[ CAS No. 88-04-0 ] {[proInfo.proName]}

Name: 88-04-0|4-Chloro-3,5-dimethylphenol|98%
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Quality Control of [ 88-04-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 88-04-0 ]

Product Details of [ 88-04-0 ]

CAS No. :	88-04-0	MDL No. :	MFCD00002324
Formula :	C₈H₉ClO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OSDLLIBGSJNGJE-UHFFFAOYSA-N
M.W :	156.61	Pubchem ID :	2723
Synonyms :	p-chloro-m-xylenol;Chloroxylenol;HSDB7427

Calculated chemistry of [ 88-04-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	43.41
TPSA :	20.23 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-4.93 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.96
Log Po/w (XLOGP3) :	3.27
Log Po/w (WLOGP) :	2.66
Log Po/w (MLOGP) :	2.72
Log Po/w (SILICOS-IT) :	2.9
Consensus Log Po/w :	2.7

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.32
Solubility :	0.0758 mg/ml ; 0.000484 mol/l
Class :	Soluble
Log S (Ali) :	-3.37
Solubility :	0.0669 mg/ml ; 0.000427 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.2
Solubility :	0.099 mg/ml ; 0.000632 mol/l
Class :	Soluble

Medicinal Chemistry

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

Safety of [ 88-04-0 ]

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 [ 88-04-0 ]

* 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 [ 88-04-0 ]
Downstream synthetic route of [ 88-04-0 ]

[ 88-04-0 ] Synthesis Path-Upstream 1~8

1
[ 108-68-9 ]
[ 88-04-0 ]

Yield	Reaction Conditions	Operation in experiment
91.8 %Chromat.	With 1,2-dithiolane; iron(III) chloride; sulfuryl dichloride In dichloromethane at 20℃; for 4 h;	General procedure: m-Xylenol (6.11 g, 50.0 mmol), FeCl3 (25 mg), DCM (25 ml) and the catalyst (30 mg) wereadded to a dried 50 ml round-bottomed flask. Freshly distilled sulfuryl chloride (4.66 ml, 57.7mmol) was added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction wasstirred at room temperature for a further 2 h. The mixture was quenched with water (20 ml),and the organic components were extracted with diethyl ether (3 × 30 ml). The ether layerswere removed, combined and dried over MgSO4. The drying agent was filtered, and the solventwas removed under reduced pressure. The crude product was weighed and then analyzed byquantitative GC
92.4 %Chromat.	With iron(III) chloride; sulfuryl dichloride; C₁₁H₂₄OS In dichloromethane at 20℃; for 4 h;	General procedure: Freshly distilled sulfuryl chloride (4.66 mL, 57.7mmol) was added slowly over 2 h, via a pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl₃ (25mg, 0.154mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2h and the reaction was quenched with water (20mL). The organic components were extracted with ether (3×30 mL). The ether layers were removed, combined and dried over MgSO₄. The drying agent was filtered and the solvent was removed under reduced pressure. The crude product was weighed and then analyzed by quantitative GC in the presence of tetradecane as added internal standard.

Reference： [1] Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7529 - 7537
[2] Patent: US2350677, 1940, ,
[3] Patent: US2350677, 1940, ,
[4] Fortsch. Ch., Phys., 1924, vol. 18, p. 38,51
[5] Journal of the Chemical Society [Section] C: Organic, 1970, p. 1982 - 1986
[6] Patent: US4245127, 1981, A,
[7] Journal of Sulfur Chemistry, 2015, vol. 36, # 1, p. 74 - 85
[8] Patent: CN107226775, 2017, A, . Location in patent: Paragraph 0016-0018
[9] Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621

2
[ 108-68-9 ]
[ 88-04-0 ]
[ 5538-41-0 ]

Yield	Reaction Conditions	Operation in experiment
7.6 %Chromat.	With iron(III) chloride; 1,2-dithiacyclooctane; sulfuryl dichloride In dichloromethane at 20℃; for 4 h;	General procedure: m-Xylenol (6.11 g, 50.0 mmol), FeCl3 (25 mg), DCM (25 ml) and the catalyst (30 mg) wereadded to a dried 50 ml round-bottomed flask. Freshly distilled sulfuryl chloride (4.66 ml, 57.7mmol) was added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction wasstirred at room temperature for a further 2 h. The mixture was quenched with water (20 ml),and the organic components were extracted with diethyl ether (3 × 30 ml). The ether layerswere removed, combined and dried over MgSO4. The drying agent was filtered, and the solventwas removed under reduced pressure. The crude product was weighed and then analyzed byquantitative GC
90 %Chromat.	With iron(III) chloride; sulfuryl dichloride; C₁₁H₂₄S₂ In dichloromethane at 20℃; for 4 h;	General procedure: Freshly distilled sulfuryl chloride (4.66 mL, 57.7mmol) was added slowly over 2 h, via a pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl₃ (25mg, 0.154mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2h and the reaction was quenched with water (20mL). The organic components were extracted with ether (3×30 mL). The ether layers were removed, combined and dried over MgSO₄. The drying agent was filtered and the solvent was removed under reduced pressure. The crude product was weighed and then analyzed by quantitative GC in the presence of tetradecane as added internal standard.

Reference： [1] Angewandte Chemie, 1912, vol. 25, p. 1944
[2] Chemische Berichte, 1923, vol. 56, p. 968
[3] Journal of Sulfur Chemistry, 2015, vol. 36, # 1, p. 74 - 85
[4] ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043
[5] Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621

3
[ 108-68-9 ]
[ 88-04-0 ]
[ 133-53-9 ]
[ 5538-41-0 ]

Yield	Reaction Conditions	Operation in experiment
75 %Chromat.	With iron(III) chloride; sulfuryl dichloride; 1,3-bis(methylthio)propane In dichloromethane at 20℃; for 4 h;	General procedure: Freshly distilled sulfuryl chloride (4.66 mL, 57.7mmol) was added slowly over 2 h, via a pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl₃ (25mg, 0.154mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2h and the reaction was quenched with water (20mL). The organic components were extracted with ether (3×30 mL). The ether layers were removed, combined and dried over MgSO₄. The drying agent was filtered and the solvent was removed under reduced pressure. The crude product was weighed and then analyzed by quantitative GC in the presence of tetradecane as added internal standard.

Reference： [1] Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621

4
[ 874-63-5 ]
[ 88-04-0 ]

Reference： [1] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1162 - 1166

5
[ 6981-15-3 ]
[ 88-04-0 ]

Reference： [1] Biochemical Journal, 1943, vol. 37, p. 592,593
[2] ACS Medicinal Chemistry Letters, 2014, vol. 5, # 10, p. 1162 - 1166

6
[ 108-68-9 ]
[ 88-04-0 ]
[ 133-53-9 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2: Physical Organic Chemistry (1972-1999), 1988, p. 385 - 392

7
[ 22012-58-4 ]
[ 88-04-0 ]

Reference： [1] Biochemical Journal, 1943, vol. 37, p. 592,593

8
[ 7782-50-5 ]
[ 64-19-7 ]
[ 108-68-9 ]
[ 88-04-0 ]

Reference： [1] Fortsch. Ch., Phys., 1924, vol. 18, p. 39,51, 52

[ 88-04-0 ] Synthesis Path-Downstream 1~69

1
[ 598-49-2 ]
[ 88-04-0 ]
[ 133-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; acetic acid

Reference： [1]Jones [Journal of the Chemical Society, 1941, p. 267,269][Journal of the Chemical Society, 1942, p. 676] Gemmell [1952, vol. 23, p. 63]

2
[ 88-04-0 ]
[ 54582-90-0 ]

Yield	Reaction Conditions	Operation in experiment
93.2%	With nitric acid; acetic acid at 5 - 25℃; for 1h;	Intermediate 1: 4-chloro-3,5-dimethyl-2-nitro-phenol To a solution of 4-chloro-3,5-dimethyl-phenol (30 g, 192 mmol) in acetic acid (450 mL) was added HNO3 (18.57 g, 192 mmol, 65 % purity) at 5 DC. The resulting mixture was stirredat 25 °C for 1 h. The reaction mixture was poured into ice-water (500 g) and stirred for10 mm. The resulting solid was collected by filtration, washed with water (200 mL x 2) anddried under high vacuum at 50 °C for 24 h to yield 4-chloro-3,5-dimethyl-2-nitro-phenol (36g, 179 mmol, 93.2 % yield) as an orange solid.1H NMR (400 MHz, CDCI3): 69.54 (s, 1H), 6.92 (s, 1H), 2.61 (s, 3H), 2.40 (s, 3H).
90.1%	With nitric acid In acetic acid at 5 - 20℃; for 1h;	1.1 Synthesis of 2-amino-3,5,diimethyl phenol Step 1: 4-Chloro-3,5-dimethyl-2-nitrophenol 4-Chloro-3,5-dimethyl-phenol (20.0 g, 128 mmol) was dissolved in glacial acid (150 ml) and the solution was cooled to 5° C. Then nitric acid 65% (12.4 g, 128 mmol) was added dropwise while temperature was kept below 20° C. by external cooling. After the addition was complete stirring was continued for 1 hour at ambient temperature. The reaction mixture was poured into ice/water (1:1, 500 g) whereupon an orange solid precipitated. The solid was filtered off, washed with water and dried. Yield: 23.2 g (90.1%). 1H-NMR (DMSO-d6): δ=11.0 (s, 1H); 6.9 (s, 1H); 2.3 (s, 3H); 2.2 ppm (s, 3H).
80%	With bismuth (III) nitrate pentahydrate In acetone at 56℃; for 6h;	1.2. General procedure for the nitration of phenolic compounds General procedure: To a solid mixture of phenol (1-3 equiv) and Bi(NO3)35H2O (1 equiv) or Fe(NO3)39H2O (1 equiv) was added acetone (10 ml/mmol). The resulting mixture was stirred at room temperature under air or at reflux for 2-24 hours, Tables 1 and 2. When the reaction was completed the insoluble materials were filtered off using a pad of Celite and the residue was washed by acetone (ca. 5 ml/mmol). The filtrate was treated by NaHCO3 (0.1 g/mmol) until evolution of CO2 stopped. Insoluble material was filtered off again, and the solvent was removed under vacuum in a water bath 25-35°C. The nitrated products were separated or purified using silica gel chromatography, to give pure phenolic compounds. All products were characterized by 1H NMR,13C NMR and IR and were identified by comparison of the spectral data and melting points with those reported in literature and characterized.

	With nitric acid; acetic acid
	With nitric acid; acetic acid
	With ammonium nickel sulfate; nitric acid In chloroform; water at 26℃; for 3h;	5.1.4 Experimental procedure B General procedure: Example 2 Experimental procedure B The phenol (1.0 mmol) and ammonium nickel sulfate (1.0 mmol) were dissolved in chloroform (10 ml) and treated with 69% HNOa(1.0 mmol) and stirred at 26°C for 3 h. After the completion of the reaction, the reaction mixture was diluted with chloroform (10 ml), filtered. The organic layer was washed with water, dried (Na2S04) and solvent evaporated under vacuum. The crude product was purified by silica gel chromatography. The process is schematically represented below. 1.4 4-chloro-3,5-dimethyl-2-nitrophenol (Nit04): The general experimental procedure B was followed. Yellow solid. M. P.: 204.7°C; IR (CHC13): v 3368, 3291, 2506, 1637, 1598, 1560, 1520, 1459, 1377, 1350, 1 105 cm-1 ; m NMR (CDC13, 200 MHz): δ 2.41 (s, 3H), 2.62 (s, 3H), 6.93 (s, 1H), 9.59 (s, 1H) ppm; NMR (CDC13, 50 MHz): δ 18.3 (q), 21.8 (q), 1 18.1 (d), 127.6 (s), 133.2 (s), 135.1 (s), 144.9 (s), 151.9 (s) ppm; ESI-MS (m/z): 223.3 [M+Na]+; Anal. Calcd for : C8H8C1N03: C, 47.66; H, 4.00; CI, 17.59; N, 6.95; Found: C, 47.71; H, 4.06; CI, 17.63; N, 7.00.

Reference： [1]Current Patent Assignee: UNIVERSITY OF MANCHESTER; UNIVERSITY OF LEICESTER - WO2019/102186, 2019, A1 Location in patent: Page/Page column 25
[2]Current Patent Assignee: PROCTER & GAMBLE CO - US2006/32002, 2006, A1 Location in patent: Page/Page column 12-13
[3]Wąsińska, Małgorzata; Korczewska, Anna; Giurg, Mirosław; Skarzewski, Jacek [Synthetic Communications, 2015, vol. 45, # 1, p. 143 - 150]
[4]v. Auwers [Fortschritte der Chemie, Physik und physikalischen Chemie, 1924, vol. 18, p. 54]
[5]Jones [Journal of the Chemical Society, 1943, p. 445]
[6]Current Patent Assignee: COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH (IN) - WO2014/87431, 2014, A1 Location in patent: Page/Page column 8; 13

3
[ 88-04-0 ]
[ 175204-32-7 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; acetic acid
	Multi-step reaction with 2 steps 1: AlBr₃; chloroform; bromine

Reference： [1]Lesser; Gad [Chemische Berichte, 1923, vol. 56, p. 968] Gleed; Peters [Journal of the Chemical Society, 1948, p. 209,211]
[2]Gleed; Peters [Journal of the Chemical Society, 1948, p. 209,211]

4
[ 88-04-0 ]
[ 108-24-7 ]
[ 22012-58-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate
	With sulfuric acid
	In pyridine	Synthesis of Ligand: 6-chloro 5, 7 dimethyl-4oxo-4H-chomene-3- carbaldehyde The ligand 6-chloro 5, 7 dimethyl-4oxo-4H-chomene-3- carbaldehyde was synthesized by the Vilsmeier-Haack reaction [21, 22]. The synthesis of 6-chloro 5, 7 dimethyl-4oxo-4H-chomene-3- carbaldehyde derivative was performing by three steps. The first step is the synthesis of 4-chloro-3, 5, dimethyl phenyl acetate (Scheme 1a) from 1 mol of 4-chloro-3, 5 dimethyl phenols by reacting with 1.15 mol acetic anhydride in the presence of 5 mL dry pyridine by reported method (Schemes 2 and 3).

In pyridine at 105 - 110℃; for 2h;

3.3. General procedure for the synthesis of aurones (4a-l) General procedure: Chloroxylenol based novel aurones have been synthesized fromp-chloro-m-xylenol(20g,0.067moles)dissolvedinminimumquantity of hot pyridine (10 ml). The solution was added withacetic anhydride (45 ml) in excess and the contents were heatedfor 2 h on boiling water bath. The reaction mixture was allowedto cool at room temperature and then poured into ice cold wa-ter containing HCl (150 ml) with constant stirring. The precipitateformed was separated through suction filtration and washed withwater. It was dried over anhydrous sodium sulfate and the forma-tion of product p-chloro-m-xylenyl acetate was confirmed by TLCin (Toulene: Ethyl acetate: Formic acid) (5:4:1). p-chloro-m-xylenylacetate (1)(8.4g,0.04mole) was mixed with anhydrous aluminumchloride to undergo the Fries Rearrangement. The reaction mixture°°was heated for 30 min at 120C -130C and was decomposedover crushed ice containing HCl (50 ml). The obtained pale white solid was dissolved in 5% NaOH solution and solution was acidifiewith conc. HCl and was separated through suction filtrartion. Thepale white solid was washed with water and product 5-chloro-2-hydroxy-4, 6-dimethyl acetophenone (2) was obtained by crystal-lization from methanol as pale white needles.°To a solution (below10C) of 5-chloro-2-hydroxy-4,6-dimethylacetophenone(0.001mole)anddesiredaromaticaldehyde(0.001mole) in ethanol (20 ml) was added with a chilled solutionof sodium hydroxide (10 ml of 30% solution). The reaction mix-°ture was covered with a layer of petroleum ether (60-80C) andleft at room temperature for a period of twelve hours. The solu-tion was diluted with water (100 ml) and was acidified with conc.HCl. The desired chalchone (3) formed was washed with water andcrystallized from ethanol. Confirmation of chalchone was done bygeneral chalchone test. To a few drops of product, a drop of sul-phuric acid was added which gave a blood red solution. For oxida-tive cyclization, the solution of the corresponding chalcones, mer-cury (II) acetate (0.001mole) in pyridine (10 ml) was refluxed for2 h. The reaction mixture was cooled and treated with dil. HCl. Ob-tained solid was filtered and crystallized from acetone to get pureaurones (4).

Reference： [1]Current Patent Assignee: LEHN FINK - US1938912, 1932, A
[2]Adams; Mecorney [Journal of the American Chemical Society, 1944, vol. 66, p. 802,804]
[3]Kolhe, Nitin H.; Jadhav, Shridhar S.; Thube, Dilip R.; Takate, Sushma J.; Bankar, Ashok V.; Moharekar, Sanjay T.; Pawar, Hari R.; Moharekar, Shubhangi S. [Research on Chemical Intermediates, 2021, vol. 47, # 2, p. 459 - 481]
[4]Bano, Sameena; Beg, Mirza Adil; Hamid, Aabid; Javed, Kalim; Lone, Mehak Saba; Nabi, Syed Ayaz; Nainwal, Lalit Mohan; Ramzan, Farhat; Samim, Mohammed; Shafi, Syed [Journal of Molecular Structure, 2022, vol. 1256]

5
[ 88-04-0 ]
[ 625-51-4 ]
[ 100129-50-8 ]

Reference： [1]Monatshefte fur Chemie,1959,vol. 90,p. 297,301

6
[ 108-68-9 ]
[ 88-04-0 ]

Yield	Reaction Conditions	Operation in experiment
98.9%	With N-chloro-N-(phenylsulfonyl)benzenesulfonamide In acetonitrile at 20 - 25℃; for 0.166667h; Green chemistry;	General procedure for the monochlorination reaction General procedure: To a solution of 4-nitroaniline, 1a (0.99 g, 7.2 mmol) in 7 mL specially dried MeCN was added N-chloro-N-(phenylsulfonyl)benzene sulfonamide (2.4 g, 7.2 mmol) in a 25 mL round bottom flask. The reaction mixture was stirred for 10-15 minutes at 20-25 °C (0 °C for 1-methyl-1H-imidazole, and N-methylindole), monitored by GC. After completion of the reaction, MeCN was distilled under vacuum at 40-45 °C. The residue was treated with 20 mL mixture of MDC and water, stirred the mixture for 10-15 minutes; MDC layer was separated and washed with 5 % sodium bicarbonate solution, after separation MDC layer was dried over sodium sulfate and evaporated under vacuum to obtain 2-chloro-4-nitroaniline, 2a, 1.22 g (98.5 % yield, 98.9 % purity) as a yellow powder.
97.2%	With hydrogenchloride; copper(II) choride dihydrate; oxygen; sodium chloride In 1,2-dichloro-ethane at 80℃; Autoclave;	1-9 3,5-dimethylphenol (1220g, 10mol),Copper chloride dihydrate (852.5g, 5mol),Sodium chloride (58.44, 1mol) and dichloroethane (5L) were added to a 10L autoclave, stirred and heated to 80°C, filled with oxygen, and maintained the gas pressure in the autoclave at 0.5MPa,Then pass in HCl gas (365g, 10mol) four times with an interval of half an hour.Heat preservation and stirring reaction, take samples and use gas chromatography normalization method to detect the residual amount of 3,5-dimethylphenol in the organic phase, and the reaction is considered complete if it is less than 0.08%.Stop the reaction, filter the materials in the kettle after cooling, distill the filtrate under reduced pressure, and recover the solvent.The remaining organic matter was recrystallized with dichloroethane to obtain 4-chloro-3,5-dimethylphenol (1539 g, purity 98.5%) as a white crystal product, with a yield of 97.2%.
94%	With sulfuryl dichloride; Fe⁽³⁺⁾*3C₈H₅O₄^(1-) In ethanol at 5℃; for 4h; Industrial scale;	1.2; 2-14 (2) Directional chlorination reaction of MX: In a 3000L open enamel reactor, add 1000±10kg of ethanol through a metering tank, and then add 1000±10kg of 3,5-dimethylphenol material, stir well and dissolve evenly. Further add 50±0.5kg of Fe-MOFs directional chlorination catalyst and stir well, gradually add 1106kg sulfuryl chloride dropwise within 2h, and control the reaction temperature at 5±3°C. After continuing the reaction for 2 hours, the content of MX in the reaction system was detected by gas chromatography to be less than 0.3%. The reaction was stopped, the catalyst was removed by filtration, and the methanol was evaporated under normal pressure for reuse. Then put in 2000kg of high-temperature water to fully dissolve the product, and then lower the temperature to 25°C to obtain a crystalline PCMX product. After washing and drying, 1189 kg of the final product was obtained, the yield was 94%, and the product purity reached 99.7%.

92.43%	With sulfuryl dichloride In 1,1,2,2-tetrachloroethylene at 25 - 80℃;	1-5; 7-8; 1-3 Example 8 Chlorination 1: Put 61g of 3,5-dimethylphenol and 305g of tetrachloroethylene into a 500mL four-necked flask, start the stirring device, keep the temperature at 2535,At this temperature, add 30.0g sulfuryl chloride dropwise at a constant speed, and the dropping time is 4 hours.After the addition was completed, sampling and analysis showed that the primary conversion rate of 3,5-dimethylphenol was 39.63%.The precipitated solid 1 is separated from the mother liquor 1 by cooling and centrifugation, and the temperature is controlled at 20-25°C. Chlorination 2: Mother liquor 1 is added to the four-neck flask again, and then the stirring device is started, and the temperature is kept between 30 and 35°C. Continue to drip 22.0g sulfuryl chloride at this temperature, and the dripping time is 2 hours,After the dripping was completed, sampling and analysis showed that the secondary conversion rate of 3,5-dimethylphenol was 29.51%.The precipitated solid 2 is separated from the mother liquor 2 by cooling and centrifugation, and the temperature is controlled at 20-25°C. Chlorination 3: Mother liquor 2 is added to the four-necked flask again, then start the stirring device, keep the temperature between 3035, continue to drip 21.2g sulfuryl chloride at this temperature, the dripping time is 2 hours,After the addition was completed, sampling and analysis showed that the three-time conversion rate of 3,5-dimethylphenol was 29.32%.The precipitated solid 3 is separated from the mother liquor 3 by cooling and centrifugation, and the temperature is controlled at 20-25°C.Combine solid 1, solid 2 and solid 3, add 108.0g of tetrachloroethylene, raise the temperature to 80°C and stir to dissolve, slowly lower the temperature to 25-30°C, after centrifugation,After drying, a white needle-like crystal product 4-chloro-3,5-dimethylphenol (72.73g, 99.37%) was obtained,The sum of the three conversion rates of the raw materials is 98.46%, and the product yield is 92.43%.The product selectivity is 93.87%, and the mother liquor of crystallization and centrifugation is used as the raw material for the next batch of reactions.
86%	With hydrogenchloride; oxygen In water at 70℃; for 9h;	2-15; 1-8 Example 2 15g (0.122mol) 3,5-dimethylphenol, 30g CuCl2/1-allyl-3-methylimidazolium chloride salt ionic liquid complex was placed in a 100mL four-mouth flask, and 15.74mL hydrochloric acid (mass fraction 37%), and the oxygen reaction was introduced at 70 °C for 9 hours, the conversion rate was greater than 96%, and the selectivity was greater than 93%. After the completion of the reaction, the resulting crude product was recrystallized with tetrachloroethylene to give 16.5g of pure product 4-chloro-3,5-dimethylphenol with a purity of 99.3%, with a yield of 86%.
76%	With iron(III) chloride; N-chloro-succinimide; 1-butyl-3-methylimidazolium trifluoromethanesulfonimide In tetrahydrofuran at 60℃; for 12h; Inert atmosphere; regioselective reaction;
	With chlorine at 25 - 30℃;
	With sulfuryl dichloride at 30 - 40℃;
	With chlorine; acetic acid
	With copper dichloride
	With sulfuryl dichloride In 1,1,2,2-tetrachloroethylene	1 EXAMPLE 1 EXAMPLE 1 Into a four-necked separable flask having a capacity of 1,000 ml, provided with a stirrer, a thermometer, a nozzle for introducing a chlorinating agent, and a reflux cooler were charged 600 g of tetrachloroethylene and 122 g (1 mole) of 3,5-xylenol. Then, 0.2 g (0.16% by weight on the basis of 3,5-xylenol) of anhydrous ferric chloride as a catalyst and 0.6 g (1.9% by weight on the basis of 3,5-xylenol) of thiophene as a promoter were added thereto, and the resulting mixture was sufficiently stirred and subjected to reaction while adding 135 g of sulfuryl chloride as a chlorinating agent drop by drop at a rate of 0.8 g/minute and keeping the temperature at 20° C. In the course of reaction, reaction product p-chloro-3,5-xylenol was started to deposit.
91.8 %Chromat.	With 1,2-dithiolane; iron(III) chloride; sulfuryl dichloride In dichloromethane at 20℃; for 4h; regioselective reaction;	4.4. Typical experimental procedure for the chlorination of m-xylenol General procedure: m-Xylenol (6.11 g, 50.0 mmol), FeCl3 (25 mg), DCM (25 ml) and the catalyst (30 mg) wereadded to a dried 50 ml round-bottomed flask. Freshly distilled sulfuryl chloride (4.66 ml, 57.7mmol) was added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction wasstirred at room temperature for a further 2 h. The mixture was quenched with water (20 ml),and the organic components were extracted with diethyl ether (3 × 30 ml). The ether layerswere removed, combined and dried over MgSO4. The drying agent was filtered, and the solventwas removed under reduced pressure. The crude product was weighed and then analyzed byquantitative GC
	With hydrogenchloride; copper(II) choride dihydrate; dihydrogen peroxide In water at 70 - 75℃; for 0.0333333h; Flow reactor;	1 244g3,5 - dimethyl phenol was heated to 70 ° C melting, 238g30% hydrogen peroxide, 25g copper chloride (CuCl2.2H0) Dissolved in 219g35% hydrochloric acid, Material molar ratio of 3,5-dimethylphenol: hydrogen peroxide: hydrochloric acid 1: 1.05: 1.05 points into three continuous flow microtubular reactor, The reaction temperature is set at 75 ° C, Stay for 120s, The reaction solution stays in the extraction equipment 100s, Extraction equipment temperature is maintained at 90 ° C. The resulting reaction liquid was analyzed by liquid chromatography, The conversion of 3,5-dimethylphenol was 98.59% The content of 4-chloro-3,5-dimethylphenol was 94.21% with a selectivity of 95.56%.
92.4 %Chromat.	With iron(III) chloride; sulfuryl dichloride; C₁₁H₂₄OS In dichloromethane at 20℃; for 4h; regioselective reaction;	4.2. Typical experimental procedure for the chlorination of m-xylenol General procedure: Freshly distilled sulfuryl chloride (4.66 mL, 57.7mmol) was added slowly over 2 h, via a pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl3 (25mg, 0.154mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2h and the reaction was quenched with water (20mL). The organic components were extracted with ether (3×30 mL). The ether layers were removed, combined and dried over MgSO4. The drying agent was filtered and the solvent was removed under reduced pressure. The crude product was weighed and then analyzed by quantitative GC in the presence of tetradecane as added internal standard.
94.4 %Chromat.	With iron(III) chloride; sulfuryl dichloride at 20℃; for 4h;	4.3. General procedure for the chlorination of m-xylenol General procedure: To a stirred mixture of m-xylenol (12.2 g, 100.0 mmol), FeCl3 (0.1 g), and the appropriate poly(alkylene sulfide) (1-26, 0.1 g) in DCM (50 ml), freshly distilled SO2Cl2 (8.9 ml,110.0 mmol) was slowly added over 2 h and the mixture was stirred for another 2 h. The mixture was worked up as described for the chlorination of cresols and the product mixture was analyzed by GC. Some reactions were conducted in different solvents, and/or with different quantities of solvent, polymer and/or ferric chloride (see results section), but were otherwise conducted in the same manner.
	With N-cyclohexylmorpholine; phosgene In 1,1,2,2-tetrachloroethylene at 80℃; for 2h; Inert atmosphere;	1-6 Example 2 Dissolve 122.16g (1.0mol) 3,5-dimethylphenol and 2.44g (2.0wt% of 3,5-dimethylphenol) 4-cyclohexylmorpholine in 122.16g tetrachloroethylene to obtain 3, 5-dimethylphenol solution;Add 122.16g of tetrachloroethylene solvent into a 1L stainless steel reactor equipped with mechanical stirring, thermometer and gas pipe connected with tail gas separation and recovery device, replace it with nitrogen atmosphere, turn on stirring and increase the temperature to 80°C, add 227.52g (2.3 mol) The phosgene and 3,5-dimethylphenol solution was slowly and uniformly introduced into the reaction kettle within 0.5h. After the feeding was completed, the reaction was kept at 80°C for 2h, and the reaction was stopped.The reaction solution is cooled to room temperature to crystallize and the crystals are filtered out to obtain 4-chloro-3,5-dimethylphenol.GC measured the conversion rate of 3,5-dimethylphenol in the reaction solution of 99.0%, the selectivity of 4-chloro-3,5-dimethylphenol was 97.8%, and P/O=52.6.
95 %	With hydrogenchloride; copper(II) choride dihydrate; oxygen; acetic acid In chlorobenzene at 70℃;	1-10 General procedure: Evaluation conditions: In a 25mL three-necked flask, 20mmol of different phenolic compounds, 10mmol of CuCl2·2H2O catalyst, 5mL of hydrochloric acid, chlorobenzene, and 10mmol of acetic acid were added. Inject 6mL/min of oxygen by means of micro oxygen bubbling, heat to the target temperature of 70-90°C and react for 1-24h.
95.81 %	With sulfuryl dichloride; sulfur dioxide at -20℃;	1- Example 1 Preparation of chlorinating agent: The sulfuryl chloride reactor is a tower reactor (20mm in diameter), with activated carbon as filler, liquid SO2 is passed through the distributor from the upper end, chlorine gas is passed from the lower end, and reacts with SO2 upwards. The liquid is withdrawn from the tower kettle. Fill the sulfuryl chloride reactor with 500mm of activated carbon, pump 200g of liquid SO2 from the top, feed 100g of chlorine gas at the bottom of the tower, control the temperature of the sulfuryl chloride reactor to -20°C, and the residence time to be 20s to obtain the reaction solution of the chlorinating agent (mass ratio 2:1). Chlorination reaction: Add 300g SO2 liquid into a 1000mL three-necked bottle, then add 150g 3,5-dimethylphenol (mass ratio 2:1), stir to dissolve fully, and pre-cool the solution to about -20°C , keep the temperature, slowly and uniformly add the reaction solution of 300g chlorination agent in the previous step (the molar ratio of chlorine to MX is 1.15:1), dropwise for 2h, after the reaction is over, take a sample and analyze it with GC, the results are shown in Figure 1, where MX : 0.59%, PCMX: 96.84%, OCMX: 1.48%, DCMX: 1.09%. Through atmospheric distillation, 300g of SO2 liquid was extracted, the extraction temperature was -10°C, the solution in the tower was concentrated into a solid-liquid mixture, the crystals were filtered out, and dried in an oven at atmospheric pressure at 40°C for 0.5h to obtain 184.23g of 4-chloro- 3,5-Dimethylphenol product, GC analysis, the result is shown in Figure 2, wherein MX: 0.12%, PCMX: 99.75%, OCMX: 0.04%, DCMX: 0.09%. Overall, the yield of PCMX was 95.81% (based on molar yield of MX).
95.7 %Chromat.	With hydrogenchloride; copper(II) choride dihydrate; oxygen In chlorobenzene at 70℃;	1-7 Evaluation conditions: General procedure: In a 500mL three-necked flask, add 320mmol of 3.5-dimethylphenol, 160mmol of copper chloride dihydrate, 800mmol of hydrochloric acid, and 60mL of chlorobenzene. The oxygen flow rate was 10-60mL/min, and the reaction was heated to 60-95°C for 8-24h. The results are shown in Table 6:

Reference： [1]Misal, Balu; Palav, Amey; Ganwir, Prerna; Chaturbhuj, Ganesh [Tetrahedron Letters, 2021, vol. 63]
[2]Current Patent Assignee: ANHUI ZHONGTANG TANYI INDUSTRIAL TECH - CN111440051, 2020, A Location in patent: Paragraph 0023-0059
[3]Current Patent Assignee: HUNAN RUIGUAN BIOCHEMICAL TECH - CN113105312, 2021, A Location in patent: Paragraph 0043-0044; 0047-0084
[4]Current Patent Assignee: ZHEJIANG NHU CO., LTD. - CN113603569, 2021, A Location in patent: Paragraph 0032-0035; 0036-0039; 0040-0043; 0044-0047; ...
[5]Current Patent Assignee: SHAANXI COAL AND CHEMICAL INDUSTRY GROUP CO. LTD. - CN114805033, 2022, A Location in patent: Paragraph 0045-0074; 0108-0123
[6]Mostafa, Mohamed A. B.; Bowley, Rosalind M.; Racys, Daugirdas T.; Henry, Martyn C.; Sutherland, Andrew [Journal of Organic Chemistry, 2017, vol. 82, # 14, p. 7529 - 7537]
[7]Current Patent Assignee: WILLIAM WIGGINS COCKER - US2350677, 1940, A
[8]Current Patent Assignee: WILLIAM WIGGINS COCKER - US2350677, 1940, A
[9]v. Auwers [Fortschritte der Chemie, Physik und physikalischen Chemie, 1924, vol. 18, p. 38,51]
[10]Crocke,H.P.; Walser,R. [Journal of the Chemical Society C: Organic, 1970, p. 1982 - 1986]
[11]Current Patent Assignee: SUMITOMO SEIKA CHEMICALS COMPANY LIMITED - US4245127, 1981, A
[12]Smith, Keith; Al-Zuhairi, Ali J.; El-Hiti, Gamal A.; Alshammari, Mohammed B. [Journal of Sulfur Chemistry, 2015, vol. 36, # 1, p. 74 - 85]
[13]Current Patent Assignee: CHINA PETROCHEMICAL CORPORATION - CN107226775, 2017, A Location in patent: Paragraph 0016-0018
[14]Smith, Keith; Al-Zuhairi, Ali J.; Elliott, Mark. C.; El-Hiti, Gamal A. [Journal of Sulfur Chemistry, 2018, vol. 39, # 6, p. 607 - 621]
[15]Smith, Keith; Hegazy, Amany S.; El-Hiti, Gamal A. [Journal of Sulfur Chemistry, 2020, vol. 41, # 4, p. 345 - 356]
[16]Current Patent Assignee: WANHUA CHEMICAL GROUP CO LTD - CN111517922, 2020, A Location in patent: Paragraph 0037-0079
[17]Current Patent Assignee: ANHUI HAIHUA TECH GROUP - CN115583869, 2023, A Location in patent: Paragraph 0030-0090
[18]Current Patent Assignee: SHANDONG XINHECHENG FINE CHEMICAL TECH CO LTD; ZHEJIANG NHU CO., LTD. - CN115466166, 2022, A Location in patent: Paragraph 0027-
[19]Current Patent Assignee: ANHUI HAIHUA TECH GROUP - CN115611710, 2023, A Location in patent: Paragraph 0025-0070

7
[ 108-68-9 ]
[ 88-04-0 ]
[ 5538-41-0 ]

Yield	Reaction Conditions	Operation in experiment
89%Chromat.; 7.6%Chromat.	With iron(III) chloride; 1,2-dithiacyclooctane; sulfuryl dichloride; In dichloromethane; at 20.0℃; for 4.0h;	General procedure: m-Xylenol (6.11 g, 50.0 mmol), FeCl3 (25 mg), DCM (25 ml) and the catalyst (30 mg) wereadded to a dried 50 ml round-bottomed flask. Freshly distilled sulfuryl chloride (4.66 ml, 57.7mmol) was added slowly over 2 h via a pressure-equalizing dropping funnel. The reaction wasstirred at room temperature for a further 2 h. The mixture was quenched with water (20 ml),and the organic components were extracted with diethyl ether (3 × 30 ml). The ether layerswere removed, combined and dried over MgSO4. The drying agent was filtered, and the solventwas removed under reduced pressure. The crude product was weighed and then analyzed byquantitative GC
90%Chromat.; 5.9%Chromat.	With iron(III) chloride; sulfuryl dichloride; C11H24S2; In dichloromethane; at 20.0℃; for 4.0h;	General procedure: Freshly distilled sulfuryl chloride (4.66 mL, 57.7mmol) was added slowly over 2 h, via a pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl3 (25mg, 0.154mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2h and the reaction was quenched with water (20mL). The organic components were extracted with ether (3×30 mL). The ether layers were removed, combined and dried over MgSO4. The drying agent was filtered and the solvent was removed under reduced pressure. The crude product was weighed and then analyzed by quantitative GC in the presence of tetradecane as added internal standard.
89.1%Chromat.; 6.6%Chromat.	With sulfure de pentamethylene; iron(III) chloride; sulfuryl dichloride; In 1,1,2,2-tetrachloroethylene; at 20.0℃; for 4.0h;	m-Xylenol (6.11 g, 50.0 mmol), FeCl3 (25 mg), tetrachloroethylene (25ml) and the appropriate cyclic sulfide 1-4 (0.05 mmol) were placed in a dried round bottom flask (50 ml).The mixture was stirred as freshly distilled sulfuryl chloride (4.44 ml, 55.0 mmol) was added slowly over 2 h via a pressure equalizing dropping funnel and then for another 2 h.The work-up and analysis of the products by GC were as previously described for other phenols.

78.3%Chromat.; 8.7%Chromat.

With iron(III) chloride; sulfuryl dichloride; at 20.0℃; for 4.0h;

General procedure: To a stirred mixture of m-xylenol (12.2 g, 100.0 mmol), FeCl3 (0.1 g), and the appropriate poly(alkylene sulfide) (1-26, 0.1 g) in DCM (50 ml), freshly distilled SO2Cl2 (8.9 ml,110.0 mmol) was slowly added over 2 h and the mixture was stirred for another 2 h. The mixture was worked up as described for the chlorination of cresols and the product mixture was analyzed by GC. Some reactions were conducted in different solvents, and/or with different quantities of solvent, polymer and/or ferric chloride (see results section), but were otherwise conducted in the same manner.

Reference： [1]Angewandte Chemie,1912,vol. 25,p. 1944
[2]Journal of Sulfur Chemistry,2015,vol. 36,p. 74 - 85
[3]ACS Catalysis,2018,vol. 8,p. 4033 - 4043
[4]Journal of Sulfur Chemistry,2018,vol. 39,p. 607 - 621
[5]Journal of Sulfur Chemistry,2019,vol. 40,p. 529 - 538
[6]Journal of Sulfur Chemistry,2020,vol. 41,p. 345 - 356

8
[ 88-04-0 ]
[ 14804-38-7 ]
[ 40843-44-5 ]

Reference： [1]Patent: DE2136828,1973,
Chem.Abstr.,1973,vol. 78

9
[ 88-04-0 ]
[ 26819-10-3 ]
[ 65262-67-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; copper(l) chloride In N,N-dimethyl-formamide Heating;

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - DE2720427, 1977, A1 [Chem.Abstr., 1978, vol. 88, # 120821][Chem.Abstr., 1978, vol. 88, # 120821]

10
[ 2832-19-1 ]
[ 88-04-0 ]
2-Chloro-N-(3-chloro-6-hydroxy-2,4-dimethyl-benzyl)-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 1414 - 1427

11
[ 2832-19-1 ]
[ 88-04-0 ]
2-Chloro-N-{3-chloro-5-[(2-chloro-acetylamino)-methyl]-6-hydroxy-2,4-dimethyl-benzyl}-acetamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1980,vol. 23,p. 1414 - 1427

12
[ 88-04-0 ]
[ 155566-46-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With air; Cu-exchange montmorillonite In chlorobenzene at 140℃; for 6h;
86%	With aluminum (III) chloride; propionic acid In nitromethane at 50℃; for 18h; Inert atmosphere;
63%	With clay; oxygen; copper In chlorobenzene for 10h; Heating;

30%	With iron(III) chloride
27%	With Cu-exchanged clay In chlorobenzene at 140℃; for 6h;

Reference： [1]Kantam, M. Lakshmi; Santhi, P. Lakshmi [Synthetic Communications, 1996, vol. 26, # 16, p. 3075 - 3079]
[2]Chanda, Tanmoy; Chowdhury, Sushobhan; Koley, Suvajit; Anand, Namrata; Singh, Maya Shankar [Organic and Biomolecular Chemistry, 2014, vol. 12, # 45, p. 9216 - 9222]
[3]Coleman; Guernon; Roland [Organic letters, 2000, vol. 2, # 3, p. 277 - 280]
[4]Higashizima, Takanori; Sakai, Nozomu; Nozaki, Kyoko; Takaya, Hidemasa [Tetrahedron Letters, 1994, vol. 35, # 13, p. 2023 - 2026]
[5]Qu, Shen; Greenhalgh, Mark D.; Smith, Andrew D. [Chemistry - A European Journal, 2019, vol. 25, # 11, p. 2816 - 2823]

13
[ 88-04-0 ]
[ 494-38-2 ]
N,N,N',N'-Tetramethyl-acridine-3,6-diamine; compound with 4-chloro-3,5-dimethyl-phenol [ No CAS ]
N,N,N',N'-Tetramethyl-acridine-3,6-diamine; compound with 4-chloro-3,5-dimethyl-phenol [ No CAS ]

Reference： [1]Berichte der Bunsengesellschaft/Physical Chemistry Chemical Physics,1984,vol. 88,p. 744 - 750
[2]Berichte der Bunsengesellschaft/Physical Chemistry Chemical Physics,1984,vol. 88,p. 750 - 759

14
[ 88-04-0 ]
[ 79-08-3 ]
[ 19545-95-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran for 12h; Heating;

Reference： [1]Abraham, D. J.; Kennedy, P. E.; Mehanna, A. S.; Patwa, D. C.; Williams, F. L. [Journal of Medicinal Chemistry, 1984, vol. 27, # 8, p. 967 - 978]

15
N,N,N',N'-Tetramethyl-acridine-3,6-diamine; compound with 4-chloro-3,5-dimethyl-phenol [ No CAS ]
[ 88-04-0 ]
[ 494-38-2 ]

Reference： [1]Berichte der Bunsengesellschaft/Physical Chemistry Chemical Physics,1984,vol. 88,p. 744 - 750

16
N,N,N',N'-Tetramethyl-acridine-3,6-diamine; compound with 4-chloro-3,5-dimethyl-phenol [ No CAS ]
[ 88-04-0 ]
[ 494-38-2 ]

Reference： [1]Berichte der Bunsengesellschaft/Physical Chemistry Chemical Physics,1984,vol. 88,p. 744 - 750

17
[ 108-68-9 ]
[ 88-04-0 ]
[ 133-53-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-chlorotriethylammonium chloride In trifluoroacetic acid Ambient temperature; Yield given. Yields of byproduct given;

Reference： [1]Smith, John R. Lindsay; McKeer, Linda C.; Taylor, Jonathan M. [Journal of the Chemical Society. Perkin transactions II, 1988, p. 385 - 392]

18
[ 107-59-5 ]
[ 88-04-0 ]
[ 19545-95-0 ]

Yield	Reaction Conditions	Operation in experiment
	(i) K₂CO₃, DMF, (ii) TsOH, toluene; Multistep reaction;

Reference： [1]Baker,B.R.; Neenan,J.P. [Journal of Medicinal Chemistry, 1972, vol. 15, # 9, p. 940 - 944]

19
[ 67-66-3 ]
[ 108-68-9 ]
sulfuryl chloride (1 mol) [ No CAS ]
[ 88-04-0 ]
[ 5538-41-0 ]

Reference： [1]Chemische Berichte,1923,vol. 56,p. 968

20
[ 88-04-0 ]
[ 7726-95-6 ]
[ 64-19-7 ]
[ 175204-32-7 ]

Reference： [1]Lesser; Gad [Chemische Berichte, 1923, vol. 56, p. 968]

21
[ 88-04-0 ]
[ 1011-54-7 ]
6-chloro-4-(2-methoxyphenyl)-5,7-dimethyl-3,4-dihydrochromen-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With trifluoroacetic acid at 100℃; for 16h;

Reference： [1]Li, Kelin; Foresee, Lindsay N.; Tunge, Jon A. [Journal of Organic Chemistry, 2005, vol. 70, # 7, p. 2881 - 2883]

22
[ 88-04-0 ]
[ 100124-07-0 ]
3,5-dimethyl-4-phenoxathiin-4-yl-phenol [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6173 - 6177

23
[ 88-04-0 ]
[ 108-68-9 ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium carbonate; isopropyl alcohol at 90℃; for 14h;
100 %Chromat.	In isopropyl alcohol for 15h; Irradiation; Inert atmosphere;

Reference： [1]Chen, Jingbo; Zhang, Yushun; Yang, Liquan; Zhang, Xiang; Liu, Jianping; Li, Liang; Zhang, Hongbin [Tetrahedron, 2007, vol. 63, # 20, p. 4266 - 4270]
[2]Location in patent: experimental part Dichiarante, Valentina; Fagnoni, Maurizio; Albini, Angelo [Green Chemistry, 2009, vol. 11, # 7, p. 942 - 945]

24
[ 4595-59-9 ]
[ 88-04-0 ]
[ 949882-24-0 ]

Yield	Reaction Conditions	Operation in experiment
85%	With tetraethoxy orthosilicate; caesium carbonate at 145℃;

Reference： [1]Zhao, Yuanhong; Wang, Yunsong; Sun, Hongwei; Li, Liang; Zhang, Hongbin [Chemical Communications, 2007, # 30, p. 3186 - 3188]

25
[ 88-04-0 ]
[ 2675-79-8 ]
[ 949882-21-7 ]

Yield	Reaction Conditions	Operation in experiment
89%	With tetraethoxy orthosilicate; caesium carbonate at 145℃;

Reference： [1]Zhao, Yuanhong; Wang, Yunsong; Sun, Hongwei; Li, Liang; Zhang, Hongbin [Chemical Communications, 2007, # 30, p. 3186 - 3188]

26
[ 88-04-0 ]
[ 586-77-6 ]
[ 150418-97-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With tetraethoxy orthosilicate; caesium carbonate at 145℃;

Reference： [1]Zhao, Yuanhong; Wang, Yunsong; Sun, Hongwei; Li, Liang; Zhang, Hongbin [Chemical Communications, 2007, # 30, p. 3186 - 3188]

27
[ 88-04-0 ]
[ 74-88-4 ]
[ 6981-15-3 ]

Yield	Reaction Conditions	Operation in experiment
92%
84%	With potassium carbonate In acetone for 3h; Inert atmosphere; Reflux;
77%	With potassium carbonate In acetone for 3h; Heating / reflux;	OH O CH31, KpC03 Acetone, CI CI 63 64 To a 1 L round-bottom flask 4-chloro-3, 5-dimethylphenol 63 (20 g, 127.7 [MMOL)] and acetone (500 mL, 0.2 M) was placed. To this solution were added potassium carbonate (35.3 g, 255.4 [MMOL)] and iodomethane (63.44 g, 447 [MMOL).] The reaction was stirred and heated to reflux for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield [4-CHLORO-3,] 5-dimethylphenyl methyl ether 64 (16.88 [G,] 77%).

With potassium carbonate In acetone for 6h; Reflux;

Reference： [1]Dichiarante, Valentina; Fagnoni, Maurizio; Albini, Angelo [Green Chemistry, 2009, vol. 11, # 7, p. 942 - 945]
[2]Wu, Linglin; Drinkel, Emma; Gaggia, Fiona; Capolicchio, Samanta; Linden, Anthony; Falivene, Laura; Cavallo, Luigi; Dorta, Reto [Chemistry - A European Journal, 2011, vol. 17, # 46, p. 12886 - 12890]
[3]Current Patent Assignee: PFIZER INC - WO2003/106446, 2003, A1 Location in patent: Page 58
[4]Schmink, Jason R.; Holcomb, Jennifer L.; Leadbeater, Nicholas E. [Organic Letters, 2009, vol. 11, # 2, p. 365 - 368]

28
[ 50-00-0 ]
[ 88-04-0 ]
[ 81322-67-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With triethylamine; magnesium chloride In tetrahydrofuran for 24h; Reflux;
59%	With triethylamine; magnesium chloride In acetonitrile for 4h; Heating / reflux;	100.1 Example 100; 6-chloro-5, 7-DIMETHYL-2- (TRIFLUROROMETHYL)-2H-CHROMENE-3-CARBOXYLIC acid; Step 1: Preparation of 3-CHLORO-6-HYDROXY-2, 4-DIMETHYLBENZALDEHYDE [0529] To a solution of 4-chloro-3,5-dimethyl-phenol (10.0 g, 63.9 mmol) in 400 mL CH3CN was added MGCL2 (9.12 g, 95.8 mmol), TEA (23.9 g, 32.9 mL, 236 mmol), and (CH20) N (13.4 g, 304 mmol). The reaction was heated at reflux for 4 h. After cooling to room temperature, 2 N HC1 was added until the reaction was pH 3. The aqueous layer was extracted two times with 300 mL OF ET20. The organic layer was filtered and the filtrate was washed one time with saturated brine, followed by drying over MGS04, and concentrated under vacuum. Crude desired (12.6 g) was isolated. Under flash chromatography conditions, 6.9 g (59 %) of pure compound was isolated.
	With magnesium chloride; triethylamine In tetrahydrofuran Reflux;

Reference： [1]Chanda, Tanmoy; Chowdhury, Sushobhan; Koley, Suvajit; Anand, Namrata; Singh, Maya Shankar [Organic and Biomolecular Chemistry, 2014, vol. 12, # 45, p. 9216 - 9222]
[2]Current Patent Assignee: PFIZER INC - WO2004/87686, 2004, A2 Location in patent: Page 253 Current Patent Assignee: PFIZER INC - WO2004/87687, 2004, A1 Location in patent: Page 253
[3]Chanda, Tanmoy; Chowdhury, Sushobhan; Anand, Namrata; Koley, Suvajit; Gupta, Ashutosh; Singh, Maya Shankar [Tetrahedron Letters, 2015, vol. 56, # 8, p. 981 - 985]

29
[ 88-04-0 ]
[ 563-47-3 ]
[ 144983-32-4 ]

Yield	Reaction Conditions	Operation in experiment
38.5%	With nitric acid; sodium methylate; magnesium chloride In methanol; hexane; water; acetic anhydride	R.6 Synthesis of 5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran REFERENCE EXAMPLE 6 Synthesis of 5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran A 50 g amount of 4-chloro-3,5-xylenol was dissolved in 50 ml of dry methanol. A 73.9 g amount of sodium methoxide (28% methanol solution) and 43.4 g of 3-chloro-2-methyl-1-propene was added thereto, and the mixture was heated under reflux with stirring for 28 hrs. The reaction mixture was cooled, the solvent was removed by evaporation, 300 ml of water was added to the residue, and the mixture was extracted with ethyl acetate (150 mlthree times). The organic layer was washed with a 5N aqueous sodium hydroxide solution (70 mltwo times), water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to provide 66.6 g of a pale yellow oleaginous substance. A 25 g amount of anhydrous magnesium chloride was added to the oleaginous substance, and the mixture was heated at 200° C. with stirring for 24 hrs. The reaction mixture was cooled, 500 ml of water was added thereto, and the mixture was extracted with methylene chloride (250 mlthree times). The organic layer was washed with a 5N aqueous sodium hydroxide solution (100 ml), a 1N aqueous hydrochloric acid solution (100 ml) and brine in that order and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to provide 64.8 g of a pale green oleaginous substance. Then, this product was dissolved in 300 ml of acetic anhydride, and 29.09 g of nitric acid (70%) was slowly added thereto under ice cooling. The stirring was continued for additional one hour to precipitate crystal. The reaction was allowed to proceed at room temperature for additional 2 hr, the reaction mixture was poured into 500 ml of water, and the mixture was extracted with ethyl acetate (300 ml3 times). The organic layer was washed with an aqueous sodium hydroxide solution (2N, 200 ml*2 times), water and saturated saline in that order and dried over anhydrous magnesium sulfate, and the solvent was removed by evaporation to provide pale brown crystals. This crystal was dissolved in 350 ml of hexane with heating, insolubles were removed by filtration, and the filtrate was subjected to recrystallization. The resultant crystals were further recrystallized from ethanol to provide 31.4 g of the intended compound (5-chloro-2,2,4,6-tetramethyl-7-nitro-2,3-dihydrobenzofuran) as pale yellow crystals (yield: 38.5%). The melting point (m.p.) was 111° to 112° C.

Reference： [1]Current Patent Assignee: TEIJIN LIMITED - US5496853, 1996, A

30
[ CAS Unavailable ]
[ 88-04-0 ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
	With tributylphosphine; diamide In toluene at 20 - 60℃; for 4h;	The starting material (0.05 mmol) was dissolved or suspended in toluene (1.00 mL). The phenol derivative (0.075 mmol) in toluene (0.50 mL) was added. TMAD (0.075 mmol) in toluene (0.50 mL) was added, followed by tributylphosphine (0.15 mmol). The reaction mixture was stirred for 2 h at rt and then 2 h at 60 °C. Sometimes it was necessary to add a second portion of tributylphosphine and to stir overnight. Sometimes, THF was necessary as cosolvent to dissolve the reactants. The reaction mixture was allowed to cool to rt, andthen water was added. The mixture was extracted with EtOAc, and the org. extracts were evaporated under reduced pressure. The residue was purified by HPLC.

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2006/21402, 2006, A1 Location in patent: Page/Page column 28-29; 62

31
[ 860213-79-2 ]
[ 88-04-0 ]
[ 81322-67-0 ]

Yield	Reaction Conditions	Operation in experiment
70%	In dichloromethane	11.i 2-[1-(Ethoxyimino)propyl]-3-hydroxy-5-(3-chloro-6-difluoromethoxy-2,4-dimethylphenyl)cyclohex-2-en-1-one (28) (i) A solution of 4-chloro-3,5-dimethylphenol (16 g, 0.1 mole) in dichloromethane (100 ml) was stirred and cooled to 2° C. in an ice bath. Titanium tetrachloride (35 g, 0.18 mole) was added dropwise over a period of 10 minutes and dichloromethylmethyl ether (11.5 g, 0.1 mole) was added slowly to the dark red solution, the temperature being kept below 10° C. throughout. After the solution had been stirred at 5° C. for 30 minutes the temperature was allowed to rise and to remain at 20° C. for 30 minutes. Finally the solution was warmed at 35° C. for 15 minutes and then poured into ice water (200 ml). The mixture was shaken vigorously until almost colourless and then the dichloromethane layer was separated and the aqueous phase was extracted with more dichloromethane (250 ml). The combined organic layers were washed with water thoroughly (4200 ml) and then dried over anhydrous magnesium sulphate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure using a rotary evaporator. The product, 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde was isolated as a white solid (13 g, 70%), mp 89°-90° C. Proton magnetic resonance spectrum (CDCl3; δ in ppm): 2.40 (3H, s); 2.64 (3H, s); 6.71 (1H, s); 10.23 (1H, s); 11.91 (1H, s).

Reference： [1]Current Patent Assignee: ORICA LIMITED - US4666510, 1987, A

32
[ 88-04-0 ]
[ 79-04-9 ]
[ 22012-63-1 ]

Yield	Reaction Conditions	Operation in experiment
89.8%	With pyridine	H.C 4-Chloro-3,5-dimethylphenyl chloroacetate 4-Chloro-3,5-dimethylphenyl chloroacetate Chloroacetyl chloride (0.1 mol, 8ml) was mixed with ether (30 ml), in a 250 ml conical flask, cooled on a cold water-bath. To this solution was added dropwise a mixture of 4-chloro-3,5-dimethylphenol (0.1 mol, 15.66g), pyridine (0.1 mol, 8 ml) in ether (100 ml), the total addition time being 30 minutes. The reaction mixture was left to stir over the cold water-bath for three hours. Then, the white precipitate of pyridinium chloride was filtered off and the reaction mixture was washed with distiled water (3x100 ml), dried over MgSO4and the solvent removed under reduced pressure, yielding 4-Chloro-3,5-dimethylphenyl chloroacetate as a grey solid (29.3g, 89.8%). C10H10Cl2O2 M= 233.09 g/mol PF: 42°C δH: (270 MHz, CDCl3) 2.37 (CH3, s, 6H), 4.27 (ArOOCCH2Cl, s, 2H), 6.92 (H aromatic, s, 2H).
	at 120℃;

Reference： [1]Current Patent Assignee: PROCTER & GAMBLE CO - EP752465, 1997, A1
[2]Bdzhola, V. G.; Bilokin, Y. V.; Borysenko, I. P.; Lukashov, S. S.; Protopopov, M. V.; Prykhod'ko, A. O.; Starosyla, S. A.; Vdovin, V. S.; Yarmoluk, S. M. [Bioorganic Chemistry, 2020, vol. 102]

33
[ 358-23-6 ]
[ 88-04-0 ]
[ 1242759-17-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 4-Chloro-3,5-dimethylphenol With triethylamine In dichloromethane at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at -78 - 20℃; for 12h; Inert atmosphere;
78%	With triethylamine In dichloromethane at 0 - 20℃;
	Inert atmosphere;

	With pyridine In dichloromethane at 0 - 20℃; for 5h;	2. Preparation of Aryl Triflates General procedure: To a solution of phenol (1.0 equiv) and pyridine (2.0 equiv) in DCM was added dropwise trifluoromethanesulfonic anhydride (1.2 equiv) at 0 °C. Then the mixture was warmed to room temperature and stirred for 5 hours. The reaction was quenched with HCl (1M). The mixture was diluted with ethyl acetate. The organic layer was washed with sat. NaHCO3, water, brine successively and concentrated under reduced pressure. The crude residue was purified with a flash column chromatography.
	Stage #1: 4-Chloro-3,5-dimethylphenol With triethylamine In dichloromethane at 20℃; Inert atmosphere; Stage #2: trifluoromethylsulfonic anhydride In dichloromethane at -78 - 20℃; Inert atmosphere;

Reference： [1]Keaveney, Sinead T.; Kundu, Gourab; Schoenebeck, Franziska [Angewandte Chemie - International Edition, 2018, vol. 57, # 38, p. 12573 - 12577][Angew. Chem., 2018, vol. 130, # 38, p. 12753 - 12757,5]
[2]So, Chau Ming; Chow, Wing Kin; Choy, Pui Ying; Lau, Chak Po; Kwong, Fuk Yee [Chemistry - A European Journal, 2010, vol. 16, # 27, p. 7996 - 8001]
[3]Lee, Hong Geun; Milner, Phillip J.; Buchwald, Stephen L. [Organic Letters, 2013, vol. 15, # 21, p. 5602 - 5605]
[4]Chen, Hui; Liao, Xuebin [Tetrahedron, 2019, vol. 75, # 31, p. 4186 - 4191]
[5]Haldar, Chabush; Bisht, Ranjana; Chaturvedi, Jagriti; Guria, Saikat; Hassan, Mirja Md Mahamudul; Ram, Bali; Chattopadhyay, Buddhadeb [Organic Letters, 2022, vol. 24, # 44, p. 8147 - 8152]

34
[ 88-04-0 ]
[ 57057-80-4 ]
[ 1257059-10-1 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate at 108℃; for 0.25h; Microwave irradiation; optical yield given as %ee;

Reference： [1]Location in patent: experimental part Ochal, Zbigniew; Durka, Krzysztof; Banach, Lukasz [Synthetic Communications, 2010, vol. 40, # 21, p. 3209 - 3213]

35
[ 88-04-0 ]
[ 100379-00-8 ]
[ 1157867-57-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With C₂₈H₄₄N₂PPd; potassium carbonate In ethanol; water at 50℃; for 10h;

Reference： [1]Lee, Dong-Hwan; Jin, Myung-Jong [Organic Letters, 2011, vol. 13, # 2, p. 252 - 255]

36
[ 88-04-0 ]
[ 6165-76-0 ]
[ 1248132-95-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	General procedure for the production of ethers 16a - 16c, 17a - 17c: General Procedure: To a solution of one of the phenols 3 - 5 (1 eq) and tosyl ester (1.2 eq) dissolved in dry DMF was added potassium carbonate (2.5 eq). The mixture was stirred at room temperature for either 20 hours (compounds C to E) or two days (F to H), at which point the starting material was no longer visible byTLC. The solvent was then removed under reduced pressure and the crude mixture was purified by flash chromatography (hexanes/ethyl acetate, 1/9), to afford the phenol-alkynes 16a - 16c, 17a - 17c as white solids (51 - 96%, 69 - 92%).

Reference： [1]Findlay, Brandon; Zhanel, George G.; Schweizer, Frank [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1499 - 1503]

37
[ 88-04-0 ]
[ 76911-01-8 ]
[ 1357190-43-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃;	General procedure for the production of ethers 16a - 16c, 17a - 17c: General Procedure: To a solution of one of the phenols 3 - 5 (1 eq) and tosyl ester (1.2 eq) dissolved in dry DMF was added potassium carbonate (2.5 eq). The mixture was stirred at room temperature for either 20 hours (compounds C to E) or two days (F to H), at which point the starting material was no longer visible byTLC. The solvent was then removed under reduced pressure and the crude mixture was purified by flash chromatography (hexanes/ethyl acetate, 1/9), to afford the phenol-alkynes 16a - 16c, 17a - 17c as white solids (51 - 96%, 69 - 92%).

Reference： [1]Findlay, Brandon; Zhanel, George G.; Schweizer, Frank [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1499 - 1503]

38
[ 88-04-0 ]
[ 1079251-34-5 ]
[ 1415968-69-2 ]

Yield	Reaction Conditions	Operation in experiment
	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 15h;
81 mg	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 15h;	2.D Step D. Preparation of ethyl 3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-lH-indole-2- carboxylate To a solution of ethyl 3-(3-hydroxypropyl)-lH-indole-2-carboxylate (70 mg, 0.28 mmol), PPh3 (110 mg, 0.51 mmol) and 3,5-diMe-4-Cl-phenol (81 mg, 0.52 mmol) in THF (3.5 mL) was added Dt-BuAD (99 mg, 0.51 mmol) at 20 °C. The reaction mixture was stirred for 15 h at 20 °C then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-10%) to give the title compound (81 mg, 0.21 mmol) as a colorless oil. MS (ES) 385.2 (M+H).

Reference： [1]Friberg, Anders; Vigil, Dominico; Zhao, Bin; Daniels, R. Nathan; Burke, Jason P.; Garcia-Barrantes, Pedro M.; Camper, Demarco; Chauder, Brian A.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W. [Journal of Medicinal Chemistry, 2013, vol. 56, # 1, p. 15 - 30]
[2]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2015/148854, 2015, A1 Location in patent: Paragraph 00409

39
[ 627-00-9 ]
[ 88-04-0 ]
6-chloro-3-(2-chloroethyl)-2-(3-chloropropyl)-5,7-dimethyl-4H-chromen-4-one [ No CAS ]

Reference： [1]Organic and Biomolecular Chemistry,2014,vol. 12,p. 9216 - 9222

40
[ 88-04-0 ]
[ 1369001-96-6 ]
[ 1666138-54-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 3-(7-bromo-2-methyl-1H-indol-3-yl)propan-1-ol With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 0℃; for 0.25h; Stage #2: 4-Chloro-3,5-dimethylphenol In tetrahydrofuran at 0 - 20℃; for 5h;	63.C Step C. Preparation of 7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2- methyl-lH-indole: Step C. Preparation of 7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2- methyl-lH-indole: To a solution of di-tert-butyl diazocarboxylate (8.96 g, 38.9 mmol) in THF (120 mL) was added triphenyl phosphine (10.2 g, 38.9 mmol) followed by addition of 3-(7- bromo-2-methyl-lH-indol-3-yl)propan-l-ol (8.02 g, 29.92 mmol) in THF (20 mL). The reaction mixture was stirred at 0°C for 15 min. 4-chloro-3,5dimethylphenol (6.05 g, 38.9 mmol) in anhydrous tetrahydrofurane (20 mL) was added to the reaction mixture at 0°C. The reaction mixture was allowed to worm up to room temperature and stirred additionally for 5 h. The solvent was removed in vacuo and the residue was purified by column chromatography using Hex/EtOAc (Combi-flash Rf, 0 to 15% EtOAc gradient) to afford the title compound (9.66 g, 80 %). 1H NMR (CDCls, 400 MHz) δ (ppm) 7.89 (s, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 6.93 (t, J = 8.0 Hz, 1H), 6.60 (s, 2H), 3.84 (t, J = 6.0 Hz, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.36 (s, 3H), 2.32 (s, 6H), 2.07 (qt, J = 6.0 Hz, 2H); LCMS (ESI) tR: 1.700 min (>99%, ELSD), m/z: 408.1 (M+H).

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2015/31608, 2015, A1 Location in patent: Paragraph 00425

41
[ 3569-21-9 ]
[ 88-04-0 ]
3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
340 mg	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 2h;	5.B Step B. Preparation of 3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-lH-indole Step B. Preparation of 3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-lH-indole To a solution of 3-(lH-indol-3-yl)propan-l-ol (250 mg, 1.43 mmol), PPh3 (560 mg, 2.14 mmol), and 4-chloro-3,5-dimethylphenol (358 mg, 2.28 mmol) in THF (14 mL) was added Dt-BuAD (493 mg, 2.14 mmol) at 20 °C. The reaction mixture was stirred for 2h at 20 °C then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf, Hexane/EtOAc gradient 0-10%) to give the title compound (340 mg, 1.08 mmol) as a colorless oil. MS (ES) 314.2 (M+H).
4.5 g	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 15h;	1.C Step C. Preparation of 3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-lH-indole To a solution of 3-(lH-indol-3-yl)propan-l-ol (2.54 g, 14.5 mmol), PPh3 (6.45 g, 24.6 mmol), and 3,5-diMe-4-Cl-phenol (4.0 g, 25.4 mmol) in THF (160 mL) was added Dt- BuAD (5.66g, 24.6 mmol) at 20 °C. The reaction mixture was stirred for 15 h at 20 °C then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-10%) to give the desire compound as a colorless oil in 4.5 g (14.3 mmol). MS (ES) 314.1 (M+H).

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2015/31608, 2015, A1 Location in patent: Paragraph 00329
[2]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2015/148854, 2015, A1 Location in patent: Paragraph 00404

42
[ 88-04-0 ]
[ 1666138-73-3 ]
[ 1666138-74-4 ]

Yield	Reaction Conditions	Operation in experiment
62%	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 3h;	115.C Step C. Preparation of 7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2- (trifluoromethyl)-lH-indole: Step C. Preparation of 7-bromo-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-2- (trifluoromethyl)-lH-indole: To a flame dried round bottom flask equipped with magnetic stir bar was added Dt-BuAD (1.36 g, 5.9 mmols) followed by anhydrous THF (25 mL). The reaction mixture was stirred at 0 °C for 15 min. PPh3 (1.54 g, 5.9 mmols) was added, followed by a solution of 3-(7-bromo-2-(trifluoromethyl)-lH-indol-3-yl)propan-l-ol and 4-chloro-3,5- dimethylphenol in anhydrous THF (10 mL). The reaction mixture was warmed up to rt and stirred additional 3 h. The reaction mixture was concentrated, and the residue was purified by flash chromatography (Combi-flash Rf, Hex/EtOAc 0-10% gradient) to give the title compound (1.3 g, 62%). 1H-NMR (CDCI3) δ 8.37 (broad s, 1H), 7.63 (d, 1H, J = 8 Hz), 7.50 (d, 1H, J = 8 Hz), 7.06 (t, 1H, J = 8 Hz), 6.63 (s, 2H), 3.94 (t, 2H, J = 8 Hz), 3.08 (t, 2H, J = 8 Hz), 2.35 (s, 6H), 2.14 (q, 2H, J= 8 Hz ); 19F-NMR (CDC13) δ -58.5.

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2015/31608, 2015, A1 Location in patent: Paragraph 00495

43
[ 88-04-0 ]
[ 1585224-81-2 ]
[ 1585224-82-3 ]

Yield	Reaction Conditions	Operation in experiment
1.15 g	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 15h;
105 mg	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 15h;	1.D Step D. Preparation of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate To a solution of ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate(101 mg,0.28 mmol),PPh3(110 mg,0.51 mmol) and 3,5-diMe-4-Cl-phenol(81mg,0.52 mmol) in THF(3.5 mL) was added Dt-BuAD(99 mg,0.51 mmol) at 20 °C. Thereaction mixture was stirred for 15 h at 20 oc then concentrated in vacuo. The residue waspurified by flash chromatography(Combi-flash Rf Hexane/EtOAc gradient 0-10%) to givethe title compound(105 mg,0.21 mmol) as a colorless oil. MS(ES) 498.0(M+H).
1.15 g	With di-tert-butyl-diazodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃; for 15h;	27.D Step D. Preparation of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate Step D. Preparation of ethyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate To a solution of ethyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (1.0 g, 0.28 mmol), PPh3 (1.1 g, 5.1 mmol) and 3,5-diMe-4-Cl-phenol (810 g, 5.2 mmol) in THF (35 mL) was added Dt-BuAD (990 mg, 5.1 mmol) at 20° C. The reaction mixture was stirred for 15 h at 20° C. then concentrated in vacuo. The residue was purified by flash chromatography (Combi-flash Rf Hexane/EtOAc gradient 0-10%) to give the title compound (1.15 g, 2.3 mmol) as a white solid. MS (ES) 498.0 (M+H).

Reference： [1]Burke, Jason P.; Bian, Zhiguo; Shaw, Subrata; Zhao, Bin; Goodwin, Craig M.; Belmar, Johannes; Browning, Carrie F.; Vigil, Dominico; Friberg, Anders; Camper, DeMarco V.; Rossanese, Olivia W.; Lee, Taekyu; Olejniczak, Edward T.; Fesik, Stephen W. [Journal of Medicinal Chemistry, 2015, vol. 58, # 9, p. 3794 - 3805]
[2]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2017/152076, 2017, A1 Location in patent: Paragraph 0089
[3]Current Patent Assignee: VANDERBILT UNIVERSITY - US2016/106731, 2016, A1 Location in patent: Paragraph 0486

44
[ 5825-45-6 ]
[ 3184-35-8 ]
[ 88-04-0 ]
1-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-amino-1,2,3,4-tetrahydroquinoline; 2-oxohexanedioic acid With sulfuric acid In ethanol at 0 - 60℃; for 2.5h; Stage #2: With diazomethyl-trimethyl-silane In methanol; hexane; benzene at 20℃; for 0.166667h; Stage #3: 4-Chloro-3,5-dimethylphenol Further stages;

45
[ 88-04-0 ]
[ 79-11-8 ]
[ 19545-95-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide

Reference： [1]Takate; Karale; Salve; Kale; Ghodechor; Zaware; Jadhav [Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2015, vol. 54B, # 5, p. 687 - 690]

46
[ 88-04-0 ]
[ 1194-02-1 ]
[ 938300-53-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h;	1 (4-(4-Chloro-3,5-dimethylphenoxy)benzonitrile) [2, NB-1 -017]. 4-Chloro-3,5- dimethyl phenol (2 g, 12.8 mmol, 1 eq.) was added to a solution of 4-fluoro benzonitrile (1 ; 1.55 g, 12.8 mmol, 1 eq.) in anhydrous DMF (30 mL). K2C03 (1.76 g, 12.8 mmol, 1 eq.) was added. The reaction was stirred at 100 °C for 16 h. The reaction mixture was then allowed to cool, and poured over ice-water (300 mL). The organic material was extracted into diethyl ether (3 x 150 mL). The combined organic layers were washed with 3 M NaOH (3 x 150 ml), water (3 x 150 mL), brine (150 mL), dried Na2S04), filtered and concentrated to yield a pale brown solid that was used without further purification (100%): NMR (400 MHz, CDCh) δ = 7.60 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.6 Hz, 2H), 6.80 (s, 2H), 2.38 (s, 6H).
	With potassium carbonate In dimethyl sulfoxide Microwave irradiation;

Reference： [1]Current Patent Assignee: MACKERELL D ALEXANDER JR; UNIVERSITY SYSTEM OF MARYLAND - WO2019/40467, 2019, A1 Location in patent: Paragraph 00184-00186
[2]Lele, Arundhati C.; Raju, Archana; Khambete, Mihir P.; Ray; Rajan; Arkile, Manisha A.; Jadhav, Nandadeep J.; Sarkar, Dhiman; Degani, Mariam S. [ACS Medicinal Chemistry Letters, 2015, vol. 6, # 11, p. 1140 - 1144]

47
[ 88-04-0 ]
[ 501-65-5 ]
[ 1895141-98-6 ]

Yield	Reaction Conditions	Operation in experiment
98%	With [{Au(IPr)}2(μ-OH)][BF4] In toluene at 80℃; for 6h; regioselective reaction;	(Z)-(1-(4-Chloro-3,5-dimethylphenoxy)ethene-1,2-diyl)dibenzene (3aj) According to the general procedure for hydrophenoxylation, a crudeproduct, which was prepared from alkyne 1a (89.0 mg, 0.50 mmol),phenol (2j) (86.0 mg, 0.50 mmol) and [{Au(IPr)}2(μ-OH)][BF4] (3.2 mg,2.5 μmol, 0.5 mol %) in toluene (1 mL) at 80 °C for 6 h, was purified bycolumn chromatography on silica gel (pentane/EtOAc = 95/5), to give3aj (164 mg, 98%, average of two runs) as a colourless solid.

Reference： [1]Gómez-Suárez, Adrián; Oonishi, Yoshihiro; Martin, Anthony R.; Nolan, Steven P. [Beilstein Journal of Organic Chemistry, 2016, vol. 12, p. 172 - 178]

48
[ 88-04-0 ]
[ 65515-32-4 ]
methyl 6-(4-chloro-3,5-dimethylphenoxy)-2-methoxynicotinate [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 827 - 833

49
[ 10320-42-0 ]
[ 88-04-0 ]
2-(4-chloro-3,5-dimethylphenoxy)-5-nitropyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		Under 2 atmosphere, 4-chloro-3, 5-dimethylphenol (240 mg, 1.52 mmol, 5 1.20 equiv) was dissolved in THF (8.40 mL, 0.181 M) and stirred at 0 °C. NaH (60.8 mg, 1.52 mmol, 1.20 equiv, 60 percent dispersion in mineral oil) was added in portionwise. After 30 min, a solution of 2-chloro- 5-nitropyrimidine (200 mg, 1.24 mmol. 1.00 equiv) in THF (4.00 mL, 0.310 M) was added and then the reaction mixture was slowly warmed 10 to 50 °C for 12h. The reaction mixture was poured to water (100 mL) , extracted with EtOAc, washed with brine. The combined organic layers was dried (MgSO.j), filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with hexanes : EtOAc (20:1 to 1:1 (v/v) ) , to afford the title compound as a 15 yellow solid (288 mg, 1.03 mmol, 83percent yield). Rf = 0.61 (hexanes : EtOAc 10:1 (v/v)). NMR Spectroscopy: XE NMR (500 MHz, CDCI3, 25 °C, delta) : 9.32 (s, 2H) , 6.94 (s, 2H) , 2.41 (s, 6H) . 13C NMR (125 MHz, CDCI3, 25 °C, delta) : 167.1, 156.5, 149.9, 139.1, 138.4, 132.7, 121.1, 21.1. Mass Spectrometry: HRMS (ESI-TOF) (m/z) : calcd for C12H11CIN3O3 ( [M + H]+) , 20 280.0483, found, 280.0483.

Reference： [1]Patent: WO2016/57931,2016,A1 .Location in patent: Page/Page column 168

50
[ 88-04-0 ]
[ CAS Unavailable ]
[ CAS Unavailable ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 48h; Inert atmosphere;
	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 48h;	4 As depicted in Scheme 4-1, quinoline-3-carboxylic acid 3 was esterified with thionyl chloride in methanol to yield ester 4. Reduction of the pyridine ring of 4 with pyridine-borane complex in glacial acetic acid then delivered racemic THQ 5 whose methyl ester was saponified to yield ±-6. Alternatively, sulfonylation of ±-5 furnished compounds ±-7, which were also saponified with lithium hydroxide to afford the 3-carboxy target compounds ±-8. Further elaboration of the phenylsulfonyl group in ±-7c was accomplished by an SNAr reaction with 4- chloro-3,5-dimethylphenol followed by ester hydrolysis to afford compound ±-2, as shown in Scheme 4-2. In addition, the phenylsulfonyl moiety in ±-2 was replaced with a more flexible propylene group through a reductive amination-saponification sequence to yield ±-11.

Reference： [1]Chen; Wilder; Drennen; Tran; Roth; Chesko; Shapiro; Fletcher [Organic and Biomolecular Chemistry, 2016, vol. 14, # 24, p. 5505 - 5510]
[2]Current Patent Assignee: UNIVERSITY SYSTEM OF MARYLAND - WO2017/11323, 2017, A1 Location in patent: Paragraph 00343; 00345

51
[ 88-04-0 ]
[ 2068868-33-5 ]
[ 2068868-34-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In dimethyl sulfoxide at 100℃;	5 further validate the design of 4-aminobenzoates, a concise SAR library was synthesized according to general procedure shown in scheme 5-1. 4-nitrobenzoic acid 3 was esterified with sulfuric acid and methanol to yield ester 4. The nitro group of compound 4 was reduced with tin chloride dihydrate to deliver compound 5, which further underwent reductive amination with isobutyraldehyde to afford compound 6. Compound 6 was coupled to different aromatic sulfonyl chlorides to generate compounds library 7a-7d, which were saponified using lithium hydroxide to yield 4-aminobenzoate compounds 8a-8d. Additionally, compound 7d can be further elaborated with 3,5-dimethyl-4-chloro-phenol by 8ΝΑΓ reaction, followed by saponification to give compound 8e; Scheme 5-1. Synthesis of 4-aminobenzoate analogs. Reagents and conditions: (a) H2S04, MeOH, 80°C, overnight; (b) SnCl2 2H20, EtOAc, 50°C, overnight; (c) Isobutyraldehyde, NaBH(OAc)3, DCE, RT, overnight; (d) RS02C1, DIPEA, DMAP, CHC13, 60°C, overnight; (e) LiOH H20, THF-MeOH-H20, 3 : 1 : 1, RT, overnight; (04-chloro-3,5-dimethylphenol, K2C03, DMSO, 100°C, overnight.
86 %	With potassium carbonate In dimethyl sulfoxide at 100℃;

Reference： [1]Current Patent Assignee: UNIVERSITY SYSTEM OF MARYLAND - WO2017/11323, 2017, A1 Location in patent: Paragraph 00358-00359
[2]Chen, Lijia; Chauhan, Jay; Yap, Jeremy L.; Goodis, Christopher C.; Fletcher, Steven; Wilder, Paul T. [2022]

52
[ 88-04-0 ]
[ 109-64-8 ]
[ 26690-28-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate In acetonitrile Reflux;	General procedure for the side chain (7a-7m) General procedure: To a suspension of phenol(or thiophenol) (60 mmol, 1 eq.) and K2CO3 powder (24.8 g, 180 mmol, 3 eq.) in acetonitrile (100 mL) with stirring was added 1,3-dibromopropane (18.5 mL,180 mmol, 3 eq.) or 1,2-dibromoethane (12.6 mL,180 mmol, 3 eq.) at room temperature. The reaction mixture was refluxed for 3h -12 h, and monitored by TLC till the phenol was disappeared. After the reaction, the K2CO3 was removed by filtration and solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate: petroleum ether(1:50-1:20). The products (7a-7m) were obtained as colorless to yellow oils with yields of 60% to 93%.
85.2%	With potassium carbonate In acetonitrile for 3h; Reflux;	1.2 (2) Preparation of 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene 4-Chloro-3,5-dimethylphenol (25.6mmol, 4g, 1eq) was dissolved in 40ml of acetonitrile, potassium carbonate (3eq) and 1,3-dibromopropane (3eq) were added, and the mixture was refluxed for 3h.After the reaction is complete, cool to room temperature, add 150ml of water, extract 3 times with EA, combine the organic phases, wash with saturated brine, dry with sodium sulfate, suspend the organic phase, make sand, and column chromatography (PE) to obtain 6g of colorless liquid. The rate is 85.2%.
75%	With potassium carbonate In acetonitrile at 90℃; for 5h;

63%	With potassium carbonate In acetone at 60℃; for 5h;	4.1.2. 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene (i2) To a mixture of K2CO3 (5.3g, 38.1mmol), 1,3-dibromopropane (3.1g, 15.3mmol) and acetone (40mL), 4-chloro-3,5-dimethylphenol (2.0g, 12.7mmol) was added and the mixture was stirred for 5h at 60°C. After cooling to room temperature, the reaction mixture was diluted with water (200mL) and extracted with EtOAc (3 times). The combined organic layer was then washed with brine. Removal of solvent in vacuo yielded a crude product without any purification. Colorless liqiud, 2.2g (yield: 63%). LC-MS m/z: 277.0 [M+H]+.
63%	With potassium carbonate In acetone at 60℃; for 5h;	4.1.2. 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene (i2) To a mixture of K2CO3 (5.3g, 38.1mmol), 1,3-dibromopropane (3.1g, 15.3mmol) and acetone (40mL), 4-chloro-3,5-dimethylphenol (2.0g, 12.7mmol) was added and the mixture was stirred for 5h at 60°C. After cooling to room temperature, the reaction mixture was diluted with water (200mL) and extracted with EtOAc (3 times). The combined organic layer was then washed with brine. Removal of solvent in vacuo yielded a crude product without any purification. Colorless liqiud, 2.2g (yield: 63%). LC-MS m/z: 277.0 [M+H]+.
	With potassium carbonate In acetonitrile at 80℃; for 6h;	22.1 The first step is 5- (3-bromopropoxy) -2-chloro-1,3-dimethylbenzene The compound 3,5-dimethyl-4-chlorophenol 22a (1.05 g, 6.75 mmol), 1,3-dibromopropane (1.5 g,8.78 mmol) and potassium carbonate (1.28 g, 8.78 mmol) were dissolved in acetonitrile and reacted at 80 ° C for 6 hours. After completion of the reaction, the reaction solutionThe filtrate was concentrated under reduced pressure, distilled water was added, extracted with ethyl acetate (50 mL x 2), washed with saturated brine, combined with organic phase,Dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 15: 1)The intermediate product 22b was obtained (yellow oil) and allowed to proceed directly to the next step.
	With potassium carbonate In acetonitrile for 12h; Reflux;	4.1.9 General procedure (H) for the synthesis of side chain (5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene) To a suspension of 4-chloro-3,5-dimethylphenol (1.0eq.) and K2CO3 powder (3.0eq.) in acetonitrile with stirring was added 1,3-dibromopropane (3.0eq.). The reaction mixture was refluxed for 12h, and monitored by TLC till the phenol was disappeared. After the reaction, the K2CO3 was removed by filtration and solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate: petroleum ether(1:50-1:20). The side chain was obtained as colorless oil [20].
	With potassium carbonate In acetonitrile for 12h; Reflux;	4.1.9 General procedure (H) for the synthesis of side chain (5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene) To a suspension of 4-chloro-3,5-dimethylphenol (1.0eq.) and K2CO3 powder (3.0eq.) in acetonitrile with stirring was added 1,3-dibromopropane (3.0eq.). The reaction mixture was refluxed for 12h, and monitored by TLC till the phenol was disappeared. After the reaction, the K2CO3 was removed by filtration and solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate: petroleum ether(1:50-1:20). The side chain was obtained as colorless oil [20].
85.2 %	With potassium carbonate In acetonitrile Reflux;	1.2 (2) Preparation of 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene Dissolve 4-chloro-3,5-dimethylphenol (25.6mmol, 4g, 1eq) in 40ml of acetonitrile, add potassium carbonate (3eq), 1,3-dibromopropane (3eq), and reflux for 3h. After the reaction is complete, cool to room temperature, add 150ml of water, extract 3 times with EA, combine the organic phases, wash with saturated brine, dry over sodium sulfate, suspend the organic phase, make sand, and perform column chromatography (PE) to obtain 6 g of a colorless liquid. The rate is 85.2%.
85.2 %	With potassium carbonate In acetonitrile Reflux;	1.1 (1) Preparation of 5-(3-bromopropoxy)-2-chloro-1,3-dimethylbenzene Dissolve 4-chloro-3,5-dimethylphenol (25.6mmol, 4g, 1eq) in 40ml of acetonitrile, add potassium carbonate (3eq), 1,3-dibromopropane (3eq), and reflux for 3h.After the reaction was complete, cool to room temperature, add 150ml of water, extract 3 times with EA, combine the organic phases, wash with saturated brine, dry over sodium sulfate, suspend and dry the organic phase, make sand, and perform column chromatography (PE) to obtain 6 g of a colorless liquid.Yield 85.2%.

Reference： [1]Luan, Shenglin; Ge, Qi; Chen, Yedong; Dai, Mingyang; Yang, Jinyu; Li, Kun; Liu, Dan; Zhao, Linxiang [Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1943 - 1948]
[2]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN112321477, 2021, A Location in patent: Paragraph 0013; 0027; 0032-0033
[3]Zhu, Peng-Ju; Yu, Ze-Zhou; Lv, Yi-Fei; Zhao, Jing-Long; Tong, Yuan-Yuan; You, Qi-Dong; Jiang, Zheng-Yu [Journal of Medicinal Chemistry, 2021, vol. 64, # 15, p. 11330 - 11353]
[4]Deng, Hongguang; Huang, Min; Liu, Hui; Zhang, Hong; Liu, Liang; Gao, Bensheng; Li, Xianlu; Li, Jinbo; Niu, Qun; Zhang, Zhenwei; Luan, Shenglin; Zhang, Jingyi; Jing, Yongkui; Liu, Dan; Zhao, Linxiang [Bioorganic Chemistry, 2022, vol. 127]
[5]Deng, Hongguang; Huang, Min; Liu, Hui; Zhang, Hong; Liu, Liang; Gao, Bensheng; Li, Xianlu; Li, Jinbo; Niu, Qun; Zhang, Zhenwei; Luan, Shenglin; Zhang, Jingyi; Jing, Yongkui; Liu, Dan; Zhao, Linxiang [Bioorganic Chemistry, 2022, vol. 127]
[6]Current Patent Assignee: HEFEI UNIVERSITY OF TECHNOLOGY - CN107056630, 2017, A Location in patent: Paragraph 0277; 0278; 0279
[7]Zhang, Zhenwei; Hou, Linghui; Bai, Lijun; Pei, Jiying; Zhao, Shan; Luan, Shenglin; Liu, Dan; Huang, Min; Zhao, Linxiang [Bioorganic Chemistry, 2022, vol. 125]
[8]Zhang, Zhenwei; Hou, Linghui; Bai, Lijun; Pei, Jiying; Zhao, Shan; Luan, Shenglin; Liu, Dan; Huang, Min; Zhao, Linxiang [Bioorganic Chemistry, 2022, vol. 125]
[9]Current Patent Assignee: CHINA PHARMACEUTICAL UNIVERSITY - CN113816889, 2021, A Location in patent: Paragraph 0025; 0029-0030
[10]Current Patent Assignee: UNIV CHINA PHARMA - CN116217457, 2023, A Location in patent: Paragraph 0030; 0033-0034

53
[ 88-04-0 ]
[ 106-93-4 ]
[ 26583-62-0 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In acetonitrile Reflux;	General procedure for the side chain (7a-7m) General procedure: To a suspension of phenol(or thiophenol) (60 mmol, 1 eq.) and K2CO3 powder (24.8 g, 180 mmol, 3 eq.) in acetonitrile (100 mL) with stirring was added 1,3-dibromopropane (18.5 mL,180 mmol, 3 eq.) or 1,2-dibromoethane (12.6 mL,180 mmol, 3 eq.) at room temperature. The reaction mixture was refluxed for 3h -12 h, and monitored by TLC till the phenol was disappeared. After the reaction, the K2CO3 was removed by filtration and solvent was removed under reduced pressure to give the crude product which was then purified by column chromatography using ethyl acetate: petroleum ether(1:50-1:20). The products (7a-7m) were obtained as colorless to yellow oils with yields of 60% to 93%.

54
[ 88-04-0 ]
[ 105-39-5 ]
[ 167995-29-1 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium carbonate In acetone for 16h; Reflux;	Synthesis of ethyl 2-(4-chloro-3,5-dimethylphenoxy)acetate (2) Mixture of 4-chloro-3,5-dimethylphenol (0.05M) (1), ethyl chloroacetate (0.05 M) and anhydrouspotassium carbonate (0.075 M) was dissolved in dried acetone solvent and refluxed for 16 h, maintaining purely anhydrous conditions. Refluxed mixture was cooled and filtered. Next, the filtrate wasdistilled off to remove excess of acetone. The crudeproduct was filtered and recrystallized frommethanol to yield desired compound (19).White solid (Yield 74%, m.p. 104106OC), IR(KBr, cm-1): 3049 (aromatic C-H), 2928 (C-H), 1716(C=O), 1240 (CO); 1H-NMR (CDCl3-d6) δ, ppm:1.45 (3H, t, J = 7.4 Hz, CH3), 2.65 (6H, s, Ar-CH3),4.35 (2H, q, J = 7.4 Hz, CH2), 6.84-6.92 (2H, m,Ar-H); EI-MS (m/z): 242 (parent ion), 214 (basepeak), 155, 171, 169, 141, 103, 139, 58; Anal. calcd.for C12H15ClO3: C (59.39) and H (6.23)%; found: C(59.41) and H (6.29)%.

Reference： [1]Fuloria, Neeraj Kumar; Fuloria, Shivkanya; Sathasivam, Kathiresan; Karupiah, Sundram; Balaji, Kaveti; Jin, Lee Wan; Jade, Ong Dee; Jing Jing, Ivy Chieng [Acta poloniae pharmaceutica, 2017, vol. 74, # 4, p. 1125 - 1130]

55
[ 88-04-0 ]
[ 459-57-4 ]
[ 938238-57-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 16h;	1 4-(4-Chloro-3,5-dimethylphenoxy)benzaldehyde [7, NB-1-043]. To a solution of 4- chloro-3,5-dimethylphenol (4 g, 25.5 mmol, 1 eq) in anhydrous DMF (30 mL) was added 4- fluorobenzaldehyde (6; 3.17 g, 25.5 mmol, 1 eq) and K2CO3 (3.53 g, 25.5 mmol, 1 eq). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was then allowed to cool, and poured over ice-water (300 mL). The organic material was extracted into diethyl ether (3 x 150 mL). The combined organic layers were washed with 3M NaOH (3 x 150 ml), water (3 x 150 mL), brine (150 mL), dried Na2S04), filtered and concentrated to yield a pale brown solid that was used without further purification (100%): NMR (400 MHz, CDCh) δ = 9.93 (s, 1H), 7.85 (d, J= 8.4 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.83 (s, 2H), 2.38 (s, 6H).
70%	With potassium carbonate In N,N-dimethyl-formamide at 110℃; Inert atmosphere;	4-(4-chloro-3,5-dimethylphenoxy)benzaldehyde (6h): 4-fluorobenzaldehyde (1 equiv) and 4-chloro-3,5-dimethylphenol (1.5 equiv) were dissolved in DMF (0.4 M solution). K2CO3 (2 equiv) was added to the resulting solution and heated overnight at 110 C. The reaction mixture was extracted with EtOAc, washed with satd. NaHCO3, brine, and dried with sodium sulfate. After filtration, the filtrate was concentrated on a rotary evaporator and the residue purified by column chromatography on silica gel (15% EtOAc in hexanes) to provide the title compound in 70% yield: 1H NMR (400 MHz, CDCl3) δ 2.40 (s, 6H, Ar-CH3), 6.82 (s, 2H, Ar), 7.03 (d, J = 8.6 Hz, 2H, Ar), 7.84 (d, J = 8.6 Hz, 2H, Ar), 9.95 (s, 1H, CHO); MS (APCI pos) m/z calcd for C15H13O2Cl [M+H]+ 261.1, found 261.1.

Reference： [1]Current Patent Assignee: MACKERELL D ALEXANDER JR; UNIVERSITY SYSTEM OF MARYLAND - WO2019/40467, 2019, A1 Location in patent: Paragraph 00200
[2]Whiting, Ellis; Raje, Mithun R.; Chauhan, Jay; Wilder, Paul T.; Van Eker, Daniel; Hughes, Samuel J.; Bowen, Nathan G.; Vickers, Gregory E.A.; Fenimore, Ian C.; Fletcher, Steven [Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 3, p. 523 - 528]

56
[ 88-04-0 ]
[ 99-91-2 ]
[ 2173326-51-5 ]

Yield	Reaction Conditions	Operation in experiment
53%	With iron(III) trifluoromethanesulfonate In 1,2-dichloro-ethane at 90℃; for 12h; Sealed tube;	Experimental Procedure General procedure: The mixture of phenols (1a-l, 1.0 mmol), ketones (2a-l, 2.5 mmol) and Fe(OTf)3 (98%, 25.1 mg, 0.05 mmol) in 1,2-dichloroethane (DCE, 1 mL) was stirred at 90 °C (sealed tube) for 12 hours, cooled to room temperature, quenched with saturated sodium bicarbonate solution (20 mL), and extracted with ethyl acetate (3 × 20 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography over silica gel to afford the 4H-chromene 3a-y.

Reference： [1]Deng, Kai; Huai, Qi-Yong; Li, Hui-Jing; Wang, Jun-Hu; Yang, Hui-Ru; Liu, Ying; Wu, Yan-Chao [Synthesis, 2018, vol. 50, # 7, p. 1482 - 1492]

57
[ 88-04-0 ]
[ 14804-38-7 ]
[ 81233-26-3 ]

Reference： [1]Patent: DE2136828,1973,
Chem.Abstr.,1973,vol. 78

58
[ 108-68-9 ]
[ 88-04-0 ]
[ 133-53-9 ]
[ 5538-41-0 ]

Yield	Reaction Conditions	Operation in experiment
75%Chromat.; 9%Chromat.; 10%Chromat.	With iron(III) chloride; sulfuryl dichloride; 1,3-bis(methylthio)propane; In dichloromethane; at 20.0℃; for 4.0h;	General procedure: Freshly distilled sulfuryl chloride (4.66 mL, 57.7mmol) was added slowly over 2 h, via a pressure equalizing dropping funnel, to a solution of m-xylenol (6.1 g, 50 mmol), FeCl3 (25mg, 0.154mmol) and an additive (30 mg) in DCM (25 mL) in a round bottomed flask (50mL). The mixture was stirred at room temperature for a further 2h and the reaction was quenched with water (20mL). The organic components were extracted with ether (3×30 mL). The ether layers were removed, combined and dried over MgSO4. The drying agent was filtered and the solvent was removed under reduced pressure. The crude product was weighed and then analyzed by quantitative GC in the presence of tetradecane as added internal standard.

Reference： [1]Journal of Sulfur Chemistry,2018,vol. 39,p. 607 - 621

59
[ 612850-65-4 ]
[ 88-04-0 ]
[ 2306157-59-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 16h; Inert atmosphere;	19 4.1.2. General procedure A. Synthesis of N-(1-Oxo-1,3-dihydroisobenzofuran-5-yl)acetamide derivatives (3-31) General procedure: A solution containing 2 (0.1g, 0.44mmol), anhydrous K2CO3 (0.18g, 1.33mmol) and appropriate hydroxyl/amino compound (0.44mmol) in dry DMF (3mL) was stirred for 16 hrs at 25°C. After completion of the reaction, the reaction mixture was quenched with brine (50mL). The precipitated product was filtered off, washed with water and dried under vacuum. The crude product was further purified by column chromatography using DCM:MeOH (95:5) as mobile phase.

Reference： [1]Shah, Chetan P.; Purushothaman, Gayathri; Thiruvenkatam, Vijay; Kirubakaran, Sivapriya; Juvale, Kapil; Kharkar, Prashant S. [Bioorganic Chemistry, 2019, vol. 87, p. 753 - 764]

60
[ 3934-20-1 ]
[ 88-04-0 ]
[ 1284518-50-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-Chloro-3,5-dimethylphenol With sodium hydroxide In N,N-dimethyl-formamide for 0.0833333h; Cooling with ice; Stage #2: 2,6-Dichloropyrimidine In N,N-dimethyl-formamide at 20℃; for 2h;	4.1.4. Synthesis of intermediates 11a-q General procedure: A reaction mixture of 2-chlorophenol (1.726 g, 13.4 mmol) andsodium hydroxide in N,N-dimethylformamide (30 mL) was stirredat ice bath for 5 min. Then 2,4-dichloropyrimidine (2.005 g,13.5 mmol) was added to the solution and continued to stir for2 h at room temperature (monitored by TLC). After completion ofthe reaction, the mixture was poured slowly to the ice brine(100 mL) under vigorous stirring, the precipitates was gathered byfiltration, washed with ice water (3 x 10 mL) and dried to get 2-chloro-4-(2-chlorophenoxy)pyrimidine 11a as a white solid(2.787 g, yield 75.4%), which was used directly in the next stepwithout further purification.The compounds 11b-p were prepared using thesame method to synthesize 11a. The compound 11q was preparedusing the conditions of NaH/THF/40°C to replace the abovementionedNaOH/N,N-dimethylformamide/rt.
	With sodium hydroxide In N,N-dimethyl-formamide at 20℃; Cooling with ice;	4.1.7. Synthesis of the intermediates 13a-r General procedure: A reaction mixture of 2,6-dimethyl-4-cyanophenol (1.84 g, 12.48mmol) and sodium hydroxide (0.50 g, 12.50 mmol) in N,N-dimethylformamide(30 mL) was stirred in ice bath. Then 2,4-dichloropyrimidine(2.01 g, 13.5 mmol) was added, and the resulting mixture wasstirred at r.t. for 2 h. Next, the mixture was poured cautiously to thechilly brine (100 mL) under vigorous stirring. Finally, the precipitateswere obtained by filtration, washed with chilly water (3 × 10 mL) anddried to afford 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile(13a) as a white solid in 80.2% yield, which was used withoutfurther treatment in the next procedure.The compounds 13b-r were also synthesized utilizing the samemethod.
	With sodium hydroxide In N,N-dimethyl-formamide at 20℃; Cooling with ice;	4.1.7. Synthesis of the intermediates 13a-r General procedure: A reaction mixture of 2,6-dimethyl-4-cyanophenol (1.84 g, 12.48mmol) and sodium hydroxide (0.50 g, 12.50 mmol) in N,N-dimethylformamide(30 mL) was stirred in ice bath. Then 2,4-dichloropyrimidine(2.01 g, 13.5 mmol) was added, and the resulting mixture wasstirred at r.t. for 2 h. Next, the mixture was poured cautiously to thechilly brine (100 mL) under vigorous stirring. Finally, the precipitateswere obtained by filtration, washed with chilly water (3 × 10 mL) anddried to afford 4-((2-chloropyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile(13a) as a white solid in 80.2% yield, which was used withoutfurther treatment in the next procedure.The compounds 13b-r were also synthesized utilizing the samemethod.

Reference： [1]Xiao, Ting; Tang, Jia-Fan; Meng, Ge; Pannecouque, Christophe; Zhu, Yuan-Yuan; Liu, Gen-Yan; Xu, Zhi-Qiang; Wu, Feng-Shou; Gu, Shuang-Xi; Chen, Fen-Er [European Journal of Medicinal Chemistry, 2020, vol. 186]
[2]Ming, Wei; Lu, Wen-Long; Pannecouque, Christophe; Chen, Jiong; Wang, Hai-Feng; Xiao, Ya-Qi; Hu, Sha; Gu, Shuang-Xi; Zhu, Yuan-Yuan; Chen, Fen-Er [European Journal of Medicinal Chemistry, 2023, vol. 248]
[3]Ming, Wei; Lu, Wen-Long; Pannecouque, Christophe; Chen, Jiong; Wang, Hai-Feng; Xiao, Ya-Qi; Hu, Sha; Gu, Shuang-Xi; Zhu, Yuan-Yuan; Chen, Fen-Er [European Journal of Medicinal Chemistry, 2023, vol. 248]

61
[ 88-04-0 ]
[ 2524-64-3 ]
[ 2579170-73-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In toluene Reflux;	Synthesis of triaryl phosphates 1a-l General procedure: Compounds 1a-l have been prepared by following aknown procedure.1 A suspension of the chosen phenol (4.03 mol) in toluene (30 mL) wasvigorously mixed with NaOH (20% aq, 1 mL) and benzyltriethylammonium chloride(0.13 mmol). The so obtained suspension was cooled to 0 °C and then diphenyl chlorophosphate(0.84 mL, 4.03 mmol, 1 equiv) was added dropwise. The reaction mixture was refluxed understirring overnight and, after cooling to room temperature, washed with water (3 × 20 mL). Theorganic phase was dried over Na2SO4, evaporated in vacuo, and the crude residue purified bycolumn chromatography (eluent: petroleum ether/ethyl acetate mixture).

Reference： [1]Qrareya, Hisham; Meazza, Lorenzo; Protti, Stefano; Fagnoni, Maurizio [Beilstein Journal of Organic Chemistry, 2020, vol. 16, p. 3008 - 3014]

62
[ 88-04-0 ]
[ 140-10-3 ]
[ 89329-21-5 ]

Yield	Reaction Conditions	Operation in experiment
93%	With Amberlyst 15 In neat (no solvent, gas phase) at 130℃; for 0.2h; Microwave irradiation;	The tandem reaction of cinnamic acid with phenol catalyzed by amberlyst-15 undermicrowave irradiation (method A) General procedure: Suitable amounts of cinnamic acid (1.5mmol, 0.222 g), phenol (2.0mmol, 0.188 g) andAmberlyst 15 (0.2 g) were added successively into the test tube (U10mm, h100mm)placed into CEM oven. The irradiation program set up at 130 C for 7minutes wasapplied to the reaction mixture. After cooling, the product mixture was extracted withdiethyl ether (415mL) and filtrated by porous filter funnel to separate and collect theacidic catalyst A-15 for recycling. Subsequently, the filtrate was stirred magnetically with10mL of aqueous sodium hydroxide 5% (to remove all excess or unreacted cinnamic acidand phenol) and then washed with water until neutralization. Organic layer was dried byanhydrous sodium sulfate and removed solvent by rotary evaporation. The remainingcrude product was analyzed by GC/MS to check the composition of crude product. Thedesired product was purified by silica gel column chromatography, and then was identifiedtheir structure by HRMS, 1H and 13C NMR spectroscopy

Reference： [1]Le, Huu-Phuoc; Duong, Cong-Thang; Nguyen, Xuan-Triet; Luu, Thi Xuan Thi [Synthetic Communications, 2021, vol. 51, # 14, p. 2187 - 2203]

63
[ 14267-92-6 ]
[ 88-04-0 ]
[ 1481010-95-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; potassium iodide In N,N-dimethyl-formamide at 85℃;

Reference： [1]Durham, Austin C.; Murphy, Ethan; Palermo, Philip N.; Scrivener, Sarah G.; Wang, Ruihan; Wang, Yi-Ming; Wang, Yidong; Zuo, Xiao-Dong [Journal of the American Chemical Society, 2021, vol. 143, # 37, p. 14998 - 15004]

64
[ 88-04-0 ]
[ 814-68-6 ]
[ 41917-91-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With 4-dimethylaminopyridine; triethylamine In dichloromethane at 0 - 20℃; for 6h;
90.5%	With tetra-n-butyl-ammonium chloride; potassium carbonate In tetrahydrofuran at 20℃; for 4h; Sealed tube; Inert atmosphere;	4 Example 4 Example 4S1, 4-chloro-3,5-dimethylphenol, alkaline substance ammonia gas, phase transfer catalyst tetrabutylammonium chloride,Put it into the reaction kettle, and then add the solvent tetrahydrofuran to dissolve it to obtain a mixed solution.In the above process, the mass ratio of 4-chloro-3,5-dimethylphenol: basic substance: phase transfer catalyst: solvent=1:1.5:0.01:5.S2, sealing the reaction kettle, and performing N2 replacement on the reaction kettle to form a protective atmosphere. After that, the temperature of the control system was 20°C,Acryloyl chloride was added dropwise while stirring at a rate of 2 drops/s. After the dropwise addition was completed, the reaction was incubated for 4h.In the above process, the mass ratio of acryloyl chloride:4-chloro-3,5-dimethylphenol in step S1=1.2:1.S3, the obtained reaction solution is filtered, the solvent is evaporated to dryness, washed with deionized water until the pH is neutral, and a pale yellow oil is obtained,The oily substance was recrystallized with solvent ethyl acetate to obtain solid antibacterial agent 4-chloro-3,5-dimethylphenol acrylate; the yield was 90.5% and the purity was 99.0%.

Reference： [1]Fernandes, Rodney A.; Kumar, Praveen; Yadav, Sandhya S. [Organic and Biomolecular Chemistry, 2022, vol. 20, # 2, p. 427 - 443]
[2]Current Patent Assignee: DALIAN UNIVERSITY OF TECHNOLOGY; YELLOW RIVER DELTA JINGBO CHEMICAL RES INSTITUTE - CN114349634, 2022, A Location in patent: Paragraph 0099-0105

65
[ 88-04-0 ]
[ 920-46-7 ]
[ 1885120-96-6 ]

Yield	Reaction Conditions	Operation in experiment
92%	With n-dodecyltrimethylammonium chloride; potassium carbonate In N,N-dimethyl-formamide at 30℃; for 4h; Sealed tube; Inert atmosphere;	5 Example 5 S1, 4-chloro-3,5-dimethylphenol, alkaline substance calcium hydroxide, phase transfer catalyst dodecyl trimethyl ammonium chloride,Put it into the reaction kettle, and then add the solvent N,N-dimethylformamide to dissolve it to obtain a mixed solution.In the above process, the mass ratio of 4-chloro-3,5-dimethylphenol: basic substance: phase transfer catalyst: solvent=1:2:0.02:5.S2, sealing the reaction kettle, and performing N2 replacement on the reaction kettle to form a protective atmosphere. After that, the temperature of the system was controlled to be 30°C,While stirring, methacryloyl chloride was added dropwise at a rate of 2 drops/s. After the dropwise addition was completed, the reaction was incubated for 4h.In the above process, the mass ratio of methacryloyl chloride:4-chloro-3,5-dimethylphenol in step S1=1.1:1.S3, the obtained reaction solution is filtered, the solvent is evaporated to dryness, washed with deionized water until the pH is neutral, and a pale yellow oil is obtained,The oily substance was recrystallized with solvent ethyl acetate to obtain solid antibacterial agent 4-chloro-3,5-dimethylphenol methacrylate; the yield was 92% and the purity was 98.7%.

Reference： [1]Current Patent Assignee: DALIAN UNIVERSITY OF TECHNOLOGY; YELLOW RIVER DELTA JINGBO CHEMICAL RES INSTITUTE - CN114349634, 2022, A Location in patent: Paragraph 0106-0112

66
[ 88-04-0 ]
[ 2795153-86-3 ]
[ 2795154-03-7 ]

Yield	Reaction Conditions	Operation in experiment
41%	With triethylamine; potassium iodide In methanol; dichloromethane at 20℃; for 40h;	General procedure for the synthesis of compounds 9-27: General procedure: To a stirred solution of 8-(1-bromoethyl)-6-methyl-2-morpholino-4H-benzo[e][1,3]oxazin-4-one (0.56 mmol) and substituted aniline (or substituted phenol) (2.24 mmol) in dichloromethane and methanol (4:1), was added potassium iodide (0.56 mmol). Triethylamine (1.4 mmol) was then added, and the mixture was stirred at room temperature for 48 hours. The solvents were evaporated, and the residue was subjected to flash chromatography (hexane-ethyl acetate, and/or ethyl acetate-methanol). Some of the compounds were obtained as oil and were precipitated as solid crystals by adding minimum amount of diethyl ether.

Reference： [1]Mohammed, Ehtesham U.R.; Porter, Zoe J.; Jennings, Ian G.; Al-Rawi, Jasim M.A.; Thompson, Philip E.; Angove, Michael J. [Bioorganic and Medicinal Chemistry, 2022, vol. 69]

67
[ 88-04-0 ]
[ 873-75-6 ]
[ 884162-57-6 ]

Yield	Reaction Conditions	Operation in experiment
80%	With triphenylphosphine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere;	4.5.2 5-((4-bromobenzyl)oxy)-2-chloro-1,3-dimethylbenzene (i45) To a suspension of 4-chloro-3,5-dimethylphenol (0.50g, 3.19mmol), 4-bromobenzyl alcohol (0.63g, 3.35mmol), and triphenylphosphine (0.88g, 3.35mmol) in dry THF (20mL) was added diethyl azodicarboxylate (1.29g, 6.38mmol) in portions at 25°C under N2, and the reaction mixture was stirred at room temperature for 12h. The reaction mixture was concentrated, redissolved in dichloromethane, and then washed with water and brine. The organic layer was filtered and concentrated in vacuo. The crude mixture was then purified by flash chromatography (petroleum ether: ethyl acetate, V: V=500: 1) to provide 832mg (yield: 80.0%) of the compound i44. 1H NMR (600MHz, DMSO-d6) δ 7.60-7.57 (m, 2H), 7.39 (d, J=8.4Hz, 2H), 6.87 (s, 2H), 5.06 (s, 2H), 2.29 (s, 6H).
80%	With triphenylphosphine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere;	4.5.2 5-((4-bromobenzyl)oxy)-2-chloro-1,3-dimethylbenzene (i45) To a suspension of 4-chloro-3,5-dimethylphenol (0.50g, 3.19mmol), 4-bromobenzyl alcohol (0.63g, 3.35mmol), and triphenylphosphine (0.88g, 3.35mmol) in dry THF (20mL) was added diethyl azodicarboxylate (1.29g, 6.38mmol) in portions at 25°C under N2, and the reaction mixture was stirred at room temperature for 12h. The reaction mixture was concentrated, redissolved in dichloromethane, and then washed with water and brine. The organic layer was filtered and concentrated in vacuo. The crude mixture was then purified by flash chromatography (petroleum ether: ethyl acetate, V: V=500: 1) to provide 832mg (yield: 80.0%) of the compound i44. 1H NMR (600MHz, DMSO-d6) δ 7.60-7.57 (m, 2H), 7.39 (d, J=8.4Hz, 2H), 6.87 (s, 2H), 5.06 (s, 2H), 2.29 (s, 6H).

Reference： [1]Deng, Hongguang; Huang, Min; Liu, Hui; Zhang, Hong; Liu, Liang; Gao, Bensheng; Li, Xianlu; Li, Jinbo; Niu, Qun; Zhang, Zhenwei; Luan, Shenglin; Zhang, Jingyi; Jing, Yongkui; Liu, Dan; Zhao, Linxiang [Bioorganic Chemistry, 2022, vol. 127]
[2]Deng, Hongguang; Huang, Min; Liu, Hui; Zhang, Hong; Liu, Liang; Gao, Bensheng; Li, Xianlu; Li, Jinbo; Niu, Qun; Zhang, Zhenwei; Luan, Shenglin; Zhang, Jingyi; Jing, Yongkui; Liu, Dan; Zhao, Linxiang [Bioorganic Chemistry, 2022, vol. 127]

68
[ 88-04-0 ]
[ 540-51-2 ]
[ 26583-62-0 ]

Yield	Reaction Conditions	Operation in experiment
32%	With triphenylphosphine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere;	4.1.1. 5-(2-bromoethoxy)-2-chloro-1,3-dimethylbenzene (i1) To a suspension of 4-chloro-3,5-dimethylphenol (0.50g, 3.19mmol), 2-bromoethanol (0.42g, 3.35mmol), and triphenylphosphine (0.88g, 3.35mmol) in dry THF (20mL) was added diethyl azodicarboxylate (1.29g, 6.38mmol) in portions at 25°C under N2, and the reaction mixture was stirred at room temperature for 12h. The reaction mixture was concentrated, redissolved in dichloromethane, and then washed with water and brine. The organic layer was filtered and concentrated in vacuo. The crude mixture was then purified by flash chromatography (petroleum ether: ethyl acetate, V: V=500: 1) to provide 270mg (yield: 32%) of the title compound. LC-MS m/z: 279.10 [M+H2O]+.
32%	With triphenylphosphine In tetrahydrofuran at 25℃; for 12h; Inert atmosphere;	4.1.1. 5-(2-bromoethoxy)-2-chloro-1,3-dimethylbenzene (i1) To a suspension of 4-chloro-3,5-dimethylphenol (0.50g, 3.19mmol), 2-bromoethanol (0.42g, 3.35mmol), and triphenylphosphine (0.88g, 3.35mmol) in dry THF (20mL) was added diethyl azodicarboxylate (1.29g, 6.38mmol) in portions at 25°C under N2, and the reaction mixture was stirred at room temperature for 12h. The reaction mixture was concentrated, redissolved in dichloromethane, and then washed with water and brine. The organic layer was filtered and concentrated in vacuo. The crude mixture was then purified by flash chromatography (petroleum ether: ethyl acetate, V: V=500: 1) to provide 270mg (yield: 32%) of the title compound. LC-MS m/z: 279.10 [M+H2O]+.

69
[ 88-04-0 ]
[ 2245716-18-9 ]
[ 2875122-54-4 ]

Yield	Reaction Conditions	Operation in experiment
49 %	With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;	1.A Step A To a stirred solution of methyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (20 g, 57.7 mmol), 4-chloro-3,5-dimethylphenol (10.84 g, 69.2 mmol), PPh3 (18.2 g, 69.4 mmol) in THF (470 mL) was added in portions (E)-N-[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (16 g, 69.5 mmol). The reaction mixture was stirred at room temperature overnight. Then the solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford methyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (13.8 g, 28.4 mmol, 49%)
49 %	With di-tert-butyl (E)-azodicarboxylate; triphenylphosphine In tetrahydrofuran at 20℃;	1.A Step A To a stirred solution of methyl 7-bromo-6-chloro-3-(3-hydroxypropyl)-1H-indole-2-carboxylate (20 g, 57.7 mmol), 4-chloro-3,5-dimethylphenol (10.84 g, 69.2 mmol), PPh3 (18.2 g, 69.4 mmol) in THF (470 mL) was added in portions (E)-N-[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (16 g, 69.5 mmol). The reaction mixture was stirred at room temperature overnight. Then the solvent was removed under reduced pressure and the residue was purified by flash chromatography to afford methyl 7-bromo-6-chloro-3-(3-(4-chloro-3,5-dimethylphenoxy)propyl)-1H-indole-2-carboxylate (13.8 g, 28.4 mmol, 49%)

Reference： [1]Current Patent Assignee: CAPTOR THERAPEUTICS - WO2022/253713, 2022, A1 Location in patent: Page/Page column 166-167
[2]Current Patent Assignee: CAPTOR THERAPEUTICS - WO2022/253713, 2022, A1 Location in patent: Page/Page column 166-167

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[ 88-04-0 ] Synthesis Path-Upstream 1~8

[ 88-04-0 ] Synthesis Path-Downstream 1~69

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