoic acid; benzyl bromide With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With sodium hydroxide In methanol; water at 80℃; for 3.5h;
80%	Stage #1: 2,3-Dihydroxybenzoic acid; benzyl bromide With potassium carbonate In acetone for 24h; Reflux; Stage #2: With lithium hydroxide monohydrate In methanol for 3h; Reflux;	2.4.4 Synthesis of 2,3-bis(benzyloxy)benzoic acid (3) Benzyl bromide (22.2g, 130mmol) was added into a solution of 2,3-dihydroxybenzoic acid (10.15g, 65.86mmol) and K2CO3 (18.0g, 130mmol) in acetone (200mL), and the mixture was refluxed for 24h. After filtration of the reaction mixture, the solvent was evaporated under reduced pressure to obtain the crude product as clear oil. The crude product was dissolved in 200mL methanol, and 15.07g LiOH·H2O (359.1mmol) was slowly added with refluxing for 3h. Then, the solution was acidified with 3M HCl until ca. pH=2 and filtered to give 3 as a white solid (17.62g, 80%). 1H NMR (400MHz, CDCl3, 298.0K) δ (ppm): 7.50-7.10 (m, 12H, Ar-H), 7.03 (t, J 8.0Hz, 1H, Ar-H), 5.12 (s, 2H, O-CH2-Ar), 5.09 (s, 2H, O-CH2-Ar); 13C NMR (150MHz, CDCl3, 298.0K) δ (ppm): 165.38 (C=O), 151.54 (Ar-C), 147.32 (Ar-C), 136.07 (Ar-CH), 134.87 (Ar-CH), 129.25 (Ar-CH), 129.07 (Ar-CH), 129.03 (Ar-CH), 128.78 (Ar-CH), 128.01 (Ar-CH), 125.25 (Ar-CH), 124.67 (Ar-CH), 123.27 (Ar-CH), 119.21 (Ar-CH), 77.35 (CH2), 71.77 (CH2); FTIR (KBr) v (cm-1): 3063, 3032, 2944, 2876, 1692, 1598, 1577, 1498, 1472, 1260, 1035, 766; APCI-MS: m/z (M-1)-=333.
80%	Stage #1: 2,3-Dihydroxybenzoic acid; benzyl bromide With potassium carbonate In acetone for 24h; Reflux; Stage #2: With lithium hydroxide monohydrate In methanol for 3h; Reflux;
	With potassium hydroxide In dimethyl sulfoxide
	With potassium carbonate In acetone
	With potassium hydroxide In dimethyl sulfoxide for 4h;
	Stage #1: 2,3-Dihydroxybenzoic acid With potassium hydroxide In dimethyl sulfoxide Stage #2: benzyl bromide In dimethyl sulfoxide

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13
[ 303-38-8 ]
[ 100-39-0 ]
[ 95922-26-2 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In N,N-dimethyl-formamide for 5h; Ambient temperature;
94%	With potassium carbonate In propan-2-one for 24h; Inert atmosphere; Reflux;	Protected Catechol Ester FIG. 23 illustrates a chemical structure of a protected catechol ester. The following is an example for preparing the protected catechol ester of FIG. 23. To a 500 mL RBF was added acetone (200 mL). The acetone was then degassed by sparging with Ar using a needle for 0.5 hr. 2,3-dihydroxybenzoic acid (1.0 g, 6.5 mmol, 1.0 eq.) was added, followed by K2CO3 (3.64 g, 26.4 mmol, 4.1 eq.) and benzyl bromide (4.7 mL, 39.5 mmol, 6.1 eq.). A reflux condenser was attached, and the RBF was flushed with Ar and heated to reflux with stirring. The solution was refluxed for 24 hrs, cooled to rt, and filtered from solids. The resulting solids were washed with acetone. The solution was concentrated to dryness and excess benzyl bromide removed under high vacuum overnight. The resulting oil was purified via Biotage flash chromatography on a silica gel column, eluting with a gradient of EtOAc/hexanes. The product containing fractions were concentrated, yielding a colorless oil that was dried under high vacuum. The oil gradually crystallized (2.59 g, 94%).
81%	With potassium carbonate In propan-2-one for 24h; Reflux; Inert atmosphere;

53%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;	1.1 (1) Synthesis of compound 2-2 Weigh 2,3-dihydroxybenzoic acid (4.818g, 31.2mmol) in a 250mL single-necked flask, add 32mL of anhydrous N,N-dimethylformamide to dissolve, add potassium carbonate (14.214g, 103mmol) and benzyl bromide (12mL, 101.6mmol), stirred at room temperature under argon protection, the solution was turbid milky white, stirred at room temperature for 24 hours, TLC spot plate found that the reaction of the raw materials was complete, then the reaction was quenched with water and saturated brine respectively, extracted with ethyl acetate Three times (3×70mL), the organic phase was washed with saturated ammonium chloride solution and saturated saline solution respectively, washed three times, combined the organic phases, dried with anhydrous sodium sulfate, and then the crude product was separated by column chromatography (petroleum ether:acetic acid) ethyl ester = 10:1 to pure dichloromethane) to give a tan-yellow oil (clearoil) about 7 g in 53% yield.
	With potassium carbonate In N,N-dimethyl-formamide
	With potassium carbonate In propan-2-one for 24h; Heating;
26.7 g	With potassium carbonate In propan-2-one for 16h; Heating;
	With potassium carbonate In propan-2-one for 24h; Reflux;	4.2. 2,3-Bis(benzyloxy)benzoic acid (2) [30] A solution of 2,3-dihydroxybenzoic acid (10.20 g, 65.9 mmol),benzyl bromide (22.2 g, 130.0 mmol), and K2CO3 (18.0 g,130 mmol) in acetone (220 mL) was refluxed for 24 h. After filtration, the solution was concentrated in vacuo to obtain the crude product as clear oil. The crude product was dissolved in methanol (200 mL), and LiOH*H2O (360.0 mmol, 15.10 g) was slowly added. The mixture was refluxed for 3 h. Then, the solution was acidified with 3 N HCl to pH 2 and filtered to obtain the product 2 as white solid (yield of 80%). 1H NMR (400 MHz, CDCl3, 300.0 K): δ (ppm) = 7.50-7.10 (m, 12H, Ar-H), 7.03 (t, J = 8.0 Hz, 1H, Ar-H),5.12 (s, 2H, O-CH2-Ar), 5.09 (s, 2H, O-CH2-Ar). 13C NMR(150 MHz, CDCl3, 298.0 K): δ ppm) = 165.4 (CO), 151.5 (ArC),147.3 (ArC), 136.1 (ArCH), 134.9 (ArCH), 129.5 (ArCH), 129.1(ArCH), 129.0 (ArCH), 128.8 (ArCH), 128.0 (ArCH), 125.3 (ArCH),124.7 (ArCH), 123.3 (ArCH), 119.2 (ArCH), 71.7 (CH2). FTIR (KBr): γ (cm-1) (3100, 2700, 1683, 1035). APCI-MS calculated for C21H22O4- = 333; Found = 333.
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16.5h;	2,3-Bis(benzyloxy)benzoic acid (6) To a stirred solution of 9 (2.414 g, 15.66 mmol) in dry DMF (16 mL) were added K2CO3 (7.202 g, 52.11 mmol) and BnBr (6.1 mL, 51 mmol). After being stirred for 16.5 h, the reaction was quenched with H2O and brine, and extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with sat. aq. NH4Cl and brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed (SiO2,n-hexane/EtOAc = 10:1) to give fractions containing the benzyl ester. This mixture was dissolved in MeOH (25 mL) and 2 M aq. NaOH (25 mL), and heated to 90 °C. After being stirred for 72 h at the same temperature, this mixture was evaporated to remove MeOH. The mixture was diluted in H2O, washed with Et2O (2 × 20 mL) and acidified with aq. HCl to form white precipitate. The precipitate was washed with H2O to give 6 (5.051 g, 15.11 mmol, 96.5%) as a white solid:
	With potassium carbonate
	Stage #1: 2,3-Dihydroxybenzoic acid With potassium carbonate In acetonitrile at 80℃; for 1h; Stage #2: benzyl bromide In acetonitrile at 80℃; for 16h;	3 A solution of 2,3-dihydrobenzoic acid (21) (9.50 g, 61.6 mmol) and K2CO3 (33.20 g, 240.07 mmol) in acetonitrile (140 mL) was heated at 80° C. for 1 h. The reaction mixture was then cooled to room temperature and a solution of benzyl bromide (29.5 mL, 246.8 mmol) in acetonitrile (50 mL) was added dropwise. The reaction mixture obtained was stirred for 16 h at 80° C. and filtered. The filtrate (containing compound 22) was concentrated under reduced pressure and then diluted in EtOH (100 mL). After adding a solution of NaOH (7.50 g, 185.0 mmol) in 20 mL of water, the reaction mixture was refluxed for 4 hours and then concentrated under reduced pressure. The residue was poured into 200 mL of water and hydrochloric acid was added until acidic pH was obtained. The precipitate that formed was filtered, washed with water and then with petroleum ether, and dried under vacuum. Compound 23 was obtained in the form of a white solid (94%) and was used without further purification. (0296) 1H NMR (300 MHz, CDCl3); δ (ppm) 5.21 (s, 2H, CH2-Benzyl), 5.26 (s, 2H, CH2-Benzyl), 7.20 (t, 1H, 3J=8.0 Hz, Ar-5-H), 7.25 (dd, 1H, J=1.8 and 8.0 Hz, Ar-4-H), 7.32 to 7.50 (m, 10H, ArHBenzyl), 7.74 (dd, 1H, J=2.0 and 8.0 Hz, Ar-6-H), 10.95 (s, 1H, COOH); 13C NMR (75 MHz, CDCl3); δ (ppm) 165.58, 151.23, 147.02, 135.87, 134.51, 129.28, 128.81 (J=2.7 Hz), 128.52, 127.74, 125.02, 124.26, 122.94, 118.93, 77.12, 71.49. MALDI: calculated for C21H18NaO4: 357.12, obtained: 357.11; calculated for C42H36NaO8: 691.24, obtained: 691.23
	With potassium carbonate sesquihydrate In propan-2-one for 24h; Reflux; Inert atmosphere;

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[10]Current Patent Assignee: HSIRI THERAPEUTICS - WO2016/27262, 2016, A1 Location in patent: Page/Page column 61; 62
[11]Current Patent Assignee: UNIVERSITY OF LYON; HOSPICES CIVILS DE LYON; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF STRASBOURG - US2016/221992, 2016, A1 Location in patent: Paragraph 0294; 0295; 0296
[12]Oh, Jinyoung; Kang, Dahyun; Hong, Sugyeong; Kim, Sun H.; Choi, Jun-Ho; Seo, Jiwon [Dalton Transactions, 2021, vol. 50, # 10, p. 3459 - 3463]

14
[ 69-72-7 ]
[ 1119-72-8 ]
[ 141-82-2 ]
[ 303-38-8 ]
[ 123-31-9 ]

Reference： [1]Water Research,1995,vol. 29,p. 2346 - 2352

15
[ 120-80-9 ]
KHCO₃ [ No CAS ]
[ 303-38-8 ]
[ 19829-72-2 ]

Reference： [1]Monatshefte fur Chemie,1917,vol. 38,p. 84
Monatshefte fuer Chemie,1922,vol. 43,p. 61

16
[ 75-11-6 ]
[ 303-38-8 ]
KOH-solution [ No CAS ]
hydrogen [ No CAS ]
[ 5768-39-8 ]

Reference： [1]Journal of the Chemical Society,1926,p. 2932

17
[ 303-38-8 ]
[ 131570-56-4 ]
[ 185116-42-1 ]
(3S)-3-([{(9H-fluoren-9-yl)methoxy}carbonyl]amino)-2-hydroxy-4-phenylbutanoic acid [ No CAS ]
Fmoc-Leu-OHFmoc-Val-OH [ No CAS ]
3-[(2R,3S)-3-((S)-2-{(S)-2-[(S)-2-Amino-3-(2,3-dihydroxy-benzoylamino)-propionylamino]-3-methyl-butyrylamino}-4-methyl-pentanoylamino)-2-hydroxy-4-phenyl-butyrylamino]-benzoic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 4354 - 4359

18
[ 303-38-8 ]
[ 100-51-6 ]
benzyl 2,3-dihydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	Stage #1: 2,3-Dihydroxybenzoic acid With dicyclohexyl-carbodiimide In acetonitrile at 50℃; for 1h; Stage #2: benzyl alcohol With dmap In acetonitrile at 65℃; for 3h;	General esterification procedure for the synthesis of B1-B11 and C1-C4 General procedure: N, N-dicyclohexylcarbodiimide (1.55 g, 7.5 mmol) was added to a solution of 2,3-dihydroxybenzoic acid (0.77 g, 5.0 mmol) in anhydrous CH3CN (20 mL). The reaction mixtures were stirred for 1 h at 50 oC until complete dissolution of the solids was achieved. Next corresponding phenol or alchol (5 mmol) and DMAP (0.06 g, 0.5 mmol) were added to the mixtures and stirred for 3 h at 65 oC, then the mixtures were concentrated under reduce vacuum. The residue was extracted with ethyl acetate three times and then filtered. The filtrate was washed with 5% aqueous citric acid solution, saturated NaHCO3 and brine successively. The organic phase was dried over Na2SO4, filtered, and then concentrated. The crude mixture was purified by column chromatography on silica gel to afford B1-B11 and C1-C4.
46%	With 1,1'-carbonyldiimidazole In acetonitrile at 65℃; for 3h;

Reference： [1]Wang, Zhenkang; Ma, Chunhua; Wang, Yujie; Xiao, Qiang; Xu, Chenghui; Li, Yingxia [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 22]
[2]Rivero-Cruz, Blanca; Rivero-Cruz, Isabel; Rodriguez-Sotres, Rogelio; Mata, Rachel [Phytochemistry, 2007, vol. 68, # 8, p. 1147 - 1155]

19
[ 303-38-8 ]
[ 154447-36-6 ]

Reference： [1]Australian Journal of Chemistry,2003,vol. 56,p. 1099 - 1106

20
[ 303-38-8 ]
[ 1668-84-4 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887

21
[ 303-38-8 ]
[ 5768-39-8 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 871 - 887
[2]Journal of Agricultural and Food Chemistry,2011,vol. 59,p. 635 - 644
[3]Patent: WO2016/131098,2016,A1
[4]Patent: CN104016960,2018,B

22
[ 303-38-8 ]
[ 72517-23-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2001,vol. 9,p. 3113 - 3122
[2]Journal of Organic Chemistry,2012,vol. 77,p. 10461 - 10467
[3]Chemistry - A European Journal,2015,vol. 21,p. 16887 - 16894

23
[ 303-38-8 ]
[ 105603-49-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,1996,vol. 6,p. 2279 - 2280
[2]Chemistry - A European Journal,2011,vol. 17,p. 6369 - 6381
[3]Patent: EP3404033,2018,A1

24
[ 303-38-8 ]
[ 148703-14-4 ]

Reference： [1]Journal of Organic Chemistry,1948,vol. 13,p. 489,493

25
[ 303-38-8 ]
[ 38871-41-9 ]

Reference： [1]Journal of Organic Chemistry,1948,vol. 13,p. 489,493
[2]Journal of Agricultural and Food Chemistry,2011,vol. 59,p. 635 - 644
[3]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 2947 - 2954

26
[ 303-38-8 ]
[ 349550-81-8 ]

Reference： [1]Journal of Organic Chemistry,1948,vol. 13,p. 489,493
[2]Bioorganic Chemistry,2020,vol. 102

27
[ 303-38-8 ]
[ 2411-83-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sulfuric acid; In methanol;	Preparation 1 Methyl 2,3-dihydroxybenzoate A mixture of 92.472 g (0.6 mol) of 2,3-dihydroxybenzoic acid (FW 154.12; Aldrich cat.# 12,620-9; RSO # 9449), 100 mL of anhydrous methanol and 3 mL of concentrated sulfuric acid was heated to reflux for 36 hrs. After cooling down, reaction mixture was concentrated down to approximately 1/3 of its volume and poured on ice. A precipitate that formed was washed thoroughly with cold water, filtered off and dried in the desiccator over calcium sulfate. Yield 98.4 g of off-white solid (98%). This was used without further purification. LC MS: AP+ 169, AP- 167.
	With sulfuric acid; In methanol;	Methyl 2,3-dihydroxybenzoate A mixture of 2,3-dihydroxybenzoic acid (3.8 g, 24.6 mmol) in methanol (300 ml) was treated dropwise with conc. Sulfuric acid (4.2 g) and the resultant solution was heated at reflux temperature overnight. Upon cooling the solvent was evaporated and the residue poured into ice-water. The mixture was extracted with dichloromethane (3*50 ml) and the combined organic fractions dried (Na2SO4) and concentrated to yield a pale tan solid (4.05 g). 1H-NMR (CDCl3, 400 MHz): delta 3.92 (s, 3H), 6.76 (t, 1H, J=7.6 Hz), 7.08 (d, 1H, J=7.2 Hz), 7.33 (d, 1H, J=7.6 Hz), 10.88 (s, 1H).
	With sulfuric acid; In methanol; water;	Reference Example 76 Methyl[2,3-bis(ethoxycarbonylmethoxy)]benzoate To a solution of 2,3-dihydroxybenzoic acid (33.0 g, 214 mmol) in methanol (200 mL) was added sulfuric acid (5.0 mL) and the mixture was refluxed for 14 hours. The solvent was then distilled off under reduced pressure. To that residue was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure to provide 35.0 g of methyl 2,3-dihydroxybenzoate.

Reference： [1]Patent: EP1340500,2003,A1
[2]Patent: US2003/216389,2003,A1
[3]Patent: US6248766,2001,B1
[4]Organic and Biomolecular Chemistry,2014,vol. 12,p. 749 - 757
[5]Journal of the American Chemical Society,2017,vol. 139,p. 16959 - 16966

28
[ 303-38-8 ]
[ 75-36-5 ]
[ 2411-83-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydrogencarbonate; In hydrogenchloride; methanol;	EXAMPLE 8K Methyl 2,3-dihydroxy-benzoate Prepare a reaction flask with 300 mL methanol and add 30 mL of acetyl chloride, under argon, in an ice bath. Add 2,3-dihydroxy-benzoic acid (21.70 g, 0.1418 mole) and stir while heating at reflux overnight. Chill in an ice bath and bubble through hydrogen chloride gas for about 10 minutes. Heat the mixture and stir at reflux overnight. Cool to ambient temperature, then concentrate to an off-white solid. Dissolve and separate into diethyl ether and water. Isolating the ether portion and extract twice with 250 mL 5% sodium bicarbonate. Separate, wash with brine and dry over magnesium sulfate. Filter and condense on a rotary evaporator to give the title compound as an off-white solid (21.1 g, 99%). m.p. 79-81 C.
99%	With sodium hydrogencarbonate; In hydrogenchloride; methanol;	Example 8K Methyl 2,3-dihydroxy-benzoate Prepare a reaction flask with 300 mL methanol and add 30 mL of acetyl chloride, under argon, in an ice bath. Add 2,3-dihydroxy-benzoic acid (21.70 g, 0.1418 mole) and stir while heating at reflux overnight. Chill in an ice bath and bubble through hydrogen chloride gas for about 10 minutes. Heat the mixture and stir at reflux overnight. Cool to ambient temperature, then concentrate to an off-white solid. Dissolve and separate into diethyl ether and water. Isolating the ether portion and extract twice with 250 mL 5% sodium bicarbonate. Separate, wash with brine and dry over magnesium sulfate. Filter and condense on a rotary evaporator to give the title compound as an off-white solid (21.1 g, 99%). m.p. 79-81C.

Reference： [1]Patent: US6004959,1999,A
[2]Patent: EP906268,2001,B1

29
[ 56-87-1 ]
[ 303-38-8 ]
[ 57981-02-9 ]
C₂₇H₂₄F₅N₃O₇ [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2008,vol. 130,p. 7554 - 7555

30
[ 3943-73-5 ]
[ 303-38-8 ]

Reference： [1]Carbohydrate Research,2009,vol. 344,p. 734 - 738

31
[ 303-38-8 ]
[ 67-64-1 ]
[ 277312-95-5 ]

Yield	Reaction Conditions	Operation in experiment
49.4%	With trifluoroacetic anhydride In trifluoroacetic acid at -4 - 20℃; for 52h;	1.1 Step 1: Synthesis of Compound 1B [0156] To the mixture of TFAA (225 mL) and TFA (370 mL) was added compound 1A (45 g, 292 mmol) slowly at -10° C., followed by the addition of acetone (60 g, 1.03 mmol) in TFA(77 mL) over 1 h. After being stirred at -4° C. for 3 h, the solution was warmed up to room temperature and stirred for 2 days before it was concentrated in vacuo to dryness. The residue was dissolved in EtOAc, washed with NaHCO3 solution, dried over Na2SO4. Column chromatography (hexanes/ethyl acetate/DCM, v/v/v, 20/1/20) gave the titled compound 1B (28 g, 49.4% yield) as slightly yellow oil.
49%	With trifluoroacetic acid; trifluoroacetic anhydride at -10 - 20℃; for 52h;	22.1 Synthesis of compound 22B To the mixture of TFAA (225 mL) and TFA (370 mL) was added compound 22 A (45 g, 292 mmol) slowly at -10 °C, followed by the addition of acetone (60 g, 1.03 mmol) in TFA(77 mL) over 1 h. After being stirred at -4 °C for 3 h, the solution was warmed up to room temperature and stirred for 2 days before it was concentrated in vacuo to dryness. The residue was dissolved in EtOAc, washed with NaHCOs solution, dried over Na2S04. Column chromatography (hexanes/ethyl acetate/DCM, v/v/v, 20/1/20) gave the titled compound 22B (28 g, 49% yield) as slightly yellow oil.
49.4%	With trifluoroacetic acid; trifluoroacetic anhydride at -10 - 20℃; for 52h;

39%	Stage #1: 2,3-Dihydroxybenzoic acid With trifluoroacetic acid; trifluoroacetic anhydride at -4℃; for 0.0833333h; Stage #2: acetone at -4 - 20℃; for 8h;	25.A EXAMPLE 25; 3-[(2-Chlorophenyl)Methoxy]-2-Hydroxybenzoic Acid Ethyl Ester EXAMPLE 25 3-[(2-Chlorophenyl)Methoxy]-2-Hydroxybenzoic Acid Ethyl Ester To a stirred solution of trifluoroacetic acid (200 ML) and trifluoroacetic anhydride (100 ML) at -4° C. was added 2,3-dihydroxybenzoic acid (20.0 g, 130 mmol) over 5 min.To this slurry was added acetone (34 ML, 460 mmol) over the course of 1 h.After an additional 3 h, the reaction was allowed to warm to room temperature in situ and stirred 4 h.The resulting solution was evaporated and the resulting residue poured into ice water (300 ML).solid sodium bicarbonate was added portionwise until the solution reached ~PH 9.The gummy residue was extracted into EtOAc (300 ML) and the aqueous phase was extracted twice with EtOAc. The extracts were combined, washed once with brine, dried (Na2SO4) and evaporated.Purification by flash chromatography on silica gel provided the title compound 9.87 g (39% yield). LC/MS gave the correct molecular ion [(M+H)+=197] for the desired compound.
34%	With trifluoroacetic acid In trifluoroacetic anhydride at -5 - 20℃; for 16.95h;	123 Example 123 4-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-9-(propan-2-yloxy)-3,4-dihydro-1,4-benzoxazepin-5(2H)-one Trifluoroacetic acid anhydride (42.0 mL, 300 mmol) was added dropwise to a cooled (-5° C.) solution of 2,3-dihydroxybenzoic acid (8.30 g, 53.9 mmol) in trifluoroacetic acid (83 mL), with stirring. Acetone (14.0 mL, 190 mmol) was then added dropwise over 27 minutes, and the mixture stirred and allowed to warm gradually to room temperature over 16.5 hours. The volatiles were concentrated under vacuum, the residue was dissolved in ethyl acetate (100 mL), and the solution slowly added to a rapidly stirred saturated aqueous sodium bicarbonate solution (200 mL). After gas evolution ceased, the mixture was extracted with ethyl acetate (3*100 mL). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate/heptane) to give 8-hydroxy-2,2-dimethyl-4H-1,3-benzodioxin-4-one (123a, 3.55 g, 34% yield) as an off-white solid.
31%	With trifluoroacetic acid; trifluoroacetic anhydride at 0 - 20℃; for 24h;

Reference： [1]Current Patent Assignee: Novartis (w/o Sandoz); NOVARTIS AG - US2014/194382, 2014, A1 Location in patent: Paragraph 0155; 0156
[2]Current Patent Assignee: QPEX BIOPHARMA INC - WO2016/3929, 2016, A1 Location in patent: Paragraph 0241
[3]Hecker, Scott J.; Reddy, K. Raja; Lomovskaya, Olga; Griffith, David C.; Rubio-Aparicio, Debora; Nelson, Kirk; Tsivkovski, Ruslan; Sun, Dongxu; Sabet, Mojgan; Tarazi, Ziad; Parkinson, Jonathan; Totrov, Maxim; Boyer, Serge H.; Glinka, Tomasz W.; Pemberton, Orville A.; Chen, Yu; Dudley, Michael N. [Journal of Medicinal Chemistry, 2020, vol. 63, # 14, p. 7491 - 7507]
[4]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2003/225091, 2003, A1 Location in patent: Page 39
[5]Current Patent Assignee: PFIZER INC - US2014/179667, 2014, A1 Location in patent: Paragraph 0943; 0944
[6]Brackett, Christopher M.; García-Casas, Ana; Castillo-Lluva, Sonia; Blagg, Brian S. J. [ACS Medicinal Chemistry Letters, 2020, vol. 11, # 11, p. 2221 - 2226]

32
[ 7491-74-9 ]
[ 303-38-8 ]
[ 1206823-86-0 ]

Reference： [1]Journal of Pharmaceutical Sciences,2010,vol. 99,p. 246 - 254

33
[ 110-91-8 ]
[ 303-38-8 ]
[ 592-87-0 ]
[ 1257411-46-3 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 2,3-Dihydroxybenzoic acid; lead(II) thiocyanate With dibromotriphenylphosphorane In tetrahydrofuran; dichloromethane at 0 - 20℃; for 4h; Inert atmosphere; Reflux; Stage #2: morpholine In 1,4-dioxane for 4h; Reflux;	To a suspension of Pb(SCN)2 (3.16 g, 9.8mmol» 1.5 eq) in CH2CI2 (50 ml_) at O0C was added dropwise a solution of PPh3Br2 (3.3 g, 7.8 mmol, 1,2 eq) in CH2CI2 (40 mL) under Ar(g). After 5 min, a solution of 2,3-dihydroxybenzoic acid (1 ,0 g, 6.5 mmol, 1 eq) in CH2CI2ZTHF (40 mL, 4:1) was slowly added, and the mixture was left to warm to rt over 1h before being refluxed for an additional 3h. The resulting solution was filtered and the filter cake was washed with CH2CI2 and hot acetone. The solvent was removed in vacuo to give a pale yellow solid (4.0 g). Dioxane (30 mL) was then added, followed by morpholine (6 mL, 65 mmol, 10 eq). The reaction mixture was refluxed for 4h. The solvent was then removed in vacuo and the residue was further purified by silica gel column chromatography with CH2CI2/Me0H (19:1- 9:1) to yield 2 as a pale yellow solid (1.53 g, 95%); 1H NMR (400 MHz, CDCI3 + 10% MeOD) δH: 7.35 - 7.41 (m, 1 H), 7.04 (d, J=4.7Hz, 2H), 3.72 - 3.79 (m, 4H), 3.64 - 3.70 (m, 4H). MS (ES+) 271.0 (100%, [M+Naf ).

Reference： [1]Current Patent Assignee: KARUS THERAPEUTICS LIMITED - WO2011/12883, 2011, A1 Location in patent: Page/Page column 13

34
4-fluoro-2-(N-methylbenzamide)-benzylamine [ No CAS ]
[ 303-38-8 ]
[ 1332325-19-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

Reference： [1]Location in patent: experimental part Fan, Xing; Zhang, Feng-Hua; Al-Safi, Rasha I.; Zeng, Li-Fan; Shabaik, Yumna; Debnath, Bikash; Sanchez, Tino W.; Odde, Srinivas; Neamati, Nouri; Long, Ya-Qiu [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 16, p. 4935 - 4952]

35
2-(2-(aminomethyl)phenyl)-N-methylacetamide [ No CAS ]
[ 303-38-8 ]
[ 1332325-18-4 ]

Yield	Reaction Conditions	Operation in experiment
39%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

36
[ 5192-03-0 ]
[ 303-38-8 ]
[ 1332325-10-6 ]

Yield	Reaction Conditions	Operation in experiment
40%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

37
[ 64-18-6 ]
[ 303-38-8 ]
[ 506-59-2 ]
[ 1332325-49-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	With triethylamine In ethanol; water at 0℃; Reflux;	5.2.67. 4-((Dimethylamino)methyl)-2,3-dihydroxybenzoic acid (23) To a stirred solution of 2,3-dihydroxybenzoic acid (300 mg, 1.95 mmol), dimethylamine hydrochloride (159 mg, 1.95 mmol), Et3N (544 μL, 3.9 mmol) in EtOH (20 mL) was added HCHO (aq) (146 μL, 1.95 mmol, 40%) at 0 °C. The above mixture was refluxed overnight. The white precipitate was filtered and washed three times with anhydrous EtOH. The residue was dried under vacuum to give 23 (186 mg, 45% yield) as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.16 (d, J = 7.8 Hz, 1H), 6.47 (d, J = 7.5 Hz, 1H), 4.14 (s, 1H), 2.72 (s, 6H). EI-MS m/z: 211 (M)+.

38
[ 61-54-1 ]
[ 303-38-8 ]
[ 1332325-09-3 ]

Yield	Reaction Conditions	Operation in experiment
42%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

39
[ 118-31-0 ]
[ 303-38-8 ]
[ 1332325-06-0 ]

Yield	Reaction Conditions	Operation in experiment
45%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

40
[ 303-38-8 ]
[ 87120-72-7 ]
[ 1350720-09-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 6.5h;	5.2.29. 2,3-Dihydroxy-N-(piperidin-4-yl)benzamide (5k) To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate (184 mg, 1.86 mmol) and triethylamine (1.29 mL, 9.29 mmol) in CH2Cl2 (200 mL, anhydrous) was added the solution of di-tert-butyl dicarbonate (810 mg, 3.72 mmol) in CH2Cl2 (20 mL, anhydrous) dropwise. After stirring at rt for 16 h, the solvent was evaporated and the residue was purified by chromatography using petroleum ether/ethyl acetate (5:1) as eluent to give compound tert-butyl 4-oxopiperidine-1-carboxylate as white solid (318 mg, 86% yield). To the solution of tert-butyl 4-oxopiperidine-1-carboxylate (360 mg) in NH3/MeOH (15 ml) was added Pd/C (15 mg). The mixture was stirred under H2 atmosphere at rt overnight. The Pd/C was filtered and the filtrate was concentrated under vacuum. The concentration provided the residue which was purified by chromatography using DCM/MeOH (12:1) as eluent to give compound 4-aminopiperidine-1-carboxylate as white solid (226 mg, 63% yield). 1H NMR (CDCl3, 300 MHz): δ 4.07 (m, 2H), 2.81-2.65 (m, 3H), 1.84-1.79 (m, 2H), 1.48 (s, 9H), 1.38 (m, 2H). EI-MS: m/z 200 (M)+. A solution of 2,3-dihydroxybenzoic acid (339 mg, 2.2 mmol), EDCI (422 mg, 2.2 mmol), DIPEA (2.2 mmol), and HOBt (297 mg, 2.2 mmol) in dry CH2Cl2 (11 mL) was stirred at room temperature. To this solution was added 4-aminopiperidine-1-carboxylate (220 mg, 1.1 mmol). The reaction mixture was stirred for 6.5 h at room temperature. After removal of most of CH2Cl2, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, saturated NH4Cl and dried over Na2SO4. The concentration provided the residue that was purified by chromatography using petroleum ether/ethyl acetate (5:1) as eluent to give compound tert-butyl 4-(2,3-dihydroxybenzamido)piperidine-1-carboxylate as white solid (190 mg, 51% yield). 1H NMR (CDCl3, 300 MHz): δ 7.04 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.76 (t, J = 8.1 Hz, 1H), 6.16 (s, 1H), 5.79 (br s, 1H), 4.15-4.10 (m, 4H), 2.90 (t, J = 9.9 Hz,2H), 2.04-1.98 (m, 3H), 1.49 (s, 9H). To the solution of 4-(2,3-dihydroxybenzoyl)piperadine-1-carboxylate (67 mg, 0.2 mmol) in anhydrous DCM (5 ml) on ice bath was added TFA(0.578 ml) dropwise. The solution was allowed to warm to rt for 2 h. The solvent was evaporated and the residue was purified by chromatography using methylene chloride/acetone (2:1) as eluent to give 5k as white solid (47 mg, 100% yield). 1H NMR (300 MHz, CD3OD): δ 7.11 (d, J = 8.4 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.62 (t, J = 7.8 Hz, 1H), 4.08-4.06 (m, 1H), 3.34 (d, J = 6.3 Hz, 2H), 2.88 (t, J = 12.3 Hz, 2H), 2.00 (d, J = 6.6 Hz, 2H), 1.82 (q, 2H). 13C NMR (100 MHz, CDCl3): δ 171.6, 150.7, 147.8, 120.3, 120.2, 119.4, 117.2, 48.9, 46.4, 44.8, 30.0. ESI-MS: m/z 237.1 [M+H]+. HRMS (ESI): calcd for C12H17N2O3 (M+H)+ 237.1239, found 237.1225. Purity: system 1, 97.0% (method D, tR = 3.38 min); system 2, 96.8% (method H, tR = 3.79 min).

41
[ 303-38-8 ]
[ 108-91-8 ]
[ 1332325-15-1 ]

Yield	Reaction Conditions	Operation in experiment
38%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

42
[ 303-38-8 ]
[ 81881-74-5 ]
[ 1332325-08-2 ]

Yield	Reaction Conditions	Operation in experiment
36%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

43
[ 303-38-8 ]
[ 140-75-0 ]
[ 1003850-04-1 ]

Yield	Reaction Conditions	Operation in experiment
57%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield). 1H NMR (300 MHz, DMSO-d6): δ 12.43 (br s, 1H), 8.33 (m, 1H), 7.40-7.32 (m, 3H), 7.20-7.14 (m, 2H), 6.94 (m, 1H), 6.71 (m, 1H), 4.48 (s, 2H). 13C NMR (100 MHz, CD3OD): δ 171.9, 163.9 (d, 1JCF = 242.6 Hz), 150.8, 147.9, 136.6, 130.9 (d, 3JCF = 8.2 Hz), 120.2, 119.2, 119.1, 117.1, 116.6 (d, 2JCF = 21.6 Hz), 43.7. EI-MS m/z: 261 (M)+. Purity: system 1, 96.3% (method A, tR = 14.44 min); system 2, 95.0% (method F, tR = 13.13 min).

44
[ 303-38-8 ]
[ 72235-53-1 ]
[ 1332325-07-1 ]

Yield	Reaction Conditions	Operation in experiment
42%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 6.5h; Inert atmosphere;	5.2.18. N-(4-Fluorobenzyl)-2,3-dihydroxybenzamide (5a) General procedure: A solution of 2,3-dihydroxybenzoic acid (154 mg, 1 mmol), EDCI (380 mg, 2 mmol), DIPEA (2 mmol), and HOBt (290 mg, 2 mmol) in dry THF (15 mL) was stirred at rt under N2. To this solution was added 90% (4-fluorophenyl)methanamine (0.152 mL, 1.2 mmol). The reaction mixture was stirred for 6.5 h at rt. After removal of most of THF, 20 mL of EtOAc was added to the residue. The solution was washed by 1 N HCl, satd NH4Cl and dried over Na2SO4. The concentration provided the residue which was purified by chromatography using petroleum ether/ethyl acetate (1:1) as eluent to give compound 5a as a white solid (51 mg, 57% yield).

45
[ 303-38-8 ]
[ 4442-53-9 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2011,vol. 59,p. 635 - 644
[2]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 2947 - 2954
[3]Patent: CN106905335,2017,A

46
[ 303-38-8 ]
[ 1369695-20-4 ]
[ 1369695-21-5 ]

Yield	Reaction Conditions	Operation in experiment
58%	With dmap; dicyclohexyl-carbodiimide In acetonitrile at 20℃; for 24h;	4.2.2.3. 3-[3-(3-(4-Chlorophenyl)-1-[4-(1,1-dimethylethyl)phenyl]methyl}-1H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,2-benzenediol (9) To a solution of amidooxime 8 (15.3 mg, 0.04 mmol), N,N'-dicyclohexylcarbodiimide DCC (8.5 mg, 0.041 mmol) and dimethylaminopyridine DMAP (0.4 mg, 0.0032 mmol) in dry acetonitrile (1.5 ml) was added carboxylic acid (6.3 mg, 0.041 mmol) under vigorous stirring. The reaction mixture was stirred at rt for 24 h. After reaction was concentrated the residue was purified by flash chromatography (0-100% EtOAc/cyclohexane) to afford pure 9 (12 mg, 58%) as a white solid.1H NMR (300 MHz, DMSO) δ: 1.22 (s, 9H, 3Me), 5.55 (d, 2H, 2xNH), 5.85 (s, 2H, CH2), 6.77 (t, 1H, 5-ArH), 7.04 (d, 1H, J = 7.50, 5-ArH), 7.20 (s, 1H, 4-H), 7.25-7.38 (m, 4H, 1-ArH), 7.48 (d, 2H, J = 8.50, 3-ArH), 7.62 (d, 1H, J = 7.50, 5-ArH), 7.81 (d, 2H, J = 8.50, 3-ArH), 9.48 (s, 1H, OH), 10.46 (s, 1H, OH); 13C NMR (75 MHz, DMSO) δ: 31.1, 34.2, 54.3, 104.1, 117.4, 119.1, 119.3, 125.4 126.8, 127.1, 128.9, 131.4, 132.3, 134.1, 137.3, 145.7, 146.1, 146.4, 148.5, 150.1, 155.6, 174.2; MS (ESI): m/z (93%) 519.4 [M+H]+

Reference： [1]Location in patent: experimental part Vujasinović, Ines; Paravić-Radičević, Andrea; Mlinarić-Majerski, Kata; Brajša, Karmen; Bertoša, Branimir [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 6, p. 2101 - 2110]

47
[ 303-38-8 ]
[ 1369695-20-4 ]
[ 1369695-22-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	With dmap; dicyclohexyl-carbodiimide In acetonitrile at 120℃; for 4h;	4.2.2.4. 3-[3-(3-(4-Chlorophenyl)-1-[4-(1,1-dimethylethyl)phenyl]methyl}-1H-pyrazol-5-yl)-1,2,4-oxadiazol-5-yl]-1,2-benzenediol (10) To a solution of amidooxime 8 (15.3 mg, 0.04 mmol), N,N'-dicyclohexylcarbodiimide DCC (8.5 mg, 0.041 mmol) and dimethylaminopyridine DMAP (0.4 mg, 0.0032 mmol) in dry acetonitrile (1.5 ml) was added carboxylic acid (6.3 mg, 0.041 mmol) under vigorous stirring. The reaction mixture was stirred at 120 °C for 4 h. After reaction was concentrated the residue was purified by flash chromatography (0-100% EtOAc/cyclohexane) to afford pure 10 (15 mg, 74%) as a white solid.1H NMR (500 MHz, DMSO) δ: 1.22 (s, 9H, 3Me), 5.85 (s, 2H, CH2), 7.14 (d, 1H, J = 8.30, 5-ArH), 7.22 (d, 2H, J = 8.30, 1-ArH), 7.33 (d, 2H, J = 8.30, 1-ArH), 7.50 (d, 2H, J = 8.50, 3-ArH), 7.55 (t, 1H, 5-ArH), 7.62 (1, 1H, 4-H), 7.96 (d, 2H, J = 8.50, 3-ArH), 8.01 (d, 1H, J = 7.50, 5-ArH), 9.40 (s, 1H, OH), 10.74 (s, 1H, OH); 13C NMR (125 MHz, DMSO) δ: 31.1, 34.2, 54.3, 106.7, 117.5, 119.0, 119.3, 125.4, 127.0, 127.1, 128.8, 130.4, 132.7, 134.0, 135.1, 145.7, 146.1, 149.5, 150.1, 157.4, 160.1, 175.0; MS (ESI): m/z (98%) 501.3 [M+H]+.

48
[ 59-66-5 ]
[ 303-38-8 ]
3C₄H₆N₄O₃S₂*C₇H₆O₄ [ No CAS ]

Reference： [1]Crystal Growth and Design,2012,vol. 12,p. 811 - 824

50
[ 303-38-8 ]
[ 100-44-7 ]
[ 95922-26-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate In N,N-dimethyl-formamide Reflux; Inert atmosphere;	2,3-Bis(benzyloxy)benzoic acid (7): To a solution of dihydroxybenzoic acid (6) (500 mg, 3.24 mmol) in 30 mL of DMF, benzyl chloride (1.33 mL, 11.6 mmol) and K2CO3 (1.71 g, 12.4 mmol) was added. The resulting mixture was then heated to reflux at 120 °C under nitrogen and stirred overnight. The reaction mixture was filtered and the filtrate was evaporated under vacuum to obtain a brown oil. The crude oil was purified via a silica plug using CH2CI2 as eluant. Evaporation of the solvent gave a clear oil (1.36 g, 3.12 mmol). Yield = 96%.
91%	With potassium carbonate In N,N-dimethyl-formamide at 90℃;

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA; NATIONAL INSTITUTES OF HEALTH - WO2012/106534, 2012, A2 Location in patent: Page/Page column 62
[2]Lee, Albert A.; Chen, Yi -Chen S.; Ekalestari, Elisa; Ho, Sheng -Yang; Hsu, Nai -Shu; Kuo, Tang -Feng; Wang, Tsung -Shing Andrew [Angewandte Chemie - International Edition, 2016, vol. 55, # 40, p. 12338 - 12342][Angew. Chem., 2016, vol. 128, # 40, p. 12526 - 12530]

51
Ca⁽²⁺⁾*2C₉H₉O₄^(1-) [ No CAS ]
[ 303-38-8 ]
[ 2150-42-7 ]

Reference： [1]Synthetic Communications,2013,vol. 43,p. 384 - 391,8

52
[ 303-38-8 ]
[ 824-94-2 ]
[ 1154500-34-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; potassium iodide In acetone for 72h; Inert atmosphere; Reflux;	4-Methoxybenzyl 2,3-bis((4-methoxybenzyl)oxy)benzoate (6) A white slurry of 2,3-dihydroxybenzoic acid (0.30 g, 1.94 mmol), 4-methoxybenzyl chloride(0.85 mL, 6.23 mmol), KI (1.03 g, 6.23 mmol), K2CO3 (1.87 g, 13.56 mmol) in acetone (14.3mL) was stirred at reflux for 3 days. The mixture was cooled to room temperature and solventremoved in vacuo. The remaining solid was dissolved in water (20 mL) and extracted withdichloromethane (3 × 25 mL). The combined organic layers were dried over anhydrousNa2SO4, filtered and solvent removed in vacuo to yield compound 6 as a brown solid (0.92 g,1.80 mmol, 92%).
70%	Stage #1: 2,3-Dihydroxybenzoic acid With tetra-(n-butyl)ammonium iodide; potassium carbonate In acetone at 25℃; for 1h; Stage #2: p-methoxybenzyl chloride In acetone Reflux;
52%	With potassium carbonate; sodium iodide In N,N-dimethyl-formamide at 70℃; for 2h;	139.1 Step (1): Compound iii-6a → Compound iii-6b Compound iii-6a (15.0 g, 97.0 mmol) was dissolved into N,N-dimethylformamide (180 mL), and thereto were then added potassium carbonate (60.5 g, 438 mmol), p-methoxybenzyl chloride (47.7 ml, 350 mmol) and sodium iodide (14.6 g, 97.0 mmol) in turn. The liquid was stirred at 70°C for 2 hours. The reaction liquid was diluted with ethyl acetate, and the organic phase was washed with water and a saturated salt solution, and dried over magnesium sulfate. Magnesium sulfate was filtrated off. The organic phase was then concentrated under reduced pressure. Thereto was added diisopropyl ether/ethyl acetate to precipitate a solid. In this way, compound iii-6b was yielded (26.3g, 52%).1H-NMR (CDCl3) δ: 7.32-7.35 (5H, m), 7.17 (2H, d, J= 8.69 Hz), 7.12-7.01 (2H, m), 6.87 (4H, t, J= 9.00 Hz), 6.75 (2H, d, J= 8.85 Hz), 5.24 (2H, s), 5.04 (2H, s), 4.94 (2H, s), 3.82 (3H, s), 3.80 (3H, s), 3.78 (3H, s).

52%

With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 2h; Inert atmosphere;

4-methoxybenzyl 2,3-bis((4-methoxybenzyl)oxy)benzoate (S13) To a solution of S12 (15.0 g, 97.0 mmol) in DMF (180 mL) were added K2CO3 (60.5 g, 438 mmol) and PMBCl (47.7 mL, 350 mmol), then the reaction mixture was stirred at 70°C for 2 h and poured into water. The aqueous layer was extracted with EtOAc and the combined extracts were washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The resulting solid was collected by filtration to give S13. 52% yield. 1H-NMR (CDCl3) δ: 7.32-7.35 (m, 5H), 7.17 (d, J = 8.69 Hz, 2H), 7.12-7.01 (m, 2H), 6.87 (t, J = 9.00 Hz, 4H), 6.75 (d, J = 8.85 Hz, 2H), 5.24 (s, 2H), 5.04 (s, 2H), 4.94 (s, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.78 (s, 3H).

Reference： [1]Tarapdar, Abed; Norris, James K.S.; Sampson, Oliver; Mukamolova, Galina; Hodgkinson, James T. [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 2646 - 2650]
[2]Loupias, Pauline; Dechamps-Olivier, Isabelle; Dupont, Laurent; Vanlemmens, Pierre; Mullié, Catherine; Taudon, Nicolas; Bouchut, Anne; Dassonville-Klimpt, Alexandra; Sonnet, Pascal [Pharmaceuticals, 2019, vol. 12, # 4]
[3]Current Patent Assignee: SHIONOGI & CO., LTD. - EP2557082, 2013, A1 Location in patent: Paragraph 0507; 0508
[4]Aoki, Toshiaki; Yoshizawa, Hidenori; Yamawaki, Kenji; Yokoo, Katsuki; Sato, Jun; Hisakawa, Shinya; Hasegawa, Yasushi; Kusano, Hiroki; Sano, Masayuki; Sugimoto, Hideki; Nishitani, Yasuhiro; Sato, Takafumi; Tsuji, Masakatsu; Nakamura, Rio; Nishikawa, Toru; Yamano, Yoshinori [European Journal of Medicinal Chemistry, 2018, vol. 155, p. 847 - 868]

53
[ 303-38-8 ]
[ 56-65-5 ]
[ 122408-18-8 ]

Reference： [1]Chemistry and Biology,2013,vol. 20,p. 92 - 101

54
[ 303-38-8 ]
[ 106-95-6 ]
[ 130432-57-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	Stage #1: 2,3-Dihydroxybenzoic acid With potassium carbonate In acetonitrile at 80℃; for 1h; Inert atmosphere; Stage #2: allyl bromide In acetonitrile at 70℃; for 17h; Inert atmosphere;	1.1 a solution of 2,3-dihydroxybenzoic acid (10.00 g, 64.89 mmol) and K2C03 (33.20 g, 240.07 mmol) in acetonitrile (140 mL) was heated at 80°C for lh. The reaction mixture was then cooled to room temperature and a solution of allyl bromide (20.80 mL, 240.07 mmol) in acetonitrile (80 mL) was added drop wise. The resulting mixture was heated 17h at 70°C and filtered. The filtrate was evaporated to dryness and diluted in EtOH (100 mL). After adding a solution of NaOH (7.40 g, 184.92 mmol) in 12 mL water, the reaction mixture was refluxed for 23h and evaporated to dryness. The so-obtained residue was dissolved in CH2C12 (100 mL) and 150 mL of HCl IN were added. The aqueous sub phase was extracted two times by using CH2C12 (200 mL) and the organic phases put together, washed twice with water (200 mL), dried (MgS04), filtered and evaporated. After recristallisation in a mixture hexane/ether (50 mL / 50 mL), compound 3 (9.88 g, 42.18 mmol) was obtained with 65% yield. White powder. M.p 138°C. 1H NMR (CDC13): 4.62 (d, 3J = 5Hz, 2H), 4.82 (d, 3J = 6Hz, 2H), 5.32- 5.50 (m, 4H), 6.01-6.15 (m, 2H), 7.16 (m, 2H), 7.75 (dd, 3J = 6 Hz, IH); C13Hi404: calc. C 66.66, H 6.02, O 27.32; found C 66.58, H 6.02, O 27.40.
65%	Stage #1: 2,3-Dihydroxybenzoic acid With potassium carbonate In acetonitrile at 80℃; for 1h; Inert atmosphere; Stage #2: allyl bromide In acetonitrile at 70℃; for 17h; Inert atmosphere; Stage #3: With water; sodium hydroxide In acetonitrile for 23h; Reflux; Inert atmosphere;	1.1 a solution of 2,3-dihydroxybenzoic acid (10.00 g, 64.89 mmol) and K2C03 (33.20 g, 240.07 mmol) in acetonitrile (140 mL) was heated at 80°C for lh. The reaction mixture was then cooled to room temperature and a solution of allyl bromide (20.80 mL, 240.07 mmol) in acetonitrile (80 mL) was added drop wise. The resulting mixture was heated 17h at 70°C and filtered. The filtrate was evaporated to dryness and diluted in EtOH (100 mL). After adding a solution of NaOH (7.40 g, 184.92 mmol) in 12 mL water, the reaction mixture was refluxed for 23h and evaporated to dryness. The so-obtained residue was dissolved in CH2C12 (100 mL) and 150 mL of HCl IN were added. The aqueous sub phase was extracted two times by using CH2C12 (200 mL) and the organic phases put together, washed twice with water (200 mL), dried (MgS04), filtered and evaporated. After recristallisation in a mixture hexane/ether (50 mL / 50 mL), compound 3 (9.88 g, 42.18 mmol) was obtained with 65% yield. White powder. M.p 138°C. 1H NMR (CDC13): 4.62 (d, 3J = 5Hz, 2H), 4.82 (d, 3J = 6Hz, 2H), 5.32- 5.50 (m, 4H), 6.01-6.15 (m, 2H), 7.16 (m, 2H), 7.75 (dd, 3J = 6 Hz, IH); C13Hi404: calc. C 66.66, H 6.02, O 27.32; found C 66.58, H 6.02, O 27.40.
65%	Stage #1: 2,3-Dihydroxybenzoic acid With potassium carbonate In acetonitrile at 80℃; for 1h; Inert atmosphere; Stage #2: allyl bromide In acetonitrile at 70℃; for 17h; Inert atmosphere; Stage #3: With sodium hydroxide In ethanol; water for 23h; Inert atmosphere; Reflux;	1.1.1 Compound 3: a solution of 2,3-dihydroxybenzoc acid (10.00 g, 64.89 mmol) and K2CO3 (33.20 g, 240.07 mmol) in acetonitrile (140 mL) was heated at 80° C. for 1 h. The reaction mixture was then cooled to room temperature and a solution of allyl bromide (20.80 mL, 240.07 mmol) in acetonitrile (80 mL) was added drop wise. The resulting mixture was heated 17 h at 70° C. and filtered. The filtrate was evaporated to dryness and diluted in EtOH (100 mL). After adding a solution of NaOH (7.40 g, 184.92 mmol) in 12 mL water, the reaction mixture was refluxed for 23 h and evaporated to dryness. The so-obtained residue was dissolved in CH2Cl2 (100 mL) and 150 mL of HCl 1 N were added. The aqueous sub phase was extracted two times by using CH2Cl2 (200 mL) and the organic phases put together, washed twice with water (200 mL), dried (MgSO4), filtered and evaporated. After recristallisation in a mixture hexane/ether (50 mL/50 mL), compound 3 (9.88 g, 42.18 mmol) was obtained with 65% yield. White powder. M.p 138° C. 1H NMR (CDCl3): 4.62 (d, 3J=5 Hz, 2 H), 4.82 (d, 3J=6 Hz, 2 H), 5.32-5.50 (m, 4 H), 6.01-6.15 (m, 2 H), 7.16 (m, 2 H), 7.75 (dd, 3J=6 Hz, IH); C13H14O4: calc. C 66.66, H 6.02, O 27.32; found C 66.58, H 6.02, O 27.40.

Reference： [1]Current Patent Assignee: UNIVERSITY OF STRASBOURG; HOSPICES CIVILS DE LYON; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF LYON - WO2013/72071, 2013, A1 Location in patent: Page/Page column 26
[2]Current Patent Assignee: UNIVERSITY OF STRASBOURG; HOSPICES CIVILS DE LYON; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF LYON - WO2013/72717, 2013, A1 Location in patent: Page/Page column 22
[3]Current Patent Assignee: UNIVERSITY OF STRASBOURG; HOSPICES CIVILS DE LYON; CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE; UNIVERSITY OF LYON - US2014/336368, 2014, A1 Location in patent: Paragraph 0140

55
[ 1521-39-7 ]
[ 303-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trichlorophosphate / toluene / 30 - 85 °C 2: triethylamine; aluminum (III) chloride / toluene / 9.5 h / 30 - 75 °C 3: water; hydrogenchloride / toluene / 0.5 h / 15 - 35 °C

Reference： [1]Current Patent Assignee: LAURUS LABS LIMITED - WO2014/13512, 2014, A1

56
[ 67984-81-0 ]
[ 303-38-8 ]

Yield	Reaction Conditions	Operation in experiment
56 g	With hydrogenchloride; water; In toluene; at 15 - 35℃; for 0.5h;	Preparation of 2, 3-dihydroxy benzoic acid form 2, 3-dimethoxy benzoic acid To a stirred solution of 2, 3-dimethoxy benzoic acid (lOOg; 0.549 mol) in dichloromethane (500 mL) and catalytic amount of DMF (~2 mL) at a temperature about 30-35°C, thionyl chloride (130.6g ; 1.102 mol) was added and stirred for a period of two hours. Reaction was monitored by TLC for completion of the starting material (NMT- 5percent).If reaction not completed added thionyl chloride (9.8 g; 0.823 mol). Upon completion of reaction, the reaction mass was quenched in to the -5°C chilled aqueous ammonia (580 mL) solution at a temperature below 15°C under stirring. The reaction mass was stirred at temperature 30-35°C over a period of 30 min. The separated organic fraction was concentrated under atmospheric distillation at below 50°C, charged toluene (100 ml) and co-distilled until the reaction mass moisture content become less than 0.5 percent. The obtained benzamide compound was dissolved in toluene (500 mL) at temperature about 30-35°C.To the reaction mass was added POCl3 (126.3 g; 0.824 mol).The temperature of the reaction mass was raised to 80-85°C and maintained over a period of 1 -2 hours for the completion of the reaction (Progress of the reaction was monitored by HPLC until the benzamide NMT 1.0 percent). If the reaction was not completed, added second lot of POCl3 (lO.lg; 0.06 mol) at 30-35°C. The reaction mass was cooled to a temperature about 30-35°C upon completion of the reaction. The reaction mixture was added to cold water (1000 mL) at 0-5°C.The organic fraction was separated and washed with 8percent sodium bicarbonate solution. The organic fraction was separated and azeotropic distilled at 110-115°C (until moisture content NMT 0.2 percent), after reaching moisture content to normal limit cooled the reaction mass temperature to 40°C and distilled reaction mass volume becomes ~3 volumes under vacuum at a temperature 40-50°C.After distillation cooled the reaction mass temperature to 30-35°C. In another RB flask charged toluene (160 ml), triethyl amine (199.7 g; 1.977 mol) at 30-35°C and stirred for 10 min. charged aluminum chloride (52.7 g 5; 1.977 mol) in five lots with the gap of 10 min between each lot addition (addition of aluminum chloride may raise the temperature to 45-50°C). The reaction mass temperature was raised to about 70-75 °C and added above reaction mass (methoxy compound) for 30 min. maintained the reaction mass at 70-75°C for 8 hr. Progress of the reaction was monitored by HPLC (until the 2,3-dimethoxybenzonitrile content 0.25 percent and 3-methoxy-2-hydroxybenzonitrile content 0.2 percent). If reaction was not completed added second lot of triethyl amine (27.7 g; 0.27 mol) and aluminum chloride (36.6 g; 0.27 mol).Upon completion of the reaction, the reaction mixture was cooled to 30-35°C and quenched with chilled aqueous HC1 (prepared by addition of water (500 ml) and Cone. HC1 (500 ml)) at 15°C. Stirred reaction mass at 25-30°C for about 30 min, filtered the obtained solids and separated aqueous and organic layers. Charged MIBK (320 ml) to the solids and charged above aqueous layer, filtered through celite and separated aqueous and organic layers. To the aqueous layer given MIBK (320+160 ml) extractions. To the combined organic layer given 20percent sodium chloride solution washing, organic layer was azeotropic distilled at 110°C to remove the water (moisture content NMT 0.2 percent).Cooled the reaction mass temperature to 30°C and filtered through 0.45 micron / 1 micron filter. To the filterate charged 1percent EDTA (400 ml), stirred for 30 min and filtered through 10 micron cloth. The organic fraction was separated and distilled off to obtain the residue. The residue was treated with dichloromethane (400 ml) and the solid obtained was filtered and dried under vacuum over 6 hr at 60-65°C to obtain the title compound 2, 3-dihydroxy benzonitrile. (56g, yield 75.4percent) Purity by HPLC 99.81 percent; Impurity A: 0.05percent Impurity B: 0.07 percent

Reference： [1]Patent: WO2014/13512,2014,A1 .Location in patent: Page/Page column 10-13

57
[ 99-50-3 ]
[ 89-86-1 ]
[ 149-91-7 ]
[ 99-10-5 ]
[ 303-38-8 ]
[ 490-79-9 ]
[ 99-06-9 ]
[ 69-72-7 ]
[ 74-88-4 ]
[ 99-96-7 ]
[ 2150-41-6 ]
[ 606-45-1 ]
[ 5368-81-0 ]
[ 121-98-2 ]
[ 2150-38-1 ]
[ 1916-07-0 ]
[ 2150-42-7 ]
[ 2150-40-5 ]
[ 2150-37-0 ]

Reference： [1]Chemical Communications,2014,vol. 50,p. 1694 - 1697

58
[ 134272-64-3 ]
[ 303-38-8 ]
N-(2-(2,5-dioxo-1H-pyrrol-1-yl)ethyl)-2,3-dihydroxybenzamide [ No CAS ]

Reference： [1]Chemical Communications,2015,vol. 51,p. 16609 - 16612

59
[ 303-38-8 ]
[ 54-11-5 ]
nicotine 2,3-dihydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	In tetrahydrofuran at 20℃; for 1h;	7 Example 7. Salts of nicotine with 2,3-dihydroxybenzoic acid To prepare nicotine 2,3-dihydroxybenzoate on a larger scale, 2,3-dihydroxybenzoic acid (4.47 g) is dissolved in THF (8.9 mL) at room temperature. Although unsuccessful on a smaller scale (as noted above), (S)-nicotine (4.7 mL) is added, causing instant precipitation of a crystalline solid. The slurry is diluted with further THF (3 mL) and stirred at room temperature for 1 hour. The solid present is isolated by filtration, washed with heptane (2 x 3 mL), and dried under vacuum at room temperature for about 60 hours to give an off-white solid (7.90 g, 86% yield).

Reference： [1]Current Patent Assignee: BRITISH AMERICAN TOBACCO P.L.C. - WO2015/183801, 2015, A1 Location in patent: Page/Page column 60; 61

60
[ 57260-73-8 ]
[ 303-38-8 ]
[ 197636-95-6 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 2,3-Dihydroxybenzoic acid With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: N-BOC-1,2-diaminoethane In N,N-dimethyl-formamide at 25℃; for 0.5h;	46 2,3-dihydroxybenzoic acid (140 mg, 419 μιτιοΙ) was dissolved in DMF (0.5 mL). DIPEA (146 μ, 838 μιτιοΙ) and HATU (176 mg, 463 μιτιοΙ) were successively added and the reaction mixture was stirred for 15 min at 25 °C. N-Boc-ethylenediamine (92 μ, 632 μιτιοΙ) was added and the reaction mixture was stirred at 25 °C for 30 min. The solution was diluted in EtOAc (20 mL), washed with water (5 mL) and brine (3x10 mL). The organic layer was dried over anhydrous sodium sulfate, giving the crude compound as a brown oil (270 mg). The crude material was adsorbed on S1O2 and purified by silica gel column chromatography (from PE:EtOAc/75:25 to PE:EtOAc/25:75). The fractions of the pure compound were collected and concentrated to yield a white solid (179 mg, 90 %).1H NMR (500 MHz, CDCI3). δ 8.08 (bt, 1 H, J = 5.7 Hz, CONH), 7.70 (m, 1 H), 7.47 (d, 2H, J = 7.2 Hz, Ar-H), 7.44-7.30 (m, 8H, Ar-H), 7.18-7.14 (m, 2H, Ar-H), 5.17 (bs, 2H, ArOCH2C6H5), 5.10 (bs, 2H, J = 6.7 Hz, ArOCH2C6H5), 3.36 (q, 2H, J = 5.9 Hz, CONHCH2), 2.67 (t, 2H, J = 5.8 Hz, CH2NH2), 1 .41 ppm (s, 9H). 13C NMR (125 MHz, CDCI3). 5166.2, 156.2, 151 .9, 147.0, 136.5, 136.4, 129.0, 129.0, 128.9, 128.9, 128.5, 127.8, 127.2, 124.6, 123.4, 1 17.4, 76.7, 71 .5, 41 .1 , 39.8, 28.5 ppm. ESI-MS: C28H33N2O5+ m/z = 477.1287 [M+H+]+, Ae = 0.7 ppm. The analyzed data showed accordance to the previous published ones9.

Reference： [1]Current Patent Assignee: Helmholtz Association - WO2016/26841, 2016, A1 Location in patent: Page/Page column 30

61
[ 536-33-4 ]
[ 303-38-8 ]
C₇H₆O₄*C₈H₁₀N₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 25℃; for 96h;	ETH (50mg, 0.301mmol) and 2,3HBA (46.39mg, 0.301mmol) were taken in 25mL beaker, dissolved in 10mL of methanol solvent at room temperature. This clear solution was then left for slow evaporation at ambient temperature. Block shaped orange colored crystal was obtained after 4days with 1:1 stoichiometry in the molecular salt.

Reference： [1]European Journal of Pharmaceutical Sciences,2017,vol. 96,p. 578 - 589

62
[ 303-38-8 ]
14-methoxy-1-tetradecanol [ No CAS ]
14-methoxytetradecyl 2,3-dihydroxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	14-Methoxytetradecyl 2,3-Dihydroxybenzoate (3c) General procedure: Compound 1b (244 mg, 1.00 mmol) was dissolved in anhydrous CH2Cl2 (20 mL), DMAP (12 mg, 0.1 mmol), EDC·HCl (575 mg, 3.0 mmol) and 2,3-dihydroxybenzoic acid (308 mg, 2.00 mmol) were added into this mixture. Kept stirring overnight at room temperature, and then the mixture was concentrated under vacuum. The crude mixture was purified by column chromatography (petroleum ether-EtOAc 20 : 1) on silica gel to afford 3c (181 mg, 48%) as a colorless powder. 1H-NMR (500 MHz, CDCl3) δ: 10.99 (1H, s), 7.37 (1H, d, J=8.0 Hz),7.10 (1H, d, J=8.0 Hz), 6.79 (1H, t, J=8.0 Hz), 5.68 (1H, s),4.34 (2H, t, J=7.0 Hz), 3.36 (2H, t, J=6.5 Hz), 3.33 (3H, s),1.78 (2H, m), 1.59-1.55 (2H, m), 1.43-1.26 (20H, m). 13C-NMR (125 MHz, CDCl3) δ: 170.4, 148.9, 145.0, 120.5, 119.7, 119.1,112.7, 73.0, 65.7, 58.5, 29.6, 29.5, 29.2, 28.5, 26.1, 25.9. HRESI-MS m/z: 403.2451 (Calcd for C22H36O5Na [M+Na]+: 403.2455).