[ CAS No. 1466-76-8 ] {[proInfo.proName]}

Name: 1466-76-8|2,6-Dimethoxybenzoic acid|98%
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Quality Control of [ 1466-76-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 1466-76-8 ]

CAS No. :	1466-76-8	MDL No. :	MFCD00002437
Formula :	C₉H₁₀O₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MBIZFBDREVRUHY-UHFFFAOYSA-N
M.W :	182.17	Pubchem ID :	15109
Synonyms :

Calculated chemistry of [ 1466-76-8 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	46.39
TPSA :	55.76 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.49
Log Po/w (XLOGP3) :	0.66
Log Po/w (WLOGP) :	1.4
Log Po/w (MLOGP) :	1.06
Log Po/w (SILICOS-IT) :	1.23
Consensus Log Po/w :	1.17

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.53
Solubility :	5.39 mg/ml ; 0.0296 mol/l
Class :	Very soluble
Log S (Ali) :	-1.41
Solubility :	7.14 mg/ml ; 0.0392 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.03
Solubility :	1.72 mg/ml ; 0.00942 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.37

Safety of [ 1466-76-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 1466-76-8 ]

* 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 [ 1466-76-8 ]
Downstream synthetic route of [ 1466-76-8 ]

[ 1466-76-8 ] Synthesis Path-Upstream 1~11

1
[ 1466-76-8 ]
[ 2150-45-0 ]

Reference： [1] Journal fuer Praktische Chemie (Leipzig), 1929, vol. <2> 124, p. 322

2
[ 1466-76-8 ]
[ 16932-44-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-iodo-succinimide; palladium diacetate In N,N-dimethyl-formamide at 80℃; for 3 h; Inert atmosphere	General procedure: A solution of 2,6-dimethoxybenzoic acid (0.1 mmol), iodine reagent, palladium catalyst, solvent (1.0 mL) was added to 10 mLIn the reaction vessel,Access to nitrogen protection,Heating reaction,The product was analyzed by GC-MS. The specific reaction conditions of each control group were shown in Table 1.
37%	With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium iodide In dimethyl sulfoxide at 160℃; for 24 h; Schlenk technique	Silak reaction tube equipped with a magnetic stirrer was charged with 3.1 mg of silver sulfate,36.3 mg of copper acetate, 36.4 mg of 2,6-dimethoxybenzoic acid,149.9 mg of sodium iodide and 1 mL of dimethylsulfoxide.The reaction was heated at 160 ° C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,19.5 mg of 2,6-dimethoxy-iodobenzene was obtained in a yield of 37percent.

Reference： [1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
[2] Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11527 - 11536
[3] Patent: CN106748604, 2017, A, . Location in patent: Paragraph 0039; 0040; 0097; 0098; 0099; 0100
[4] Patent: CN107325002, 2017, A, . Location in patent: Paragraph 0133

3
[ 1466-76-8 ]
[ 20469-63-0 ]
[ 16932-44-8 ]
[ 1195513-07-5 ]

Reference： [1] Patent: CN106748604, 2017, A, . Location in patent: Paragraph 0097; 0098; 0099; 0100
[2] Patent: CN106748604, 2017, A, . Location in patent: Paragraph 0097; 0098; 0099; 0100

4
[ 1466-76-8 ]
[ 16932-44-8 ]
[ 1195513-07-5 ]

Reference： [1] Patent: CN106748604, 2017, A, . Location in patent: Paragraph 0097; 0098; 0099; 0100

5
[ 1466-76-8 ]
[ 16932-45-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With silver carbonate; copper(ll) bromide; palladium dichloride In tetrahydrofuran at 110℃; for 24 h;	General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.

Reference： [1] Tetrahedron Letters, 2013, vol. 54, # 24, p. 3079 - 3081
[2] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
[3] Chemical Science, 2018, vol. 9, # 15, p. 3860 - 3865

6
[ 1466-76-8 ]
[ 3147-64-6 ]

Reference： [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 1039 - 1043

7
[ 1466-76-8 ]
[ 7051-15-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	With silver carbonate; copper dichloride; palladium dichloride In tetrahydrofuran at 110℃; for 24 h;	General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.

Reference： [1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803
[2] Tetrahedron Letters, 2013, vol. 54, # 24, p. 3079 - 3081

8
[ 1466-76-8 ]
[ 16932-49-3 ]

Reference： [1] Journal of Organic Chemistry, 2016, vol. 81, # 7, p. 2794 - 2803

9
[ 931-97-5 ]
[ 1466-76-8 ]
[ 16932-49-3 ]

Reference： [1] Synlett, 2010, # 14, p. 2083 - 2086

10
[ 1466-76-8 ]
[ 55305-43-6 ]
[ 16932-49-3 ]

Reference： [1] Journal of Organic Chemistry, 2017, vol. 82, # 7, p. 3530 - 3537

11
[ 1466-76-8 ]
[ 2734-70-5 ]

Reference： [1] Patent: US6124341, 2000, A,

[ 1466-76-8 ] Synthesis Path-Downstream 1~88

1
[ 908094-01-9 ]
[ 1466-76-8 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; diethyl ether

Reference： [1]Mauthner [Journal fur praktische Chemie (Leipzig 1954), 1929, vol. <2> 121, p. 262][Journal fuer Praktische Chemie (Leipzig), 1929, vol. <2> 124, p. 320]

2
[ 67-56-1 ]
[ 1466-76-8 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With sulfuric acid for 18h; Reflux;
92%	With sulfuric acid at 0℃; for 16h; Reflux;
77%	With di(methoxycarbonyl)methylene tri-n-butylphosphorane In toluene at 70℃; for 24h;

77%	In toluene
65%	With sulfuric acid at 70℃; for 2h;
	With hydrogenchloride
	Stage #1: 2-6-dimethoxybenzoic acid With oxalyl dichloride In N,N-dimethyl-formamide for 1h; Heating; Stage #2: methanol With triethylamine at 20℃; for 0.166667h; Further stages.;

Reference： [1]Moghaddam, Firouz Matloubi; Farimani, Mahdi Moridi [Tetrahedron Letters, 2010, vol. 51, # 3, p. 540 - 542]
[2]Arndt, Hans-Dieter; Nasufovic, Veselin; Sauer, Maria; Vilotijevic, Ivan [Organic and biomolecular chemistry, 2020, vol. 18, # 8, p. 1567 - 1571]
[3]McNulty, James; Capretta, Alfredo; Laritchev, Vladimir; Dyck, Jeff; Robertson, Al J. [Journal of Organic Chemistry, 2003, vol. 68, # 4, p. 1597 - 1600]
[4]Current Patent Assignee: SOLVAY; ROBERTSON ALLEN JAMES (inventor) - WO2004/778, 2003, A1 Location in patent: Page 23-24
[5]Hayrapetyan, Davit; Rit, Raja K.; Kratz, Markus; Tschulik, Kristina; Gooßen, Lukas J. [Chemistry - A European Journal, 2018, vol. 24, # 44, p. 11288 - 11291]
[6]Mauthner [Journal fur praktische Chemie (Leipzig 1954), 1929, vol. <2> 121, p. 262][Journal fuer Praktische Chemie (Leipzig), 1929, vol. <2> 124, p. 320]
[7]Hayashi, Yujiro; Sekizawa, Hiromi; Yamaguchi, Junichiro; Gotoh, Hiroaki [Journal of Organic Chemistry, 2007, vol. 72, # 17, p. 6493 - 6499]

3
[ 1466-76-8 ]
[ 1989-53-3 ]

Yield	Reaction Conditions	Operation in experiment
81.2%	With thionyl chloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 20℃; for 8.5h;	Add 1821 mg of 2,6-dimethoxybenzoic acid to the reactor.Add 40 ml of tetrahydrofuran and stir.0.5 ml of N,N-dimethylformamide was added at room temperature.Then, the mixture was stirred at room temperature for 0.5 hour, and 3 g of thionyl chloride was added dropwise.The reaction was then stirred at room temperature for 8 hours. After the reaction is completed,After the post-treatment and purification process,The compound 2,6-dimethoxybenzoyl chloride was obtained in a yield of 81.2%.
	With oxalyl dichloride; In dichloromethane; at 20℃; for 24h;	General procedure: To a solution of dimethoxylbenzoic acid (2.39 g, 13.14 mmol) in dry dichlormethane (60 mL) was added oxalyl chloride (5.73 mL, 65.7 mmol). The mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure to afford dimethoxylbenzoyl chloride 3a-d as colorless residue. To a solution of 3a-d and 1,2,3-trimethoxybenzene (2, 2.43 g, 14.45 mmol) in 20 mL anhydrous ether, aluminum trichloride (5.26 g, 39.42 mmol) was added at 0 C. The resulting mixture was stirred for 12 h at room temperature under N2 protection. Then a mixture of 15% hydrochloric acid and ethyl acetate (100 mL, V/V = 1:1) were added. The ethyl acetate layer was partitioned, washed with brine (30 mL × 3), dried over magnesium sulfate and concentrated under reduced pressure. The residue was suspended in a solution that contained methanol (22.4 mL), water (14.9 mL) and sodium hydrate (4.9 g, 0.12 mol) at 0 C. Then the reaction mixture was heated to 110 C for next 36 h. After cooled to 0 C, the mixture was acidified with 2 mol/L HCl solution till pH = 2-3. The precipitation was formed, filtered, washed with cold water and dried to provide 4a-d, respectively.
	With oxalyl dichloride; In benzene; at 20℃; for 24h;	In preparation of 1,5,6-trimethoxy-9H-xanthenone, 9.6 g (52.8 mmol) of <strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> is dissolved in 140 mL of dried benzene, 24 mL of oxalyl chloride is added and mixed at room temperature for 24 hours. Subsequently, the solvent and remaining oxalyl chloride are removed via vacuum distillation; 160 mL of dried ethyl ether is added to dissolve the remains; 8.8 g (52.4 mmol) of 1,2,3-trimethoxybenzene is added; the mixture is stirred for 30 minutes in an ice-bath; 20 g (152 mmol) of anhydrate AlCl3 is added and reacted at room temperature for 20 hours; the over amount of AlCl3 is quenched with the diluted HCl solution (15%) and then extracted with ethyl acetate (2*100 mL); the organic phase is dried with anhydrous sodium sulfate and condensed; and as a result, 16 g of yellow solid is obtained. The obtained solid is directly dispersed in 240 mL of mixed solution containing methanol and water (methanol: water=5:3) without purification; 23.2 g (58.36 mmol) of NaOH is added; the mixture is stirred and refluxed at 110 C. for 36 hours; 6 mol/L of HCl is added until the pH value is adjusted to 6-8; and as a result, a large amount of solid is precipitated. The said precipitation is filtered, and the resulting filter cake is purified with the aid of column chromatography, wherein the eluent is the mixed solution containing petroleum ether and ethyl acetate (petroleum ether:ethyl acetate=4:1), and as a result, 12.8 g white solid is obtained, and the productivity is 85%; m.p. is 144.6 C.-145.7 C.; 1H-NMR (300 MHz, CD3COCD3): 3.95 (m, 6H), 4.01 (s, 3H), 6.97 (d, 1H, J1=8.4 Hz, J2=0.6 Hz), 7.14 (d, 1H, J1=8.4 Hz, J2=0.6 Hz), 7.15 (d, 1H, J=9.0 Hz), 7.69 (t, 1H, J=8.4 Hz), 7.89 (d, 1H, J=9 Hz); EI-MS (m/z): 286 (M+).

	With thionyl chloride; In N,N-dimethyl-formamide; toluene; at 20℃;Inert atmosphere;	General procedure: To a solution of carboxylic acids (1.7 mmol) in dry DMF (100 muL) and dry toluene (15 mL) under nitrogen atmosphere, freshly distillated thionyl chloride (3.4 mmol) was added and the solution was stirred at room temperature overnight. The solvent and thionyl chloride were removed under vacuum. The acid chloride was dissolved with dichloromethane (15 mL) under nitrogen atmosphere and directly used for the synthesis of the boronic acid.
	With thionyl chloride; N,N-dimethyl-formamide; at 80 - 90℃; for 2h;Reflux;	General procedure: A solution of 4-methoxybenzoic acid 1a (1.0 g) and DMF (catalytic amount) in thionyl chloride (5 mL) was stirred at 80-90C for 2 h. After reclaimed the thionyl chloride under reduced pressure, 4-methoxybenzoyl chloride 2a was yielded. 4-methoxybenzoyl chloride 2a was dissolved in dried CH2Cl2 and reacted with excess furan (5mL) catalyzed by AlCl3. The reaction mixture was stirred at 0C for 2 h and then warmed to room temperature and stirred for additional 12 h. After the reaction was completed, the reaction was quenched by carefully pouring the mixture into iced water (100 mL) and the resultant compound was collected by filtration. Then, the filtrate was extracted with CH2Cl2 (320mL), and dried with anhydrous Na2SO4. The solvent was removed under reduced pressure to yield brown solid. The brown solid was purified by silica gel column chromatography (Petroleum ether/EtOAc 80:20, v/v) to give compound 3a as light yellow solid. 10% (eq) BBr3 (5 mL) was added to a solution of compound 3a in CH2Cl2 (20 mL). The reaction mixture was stirred at -78C for 30 min and then warmed to room temperature and stirred for additional 3.5 h. After the reaction was completed, it was quenched by carefully pouring the mixture into iced water (100 mL), extraction of the aqueous layer three times with EtOAc, washing with 5% NaHSO3 (40 mL) and water (100 mL), and drying with anhydrous Na2SO4. The solvent was removed under reduced pressure to yield a light red solid 4a (0.643 g, 58% yield).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 25℃; for 0.5h;	Example 98: 2,6-Dimethoxy- -[2-(quinolin-2-ylmethyl)cyclopentyl]benzamide To a solution of 2,6-dimethoxybenzoic acid (CAS number 1466-76-8 ; 0.036 g, 0.331 mmol) in DCM (5 ml) was added a catalytic amount of DMF, followed by oxalyl chloride (0.050 g, 0.398 mmol) at 0C and then the reaction mixture was stirred at ambient temperature for 30 minutes. Separately, to the solution of 2-(quinolin-2- ylmethyl)cyclopentanamine hydrochloride (Intermediate 8, isomer 2; 0.075 g, 0.398 mmol) in DCM (5 ml) was added triethylamine (0.167 g, 1.659 mmol), followed by the pre-made solution of the acid chloride at 0C. The reaction mixture was stirred at room temperature for 2 hours and then was poured into water (20 ml) and extracted with DCM (15 ml x 3). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-40% ethyl acetate / n-hexane) to afford the title compound.1H NMR (400 MHz, DMSO-d); delta ppm 1.32-1.34 (m, IH), 1.48- 1.63 (m, 4H), 1.93-1.97 (m, IH), 2.27-2.31 (m, IH), 2.69-2.75 (m, IH), 3.38-3.39 (m, IH), 3.73 (s, 6H), 3.97-4.01 (m, IH), 6.66-6.70 (m, 2H), 7.26-7.31 (m, IH), 7.44-7.46 (m, IH), 7.52-7.56 (m, IH), 7.69-7.73 (m, IH), 7.92-7.94 (m, 2H), 8.11-8.13 (m, IH), 8.26-8.28 (m, IH)MS ES+: 391

Reference： [1]Cell Chemical Biology,2020,vol. 27,p. 586 - 597
[2]Patent: CN108794327,2018,A .Location in patent: Paragraph 0007-0010
[3]Chemische Berichte,1966,vol. 99,p. 1906 - 1911
[4]European Journal of Medicinal Chemistry,1990,vol. 25,p. 507 - 517
[5]Journal of Organic Chemistry,1990,vol. 55,p. 4520 - 4522
[6]Journal of Heterocyclic Chemistry,1981,vol. 18,p. 191 - 192
[7]Journal of the American Chemical Society,1939,vol. 61,p. 1418
[8]Journal of Medicinal Chemistry,1982,vol. 25,p. 1280 - 1286
[9]Journal of Medicinal Chemistry,1985,vol. 28,p. 1263 - 1269
[10]Synthetic Communications,1982,vol. 12,p. 1139 - 1146
[11]Archiv der Pharmazie,1985,vol. 318,p. 78 - 84
[12]Chemical and Pharmaceutical Bulletin,1992,vol. 40,p. 202 - 211
[13]Journal of Medicinal Chemistry,1988,vol. 31,p. 1039 - 1043
[14]Il Farmaco,1996,vol. 51,p. 159 - 174
[15]Phytochemistry,1996,vol. 42,p. 1195 - 1198
[16]Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy,2000,vol. 56 A,p. 2439 - 2450
[17]Il Farmaco,2000,vol. 55,p. 469 - 476
[18]Chemical and Pharmaceutical Bulletin,2003,vol. 51,p. 1075 - 1080
[19]European Journal of Medicinal Chemistry,2011,vol. 46,p. 1280 - 1290
[20]Molecules,2011,vol. 16,p. 4897 - 4911
[21]Patent: US2012/59050,2012,A1 .Location in patent: Page/Page column 6
[22]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3915 - 3924
[23]Organic and Biomolecular Chemistry,2013,vol. 11,p. 3341 - 3348
[24]Journal of the American Chemical Society,2014,vol. 136,p. 11224 - 11227
[25]Medicinal Chemistry,2013,vol. 9,p. 303 - 311
[26]Patent: WO2015/55994,2015,A1 .Location in patent: Page/Page column 152; 153
[27]European Journal of Organic Chemistry,2016,vol. 2016,p. 2336 - 2350
[28]Chemistry - A European Journal,2018,vol. 24,p. 11288 - 11291
[29]Drug Development Research,2018,vol. 79,p. 352 - 361
[30]Journal of Enzyme Inhibition and Medicinal Chemistry,2020,vol. 35,p. 974 - 992

4
[ 16932-49-3 ]
[ 1466-76-8 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1883,vol. 2,p. 237
Recueil des Travaux Chimiques des Pays-Bas,1894,vol. 13,p. 124

5
[ 16932-49-3 ]
[ 1466-76-8 ]
[ 21864-67-5 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1929,vol. <2> 121,p. 262
Journal fuer Praktische Chemie (Leipzig),1929,vol. <2> 124,p. 320

6
[ 124-38-9 ]
[ 151-10-0 ]
[ 1466-76-8 ]

Yield	Reaction Conditions	Operation in experiment
71%		5.90 g (0.256 M) of sodium and 200 ml of anhydrous toluene are introduced into a reactor. The mixture is refluxed for 30 min and then stirred vigorously at room temperature. 12.6 g (0.09 M) of 1,3-dimethoxybenzene and 17.7 g (0.119 M) of chlorooctane are then added successively. After stirring for 2 h at room temperature, about 35 g of CO2 are added and the reaction is stirred for 12 h at room temperature. The excess sodium is then neutralized with 10 ml of methanol. After acidification using concentrated hydrochloric acid solution, the medium is concentrated under partial pressure. The residue is dissolved in acetone. The inorganic salts are removed by filtration. Recrystallization is carried out in an acetone/hexane mixture. 11.3 g of 2,6-dimethoxybenzoic acid (yield=68%) are thus obtained. Characteristics of the product obtained: 1H NMR DMSO-d6) =3.89 ppm (s, 6H), 6.60 ppm (d, 2 H), 7.34 (t, 1H), 8-9 (s,1H). By replacing the chlorooctane with chloropropane, 2,6-dimethoxybenzoic acid is obtained in a yield of 71%.
68%		5.90 g (0.256 M) of sodium and 200 ml of anhydrous toluene are introduced into a reactor. The mixture is refluxed for 30 min and then stirred vigorously at room temperature. 12.6 g (0.09 M) of 1,3-dimethoxybenzene and 17.7 g (0.119 M) of chlorooctane are then added successively. After stirring for 2 h at room temperature, about 35 g of CO2 are added and the reaction is stirred for 12 h at room temperature. The excess sodium is then neutralized with 10 ml of methanol. After acidification using concentrated hydrochloric acid solution, the medium is concentrated under partial pressure. The residue is dissolved in acetone. The inorganic salts are removed by filtration. Recrystallization is carried out in an acetone/hexane mixture. 11.3 g of 2,6-dimethoxybenzoic acid (yield=68%) are thus obtained. Characteristics of the product obtained: 1H NMR DMSO-d6) =3.89 ppm (s, 6H), 6.60 ppm (d, 2 H), 7.34 (t, 1H), 8-9 (s,1H).

Reference： [1]Patent: US6384273,2002,B1 .Location in patent: Page column 7-8
[2]Angewandte Chemie - International Edition,2002,vol. 41,p. 340 - 343
[3]Patent: US6384273,2002,B1 .Location in patent: Page column 7, 8
[4]Journal of Organic Chemistry,1974,vol. 39,p. 3559 - 3564
[5]Chemische Berichte,1964,vol. 97,p. 3098 - 3105
[6]Chemische Berichte,1963,vol. 96,p. 2042 - 2046

7
[ 1466-76-8 ]
[ 16700-55-3 ]

Reference： [1]Tetrahedron,2001,vol. 57,p. 2871 - 2884
[2]Journal of the Chemical Society. Perkin transactions II,1986,p. 1751 - 1756
[3]Tetrahedron Letters,2000,vol. 41,p. 8311 - 8315
[4]Chemistry Letters,1990,p. 389 - 392

8
[ 1466-76-8 ]
[ 84225-86-5 ]

Yield	Reaction Conditions	Operation in experiment
85.9%	With bromine; In dichloromethane; at 20℃;	A solution of bromine (14.06 mL, 274 mrnol, 1 eq.) in CH2C12 (20 mL) was added slowly over 8 h to a suspension of 2,6-dimethoxybenzoic acid (1A) (50 g, 274 mmol) in CH2CI2 (200 mL). After stirring at rt overnight, the light orange slurry was heated and a portion of the solvent (methyl bromide, hydrogen bromide and CH2CI2) was removed by distillation at atmospheric pressure (total volume distilled 100 mL). Ethanol (150 mL) was added and the remaining CH2CI2 was distilled off at atmospheric pressure, slowly increasing the bath temperature to 90 C. Upon completion of the distillation (1 h), the heterogeneous mixture was cooled to rt. After stirring 1 h at rt, the slurry was cooled to 0 C. After stirring at 0 C for 2 h, the solids were collected by filtration. The filtrate was recirculated to rinse the flask and stir bar. The solids were rinsed with ethanol at 0 C (2 x 50 mL), air dried, then dried under high vacuum to give IB as fine white needles (58.23 g, 85.9%).
85.9%	With bromine; In dichloromethane; at 20℃;	A solution of bromine (14.06 mL, 274 mmol, 1 eq.) in CH2CI2 (20 mL) was added slowly over 8 h to a suspension of 2,6-dimethoxybenzoic acid (2A) (50 g, 274 mmol) in CH2CI2 (200 mL). After stirring at rt overnight, the light orange slurry was heated and a portion of the solvent (methyl bromide, hydrogen bromide and CH2CI2) was removed by distillation at atmospheric pressure (total volume distilled 100 mL). Ethanol (150 mL) was added and the remaining CH2CI2 was distilled off at atmospheric pressure, slowly increasing the bath temperature to 90 C. Upon completion of the distillation (1 h), the heterogeneous mixture was cooled to rt. After stirring 1 h at rt, the slurry was cooled to 0 C. After stirring at 0 C for 2 h, the solids were collected by filtration. The filtrate was recirculated to rinse the flask and stir bar. The solids were rinsed with ethanol at 0 C (2 x 50 mL), air dried, then dried under high vacuum to give compound 2B as fine white needles (58.23 g, 85.9%).
48%	With bromine; In chloroform; at 0 - 25℃; for 30h;	Step 1: Synthesis of 12B [0253] To a solution of 2,6-dimethoxybenzoic acid (12A) (50 g, 0.275 mol) in CHC13 (1 L) at 0 oC was added dropwise bromine (14.4 mL, 0.263 mol). The reaction mixture was stirred at 25 oC for 30 hours, before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 12B (32.5 g, 48 %) as white solid.

48%	With bromine; In chloroform; at 0 - 25℃; for 30h;	To a solution of 2, 6-dimethoxybenzoic acid (26A) (50 g, 0.275 mol) in CHC13 (1 L) at 0 C was added dropwise bromine (14.4 mL, 0.263 mol). The reaction mixture was stirred at 25 C for 30 hours, before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 26B (32.5 g, 48 %) as white solid.
48%	With bromine; In chloroform; at 0 - 25℃; for 30h;	To a solution of 2, 6-dimethoxybenzoic acid (7A) (50 g, 0.275 mol) in CHCI3 (1 L) at 0 C was added dropwise bromine (14.4 mL, 0.263 mol). The reaction mixture was stirred at 25 oC for 30 hours, before it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate/hexanes) to afford compound 7B (32.5 g, 48 %) as white solid.
	With bromine; In chloroform;	Example 8 N-Ethyl-2-(2-acetoxy-3-bromo-6-methoxybenzamidomethyl)pyrrolidine To a suspension of <strong>[1466-76-8]2-6-dimethoxybenzoic acid</strong> (80 g, 0.44 mole) in 1.5 l of dry chloroform was added dropwise with stirring a solution of 70.4 g bromine in 100 ml of dry chloroform during 3 h at 0 C. The solution is allowed to reach room temperature slowly during 20 h. The solvent was evaporated in vacuo and the residual crystalline mass was recrystallized from methanol giving 3-bromo-2-hydroxy-6-methoxybenzoic acid. Yield 82 g (76%). M.p. 143-4 C.

Reference： [1]Patent: WO2018/5662,2018,A1 .Location in patent: Paragraph 0200
[2]Patent: WO2019/204419,2019,A1 .Location in patent: Paragraph 0184
[3]Journal of Medicinal Chemistry,1985,vol. 28,p. 1263 - 1269
[4]Tetrahedron,2010,vol. 66,p. 197 - 207
[5]Patent: WO2015/179308,2015,A1 .Location in patent: Paragraph 0253
[6]Patent: WO2016/3929,2016,A1 .Location in patent: Paragraph 0266
[7]Patent: WO2016/149393,2016,A1 .Location in patent: Paragraph 0246
[8]Patent: US4789683,1988,A

9
[ 1466-76-8 ]
[ 77-78-1 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate In acetone for 23h; Heating;

Reference： [1]Tsuchida, Eishun; Hasegawa, Etsuo; Komatsu, Teruyuki; Nakata, Taisaku; Nishide, Hiroyuki [Chemistry Letters, 1990, # 3, p. 389 - 392]

10
[ 1466-76-8 ]
[ 3147-64-6 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1039 - 1043

11
[ 601-84-3 ]
[ 124-41-4 ]
[ 1466-76-8 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1966,vol. 694,p. 98 - 109

12
[ 1466-76-8 ]
[ 20491-92-3 ]
[ 22961-81-5 ]

Reference： [1]Tetrahedron,1969,vol. 25,p. 1947 - 1960

13
[ 1466-76-8 ]
[ 4136-22-5 ]
[ 176650-86-5 ]

Reference： [1]Journal of the American Chemical Society,1996,vol. 118,p. 4550 - 4559

14
[ 1466-76-8 ]
[ 5680-79-5 ]
[ 51579-20-5 ]

Yield	Reaction Conditions	Operation in experiment
65%	With diphenyl phosphoryl azide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 0 - 20℃;Inert atmosphere;	<strong>[1466-76-8]2,6-Dimethoxybenzoic acid</strong> (1.83 g, 10 mmol) in 20 mL DMF was mixed with the glycine methyl ester (HCl, 1.39 g, 11 mmol). Under nitrogen atmosphere the solution was cooled at 0 C. 2.6 mL Diphenylphosphoryl azide (DPPA) (10 mmol) and 3.75 mL di-isopropyl ethylamine (0.02 mol) were slowly added. After 4 h at 0 C the solution was stirred overnight at room temperature. The reaction was followed by TLC (silica gel 60, ethyl acetate, RF (product): 0.62). After the addition of 100 mL dichloromethane the solution was washed first with 2 N HCl and then with NaHCO3 (5% w/v) and dried over Na2SO4. After filtration and the solvents removal the product was solubilized in a small amount of dichloromethane and purified by filtration through silica gel using ethyl acetate/petroleum ether 40-60, 4:1. After the elimination of the solvent under vacuum a white solid (1.65 g, 0.0065 mol, yield: 65%) was obtained. The product was mixed with 2 equiv LiOH solved in THF/water 1:1 v/v (20 mL). The pH of the solution was adjusted to 1 with 6 N HCl. After the extraction of the product with ethyl acetate the solution was washed with water and dried over Na2SO4. After filtration the solvent was removed under vacuum and a white solid (1.52 g, 6.4 mmol, yield: 98%) was obtained.

Reference： [1]Synthetic Communications,1999,vol. 29,p. 1965 - 1976
[2]Bioorganic and Medicinal Chemistry,2012,vol. 20,p. 3915 - 3924

15
[ 16932-49-3 ]
concentrated aq. barium hydroxide solution [ No CAS ]
[ 1466-76-8 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1883,vol. 2,p. 237
Recueil des Travaux Chimiques des Pays-Bas,1894,vol. 13,p. 124

16
[ 16932-49-3 ]
KOH-solution [ No CAS ]
[ 1466-76-8 ]
[ 21864-67-5 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1929,vol. <2> 121,p. 262
Journal fuer Praktische Chemie (Leipzig),1929,vol. <2> 124,p. 320

17
[ 1466-76-8 ]
[ 616-38-6 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 1,8-diazabicyclo[5.4.0]undec-7-ene for 4h; Heating;
98%	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 160℃; for 0.2h; microwave irradiation;

Reference： [1]Shieh, Wen-Chung; Dell, Steven; Repic, Oljan [Journal of Organic Chemistry, 2002, vol. 67, # 7, p. 2188 - 2191]
[2]Shieh, Wen-Chung; Dell, Steven; Repič, Oljan [Tetrahedron Letters, 2002, vol. 43, # 32, p. 5607 - 5609]

18
[ 292638-84-7 ]
[ 1466-76-8 ]
[ 55288-33-0 ]

Reference： [1]Organic Letters,2009,vol. 11,p. 2341 - 2344
[2]Journal of Organic Chemistry,2016,vol. 81,p. 2521 - 2533
[3]Journal of the American Chemical Society,2002,vol. 124,p. 11250 - 11251

19
[ 1445-45-0 ]
[ 1466-76-8 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
96%	In various solvent(s) at 80℃; for 2h;

Reference： [1]Yoshino, Tomonori; Imori, Satomi; Togo, Hideo [Tetrahedron, 2006, vol. 62, # 6, p. 1309 - 1317]

20
[ 1466-76-8 ]
[ 2150-45-0 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1929,vol. <2> 124,p. 322

21
[ 1466-76-8 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile	1 Preparation of Methyl 2,6-dimethoxybenzoate EXAMPLE 1 Preparation of Methyl 2,6-dimethoxybenzoate A solution containing 2,6-dimethoxybenzoic acid (5.0 g, 27.5 mmol), DBU (4.2 g, 27.5 mmol), DMC (50 mL), and acetonitrile (50 mL) was circulated at 20 mL/min by a pump through a Milestone ETHOS-CFR continuous-flow reactor, which had been preheated to 160° C. at 20 bar by microwave irradiation. The reaction mixture was analyzed by HPLC after each cycle (6 minutes microwave irradiation). The yield of methyl 2,6-dimethoxybenzoate after two cycles (12 minutes microwave irradiation time) as determined by HPLC was 99% conversion. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc (100 mL) and H2O (80 mL).
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile	1 Preparation of methyl 2,6-dimethoxybenzoate EXAMPLE 1 Preparation of methyl 2,6-dimethoxybenzoate A solution containing 2,6-dimethoxybenzoic acid (5.0 g, 27.5 mmol), DBU (4.2 g, 27.5 mmol), DMC (50 mL), and acetonitrile (50 mL) was circulated at 20 mL/min by a pump through a Milestone ETHOS-CFR continuous-flow reactor, which had been preheated to 160° C. at 20 bar by microwave irradiation. The reaction mixture was analyzed by HPLC after each cycle (6 minutes microwave irradiation). The yield of methyl 2,6-dimethoxybenzoate after two cycles (12 minutes microwave irradiation time) as determined by HPLC was 99% conversion. The reaction mixture was concentrated under vacuum. The residue was diluted with EtOAc (100 mL) and H2O (80 mL).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2003/144543, 2003, A1
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US6653503, 2003, B2

22
1,8-Diazabicyclo[5.4.0]undec-7-ene [DBU] [ No CAS ]
[ 1466-76-8 ]
[ 144-55-8 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride In dimethyl carbonate (DMC); water	1 Preparation of methyl 2,6-dimethoxybenzoate using DBU catalyst EXAMPLE 1 Preparation of methyl 2,6-dimethoxybenzoate using DBU catalyst 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), (836 mg, 5.49 mmol), was added to a mixture of 2,6-dimethoxybenzoic acid (1), (1.0 g, 5.49 mmol), in dimethyl carbonate (DMC) (10 mL) and the resulting mixture was heated to reflux at 90° C. for 4 hours. The reaction mixture was cooled to 25° C. and diluted with EtOAc (30 mL) and water (30 mL). The organic layer was separated and washed in sequence with 10 mL of water, 2 M HCl (230 mL), saturated aqueous NaHCO3 (230 mL) and water (2*25 mL). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give methyl 2,6-dimethoxybenzoate (2) as a white solid. The yield of the 2,6-dimethoxybenzoate as determined by HPLC was 97-98% conversion.

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US6515167, 2003, B1

23
[ 1466-76-8 ]
[ 2734-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; diphenylphosphoranyl azide; hydrogen; copper(I) iodide; benzyl alcohol;palladium; In methanol; 1,2-dichloro-ethane;	Example 16A 2,6-Dimethoxyaniline To a stirred solution of 2,6-dimethoxybenzoic acid (2.00 g, 11.0 mmol) in 1,2-dichloroethane (45 mL) at ambient temperature was successively added N-methylmorpholine (1.45 mL, 13.2 mmol) and diphenylphosphoryl azide (2,60 mL, 12.1 mmol). After heating the mixture for 2 hours at 75 C., cuprous iodide (150 mg) and benzyl alcohol (2.27 mL, 22.0 mmol) were added and heating was continued overnight. Solvents were removed in vacuo and the residue was chromatographed on silica gel, eluding with 4:1 hexane-ethyl acetate to give the intermediate carbamate (1.50 g, 48 % yield) as a white, crystalline solid. The solid was dissolved in methanol (15 mL) and added to a flask purged with nitrogen containing 10% palladium-on-charcoal (500 mg). The mixture was placed under a balloon of hydrogen and stirred 4 hours at ambient temperature. The mixture was filtered through a pad of Celite and solvents were removed in vacuo to give the title compound (800 mg, 48% yield).

Reference： [1]Patent: US6124341,2000,A

24
[ 117284-59-0 ]
[ 1466-76-8 ]
[ 1972-28-7 ]
[ 117388-11-1 ]

Yield	Reaction Conditions	Operation in experiment
	With triphenylphosphine;	EXAMPLE 3 2-(2,2-Difluorocyclopropyl)ethyl 2,6-dimethoxybenzoate A solution of 3.5 g (13.6 mmol) triphenylphosphine and 2.5 g (20 mmol) <strong>[117284-59-0]2-(2,2-difluorocyclopropyl)ethanol</strong> in 30 ml ether was added dropwise at RT to a solution of 2.48 g (13.6 mmol) 2,6-dimethoxybenzoic acid and 2.35 g (13.6 mmol) diethyl azodicarboxylate in 30 ml ether. The mixture was stirred for 6 hours at RT and allowed to stand overnight. After evaporation of the solvent, the residue was chromatographed over silica gel (hexane/ethyl acetate =95:5). Yield: 3 g (77% of theory). TLC: Eluent=hexane:ethyl acetate=8:2, Rf =0.26. nD20: 1.4974.

Reference： [1]Patent: US4889870,1989,A

25
[ 84563-54-2 ]
[ 1466-76-8 ]
[ 1039364-47-0 ]

Reference： [1]Organic Letters,2008,vol. 10,p. 3161 - 3164

26
[ 22362-86-3 ]
[ 1466-76-8 ]
[ 151-10-0 ]
9-(2',6'-dimethoxyphenyl)-anthracene [ No CAS ]

Reference： [1]Chemical Communications,2008,p. 6312 - 6314

27
[ 931-97-5 ]
[ 1466-76-8 ]
[ 16932-49-3 ]

Reference： [1]Synlett,2010,p. 2083 - 2086

28
[ 109-74-0 ]
[ 1466-76-8 ]
1-(2,6-dimethoxyphenyl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%	With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 0.5h;Microwave irradiation;	General procedure: A 5 mL microwave vial was charged with 6-methyl-2,2'-bipyridine(16.3 mg, 0.096 mmol), Pd(O2CCF3)2 (26.6 mg,0.08 mmol) and 2 mL THF. After stirring at room temperature for 5 minutes,<strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> (182.2 mg, 1 mmol), nitrile (2 mmol), water (200 muL) and TFA (77 muL, 1 mmol) were added and the mixture heated in the microwave for 30minutes at 130 C. Themixture was diluted with DCM (15 mL) and 0.1 M NaOH (15 mL, 3d, 3g, 3i and 3l) or 1% HCl (15 mL, 3b, 3e, 3f, 3h, 3j and 3k), the phaseswere separated and extracted with DCM (2 × 15mL), dried with Na2SO4, filtered and concentrated underreduced pressure. Purification by flash chromatography afforded ketones 3b,3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k or 3l in the yields stated in Tables 1and 2.

Reference： [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 7733 - 7737
[2]Tetrahedron Letters,2014,vol. 55,p. 2376 - 2380

29
[ 1466-76-8 ]
[ 140-29-4 ]
[ 52856-19-6 ]

Yield	Reaction Conditions	Operation in experiment
89%	With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 0.5h;Microwave irradiation;	General procedure: A 5 mL microwave vialwas charged with 6-methyl-2,2'-bipyridine (16.3 mg, 0.096 mmol), Pd(O2CCF3)2(26.6 mg, 0.08 mmol) and 2 mL THF. After stirring at room temperature for 5minutes, <strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> (182.2 mg, 1 mmol), nitrile (5 mmol), water(200 muL) and TFA (77 muL,1 mmol) were added and the mixture heated in the microwave for 30 minutes at130 C. The mixture was diluted with DCM (15 mL) and0.1 M NaOH (15 mL, 3a) or 1% HCl (15mL, 3c, 3d and 3e), the phaseswere separated and extracted with DCM (2 ×15 mL), dried with Na2SO4, filtered and concentratedunder reduced pressure. Purification by flash chromatography afforded ketones 3a, 3c, 3d or 3e in the yields stated in Table 1.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2376 - 2380
[2]Angewandte Chemie - International Edition,2010,vol. 49,p. 7733 - 7737

30
[ 1466-76-8 ]
[ 100-47-0 ]
[ 25855-75-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 0.5h;Microwave irradiation;	General procedure: A 5 mL microwave vialwas charged with 6-methyl-2,2'-bipyridine (16.3 mg, 0.096 mmol), Pd(O2CCF3)2(26.6 mg, 0.08 mmol) and 2 mL THF. After stirring at room temperature for 5minutes, <strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> (182.2 mg, 1 mmol), nitrile (5 mmol), water(200 muL) and TFA (77 muL,1 mmol) were added and the mixture heated in the microwave for 30 minutes at130 C. The mixture was diluted with DCM (15 mL) and0.1 M NaOH (15 mL, 3a) or 1% HCl (15mL, 3c, 3d and 3e), the phaseswere separated and extracted with DCM (2 ×15 mL), dried with Na2SO4, filtered and concentratedunder reduced pressure. Purification by flash chromatography afforded ketones 3a, 3c, 3d or 3e in the yields stated in Table 1.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2376 - 2380
[2]Angewandte Chemie - International Edition,2010,vol. 49,p. 7733 - 7737

31
[ 1466-76-8 ]
[ 75-05-8 ]
[ 2040-04-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With palladium(II) trifluoroacetate; 6-methyl-2,2'-bipyridine In water at 100℃; for 48h;
71%	With Pd⁽²⁺⁾*2C₅F₉O₂^(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine In tetrahydrofuran; water at 130℃; for 0.5h; Microwave irradiation;	Procedure for the synthesis of ketones 3a, 3c,3d and 3e, Table 1 conditions [a] General procedure: A 5 mL microwave vialwas charged with 6-methyl-2,2'-bipyridine (16.3 mg, 0.096 mmol), Pd(O2CCF3)2(26.6 mg, 0.08 mmol) and 2 mL THF. After stirring at room temperature for 5minutes, 2,6-dimethoxy benzoic acid (182.2 mg, 1 mmol), nitrile (5 mmol), water(200 µL) and TFA (77 µL,1 mmol) were added and the mixture heated in the microwave for 30 minutes at130 °C. The mixture was diluted with DCM (15 mL) and0.1 M NaOH (15 mL, 3a) or 1% HCl (15mL, 3c, 3d and 3e), the phaseswere separated and extracted with DCM (2 ×15 mL), dried with Na2SO4, filtered and concentratedunder reduced pressure. Purification by flash chromatography afforded ketones 3a, 3c, 3d or 3e in the yields stated in Table 1.
49%	With [2,2]bipyridinyl; palladium(II) trifluoroacetate; water In neat (no solvent) at 130℃; for 0.5h; Microwave irradiation;

Reference： [1]Lindh, Jonas; Sjoeberg, Per J. R.; Larhed, Mats [Angewandte Chemie - International Edition, 2010, vol. 49, # 42, p. 7733 - 7737]
[2]Axelsson, Linda; Veron, Jean-Baptiste; Sävmarker, Jonas; Lindh, Jonas; Odell, Luke R.; Larhed, Mats [Tetrahedron Letters, 2014, vol. 55, # 15, p. 2376 - 2380]
[3]Svensson, Fredrik; Mane, Rajendra S.; Saevmarker, Jonas; Larhed, Mats; Skoeld, Christian [Organometallics, 2013, vol. 32, # 2, p. 490 - 497]

32
[ 827605-29-8 ]
[ 1466-76-8 ]
[ 938764-37-5 ]

Reference： [1]Chemical Communications,2011,vol. 47,p. 677 - 679

33
[ 1003858-50-1 ]
[ 1466-76-8 ]
[ 95742-32-8 ]

Reference： [1]Chemical Communications,2011,vol. 47,p. 677 - 679

34
[ 1466-76-8 ]
[ 1195513-07-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With N-iodo-succinimide; palladium diacetate; In N,N-dimethyl-formamide; at 120℃; for 3h;Inert atmosphere; Sealed tube;	2,6-dimethoxybenzoic acid (36.4 mg, 0.2 mmol), NIS (135.0 mg, 0.6 mmol), palladium acetate(0.9 mg, 0.002 mmol), and a stirrer were placed in the reaction tube. After replacing the inert gas, 1 ml of solvent DMF was added, Sealed reaction tube. The reaction tube was placed in an oil bath reaction reactor at 120 C and stirred for 3 hours. After cooling to room temperature, use 2 mol / L Sodium hydroxide solution to adjust pH = 10. The reaction tube was diluted with 5 ml of water and extracted with ethyl acetate. Combined extract, And dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and then extracted with ethyl acetate: petroleum ether = 0 to 1: 30 (volume ratio) The crude product was subjected to column chromatography to give pure 2,6-dimethoxy-1,3-diiodobenzene (69.4 mg, 89%).

Reference： [1]Patent: CN106748604,2017,A .Location in patent: Paragraph 0075; 0076; 0107; 0108; 0109; 0110; 0111; 0112
[2]Synlett,2011,p. 1563 - 1566

35
[ 34948-79-3 ]
[ 1466-76-8 ]
[ 1323988-55-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With palladium diacetate; triphenylphosphine; silver carbonate In dimethyl sulfoxide; N,N-dimethyl-formamide at 80℃; for 4h; Inert atmosphere; stereoselective reaction;

Reference： [1]Xiang, Shaohua; Cai, Shuting; Zeng, Jing; Liu, Xue-Wei [Organic Letters, 2011, vol. 13, # 17, p. 4608 - 4611]

36
[ 6280-88-2 ]
[ 1466-76-8 ]
[ 1352638-54-0 ]
[ 56978-50-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 73% 2: 21%	With triphenylphosphine; silver carbonate; palladium dichloride In dimethyl sulfoxide at 130℃; for 6h; Inert atmosphere;

Reference： [1]Xie, Kai; Wang, Sizhuo; Yang, Zhiyong; Liu, Jidan; Wang, Anwei; Li, Xiujian; Tan, Ze; Guo, Can-Cheng; Deng, Wei [European Journal of Organic Chemistry, 2011, # 29, p. 5787 - 5790]

37
[ 4771-47-5 ]
[ 1466-76-8 ]
[ 1352638-56-2 ]
[ 1352638-64-2 ]

Reference： [1]European Journal of Organic Chemistry,2011,p. 5787 - 5790

38
[ 1455-18-1 ]
[ 1466-76-8 ]
[ 1356488-13-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With palladium diacetate; silver carbonate; tricyclohexylphosphine In 1,2-dimethoxyethane; dimethyl sulfoxide at 120℃; for 24h; Inert atmosphere;

Reference： [1]Hu, Peng; Zhang, Min; Jie, Xiaoming; Su, Weiping [Angewandte Chemie - International Edition, 2012, vol. 51, # 1, p. 227 - 231]

39
[ 609-40-5 ]
[ 1466-76-8 ]
[ 1356488-09-9 ]

Reference： [1]Angewandte Chemie - International Edition,2012,vol. 51,p. 227 - 231

40
[ 1466-76-8 ]
[ 100-46-9 ]
[ 1797-79-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With Bromotrichloromethane; 4-(diphenylphosphino)-benzyltrimethylammonium bromide; triethylamine; In tetrahydrofuran; at 60℃; for 6h;Inert atmosphere;	General procedure: IS-PPh3 (746 mg, 1.8 mmol) was dried by a vacuum pump for 2 h at 70 C. To a flask containing IS-PPh3 were added 4-methoxycarboxylic acid (152 mg, 1.0 mmol), BrCCl3 (357 mg, 1.8 mmol), benzylamine (129 mg, 1.2 mmol), triethylamine (0.14 mL, 1.0 mmol), and THF (4 mL). The obtained mixture was stirred for 6 h at 60 C under Ar atmosphere. After the reaction, diethyl ether (10 mL) and aq HCl (1 M, 2 mL) were added at 0 C and the obtained mixture was stirred for 15-30 min at room temperature. Then, the reaction mixture was poured into water (8 mL) and the obtained mixture was extracted with diethyl ether (10 mL×4). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over Na2SO4. After removal of the solvent under reduced pressure, N-benzyl-4-methoxybenzamide was obtained in 93% yield with 99% purity, as estimated by 1H NMR measurement. For cinnamic and aliphatic amides (entries 18-25 in Table 2) and indole-2-carboxamide (entry 16 in Table 2), the reaction mixture was poured into water (8 mL) and the obtained mixture was extracted with chloroform (10 mL×4). The combined organic layer was washed with water (10 mL) and brine (10 mL), and then dried over Na2SO4. After removal of the solvent under reduced pressure, N-benzylamide was obtained. or the recovery of IS-Ph3PO, NaCl (5.0 g) was added to the aqueous layer. The aqueous solution was extracted with CHCl3 (10 mL×5) and the combined organic layer was dried over NaSO4. After removal of the solvent, IS-Ph3PO containing a trace amount of IS-Ph3P was obtained in 95% yield.
87%	With oxygen; potassium carbonate; eosin y; In toluene; at 20℃;Irradiation; Green chemistry;	General procedure: A flame-dried 10 mL flask was charged with amine 2 (0.5 mmol), potassium acetic acid 1 (1.5 mmol), potassium carbonate (2.0 mmol) and toluene (3 mL). Eosin Y (0.01 mmol) was added to the mixture. The mixture was allowed to stir at room temperature opening in air, and be irradiated with a Luxeon Rebel high power green LEDs [2.50 W, lambda = 535 nm] for 60-180 min. at room temperature, until all of the starting material disappeared. Then, the mixture was poured into water (10 mL), extracted with EtOAc (4 * 10 mL), washed with brine (15 mL), and dried over Na2SO4. The crude organic phase was concentrated in vacuo and purified with a short flash column chromatography (silica gel, hexane/EtOAc = 5:1) to afford the corresponding product 3(a-n) in high yield (71-95%) in Table 2.

Reference： [1]Tetrahedron,2013,vol. 69,p. 3971 - 3977
[2]Nature Chemistry,2017,vol. 9,p. 571 - 577
[3]Tetrahedron Letters,2019,vol. 60,p. 40 - 43

41
[ 1466-76-8 ]
[ 16932-45-9 ]

Yield	Reaction Conditions	Operation in experiment
84%	With silver carbonate; copper(ll) bromide; palladium dichloride; In tetrahydrofuran; at 110℃; for 24h;	General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 3079 - 3081
[2]Journal of Organic Chemistry,2016,vol. 81,p. 2794 - 2803
[3]Chemical Science,2018,vol. 9,p. 3860 - 3865
[4]Chemical Communications,2019,vol. 55,p. 6445 - 6448

42
[ 1466-76-8 ]
[ 7051-15-2 ]

Yield	Reaction Conditions	Operation in experiment
25%	With silver carbonate; copper dichloride; palladium dichloride; In tetrahydrofuran; at 110.0℃; for 24.0h;	General procedure: A mixture of carboxylic acid (1 equiv., 0.5 mmol), CuBr2 or CuCl2 (2 equiv., 1 mmol), Ag2CO3 (1 equiv., 0.5 mmol) and PdCl2 (0.1 equiv.) was heated inTHF (3 mL) under reflux at 110 oC for 24 h. After the reaction finished, the mixture was evaporated under vacuum and purified by columnchromatography to afford the desired product.

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 2794 - 2803
[2]Tetrahedron Letters,2013,vol. 54,p. 3079 - 3081

43
[ 75-91-2 ]
[ 1466-76-8 ]
[ 2065-27-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With copper quinolate In water; dimethyl sulfoxide at 120℃; for 24h;
84%	With copper doped mesoporous polymelamine-formaldehyde In water; dimethyl sulfoxide at 100℃; for 16h;

Reference： [1]Zhu, Yan; Yan, Hong; Lu, Linhua; Liu, Defu; Rong, Guangwei; Mao, Jincheng [Journal of Organic Chemistry, 2013, vol. 78, # 19, p. 9898 - 9905]
[2]Molla, Rostam Ali; Iqubal, Md. Asif; Ghosh, Kajari; Kamaluddin; Islam, Sk. Manirul [Dalton Transactions, 2015, vol. 44, # 14, p. 6546 - 6559]

44
[ 151-10-0 ]
[ 700-44-7 ]
[ 16700-55-3 ]
[ 1466-76-8 ]

Reference： [1]Organic Process Research and Development,2004,vol. 8,p. 897 - 902

45
[ 3392-97-0 ]
[ 700-44-7 ]
[ 16700-55-3 ]
[ 1466-76-8 ]

Reference： [1]Organic Process Research and Development,2004,vol. 8,p. 897 - 902

46
hydroxy(1,5-cyclooctadiene)rhodium(I) dimer [ No CAS ]
[ 1466-76-8 ]
[ 84783-64-2 ]
{(2,2'-bis(diphenylphosphino)-1,1'-biphenyl)RhOCO[η²-OCO(2,6-OMe-C₆H₃)] [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	Stage #1: hydroxy(1,5-cyclooctadiene)rhodium(I) dimer; 2,2'-bis(diphenylphosphino)biphenyl In tetrahydrofuran at 80℃; for 1h; Inert atmosphere; Stage #2: 2-6-dimethoxybenzoic acid In tetrahydrofuran at 60℃; for 2h; Inert atmosphere;

Reference： [1]Zhang, Jing; Liu, Jun-Feng; Ugrinov, Angel; Pillai, Anthony F. X.; Sun, Zhong-Ming; Zhao, Pinjing [Journal of the American Chemical Society, 2013, vol. 135, # 46, p. 17270 - 17273]

47
[ 1466-76-8 ]
[ 14790-72-8 ]
[ 1529516-07-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium(II) trifluoroacetate; triphenylphosphine; silver carbonate; In dimethyl sulfoxide; N,N-dimethyl-formamide; at 100℃; for 4h;Schlenk technique;	General procedure: Zerumbone (1 equiv.), arenecarboxylic acid (2equiv.), oxidant (3 equiv.) and Pd catalyst (0. 2 equiv.) and ligand (0.4equiv.) were taken in a Schlenk tube and degassed. The mixture was dissolved1:20 mixture of DMSO and DMF (3 mL) and stirred at 100oC for 4hours. After the completion of the reaction (as indicated by TLC), the reactionmixture was extracted with ethyl acetate (3 x 25 mL). The organic layer wasthen dried over anhydrous sodium sulphate and the solvent was evaporated invacuo. The residue on silica gel (100-200 mesh) column chromatography using4-7% ethyl acetate in hexane afforded the coupled product in low to moderateyield

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 665 - 670

48
[ 1466-76-8 ]
[ 22795-99-9 ]
[ 96947-76-1 ]

Yield	Reaction Conditions	Operation in experiment
84.5%		Synthesis of Compound (1) (S)-(-)-N-[(1-Ethyl-2-pyrrolidinyl)methyl]-2,6-dimethoxybenzamide Take 2.8 g (15.4 mmol) 2,6-dimethoxybenzoic acid and add with 20 mL hexane and 2.4 mL (33.3 mmol) thionyl chloride. Heat and reflux for 2 hours and evaporate all volatile substances under reduced pressure. Then dissolve the residue in methylene chloride (20 mL) and slowly drop 20 mL methylene chloride containing 2.0 g (15.6 mmol) (S)-(-)-2-aminomethyl-1-ethylpyrrolidine into the methylene chloride solution. Stir the solution at room temperature overnight. Next wash the reaction solution with saturated sodium bicarbonate aqueous solution (40 mL) and the reaction solution separates into two phases. The organic phase is dried by anhydrous sodium sulfate (Na2SO4) and then is concentrated under reduced pressure. The residue is separated and purified by liquid chromatography (silicon dioxide(SiO2), dichloromethane(CH2Cl2): methanol(CH3OH)=100:15) to get colorless solid product, the compound (1) (3.8 g, 84.5%). [0034] Compound data of the product: [0035] IR (KBr) nu 3324 (NH), 1663 (CO) cm-1. [0036] 1H NMR (CDCl3) delta 7.15 (t, J=8.4 Hz, 1H, Ph), 6.45 (d, J=8.4 Hz, 2H, Ph), 6.32 (br, 1H, NH), 3.69 (m, 7H, OCH3 and NHCH2), 3.16 (m, 1H, NHCH2), 3.03 (m, 1H, CH2CH2CH2N), 2.77 (m, 1H, CH2CH3), 2.57 (m, 1H, CH), 2.11 (m, 2H, CH2CH3 and CH2CH2CH2N), 1.84-1.58 (m, 3H, CH2CH2CH2N), 0.99 (t, J=7.4 Hz, 3H, CH2CH3). 13C NMR (CDCl3) delta 165.19 (CO), 156.26, 129.36, 115.29 and 102.92 (Ph), 61.72 (CH), 54.79 (OCH3), 52.47 (CH2), 47.05 (CH2), 39.53 (CH2), 26.70 (CH2), 21.70 (CH2), 21.70 (CH2), 12.60 (CH3). MS m/z 292 (M+), 264 (M+-CH2CH3+1), 195 (M+-CH3CH2N(CH2)3CH+1), 165 (M+-CH3CH2N(CH2)3CHCH2N), 98 ((CH3CH2N-(CH2)3CH)+).
80%		General procedure: Benzoic acid derivatives (1 mmol) and heterogeneous catalyst (10 mg) were mixed for 5 min in 1 mL of anhydrous toluene. Then, the amine (1.2 mmol) was added and the mixture was reacted under ultrasound for about 15-60 min at room temperature. After completion of the reaction (monitored by TLC), the catalyst was separated through filtration and the solvent was removed in vacuo. The obtained residue was dissolved in chloroform (10 ml) and washed with 10% NaHCO3 (10 ml) and HCl (1 M, 10 ml). The organic layer was extracted and dried over Na2SO4 and concentrated under reduced pressure to afford the amide, which was purified by recrystallization or column chromatography.

Reference： [1]Patent: US2014/73803,2014,A1 .Location in patent: Paragraph 0033; 0034; 0035; 0036
[2]Research on Chemical Intermediates,2018,vol. 44,p. 7873 - 7889

49
[ 3195-78-6 ]
[ 1466-76-8 ]
N-(1-(2,6-dimethoxyphenyl)vinyl)-N-methylacetamide [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2014,vol. 356,p. 870 - 878

50
[ 3195-78-6 ]
[ 1466-76-8 ]
C₂₄H₂₆N₃O₃Pd⁽¹⁺⁾*C₂F₃O₂^(1-) [ No CAS ]

Reference： [1]Advanced Synthesis and Catalysis,2014,vol. 356,p. 870 - 878

51
[ 100-54-9 ]
[ 1466-76-8 ]
[ 52856-17-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 0.5h;Microwave irradiation;	General procedure: A 5 mL microwave vial was charged with 6-methyl-2,2'-bipyridine(16.3 mg, 0.096 mmol), Pd(O2CCF3)2 (26.6 mg,0.08 mmol) and 2 mL THF. After stirring at room temperature for 5 minutes,<strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> (182.2 mg, 1 mmol), nitrile (2 mmol), water (200 muL) and TFA (77 muL, 1 mmol) were added and the mixture heated in the microwave for 30minutes at 130 C. Themixture was diluted with DCM (15 mL) and 0.1 M NaOH (15 mL, 3d, 3g, 3i and 3l) or 1% HCl (15 mL, 3b, 3e, 3f, 3h, 3j and 3k), the phaseswere separated and extracted with DCM (2 × 15mL), dried with Na2SO4, filtered and concentrated underreduced pressure. Purification by flash chromatography afforded ketones 3b,3d, 3e, 3f, 3g, 3h, 3i, 3j, 3k or 3l in the yields stated in Tables 1and 2.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2376 - 2380

52
[ 1466-76-8 ]
[ 14714-50-2 ]
[ 62924-07-6 ]

Yield	Reaction Conditions	Operation in experiment
53%	With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; at 130℃; for 1h;Microwave irradiation;	General procedure: A 5 mL microwave vialwas charged with 6-methyl-2,2'-bipyridine (16.3 mg, 0.096 mmol), Pd(O2CCF3)2(26.6 mg, 0.08 mmol) and 2 mL dry THF. After stirring at room temperature for 5minutes, 2,6-dimethoxy benzoic acid (182.2 mg, 1 mmol), nitrile (2 mmol), andTFA (231 µL, 3 mmol) were added andthe mixture heated in the microwave for 1 hour at 130 C. The mixture was diluted with DCM (15 mL) and0.1 M NaOH (15 mL), the phases were separated and extracted with DCM (2 × 15 mL), dried with Na2SO4,filtered and concentrated under reduced pressure. Purification by flashchromatography afforded benzofuran 3min the yield stated in Table 2.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2376 - 2380

53
[ 16532-79-9 ]
[ 1466-76-8 ]
[ 1183207-57-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With Pd(2+)*2C5F9O2(1-); trifluoroacetic acid; 6-methyl-2,2'-bipyridine; In tetrahydrofuran; water; at 130℃; for 0.5h;Microwave irradiation;	General procedure: A 5 mL microwave vialwas charged with 6-methyl-2,2'-bipyridine (16.3 mg, 0.096 mmol), Pd(O2CCF3)2(26.6 mg, 0.08 mmol) and 2 mL THF. After stirring at room temperature for 5minutes, <strong>[1466-76-8]2,6-dimethoxy benzoic acid</strong> (182.2 mg, 1 mmol), nitrile (5 mmol), water(200 muL) and TFA (77 muL,1 mmol) were added and the mixture heated in the microwave for 30 minutes at130 C. The mixture was diluted with DCM (15 mL) and0.1 M NaOH (15 mL, 3a) or 1% HCl (15mL, 3c, 3d and 3e), the phaseswere separated and extracted with DCM (2 ×15 mL), dried with Na2SO4, filtered and concentratedunder reduced pressure. Purification by flash chromatography afforded ketones 3a, 3c, 3d or 3e in the yields stated in Table 1.

Reference： [1]Tetrahedron Letters,2014,vol. 55,p. 2376 - 2380

54
[ 3581-87-1 ]
[ 1466-76-8 ]
[ 1644068-86-9 ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 4230 - 4233

55
[ 72590-65-9 ]
[ 1466-76-8 ]
C₁₈H₂₃NO₄ [ No CAS ]

Reference： [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 4230 - 4233

56
[ 1466-76-8 ]
[ 110-83-8 ]
cyclohex-2-en-1-yl 2,6-dimethoxybenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With di-tert-butyl peroxide; copper 5,10,15,20-tetrakis(ethoxycarbonyl)porphyrin; In benzene; at 100℃; for 24h;	General procedure: Benzoic acids 1 (0.5 mmol), alkene 2 (5 mmol), DTBP (1 mmol),CuTECP (0.1 mol%), and benzene (1 mL) were added to a Schlenk tube and stirred at 100 C for 24 h. The reaction mixture was concentrated to remove solvent in a rotary evaporator after the Schlenk tube was cooled to room temperature. The crude products were purified by silica gel (300-400 mesh size) column chromatography (hexane/ethylacetate=50:1).

Reference： [1]Catalysis Communications,2019,vol. 125,p. 93 - 97
[2]Journal of the American Chemical Society,2015,vol. 136,p. 17292 - 17301

57
[ 1885-38-7 ]
[ 1466-76-8 ]
3-(2,6-dimethoxyphenyl)-3-phenylacrylonitrile [ No CAS ]
3-(2,6-dimethoxyphenyl)-3-phenylacrylonitrile [ No CAS ]

Reference： [1]Organic Letters,2014,vol. 16,p. 6282 - 6285
[2]Organic Letters,2014,vol. 16,p. 6282 - 6285

58
[ 1466-76-8 ]
[ 75-36-5 ]
acetic2,6-dimethoxybenzoic anhydride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With triethylamine; In tetrahydrofuran; at -10 - 20℃; for 6h;	General procedure: Triethylamine(2.0 equiv.) was added dropwise at ambient temperature to a 0.25M solution ofthe indicated benzoic acid (1.0 equiv.) in dry THF. The mixture was cooled to -10 Cand acetyl chloride (1.1 equiv.) was added dropwise. The mixture was stirred at room temperature for 6 hours, filtered, and evaporated. The crude anhydride was filtered through a pad of silica with ethyl acetate to afford 9.

Reference： [1]Tetrahedron Letters,2015,vol. 56,p. 4392 - 4396

59
[ 2049-80-1 ]
[ 1466-76-8 ]
[ 1159205-64-7 ]

Yield	Reaction Conditions	Operation in experiment
85%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249
[2]Journal of Organic Chemistry,2016,vol. 81,p. 2521 - 2533

60
[ 1466-76-8 ]
potassium ferrocyanide [ No CAS ]
[ 16932-49-3 ]

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 2794 - 2803

61
[ 1466-76-8 ]
[ 16932-44-8 ]

Yield	Reaction Conditions	Operation in experiment
93%	With N-iodo-succinimide; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;	General procedure: A solution of 2,6-dimethoxybenzoic acid (0.1 mmol), iodine reagent, palladium catalyst, solvent (1.0 mL) was added to 10 mLIn the reaction vessel,Access to nitrogen protection,Heating reaction,The product was analyzed by GC-MS. The specific reaction conditions of each control group were shown in Table 1.
37%	With 2.9-dimethyl-1,10-phenanthroline; oxygen; copper (I) acetate; silver sulfate; sodium iodide; In dimethyl sulfoxide; at 160℃; for 24h;Schlenk technique;	Silak reaction tube equipped with a magnetic stirrer was charged with 3.1 mg of silver sulfate,36.3 mg of copper acetate, 36.4 mg of 2,6-dimethoxybenzoic acid,149.9 mg of sodium iodide and 1 mL of dimethylsulfoxide.The reaction was heated at 160 C for 24 hours in the presence of oxygen.After the reaction was completed, distilled water was added to quench the reaction,Extraction with ethyl acetate 3 times, each time 10mL,The combined organic phases are concentrated,19.5 mg of 2,6-dimethoxy-iodobenzene was obtained in a yield of 37%.

Reference： [1]Journal of Organic Chemistry,2016,vol. 81,p. 2794 - 2803
[2]Journal of the American Chemical Society,2017,vol. 139,p. 11527 - 11536
[3]Patent: CN106748604,2017,A .Location in patent: Paragraph 0039; 0040; 0097; 0098; 0099; 0100
[4]Organic Letters,2019,vol. 21,p. 4632 - 4637
[5]Patent: CN107325002,2017,A .Location in patent: Paragraph 0133
[6]Chemical Communications,2019,vol. 55,p. 6445 - 6448

62
[ 201230-82-2 ]
[ 16932-44-8 ]
[ 1466-76-8 ]

Yield	Reaction Conditions	Operation in experiment
16%	With water; palladium diacetate; triethylamine; triphenylphosphine; In 1,4-dioxane; at 110℃; under 11251.1 Torr; for 2h;Flow reactor;	General procedure: For a typical reaction, a Vapourtec 2R+ Series was used as the platform with a Vapourtec Gas/Liquid Membrane Reactor to load the carbon monoxide. The HPLC pump were both set at 0.125 mL/min, temperature of the reactor at 110 C, pressure of CO at 15 bar with a back pressure regulator of 250 psi (17.24 bar). The system was left running for 2 h to reach steady state after which time the flow streams were switched to pass from the loops where the substrates and catalysts were loaded. The first loop (5 mL) was filled with a solution of palladium acetate (20 mg, 0.08 mmol), triphenylphosphine (48 mg, 0.168 mmol) in 6 mL of 1,4-dioxane while the second loop (5 mL) was filled with a solution made from the ortho-substituted iodoarene substrate (1.68 mmol), triethylamine (0.272 g, 0.374 mL, 2.69 mmol) and water (0.505 g, 28 mmol) in 5.8 mL of 1,4-dioxane. An Omnifit column filled with 1.71 cm3 (r = 0.33 cm, h = 5.00 cm) of cotton was positioned just before the back pressure regulator to trap any particulate matter formed to avoid blocking of the back pressure regulator. After the substrates were passed through the system, the outlet of the flow stream was directed into a receptacle where the excess carbon monoxide gas was vented off in the fume cupboard. The reaction mixture was then evaporated to dryness, ethyl acetate (25 mL) and sodium carbonate solution (2 M, 10 mL) were added and transferred to a separating funnel. After collecting the aqueous layer, the organic layer was extracted with sodium carbonate solution (2 M, 2 × 10 mL). The combined aqueous layers were acidified by the addition of 2 M HCl solution which was then extracted with ethyl acetate (3 x 25 mL). The organic layer was dried over sodium sulfate, and the solvent evaporated under vacuum to give the crude product as a solid. The crude product was then recrystallised from the appropriate solvent.

Reference： [1]Beilstein Journal of Organic Chemistry,2016,vol. 12,p. 1503 - 1511

63
[ 1466-76-8 ]
[ 68-12-2 ]
[ 71955-53-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With trichlorophosphate; at 120℃; for 1h;Sealed tube;	Equipped with magnetic sub 20mL reaction flask was added <strong>[1466-76-8]2,6-dimethoxy-benzoic acid</strong> (0.055 g, 0.3 mmol), of POCl3(lequiv), of DMF (2mL), tighten the cap, an external temperature of 120 sealed reactor IH; complete reaction was monitored by gas chromatography; after the reaction solutionwas cooled, to which was added 10mL of saturated of Na2CO.3aqueous solution, extracted with ethyl acetate (3 × 10mL), the combined organic phase was dried over anhydrousmagnesium sulfate, and solvent was removed by rotary evaporation , by column chromatography: after separation (ethyl acetate n-hexane = 1/1) to give a pale yellow solid,yield 79%
79%	With trichlorophosphate; at 120℃; for 1h;	General procedure: Carboxylic acids (0.3 mmol), POCl3(1equiv.) and N-substituted formamides (2 mL) were mixed in a 20 mL tube. Tighten the cap and the mixture was stirred at 120 C for 1h. The mixture was cooled to room temperature, and Na2CO3 saturated solution (10 mL) was added. Then the solution was extracted with ethyl acetate (3×10 mL), combined the organic layers and dried with anhydrous MgSO4 over night. The solution was evaporated under reduced pressure and the crude product was purified by column chromatography (silica gel, n-hexane-EtOAc, 1:1).
52%	With tert.-butylhydroperoxide; iron(III) chloride; In pyridine; water; toluene; at 85℃; for 8h;Inert atmosphere; Sealed tube;	Inthe reaction flask equipped with a magnetic 20mL was added <strong>[1466-76-8]2,6-dimethoxy-benzoic acid</strong> (0.055g, 0.3mmol),FeCl3 (0.0049 g, 0.03 mmol),TBHP (0.116 g, 0.9 mmol, 70% aqueous solution),DMF (1 mL),Toluene (1 mL),Pyridine (0.118 g, 1.5 mmol),Fill it with argon,Tighten the cap,External temperature 85 C closed reaction 8h;Gas chromatography monitoring;After the reaction is completed,Rotary evaporation to remove the solvent,After column chromatography (ethyl acetate: petroleum ether = 4:1), a white solid was obtained.Yield 52%.

45%

With dipotassium peroxodisulfate; tetrakis(triphenylphosphine) palladium(0); at 160℃; for 18h;

In a 20 mL reaction flask equipped with a magnet, 2,6-dimethoxybenzoic acid (0.055 g, 0.3 mmol)Pd (PPh3) 4 (0.017 g, 0.015 mmol),K2S2O8 (0.162 g, 0.6 mmol), DMF (1.5 mL),Tighten the cap,External temperature 160 reaction 18h;Gas chromatography monitoring;After the reaction is completed,Rotary evaporation of the solvent,After separation by column chromatography (ethyl acetate: petroleum ether = 4: 1), a white solid was obtained,Yield 45%.

Reference： [1]Patent: CN106187803,2016,A .Location in patent: Paragraph 0125; 0126; 0127; 0128; 0129
[2]Phosphorus, Sulfur and Silicon and the Related Elements,2019,vol. 194,p. 236 - 240
[3]Patent: CN107382643,2017,A .Location in patent: Paragraph 0085; 0086; 0087; 0088; 0089
[4]Patent: CN107382766,2017,A .Location in patent: Paragraph 0066; 0067; 0068; 0069; 0070

64
[ 1466-76-8 ]
N'-(2,6-dimethoxybenzoyl)-2,6-dimethoxybenzohydrazide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With hydrazine hydrate; Vilsmeier reagent; triethylamine; In acetonitrile; at 20℃; for 7h;	General procedure: Hydrazine hydrate (0.2 mmol) was added to a solution of carboxylic acid (1.0 mmol), Vilsmeier reagent (1.0 mmol) and Et3N (4.0 mmol) in dry CH3CN (15 mL) at room temperature and the mixture was stirred 7 h. Saturated NaHCO3 (15 mL) was added and the mixture was extracted with EtOAc (3 9 15 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from ethanol 95 %. Spectral data for 6-7,10, 13 and 15 have been previously reported [30-34].

Reference： [1]Research on Chemical Intermediates,2017,vol. 43,p. 1909 - 1918
[2]Tetrahedron,2017,vol. 73,p. 1867 - 1872

65
[ 1466-76-8 ]
[ 115269-99-3 ]
(E)-N,N-bis(tert-butoxycarbonyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product. 4.2.1. (E)-N,N-bis(tert-butoxycarbonyl)-3-(2,6-dimethoxyphenyl)prop-2-en-1-amine (3aa) White solid, mp: 70-71 C; 1H NMR (400 MHz, CDCl3) delta 1.53 (s, 18H), 3.82 (s, 6H), 4.33 (dd, J 1.0, 6.5 Hz, 2H), 6.54 (d, J 8.4 Hz, 2H), 6.61 (dt, J 6.5, 16.1 Hz, 1 H), 6.85 (d, J 16.2 Hz, 1H), 7.14 (t, J 8.4 Hz, 1H); 13C NMR (100.6 MHz, CDCl3) delta 28.0, 49.9, 55.6, 82.0, 103.9, 114.1, 123.1, 128.0, 128.8, 152.3, 158.5; HRMS (ESI) calcd. for C21H31NNaO6 [MNa]: 416.2044, found: 416.2033.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

66
[ 5428-09-1 ]
[ 1466-76-8 ]
(E)-2-(3-(2,6-dimethoxyphenyl)allyl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

67
[ 7065-05-6 ]
[ 1466-76-8 ]
(E)-2-(4-(2,6-dimethoxyphenyl)but-3-en-2-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

68
2-(pent-1-en-3-yl)isoindoline-1,3-dione [ No CAS ]
[ 1466-76-8 ]
(E)-2-(1-(2,6-dimethoxyphenyl)pent-1-en-3-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

69
[ 1466-76-8 ]
[ 169268-90-0 ]
(E)-tert-butyl (3-(2,6-dimethoxyphenyl)allyl)(methyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

70
[ 1466-76-8 ]
[ 78888-18-3 ]
(E)-tert-butyl (3-(2,6-dimethoxyphenyl)allyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

71
[ 52898-32-5 ]
[ 1466-76-8 ]
(E)-2-(4-(2,6-dimethoxyphenyl)but-3-en-1-yl)isoindoline-1,3-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With palladium(II) trifluoroacetate; silver carbonate In tetrahydrofuran; dimethyl sulfoxide at 100℃; for 8h; Inert atmosphere; stereoselective reaction;	4.2. General procedure for the decarboxylative arylation of olefins with aryl carboxylic acids General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 °C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Qin, Xubo; Chen, Changjun; Zhang, Lingjuan; Xu, Jianbin; Pan, Yixiao; Zhao, Haoqiang; Han, Jiahong; Li, Huanrong; Xu, Lijin [Tetrahedron, 2017, vol. 73, # 16, p. 2242 - 2249]

72
[ 1968-40-7 ]
[ 1466-76-8 ]
(E)-ethyl 5-(2,6-dimethoxyphenyl)pent-4-enoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With palladium(II) trifluoroacetate; silver carbonate In tetrahydrofuran; dimethyl sulfoxide at 100℃; for 8h; Inert atmosphere; stereoselective reaction;	4.2. General procedure for the decarboxylative arylation of olefins with aryl carboxylic acids General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 °C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Qin, Xubo; Chen, Changjun; Zhang, Lingjuan; Xu, Jianbin; Pan, Yixiao; Zhao, Haoqiang; Han, Jiahong; Li, Huanrong; Xu, Lijin [Tetrahedron, 2017, vol. 73, # 16, p. 2242 - 2249]

73
[ 300-57-2 ]
[ 1466-76-8 ]
(E)-1,3-dimethoxy-2-(3-phenylprop-1-en-1-yl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

74
[ 140-67-0 ]
[ 1466-76-8 ]
(E)-1,3-dimethoxy-2-(3-(4-methoxyphenyl)prop-1-en-1-yl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

75
[ 695-12-5 ]
[ 1466-76-8 ]
(E)-2-(2-cyclohexylvinyl)-1,3-dimethoxybenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With palladium(II) trifluoroacetate; silver carbonate; In tetrahydrofuran; dimethyl sulfoxide; at 100℃; for 8h;Inert atmosphere;	General procedure: To an oven-dried pressure tube were sequentially added aryl carboxylic acid 1 (0.2 mmol), olefin 2 (0.24 mmol), Pd(TFA)2 (3.33 mg, 5.0 mol%), Ag2CO3 (55.2 mg, 0.2 mmol), THF (2.0 mL) and DMSO (0.10 mL) under nitrogen at room temperature. After degassing three times, the reaction mixture was heated at 100 C for 8 h, and then was cooled to room temperature. Water (20.0 mL)was added, and the mixture was extracted with ethyl acetate (3 5.0 mL). The combined organic layer was washed with brine, dried over anhydrious Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate) to give the pure target product.

Reference： [1]Tetrahedron,2017,vol. 73,p. 2242 - 2249

76
[ 1466-76-8 ]
2,5-bis(2,6-dimethoxyphenyl)-1,3,4-thiadiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: Hydrazine hydrate (0.3 mmol) was added to a solution of carboxylic acid (1.0 mmol), Vilsmeier reagent (1.0 mmol) and Et3N (2.0 mmol) in dry THF (20 mL) at room temperature. After 2 h Vilsmeier reagent (0.4 mmol), Et3N (1.0 mmol) and Lawesson's reagent (0.8 mmol) was added and the mixture was stirred at room temperature 13 h. Saturated NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3 20 mL). The organic layerwas washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from 95% ethanol.

Reference： [1]Tetrahedron,2017,vol. 73,p. 1867 - 1872

77
[ 1466-76-8 ]
[ 55305-43-6 ]
[ 16932-49-3 ]

Reference： [1]Journal of Organic Chemistry,2017,vol. 82,p. 3530 - 3537

78
[ 1466-76-8 ]
[ 20469-63-0 ]
[ 16932-44-8 ]
[ 1195513-07-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-iodo-succinimide; palladium dichloride; In dichloromethane; at 80℃; for 3h;Inert atmosphere;	General procedure: A solution of 2,6-dimethoxybenzoic acid (0.1 mmol), iodine reagent, palladium catalyst, solvent (1.0 mL) was added to 10 mLIn the reaction vessel,Access to nitrogen protection,Heating reaction,The product was analyzed by GC-MS. The specific reaction conditions of each control group were shown in Table 1.
	With N-iodo-succinimide; palladium dichloride; In water; at 80℃; for 3h;Inert atmosphere;	General procedure: A solution of 2,6-dimethoxybenzoic acid (0.1 mmol), iodine reagent, palladium catalyst, solvent (1.0 mL) was added to 10 mLIn the reaction vessel,Access to nitrogen protection,Heating reaction,The product was analyzed by GC-MS. The specific reaction conditions of each control group were shown in Table 1.

Reference： [1]Patent: CN106748604,2017,A .Location in patent: Paragraph 0097; 0098; 0099; 0100
[2]Patent: CN106748604,2017,A .Location in patent: Paragraph 0097; 0098; 0099; 0100

79
[ 1466-76-8 ]
[ 16932-44-8 ]
[ 1195513-07-5 ]

Yield	Reaction Conditions	Operation in experiment
	With N-iodo-succinimide; palladium diacetate; In N,N-dimethyl-formamide; at 80℃; for 3h;Inert atmosphere;	General procedure: A solution of 2,6-dimethoxybenzoic acid (0.1 mmol), iodine reagent, palladium catalyst, solvent (1.0 mL) was added to 10 mLIn the reaction vessel,Access to nitrogen protection,Heating reaction,The product was analyzed by GC-MS. The specific reaction conditions of each control group were shown in Table 1.

Reference： [1]Patent: CN106748604,2017,A .Location in patent: Paragraph 0097; 0098; 0099; 0100

80
[ 60-12-8 ]
[ 1466-76-8 ]
2,6-dihydroxybenzoic acid phenylethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.9%		100 mg of 2,6-dimethoxybenzoic acid was weighed and placed in a dry round bottom flask, Add 10 mL of anhydrous CH2Cl2 to stir; the ice bath so that the temperature of the mixture in the device was reduced to 0 C, 150 mg of dicyclohexylcarbodiimide was added, and after stirring for 50 minutes, 0.06 mL of phenylethyl alcohol, 3 mg of 4-N, Methyl-4-aminopyridine, stirred at room temperature, TLC detection, the reaction is complete, the direct filtration, The mother liquor was concentrated and purified by silica gel column chromatography (petroleum ether: chloroform-2: 3) The 2,6-dimethylbenzoic acid was isolated Phenylethyl alcohol, Yield 89.9%. Add l0mLCH2Cl2, stir, add 3.3 equivalents of AICl3, room temperature stirring, TLC detection, the reaction is complete, the reaction solution slowly poured into 20mL water, extraction and separation of organic layer, the organic layer, concentrated, And the reaction solution was slowly poured into 1000mL water. After the temperature dropped to room temperature, the organic layer was extracted and concentrated to obtain an organic layer. The reaction mixture was stirred at room temperature, Crystallization of 4,6-dihydroxy-5-phenethyloxycarbonyl-1,3-benzenedisulfonic acid in a yield of 92.9%.

Reference： [1]Patent: CN105037221,2017,B .Location in patent: Paragraph 0022; 0023

81
[ 1466-76-8 ]
2,5-bis(2,6-dimethoxyphenyl)-1,3,4-oxadiazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With Vilsmeier reagent; hydrazine hydrate; triethylamine; In acetonitrile; at 20℃; for 8h;	General procedure: Hydrazine hydrate (0.3 mmol) was added to a solution of carboxylic acid (1.0 mmol),Vilsmeier reagent (1.0 mmol) and Et3N (2.0 mmol) in dry CH3CN (20 mL) at room temperature.After 2 hours Vilsmeier reagent (0.4 mmol) and Et3N (1.0 mmol) were addedand the mixture was stirred at room temperature for 8 hours. Saturated NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3 £ 20 mL). The organic layerwas washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removedunder reduced pressure to give the crude products. The crude residues were purified bycrystallization from 95% ethanol. Spectral data for 5a-b, 5d, 5f-h and 5j have been previouslyreported,26-32 and were matched by the products of this work.

Reference： [1]Organic Preparations and Procedures International,2017,vol. 49,p. 355 - 362

82
[ 2343-89-7 ]
[ 1466-76-8 ]
(Z)-methyl 2-fluoro-3-(2,6-dimethoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium(II) trifluoroacetate; silver carbonate In 1,4-dioxane; dimethyl sulfoxide at 120℃; for 12h; Sealed tube; diastereoselective reaction;

Reference： [1]Bouazzaoui, Ouafa; Rousée, Kevin; Mulengi, Joseph Kajima; Pannecoucke, Xavier; Bouillon, Jean-Philippe; Couve-Bonnaire, Samuel [European Journal of Organic Chemistry, 2018, vol. 2018, # 27, p. 3705 - 3715]

83
[ 3182-95-4 ]
[ 1466-76-8 ]
N-((S)-1-hydroxy-3-phenylpropan-2-yl)2,6-dimethoxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		General procedure: Benzoic acid derivatives (1 mmol) and heterogeneous catalyst (10 mg) were mixed for 5 min in 1 mL of anhydrous toluene. Then, the amine (1.2 mmol) was added and the mixture was reacted under ultrasound for about 15-60 min at room temperature. After completion of the reaction (monitored by TLC), the catalyst was separated through filtration and the solvent was removed in vacuo. The obtained residue was dissolved in chloroform (10 ml) and washed with 10% NaHCO3 (10 ml) and HCl (1 M, 10 ml). The organic layer was extracted and dried over Na2SO4 and concentrated under reduced pressure to afford the amide, which was purified by recrystallization or column chromatography.

Reference： [1]Research on Chemical Intermediates,2018,vol. 44,p. 7873 - 7889

84
[ 1466-76-8 ]
[ 298-12-4 ]
[ 121-61-9 ]
C₁₈H₂₀N₂O₇S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With palladium(II) trifluoroacetate In nitromethane; dimethyl sulfoxide at 60℃; for 12h;

Reference： [1]Diehl, Andreas M.; Manolikakes, Georg [ChemCatChem, 2020, vol. 12, # 13, p. 3463 - 3466]

85
[ 1576-47-2 ]
[ 1466-76-8 ]
[ 298-12-4 ]
C₂₀H₁₉NO₆S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With palladium(II) trifluoroacetate In nitromethane; dimethyl sulfoxide at 60℃; for 12h;

Reference： [1]Diehl, Andreas M.; Manolikakes, Georg [ChemCatChem, 2020, vol. 12, # 13, p. 3463 - 3466]

86
[ 6339-87-3 ]
[ 1466-76-8 ]
[ 298-12-4 ]
C₁₄H₁₅NO₆S₂ [ No CAS ]

Reference： [1]ChemCatChem,2020

87
[ 24243-71-8 ]
[ 1466-76-8 ]
[ 298-12-4 ]
C₁₃H₁₉NO₆S [ No CAS ]

Reference： [1]ChemCatChem,2020

88
[ 1466-76-8 ]
[ 34813-49-5 ]
[ 298-12-4 ]
C₁₄H₂₁NO₆S [ No CAS ]

Reference： [1]ChemCatChem,2020,vol. 12,p. 3463 - 3466

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H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 1466-76-8 ] {[proInfo.proName]}

Quality Control of [ 1466-76-8 ]

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[ 1466-76-8 ] Synthesis Path-Upstream 1~11

[ 1466-76-8 ] Synthesis Path-Downstream 1~88

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