Name: 1996-41-4|2-Chloro-4-fluorophenol|98%
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SKU: A223158
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1
[ 2267-25-6 ]
[ 1996-41-4 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

2
[ 2832-19-1 ]
[ 1996-41-4 ]
2-Chloro-N-(3-chloro-5-fluoro-2-hydroxy-benzyl)-acetamide [ No CAS ]

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

3
[ 1996-41-4 ]
[ 109-64-8 ]
[ 135062-11-2 ]

Yield	Reaction Conditions	Operation in experiment
49%	With potassium carbonate; potassium iodide In propan-2-one for 24h; Reflux;	4.2.3. General procedure for alkylation of phenols (1-5) General procedure: Compounds (1b-5b) were synthesized according to the followingprocedure. To a stirred solution of disubstituted phenol in acetone (200mL), 1,3-dibromopropane (4 equiv.) and K2CO3 (4 equiv.) were added.The resulting reaction mixture was refluxed for 24 h then cooled to roomtemperature, filtered and concentrated. Purification was then achievedby column chromatography.
49%	With potassium carbonate; potassium iodide In propan-2-one for 24h; Reflux;	4.2.3. General procedure for alkylation of phenols (1-5) General procedure: Compounds (1b-5b) were synthesized according to the followingprocedure. To a stirred solution of disubstituted phenol in acetone (200mL), 1,3-dibromopropane (4 equiv.) and K2CO3 (4 equiv.) were added.The resulting reaction mixture was refluxed for 24 h then cooled to roomtemperature, filtered and concentrated. Purification was then achievedby column chromatography.
	With sodium hydroxide for 3h; Heating;

With Cs₂CO₃

Reference： [1]Al-Mughaid, Hussein; Al-Zoubi, Raed M.; Jaradat, Younis; Naser, Heba; Nawasreh, Shorooq [Carbohydrate Research, 2022, vol. 515]
[2]Al-Mughaid, Hussein; Al-Zoubi, Raed M.; Jaradat, Younis; Naser, Heba; Nawasreh, Shorooq [Carbohydrate Research, 2022, vol. 515]
[3]Ohmomo; Hirata; Murakami; Magata; Tanaka; Yokoyama [Chemical and Pharmaceutical Bulletin, 1991, vol. 39, # 4, p. 1038 - 1040]
[4]Koyama, Hiroo; Boueres, Julia K.; Miller, Daniel J.; Berger, Joel P.; MacNaul, Karen L.; Wang, Pei-Ran; Ippolito, Marc C.; Wright, Samuel D.; Agrawal, Arun K.; Moller, David E.; Sahoo, Soumya P. [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3347 - 3351]

4
[ 371-41-5 ]
[ 1996-41-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With 1,3-dichloro-5,5-dimethylhydantoin; diisopropylamine hydrochloride In toluene at 0℃; for 4h; Darkness; regioselective reaction;
51%	With aluminum (III) chloride; bis-[(trifluoroacetoxy)iodo]benzene In acetonitrile at 23℃; regioselective reaction;
	With chlorine; iron

	With sodium hydroxide; tert-butylhypochlorite; sodium chloride at 14.85℃;
	With diisobutylamine; sulfuryl dichloride
	With sulfuryl dichloride In water
	With aluminum (III) chloride; N-chloro-succinimide In dichloromethane at 20℃;
	With aluminum (III) chloride; N-chloro-succinimide In dichloromethane at 20℃;

Reference： [1]Xiong, Xiaodong; Yeung, Ying-Yeung [ACS Catalysis, 2018, vol. 8, # 5, p. 4033 - 4043]
[2]Nahide, Pradip D.; Ramadoss, Velayudham; Juárez-Ornelas, Kevin A.; Satkar, Yuvraj; Ortiz-Alvarado, Rafel; Cervera-Villanueva, Juan M. J.; Alonso-Castro, Ángel J.; Zapata-Morales, Juan R.; Ramírez-Morales, Marco A.; Ruiz-Padilla, Alan J.; Deveze-Álvarez, Martha A.; Solorio-Alvarado, César R. [European Journal of Organic Chemistry, 2018, vol. 2018, # 4, p. 485 - 493]
[3]Srivastava,K.C. [Bulletin of the Chemical Society of Japan, 1964, vol. 37, p. 583 - 584]
[4]Moodithaya; Gowda, B. Thimme [Journal of the Indian Chemical Society, 2002, vol. 79, # 5, p. 420 - 425]
[5]Koyama, Hiroo; Boueres, Julia K.; Miller, Daniel J.; Berger, Joel P.; MacNaul, Karen L.; Wang, Pei-Ran; Ippolito, Marc C.; Wright, Samuel D.; Agrawal, Arun K.; Moller, David E.; Sahoo, Soumya P. [Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 14, p. 3347 - 3351]
[6]Location in patent: scheme or table Xue, Na; Zhou, Yuhan; Wang, Guowei; Miao, Weirong; Qu, Jingping [Journal of Heterocyclic Chemistry, 2010, vol. 47, # 1, p. 15 - 21]
[7]Location in patent: scheme or table Arcadi, Antonio; Blesi, Federico; Cacchi, Sandro; Fabrizi, Giancarlo; Goggiamani, Antonella [Tetrahedron Letters, 2011, vol. 52, # 40, p. 5149 - 5152]
[8]Arcadi, Antonio; Blesi, Federico; Cacchi, Sandro; Fabrizi, Giancarlo; Goggiamani, Antonella; Marinelli, Fabio [Tetrahedron, 2013, vol. 69, # 7, p. 1857 - 1871]

5
[ 1996-41-4 ]
[ 75-03-6 ]
[ 181305-71-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With potassium carbonate In acetone at 60℃; for 5h;
	With potassium carbonate
	With potassium carbonate In acetone at 55℃;

Reference： [1]Cantrell, Amanda S.; Engelhardt, Per; Högberg, Marita; Jaskunas, S. Richard; Johansson, Nils Gunnar; Jordan, Christopher L.; Kangasmetsä, Jussi; Kinnick, Michael D.; Lind, Peter; Morin Jr., John M.; Muesing; Noreén, Rolf; Öberg, Bo; Pranc, Paul; Sahlberg, Christer; Ternansky, Robert J.; Vasileff, Robert T.; Vrang, Lotta; West, Sarah J.; Zhang, Hong [Journal of Medicinal Chemistry, 1996, vol. 39, # 21, p. 4261 - 4274]
[2]Sahlberg, Christer; Noreen, Rolf; Engelhardt, Per; Hoegberg, Marita; Kangasmetsae, Jussi; Vrang, Lotta; Zhang, Hong [Bioorganic and Medicinal Chemistry Letters, 1998, vol. 8, # 12, p. 1511 - 1516]
[3]Högberg, Marita; Sahlberg, Christer; Engelhardt, Per; Noréen, Rolf; Kangasmetsä, Jussi; Johansson, Nils Gunnar; Öberg, Bo; Vrang, Lotta; Zhang, Hong; Sahlberg, Britt-Louise; Unge, Torsten; Lövgren, Seved; Fridborg, Kerstin; Bäckbro, Kristina [Journal of Medicinal Chemistry, 1999, vol. 42, # 20, p. 4150 - 4160]

6
[ 1996-41-4 ]
[ 79-22-1 ]
[ 84478-88-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide at 5 - 10℃; for 0.25h;
98.9%	With sodium hydroxide In water at 10℃; for 0.166667h;	4.8 Sodium hychoride (10 g) and water (162 ml) were stirred in a 1 liter flask and cooled using an ice bath. 2-Chloro-4-fluoro-phenol (30 g, 0.0204 mol) was added. Methyl chloroformate (24.90 g, 20.4 ml) was added dropwise keeping the reaction temperature below 10° C. The reaction mixture was stirred for 10 minutes after complete addition before the solids were collected by filtration. The product was washed with water and dried to yield a white power (41.4 g, 98.9%).
95%	Stage #1: 2-chloro-4-fluorophenol With sodium carbonate In water at 40 - 45℃; for 1h; Large scale; Stage #2: methyl chloroformate In water at 10 - 25℃; for 1h; Large scale;

79%	With sodium hydroxide In water at -10℃;	A.24 Example A24 Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a -10° C. solution of 2-chloro-4-fluorophenol (10 g, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition, the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.62 (dd, J=8.1, 2.7 Hz, 1H), 7.50 (dd, J=9.0, 5.4 Hz, 1H), 7.30 (td, J=8.1, 3.0 Hz, 1H), 3.86 (s, 3H); MS (ESI) m/z: 205.2 (M+H+).
79%	With sodium hydroxide In water at -10℃;	A.16 Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a -10 °C solution of 2-chloro-4-fluorophenol (10Og, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition, the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluorophenyl methyl carbonate (110 g, 79% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.62 (dd, J= 8.1, 2.7 Hz, 1 H), 7.50 (dd, J= 9.0, 5.4 Hz, 1 H), 7.30 (td, J= 8.1, 3.0 Hz, 1 H), 3.86 (s, 3 H); MS (ESI) m/z: 205.2 (M+H+).
79%	With sodium hydroxide In water at -10℃;	A24 Methyl chloroformate (77.3 g, 0.82 mol) was added dropwise to a -10 °C solution of 2-chloro-4-fluorophenol (lOOg, 0.68 mol) and sodium hydroxide (32.8 g, 0.82 mol) in water (550 mL). After complete addition, the precipitated solid was collected by filtration and washed with water to give 2-chloro-4-fluorophenyl methyl carbonate (1 10 g, 79 % yield). FontWeight="Bold" FontSize="10" H NMR (300 MHz, DMSO-i/6) δ 7.62 (dd, J = 8.1 , 2.7 Hz, 1 H), 7.50 (dd, J = 9.0, 5.4 Hz, 1 H), 7.30 (td, J = 8.1, 3.0 Hz, 1 H), 3.86 (s, 3 H); MS (ESI) m/z: 205.2 (M+H+).
	With sodium hydroxide In water	II Step A--Methyl (2-chloro-4-fluorophenyl)carbonate Step A--Methyl (2-chloro-4-fluorophenyl)carbonate To a stirred solution of 20.0 g (0.14 mole) of 2-chloro-4-fluorophenol and 6.64 g (0.17 mole) of sodium hydroxide in 100 mL of water at 15° C. was added 17.7 g (0.19 mole) of methyl chloroformate. After complete addition, the mixture was stirred for 15 minutes then extracted with ethyl acetate. The organic phase was washed with a 1N sodium hydroxide solution, then dried over anhydrous magnesium sulfate. The dried extract was filtered, and the filtrate evaporated under reduced pressure to provide methyl (2-chloro-4-fluorophenyl) carbonate as a solid.

Reference： [1]Hennequin, Laurent F.; Thomas, Andrew P.; Johnstone, Craig; Stokes, Elaine S. E.; Plé, Patrick A.; Lohmann, Jean-Jacques M.; Ogilvie, Donald J.; Dukes, Mike; Wedge, Steve R.; Curwen, Jon O.; Kendrew, Jane; Lambert-Van Der Brempt, Christine [Journal of Medicinal Chemistry, 1999, vol. 42, # 26, p. 5369 - 5389]
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2008/234267, 2008, A1 Location in patent: Page/Page column 15
[3]Ishimoto, Kazuhisa; Fukuda, Naohiro; Nagata, Toshiaki; Sawai, Yasuhiro; Ikemoto, Tomomi [Organic Process Research and Development, 2014, vol. 18, # 1, p. 122 - 134]
[4]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - US2008/90856, 2008, A1 Location in patent: Page/Page column 38
[5]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2010/51373, 2010, A1 Location in patent: Page/Page column 75
[6]Current Patent Assignee: DECIPHERA PHARMACEUTICALS LLC - WO2013/36232, 2013, A2 Location in patent: Paragraph 00250
[7]Current Patent Assignee: FMC CORP - US4906286, 1990, A

7
[ 1978-39-8 ]
[ 1996-41-4 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

8
[ 445-83-0 ]
[ 1996-41-4 ]

Reference： [1]Journal of the American Chemical Society,1959,vol. 81,p. 94,95, 97

9
[ 1996-41-4 ]
[ 58348-98-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With nitric acid; acetic acid In water at 0℃; for 5h;	77.77(A) Example 77; 7-Chloro-5-fluoro-2-(4-( pyridin-2- )but-3-ynyl)benzo[d]oxazole; 77(A) 2-Chloro-4-fluoro-6-nitrophenol; 2-Chloro-4-fluorophenol (5.64 g, 38.5 mmol) was added to a solution of acetic acid (16.5 mL), nitric acid (8.66 mL) and water (7.5 mL) at 0°C. The reaction mixture was stirred vigorously for 5 hours at 0°C. The resulting precipitate was filtered, washed with water and dried under vacuum to yield 2-chloro-4-fluoro-6-nitrophenol (6.12 g, 32.0 mmol, 83%) as a yellow powder.
	With nitric acid	1.1 Preparation of 4-Amino-7-chloro-2-ethyl-5-fluorobenzoxazole (Compound no. 14-3) Step 1 Preparation of 2-Chloro-4-fluoro-6-nitrophenol as an Intermediate. 2-Choro-4-fluorophenol (24 g) was slowly added to nitric acid (69%, 100 ml) at 0° C. The mixture was stirred for 20 minutes and then poured into ice-water (250 ml), the resulting yellow crystals were separated by filtration and washed with cold water, and dried in vacuum to afford the title compound (29 g). 1H-NMR (CDCl3, 300 MHz): 7.53(1H, dd, J=3.0 Hz, 7.2 Hz), 7.79(1H, dd, J=3.1 Hz, 8.0 Hz), 10.78(1H, s) ppm.

Reference： [1]Current Patent Assignee: ADDEX THERAPEUTICS SA - WO2005/123703, 2005, A2 Location in patent: Page/Page column 133
[2]Current Patent Assignee: ISHIHARA SANGYO KAISHA, LTD. - US6573218, 2003, B1

10
[ 869088-47-1 ]
[ 1996-41-4 ]
[ 869088-48-2 ]

Yield	Reaction Conditions	Operation in experiment
	With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 0 - 20℃;	37 flask was charged with 400 mg (1.29 mmol) (2S)-2-[(1R)-(3-fluoro-phenyl)-hydroxy-methyl]-morpholine-4-carboxylic carboxylic acid tert-butyl ester 5 and 15 ml toluene. To the solution was added 543 μl (5.14 mmol) 2-chloro-4-fluorophenol and 876 mg (3.34 mmol) triphenyl phosphine. This mixture was cooled in a 0° C. bath, and 622 μl (3.21 mmol) diisopropyl azodicarboxylate (DIAD) was added slowly. The mixture was allowed to warm slowly to room temperature overnight (by the melting of the ice). The mixture was stirred until the chiral alcohol 5 was no longer detectable by thin layer chromatography. The toluene was removed under reduced pressure, and the resulting crude oil was purified directly using column chromatography and 9:1 Hexanes/Ethyl Acetate as the eluent. This procedure provided 351 mg of 6 (2S)-2-[(1S)-(2-chloro-4-fluorophenoxy)-(3-fluorophenyl)methyl]morpholine-4-carboxylic acid tert-butyl ester) as a foam.

Reference： [1]Current Patent Assignee: PFIZER INC - US2005/250775, 2005, A1 Location in patent: Page/Page column 47

11
[ 33301-41-6 ]
[ 1996-41-4 ]
[ 141483-09-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetonitrile for 4.5h; Heating / reflux;	78 Preparation 78: 3-(2-Chloro-4-fluorophenoxy)-1-(diphenylmethyl)azetidine A mixture of 1-(diphenylmethyl)-3-azetidinyl methanesulfonate (363.8 g, 1.15 mol), potassium carbonate (330 g, 2.38 mol) and 2-chloro-4-fluorophenol (140 g, 0.96 mol) in acetonitrile (2.5 L) was heated under reflux for 4.5 hours. The cooled reaction mixture was then concentrated in vacuo and the residue was partitioned between ethyl acetate (1 L) and water (500 mL). The organic layer was separated, dried over sodium sulfate concentrated in vacuo and the residue was triturated with ethyl acetate/pentane/dichloromethane, 90:10:1, to afford the title compound as a white solid in quantitative yield, 350 g. 1H NMR(400 MHz, CDCl3) δ: 3.19(m, 2H), 3.75(m, 2H), 4.45(m, 1H), 4.78(m, 1H), 6.60(m, 1H), 6.83(m, 1H), 7.14(m, 1H), 7.18-7.50(m, 10H)
100%	With potassium carbonate In acetonitrile Reflux;

Reference： [1]Current Patent Assignee: IXCHELSIS - US2006/160786, 2006, A1 Location in patent: Page/Page column 37
[2]Location in patent: scheme or table Brown, Alan; Brown, T. Bruce; Calabrese, Andrew; Ellis, Dave; Puhalo, Nicholas; Ralph, Michael; Watson, Lesa [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 2, p. 516 - 520]

12
[ 1996-41-4 ]
[ 22649-28-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 133 STR155 2-Chloro-4-fluorophenol was converted to the title compound by a procedure similar to that described in Example 2: mp 240-241 C. 1 H NMR (CD3 OD/300 MHz) 7.77 (s, 1H), 7.26 (dd, 1H, J=8.3, 2.9), 7.14 (dd, 1H, J=8.1, 2.9), 5.87 (q, 1H, J=6.8 Hz). EIHRMS m/z 295.9836 (Calc'd 295.9863). Anal. Calc'd for C11 H5 ClF4 O3: C, 44.54; H, 1.70. Found C, 44.70; H, 1.73. EXMAPLE 134 STR156 The 2H-1-benzopyran-3-carboxylic acid was prepared by a procedure similar to the method described in Example 1: mp 243-244 C. 1 H NMR (CD3 OD/300 MHz) 8.07 (d, 1H, J=2.0 Hz), 7.71 (s, 1H), 7.70 (d, 1H, J=2.0 Hz), 5.89 (q, 1H, J=6.8 Hz). ESHRMS m/z 494.8174 (Calc'd for M-H 494.8202) Anal. Calc'd for C11 H5 F3 I2 O3: C, 26.64; H, 1.02. Found C, 26.75; H, 1.06.

Reference： [1]Patent: US6034256,2000,A

13
[ 1996-41-4 ]
[ 54042-93-2 ]
[ 128106-56-9 ]

Yield	Reaction Conditions	Operation in experiment
80.8%	With potassium carbonate In acetone	2 3-allyl-5-[(2-chloro-4-fluorophenoxy)methyl]-1,2,4-oxadiazole: Example 2 3-allyl-5-[(2-chloro-4-fluorophenoxy)methyl]-1,2,4-oxadiazole: Compound No. 145 0.71 g of 2-chloro-4-fluorophenol, 0.77 g of 3-allyl-5-chloromethyl-1,2,4-oxadiazole and 0.83 of potassium carbonate were added to 20 ml of acetone. After completion of the reaction, the resulting precipitates were filtered out from the mixture and then acetone was removed by distillation, and the residue was purified by column chromatography (benzene:hexane=1:1) to obtain 1.05 g of the desired product(yield: 80.8%).

Reference： [1]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - US5242890, 1993, A

14
[ 1996-41-4 ]
[ 503-38-8 ]
[ 141852-65-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In dichloromethane	R.1 Reference Example 1 STR110 2-Chloro-4-fluorophenol (4.4 Kg, 30 mol), triethylbenzylammonium chloride (17.1 g) and methylene chloride (7 liters) were placed in a 20 L three-necked flask equipped with a stirrer and a dropping funnel and cooled in an ice bath. Then, a 5N aqueous sodium hydroxide solution (6 liters) was slowly added thereto, followed by stirring vigorously. Then, trichloromethyl chloroformate (885 ml, 7.35 mol) was added dropwise thereto slowly over about 6 hours at room temperature, and, after dropwise addition, the reaction solution was stirred overnight. After completion of the reaction, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (1000 ml*2 portions). The organic layers were combined, washed with a 1N aqueous sodium hydroxide solution (4 liters) and water (5 liters), and dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the solvent was distilled off from the organic layer under reduced pressure to obtain bis(2-chloro-4-fluorophenyl)carbonate as a white solid (4.9 Kg, 15.4 mol, 100% yield). Melting point: 91.0°-92.0° C. 1 H-NMR(CDCl3,TMS,ppm): δ6.87-7.4(6H,m). IR(KBr disk, cm-1): 1180, 1250, 1290, 1500, 1605, 1780.
	With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In dichloromethane	3 EXAMPLE 3 STR12 EXAMPLE 3 STR12 2-Chloro-4-fluorophenol (4.4 kg, 30 mol), triethylbenzylammonium chloride (17.1 g) and methylene chloride (7 liters) were put in a 20-liter three-neck flask as equipped with a stirrer and a dropping funnel, and cooled in an ice-water bath. 5 N sodium hydroxide aqueous solution (6 liters) was gradually added thereto with stirring vigorously. Next, trichloromethyl chloroformate (885 ml, 7.35 mol) was gradually dropwise added thereto over a period of about 6 hours. After addition, the reaction liquid was stirred overnight. After reaction, the organic layer was separated, and the aqueous layer was extracted with methylene chloride (1000 ml *2). The organic layers were combined, washed with 1 N sodium hydroxide aqueous solution (4 liters) and water (5 liters) and then dried with anhydrous magnesium sulfate. The drying agent was taken out by filtration, and the solvent was removed from the organic layer by distillation under reduced pressure to obtain a white solid of bis(2-chloro-4-fluorophenyl)carbonate (4.9 kg, 15.4 mol). Yield: 100 %. Spectral data and other data of the product are those as shown in Example 2.

Reference： [1]Current Patent Assignee: SAGAMI CHEMICAL RESEARCH INSTITUTE - US5506190, 1996, A
[2]Current Patent Assignee: SAGAMI CHEMICAL RESEARCH INSTITUTE; KAKEN PHARMACEUTICAL CO LTD - US5281742, 1994, A

15
[ 21617-12-9 ]
[ 1996-41-4 ]
8-chloro-4-(2-chloro-4-fluoro-phenoxy)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%		EXAMPLE 35 8-chloro-4-(2-chloro-4-fluorophenoxy)quinoline A mixture of 2.0 g of <strong>[21617-12-9]4,8-dichloroquinoline</strong> and 2.96 g of 2-chloro-4-fluorophenol was heated to 160 C. and stirred. Progress of the reaction was monitored using TLC. When no <strong>[21617-12-9]4,8-dichloroquinoline</strong> remained, the product was washed with base to remove phenol, then purified using HPLC. A brown solid resulted, which was recrystallized in heptane to give 1.54 g of the title product as yellow crystals. Yield: 49%. M.P. 99-101 C. Analysis: Theory: C, 58.47; H, 2.62; N, 4.55; Found: C, 58.39; H, 2.85; N, 4.49.

Reference： [1]Patent: US5145843,1992,A

16
[ 1996-41-4 ]
[ 79-22-1 ]
[ 85953-29-3 ]

Yield	Reaction Conditions	Operation in experiment
	In water;	EXAMPLE 3 Production of the nitrophenol (V) 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodum hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl(2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.
	With sodium hydroxide; In water;	EXAMPLE 7 Production of the nitrophenol (VII: X=Cl): 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.
	With sodium hydroxide; In water;	EXAMPLE 10 Production of the nitrophenol (V: X=Cl): 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature of below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.

	With sodium hydroxide; In water;	EXAMPLE 10 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69-71 C.
	With sodium hydroxide; In water;	EXAMPLE 12 2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10 C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl) formate (134.8 g). M.P., 69-71 C.

Reference： [1]Patent: US4670046,1987,A
[2]Patent: US4427438,1984,A
[3]Patent: US4431822,1984,A
[4]Patent: US4437877,1984,A
[5]Patent: US4452981,1984,A

17
[ 626-55-1 ]
[ 1996-41-4 ]
[ 944744-91-6 ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate In DMA at 155 - 160℃; for 7 - 8h;	16 This reaction produces a compound of Formula (XXIV) from a compound of Formula (XDC).2-Chloro-4-fluoro-phenol and 3-Bromo-pyridine were dissolved in DMA. Solid Potassium carbonate and copper(I)oxide were added in one portion. The in homogeneous reaction mixture was stirred at 155-160 0C for 7-8 h. After cooling to room temperature the mixture was filtered through Hyflo and evaporated (80 °C / 10 mbar). The crude product was distilled (b.p. 110 °C /0.7 mbar). Yield 60%.1H NMR f CDCU): 7.0-7.3 (m, 5H), 8.3-8.4 (m, 2H).

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2007/83090, 2007, A2 Location in patent: Page/Page column 32

18
[ 67-66-3 ]
[ 1996-41-4 ]
3-chloro-5-fluoro-2-hydroxybenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	With sodium hydroxide In water for 4h; Reflux;	B.1 Step 1. To a solution of sodium hydroxide (50 g.) in chloroform/water (60 mL, v/v=l : l) was added A-2-1 (10 g, 0.068 mole). The mixture was refluxed for 2 hours. Chloroform (30 ml.) was added again and refluxed for another 2 hours. The reaction mixture was cooled to room temperature and crude product recovered as the sodium salt by filtration. The filter cake was taken into water and acidified with 1 N hydrochloric acid to PH=6 and then diluted by water (30 mL), extracted with ethyl acetate (45 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give A-2-2 (3.20 g, yield 27%) as a colorless oil. 1H NMR (400MHz, CDC13) δ 11.23 (s, 1H), 9.87 (s, 1H), 7.43 (dd, /=3.2, 8.0 Hz, 1H), 7.24 (dd, =3.2, 7.2 Hz, 1H).
	With sodium hydroxide; water for 8h; Heating / reflux;	8 8. Preparation of 3-chloro-5-fluoro-2-hydroxybenzaldehyde; A solution of 2-chloro-4-fluorophenol (15.0 g, 102 mmol) in 150 g of 50% sodium hydroxide, water (30 mL) and chloroform (45 mL) were heated under reflux for 8 hours, additional chloroform (45 mL) was added every 2 hours. The mixture was then cooled and allowed to stand for 18 hours and the the precipitated sodium salt was collected. The solid was slurried in water (200 mL) and the pH adjusted to 1.5 with 6N hydrochloric acid and then extracted with ethyl acetate (2×100 mL). The combined extracts were washed with brine, dried and concentrated. The residue was purified by chromatography (1:1 methylene chloride:hexanes) to give 3-chloro-5-fluoro-2-hydroxybenzaldehyde (5.0 g, 29 mmol): LC/MS (m/z=174).

Reference： [1]Current Patent Assignee: TURNING POINT THERAPEUTICS INC - WO2018/22911, 2018, A1 Location in patent: Paragraph 0266; 0267
[2]Current Patent Assignee: CORTEVA INC - US2007/179060, 2007, A1 Location in patent: Page/Page column 9

19
[ 67271-66-3 ]
[ 1996-41-4 ]
[ 944744-84-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 2-chloroacetoacetic acid amide; 2-chloro-4-fluorophenol With potassium carbonate In tert-butyl methyl ether at 55℃; Stage #2: With hydrogenchloride In tert-butyl methyl ether; water	9 This reaction produces a compound of Formula (XVIII) from a compound of Formula (XIX)The 2-chloro-4-fluorophenol, TBME and potassium carbonate were charged to a reactor and heated to 550C. 2-Chloroacetoacetamide was added. After stirring over night the mixture was cooled, acidified with aq.-HCl, diluted with water and filtered. The solid product 2-(2-chloro-4-fluoro-phenoxy)-3-oxo-butyramide, was washed well with water. Yield 60%.'H NMR fdfi-DMSOV 2.3 (s, 3H), 5.3, ( s, 2H), 7.0 (br, IH), 7.1-7.2 (m, IH), 7.5 (br, IH), 7.1-7.3 (br, d, 2H).

Reference： [1]Current Patent Assignee: SINOCHEM HOLDINGS CORPORATION LTD; Syngenta (in: Sinochem Holdings) - WO2007/83090, 2007, A2 Location in patent: Page/Page column 25

20
[ 1996-41-4 ]
[ 109384-19-2 ]
[ 950648-98-3 ]

Yield	Reaction Conditions	Operation in experiment
73%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃;	34.A Step A: 4-(2-Chloro-4-fluoro-phenoxy)-piperidine- 1 -carboxylic acid tert-butyl ester tert-Butyl 4-hydroxy-piperidine- 1 -carboxylate (2.74 g, 13.6 mmol), 2-chloro-4-fluoro- phenol (1.00 g, 6.80 mmol), diisopropyl azo-dicarboxylate (2.75 g, 13.6 mmol), triphenylphosphine (3.6 g, 13.6) and anhydrous tetrahydrofuran (100 mL) are stirred at 0 0C and allowed to warm to room temperature overnight. After the completion of the reaction, the mixture is condensed in vacuo and purified by flash chromatography (ethyl acetate/heptane) to give the title compound (1.63 g, 73 %).
	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃;
	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 25℃; for 16h;	33.1 Step 1: Preparation of tert-butyl 4-(2-chloro-4-fluorophenoxy)piperidine-1-carboxylate To a solution of 2-chloro-4-fluorophenol (2.0 g, 13.7 mmol), tert-butyl 4-hydroxypiperidine-1- carboxylate (2.76 g, 13.7 mmol) and triphenylphosphine (4.31 g, 16.4 mmol) in tetrahydrofuran (15 mL) at 25 C was added diisopropyl azodicarboxylate (3.32 g, 16.4 mmol). The mixture was stirred at 25 C for 16 h. The volatiles were removed under reduced pressure and the residue was further purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 10/1) to give tert-butyl 4-(2-chloro-4- fluorophenoxy)piperidine-1-carboxylate as an opaque oil (4.3 g, crude). LCMS (ESI) m/z: 274.1 [M- 56+H]+.

Reference： [1]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2007/106705, 2007, A1 Location in patent: Page/Page column 94-95
[2]Xin, Zhili; Zhao, Hongyu; Serby, Michael D.; Liu, Bo; Liu, Mei; Szczepankiewicz, Bruce G.; Nelson, Lissa T.J.; Smith, Harriet T.; Suhar, Tom S.; Janis, Rich S.; Cao, Ning; Camp, Heidi S.; Collins, Christine A.; Sham, Hing L.; Surowy, Teresa K.; Liu, Gang [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 15, p. 4298 - 4302]
[3]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2020/154571, 2020, A1 Location in patent: Page/Page column 98; 99

21
[ 1996-41-4 ]
[ 6226-25-1 ]
[ 1036383-31-9 ]

Yield	Reaction Conditions	Operation in experiment
85.3%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 20℃; for 90h;	17.1 Example 17: Synthesis of 2-chloro-6-fluoro-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde 125.[0189] 2-Chloro-6-fluoio-3-(2,2,2-tϖfluoro-ethoxy)-benzaldehyde 125 was synthesized in 2 steps from 2-chloro-4-fluorophenol 52 as shown in Scheme 39Scheme 39 Step 1 - Preparation of2-chloro-4-fluoro-l-(2,2,2-trifluoro-ethoxy)-benzene (124): [0190] To 2-chloro-4-fluorophenol (52, 1.58 g, 0.0108 mol) in N-methylpyrrolidinone (25.0 mL), cesium carbonate (7.02 g, 0.0215 mol) and trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester (2.50 g, 0.0108 mol) were added under an atmosphere of nitrogen. The reaction was stirred at room temperature for 90 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% to 100% ethyl acetate in hexane to give a colorless oil (124, 2.10 g, 85.3%).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2008/80001, 2008, A2 Location in patent: Page/Page column 78-79

22
[ 1996-41-4 ]
[ 6482-24-2 ]
[ 1036383-28-4 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In acetonitrile at 80℃; for 12h;	A A. 2-Chloro-4-fluoro- 1 -(2-methoxyethoxy)benzene. To a solution of 2-chloro-4- fluoro-phenol (5 g, 34.12 mmol) and 1-bromo-2-methoxy-ethane (5.69 g, 40.94 mmol, 3.85 mL) in MeCN (100 mL) was added K2CO3 (9.43 g, 68.24 mmol). The reaction mixture was stirred at 80 °C for 12 hrs. The reaction mixture was cooled and diluted with H2O (50 mL), and then diluted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrousNa2SO4, filtered and concentrated under reduced pressure. Purification (FCC, SiO2, Petroleum ether/Ethyl acetate=1/0 to 20/1) afforded the title compound (6.9 g, 98%) as yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.14 - 7.12 (m, 1H), 6.93 - 6.91 (m, 2H), 4.15 (t, J= 4.8 Hz, (0306) 2H), 3.78 (t, J= 4.8 Hz, 2H), 3.18 (s, 3H).
34.4%	With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	16.1 Example 16: Synthesis of 2-chloro-6-fluoro-3-(2-methoxy-ethoxy)-benzaldehyde 123.[0186] 2-Chloro-6-fluoro-3-(2-methoxy-ethoxy)-benzaldehyde 123 was synthesized in 2 steps from 2-chloro-4-fluorophenol 52 as shown in Scheme 38Step 1 - Preparation of2-chloro-4-fluoro-l-(2-methoxy-ethoxy)-benzene (122) [0187] To 2-chloro-4-fluorophenol (52, 2 40 mL, 0 0213 mol) in N.N-dimethylfonnamide (30 0 mL), 1 -bromo-2-methoxy-ethane (2 00 mL, 0 0213 mol) and potassium carbonate (3 00 g, 0 0217 mol) were added under an atmosphere of nitrogen l he reaction was stirred at 80 0C for 2 hours The reaction was poured into water and extracted with ethyl acetate The organic layer was dried over anhydrous sodium sulfate and filtered The filtrate was concentrated and purified by silica gel column chromatography elutmg with 20% ethyl acetate in hexane to give a colorless oil (122, 1 50 g, 34 .

Reference： [1]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/156787, 2021, A1 Location in patent: Page/Page column 81
[2]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2008/80001, 2008, A2 Location in patent: Page/Page column 78

23
cis-tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate [ No CAS ]
[ 1996-41-4 ]
trans-4-(2-chloro-4-fluorophenoxy)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium hydroxide In 1,4-dioxane for 20h; Heating / reflux;	68.C.68.1 68.1 Trans 4-(2-Chloro-4-fluoro-phenoxy)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester 68.1 Trans 4-(2-Chloro-4-fluoro-phenoxy)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester The title compound was prepared as follows. Rac-cis-7-Oxa-3-aza-bicyclo[4.1.0]heptane-3-carboxylic acid tert-butyl ester (1 g, 5 mmol) was solvated in dioxane (5 mL), 2-Chloro-4-Fluorophenol was added (1.471 g, 10 mmol) and sodium hydroxide (0.401 g, 10 mmol). After 20 hours refluxing, the mixture was cooled, ammonium chloride was added and the mixture extracted three times with ethyl acetate. The combined organic phases were dried with magnesium sulfate and concentrated under vacuum. After a flash chromatography with heptane/ethyl acetate 1:1 to 1:2 heptane/ethyl acetate a solid the title compound was obtained as solid (0.778 g, 45% yield). MS (m/e): 404.5 (M+AcO-).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2008/103174, 2008, A1 Location in patent: Page/Page column 24

24
[ 1996-41-4 ]
[ 78-95-5 ]
[ 1036762-59-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide In acetone Heating;
	With potassium carbonate In acetone for 4h; Reflux;	3.A A mixture of 2-chloro-4-fluorophenol (3.00 g, 20.4 mmol), chloroacetone (2.12 mL, 26.6 mmol), potassium carbonate (4.24 g, 30.7 mmol) and potassium iodide (0.20 g, catalytic) in acetone (30 mL) was heated at reflux for 4 h, cooled and filtered. The filtrate was concentrated under reduced pressure to provide the title compound as a yellow solid (4.05 g)..H NMR ^DC^): δ 7.16 (dd, J= 8.0, 3.0 Hz, 1H), 6.93 (m, 1H), 6.76 (m, 1H), 4.53 (s, 2H), 2.34 (s, 3H).

Reference： [1]Ducray, Pierre; Gauvry, Noelle; Pautrat, Francois; Goebel, Thomas; Fruechtel, Joerg; Desaules, Yves; Weber, Sandra Schorderet; Bouvier, Jacques; Wagner, Trixie; Froelich, Olivier; Kaminsky, Ronald [Bioorganic and Medicinal Chemistry Letters, 2008, vol. 18, # 9, p. 2935 - 2938]
[2]Current Patent Assignee: FMC CORP - WO2012/30922, 2012, A1 Location in patent: Page/Page column 46

25
[ 1996-41-4 ]
[ 541-41-3 ]
[ 153406-19-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In dichloromethane at 0 - 20℃; for 16h;	47.47A To a solution of 2-chloro-4-fluoro-phenol (0.8 mL, 7.64 mmol) and triethylamine (1.3 mL, 9.16 mmol) in dichloromethane (10 mL) at 0 0C was added ethyl chloroformate (0.9 mL, 9.16 mmol) dropwise. The ice bath was removed and the solution was allowed to warm to room temperature and stirred for an additional 16 hours. Afterwards dichloromethane (20 mL) was added to the mixture, the organic solution was washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide the title product as an oil (1.65 g, 100%).
94%	Stage #1: 2-chloro-4-fluorophenol With sodium hydroxide at 20℃; for 0.5h; Large scale; Stage #2: chloroformic acid ethyl ester at 20℃; for 2h; Large scale;	8 In a three-neck flask (20L) equipped with astirrer, 2- chloro-4-fluoro phenol (2.88kg, 19.7mol) was weighed out, and tothis, 2.5N sodium hydroxide solution (8L) was added slowly over a period of 30minutes while stirring at room temperature. To this solution, ethylchloroformate (2.11kg, 19.4mol) was added dropwise at room temperature and afterdropwise addition, further stirred for 2 hours. After completion of thereaction, the organic layer was separated and further the aqueous layer wasextracted with dichloromethane (3.0L × 2). The organic layers were combined andwashed with water (2.0 L), and dried over anhydrous magnesium sulfate. Afterthe desiccant was filtered, by distilling off the solvent under reducedpressure from the filtrate, oil of (2-chloro-4-fluorophenyl) ethyl carbonate(3.98 kg, yield: 94%) was obtained .
93.9%	Stage #1: 2-chloro-4-fluorophenol With sodium hydroxide In water at 20℃; for 0.5h; Large scale; Stage #2: chloroformic acid ethyl ester In water at 20℃; for 2h; Large scale;	24 Reference Example-24 2-Chloro-4-fluorophenol (2.88 kg, 19.7 mol) was measured and put into a three-neck flask (20 L) provided with a stirrer, and a 2.5N sodium hydroxide aqueous solution (8 L) was slowly added thereto over 30 minutes while stirring at room temperature. Ethyl chloroformate (2.11 kg, 19.4 mol) was added dropwise to the solution at room temperature, followed by further stirring for 2 hours. After the reaction was completed, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (3.0 L*2). The organic layers were combined, and the resultant product was washed with water (2.0 L), and dried over anhydrous magnesium sulfate. After the desiccant was separated by filtration, the solvent was distilled off from the filtrate under reduced pressure, whereby (2-chloro-4-fluorophenyl)ethyl carbonate (3.98 kg, yield: 93.9%) was obtained as a oily material. 1H-NMR (400 MHz, CDCl3): δ1.40 (t, J=7.1 Hz, 3H), 4.35 (q, J=7.1 Hz, 2H), 7.00 (ddd, J=3.0, 7.7 and 9.1 Hz, 1H), 7.18-7.22 (m, 2H). 19F-NMR (376 MHz, CDCl3): δ-113.9 (s, 1F).

93.9%

Stage #1: 2-chloro-4-fluorophenol With sodium hydroxide at 20℃; for 0.5h; Large scale; Stage #2: chloroformic acid ethyl ester at 20℃; for 2h; Large scale;

2 Ina three-neck flask (20L) equipped with a stirrer, 2- chloro-4-fluoro phenol (2.88kg,19.7mol) was weighed out, and to this, 2.5N sodium hydroxide solution (8L) wasadded slowly over a period of 30 minutes while stirring at room temperature. Tothis solution, ethyl chloroformate (2.11kg, 19.4mol) was added dropwise at room temperature and after dropwise addition, further stirred for 2 hours. Aftercompletion of the reaction, the organic layer was separated and further the aqueous layer was extracted with dichloromethane (3.0L × 2). The organic layerwas combined, washed with water (2.0 L), and dried over anhydrous magnesium sulfate. After the desiccant was filtrated, and by distilling off the solventfrom the filtrate under reduced pressure, ethyl (2-chloro-4-fluorophenyl) carbonate oily substance (3.98kg, yield: 93.9 %) was obtained

Reference： [1]Current Patent Assignee: ABBVIE INC - WO2008/133753, 2008, A2 Location in patent: Page/Page column 88-88
[2]Current Patent Assignee: KAKEN PHARMACEUTICAL CO LTD; SAGAMI CHEMICAL RESEARCH INSTITUTE - JP2016/56157, 2016, A Location in patent: Paragraph 0161
[3]Current Patent Assignee: KAKEN PHARMACEUTICAL CO LTD; SAGAMI CHEMICAL RESEARCH INSTITUTE - US2016/24110, 2016, A1 Location in patent: Paragraph 0577; 0578
[4]Current Patent Assignee: KAKEN PHARMACEUTICAL CO LTD; SAGAMI CHEMICAL RESEARCH INSTITUTE - JP2016/60742, 2016, A Location in patent: Paragraph 0242

26
[ 373-52-4 ]
[ 1996-41-4 ]
[ 1083103-36-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In acetonitrile at 0 - 120℃; for 0.5h; Irradiation;	1.2 A MW reaction vessel was charged with 2-chloro-4-fluorophenol (1.03 g, 7.05 mmol), K2CO3 (1.31g, 9.48 mmol) and CH3CN (4 mL). The mixture was cooled to 0 0C before addition of bromofluoromethane (0.50 mL, 7.80 mmol). The vessel was capped and heated to 120 0C for 30 min. After cooling to room temperature the mixture was diluted with diethyl ether (200 mL). The organic layer was washed with H2O, 2M NaOH, brine and then dried over Na2SO4 and evaporated to dryness to give the pure title compound as a colorless liquid that solidified on standing. Yield 1.12 g (89%). 1H NMR (400 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 6.99-6.94 (m, IH), 5.74 (s, IH), 5.61 (s, IH).

Reference： [1]Current Patent Assignee: GENERAL ELECTRIC CO - WO2008/141239, 2008, A1 Location in patent: Page/Page column 52

27
[ 1996-41-4 ]
[ 41978-69-2 ]
[ 947295-84-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate
	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 16h;	20 4.1.1.4. General synthesis (D) of 2-phenoxypropanoic acids 11c-h. General procedure: To stirred solutions of the corresponding phenol (15.0 mmol)in DMF (25 mL) are added K2CO3 (2.60 g, 19 mmol) and ethyl 2-bromopropanoate (2.5 mL, 19 mmol). The mixtures were stirredat 50 C for 16 h, then cooled to room temperature and filtered toremove the inorganic solids. The filtrates were evaporated underhigh vacuum (<1 mmHg) to provide clear oils that were dissolvedin absolute ethanol (25 mL). Aqueous solutions of NaOH (2.0 M,12 mL, 24 mmol) were added, and the combined solutions heatedto reflux for 4 h. The resulting mixtures were cooled to room temperatureand evaporated under reduced pressure to provide residuesthat were dissolved in water (75 mL). The aqueous solutionswere acidified (pH 2) with aqueous HCl (2.0 M) to provide precipitatesthat were filtered, rinsed with water (20 mL), and driedunder vacuum to provide the products 11c-h.

Reference： [1]Location in patent: scheme or table Li, Yan-Jun; He, Hong-Wu [Phosphorus, Sulfur and Silicon and the Related Elements, 2008, vol. 183, # 2-3, p. 712 - 713]
[2]Williams, John D.; Torhan, Matthew C.; Neelagiri, Venugopal R.; Brown, Carson; Bowlin, Nicholas O.; Di, Ming; McCarthy, Courtney T.; Aiello, Daniel; Peet, Norton P.; Bowlin, Terry L.; Moir, Donald T. [Bioorganic and Medicinal Chemistry, 2015, vol. 23, # 5, p. 1027 - 1043]

28
[ 1996-41-4 ]
[ 6332-96-3 ]
[ 1143464-62-3 ]

Yield	Reaction Conditions	Operation in experiment
72%	With copper(I) triflate; caesium carbonate; In toluene; at 120℃; for 16.0h;	[00251] 4-terf-Butyl-2-(2-chloro-4-fluorophenoxy)benzoic acid; <n="72"/>[00252] In a pressure-vessel, a stirring mixture of <strong>[6332-96-3]2-bromo-4-tert-butylbenzoic acid</strong> (1.00 g, 3.89 mmol) and 2-chloro-4-fluorophenol (860 mg, 620 muL, 5.87 mmol) in toluene (20 mL) was added CS2CO3 (2.53 g, 7.78 mmol) followed by copper(I) triflate benzene complex (98 mg, 0.19 mmol). The sealed vessel was heated to 120 0C for 16 h. After cooling to room temperature, the reaction mixture was partitioned between 50 mL EtOAc and 50 mL H2O. The aqueous layer was acidified using 2.0 N HCl(aq) and re-extracted with EtOAc. The combined organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-3% MeOH/CH2Cl2 to give the product, 4- tert-butyl-2-(2-chloro-4-fluorophenoxy)benzoic acid as a white solid (907 mg, 2.81 mmol) in 72% yield. LC/MS: m/z 323.2 (M+H)+ at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). [00253] 2-Bromo-iV-(3-carbamoylphenyl)benzamide
	With caesium carbonate;copper(I) triflate benzene complex; In toluene; at 120℃; for 16.0h;	In a pressure-vessel, a stirring mixture of <strong>[6332-96-3]2-bromo-4-tert-butylbenzoic acid</strong> (1.00 g, 3.89 mmol) and 2-chloro-4-fluorophenol (860 mg, 620 muL, 5.87 mmol) in toluene (20 mL) was added Cs2CO3 (2.53 g, 7.78 mmol) followed by copper(I) triflate benzene complex (98 mg, 0.19 mmol). The sealed vessel was heated to 120 0C for 16 h. After cooling to room temperature, the reaction mixture was partitioned between 50 mL EtOAc and 50 mL H2O. The aqueous layer was acidified using 2.0 N HCl(aq) and re-extracted with EtOAc. The combined organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified via silica gel chromatography using 0-3% MeOH/CH2Cl2 to give the product, 4- tert-butyl-2-(2-chloro-4-fluorophenoxy)benzoic acid as a white solid (907 mg, 2.81 mmol) in 72% yield. LC/MS: m/z 323.2 (M+H)+ at 1.99 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).

Reference： [1]Patent: WO2009/49183,2009,A1 .Location in patent: Page/Page column 70-71
[2]Patent: WO2009/49181,2009,A1 .Location in patent: Page/Page column 62

29
[ 375-72-4 ]
[ 1996-41-4 ]
[ 1131890-95-3 ]

Yield	Reaction Conditions	Operation in experiment
92%	With dmap; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h; Inert atmosphere;

Reference： [1]Barluenga, Jose; Jimenez-Aquino, Agustin; Aznar, Fernando; Valdes, Carlos [Journal of the American Chemical Society, 2009, vol. 131, p. 4031 - 4041]

30
[ 358-23-6 ]
[ 1996-41-4 ]
[ 198206-02-9 ]

Yield	Reaction Conditions	Operation in experiment
95%	With diisopropylamine In dichloromethane at 0 - 20℃; Inert atmosphere;
94%	With triethylamine In dichloromethane at 0 - 20℃; for 1.25h; Inert atmosphere;

Reference： [1]Barluenga, Jose; Jimenez-Aquino, Agustin; Aznar, Fernando; Valdes, Carlos [Journal of the American Chemical Society, 2009, vol. 131, p. 4031 - 4041]
[2]Baxter, Carl A.; Cleator, Ed; Alam, Mahbub; Davies, Antony J.; Goodyear, Adrian; o'Hagan, Michael [Organic Letters, 2010, vol. 12, # 4, p. 668 - 671]

31
[ 1996-41-4 ]
[ 1208101-54-5 ]
[ 1208101-55-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2-chloro-4-fluorophenol With sodium hydride In N,N-dimethyl-formamide at 0℃; Inert atmosphere; Stage #2: [5-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester In N,N-dimethyl-formamide at 0 - 100℃;	2-1; C {5-[5-Bromo-6-(2-chloro-4-fluoro-phenoxy)-pyridine-3-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester; To a stirred solution of 2-chloro-4-fluoro-phenol (292 mg, 2.0 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (28.8 mg, 1.2 mmol) portionwise at 0° C. under nitrogen and stirred at the same temperature for 15 minutes. To the above mixture was added [5-(5-bromo-6-chloro-pyridine-3-sulfonylamino)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (212 mg, 0.4 mmol) portionwise at 0° C. Then the reaction mixture was heated at 100° C. overnight. After being cooled to room temperature, the reaction was quenched with water (2 mL), and diluted with ethyl acetate (50 mL). The resulting solution was washed subsequently with water (10 mL), 1N sodium hydroxide solution (10 mL), and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give {5-[5-bromo-6-(2-chloro-4-fluoro-phenoxy)-pyridine-3-sulfonylamino]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid tert-butyl ester, which was used in the next step without further purification. MS cald. for C27H27BrClFN2O6S 640, obsd. 641 [(M+H)+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/41714, 2010, A1 Location in patent: Page/Page column 27

32
[ 1996-41-4 ]
[ 2267-25-6 ]

Reference： [1]Journal of Heterocyclic Chemistry,2010,vol. 47,p. 15 - 21

33
[ 1996-41-4 ]
[ 951671-77-5 ]

Yield	Reaction Conditions	Operation in experiment
99%	With iodine; silver sulfate In ethanol at 20℃;
79%	With iodine; potassium iodide; sodium hydroxide In water at 0 - 20℃;
	With iodine; potassium iodide; sodium hydroxide In water at 20℃; for 1.5h;

With iodine; silver sulfate In ethanol at 20℃;

Reference： [1]Arcadi, Antonio; Blesi, Federico; Cacchi, Sandro; Fabrizi, Giancarlo; Goggiamani, Antonella; Marinelli, Fabio [Tetrahedron, 2013, vol. 69, # 7, p. 1857 - 1871]
[2]Location in patent: experimental part Francke, Robert; Schnakenburg, Gregor; Waldvogel, Siegfried R. [European Journal of Organic Chemistry, 2010, # 12, p. 2357 - 2362]
[3]Location in patent: scheme or table Francke, Robert; Schnakenburg, Gregor; Waldvogel, Siegfried R. [Organic Letters, 2010, vol. 12, # 19, p. 4288 - 4291]
[4]Location in patent: scheme or table Arcadi, Antonio; Blesi, Federico; Cacchi, Sandro; Fabrizi, Giancarlo; Goggiamani, Antonella [Tetrahedron Letters, 2011, vol. 52, # 40, p. 5149 - 5152]

34
[ 1996-41-4 ]
[ 100-39-0 ]
[ 918524-11-5 ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: 2-chloro-4-fluorophenol With sodium hydride In tetrahydrofuran at 20℃; for 0.75h; Stage #2: benzyl bromide In tetrahydrofuran at 20℃;	41.1 To a solution of 2-chloro-4-fluorophenol (617, 7 g, 0.05 mol) in tetrahydrofuran (100 mL) was added sodium hydride (1.8 g, 95% dry powder, 0.071 mol) at room temperature over 15 minutes under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. Benzyl bromide (10 g, 0.060 mol) was added slowly to the reaction mixture, then stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with hydrochloric acid (10%), water, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide compound as a white solid (618, 7,6 g, 60%).

Reference： [1]Current Patent Assignee: DAIICHI SANKYO COMPANY, LIMITED - WO2007/2325, 2007, A1 Location in patent: Page/Page column 201

35
[ 1996-41-4 ]
(1SR,3RS)-3-methanesulfonyloxycyclopentanecarboxylic acid tert-butyl ester [ No CAS ]
(1SR,3SR)-3-(2-chloro-4-fluorophenylsulfanyl)cyclopentanecarboxylic acid tert-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 2-chloro-4-fluorophenol With sodium hydride In tetrahydrofuran; mineral oil at 0 - 5℃; for 0.25h; Stage #2: (1SR,3RS)-3-methanesulfonyloxycyclopentanecarboxylic acid tert-butyl ester In tetrahydrofuran; mineral oil at 0 - 20℃;	79.4 Step 4: Rac-(1S,3S)-3-(2-Chloro-4-fluoro-phenylsulfanyl)-cyclopentanecarboxylic acid tert-butyl ester To a mixture of 2-chloro-4-fluorophenol (1.06 g) in tetrahydrofuran (15 mL) was added sodium hydride (55% dispersion in oil, 322 mg) and the white suspension was stirred 15 min then cooled down to 0-5° C. A solution of Rac-(1S,3R)-3-Methanesulfonyloxy-cyclopentanecarboxylic acid tert-butyl ester in tetrahydrofuran (15 mL) was added slowly and the reaction mixture was stirred at room temperature overnight. Hydrochloric acid (1M) was added and the reaction mixture was extracted with ethyl acetate. Combined organic layers were washed with an aqueous saturated solution of sodium carbonate and brine then dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with a gradient of cyclohexane/ethyl acetate (99:1 to 98:2 v/v) as eluant to afford the title compound (0.793 g, 88%) as light yellow oil. MS (EI): 348.2 (M+NH4)+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2010/317647, 2010, A1 Location in patent: Page/Page column 58

36
[ 1996-41-4 ]
[ 1312764-41-2 ]
[ 1312764-42-3 ]

Yield	Reaction Conditions	Operation in experiment
	With (4-chlorophenyl)methyl (NE)-N-[(4-chlorophenyl)methoxycarbonylimino]carbamate; triphenylphosphine In dichloromethane at 45℃;	20a Compound 20a: 4-(2-(tert-butyldimethylsilyloxy)-1-(2-chloro-4-fluorophenoxy)ethyl)- pyrimidin-2-amine; To a solution of 1 -(2-aminopyrimidin-4-yl)-2-(tert-butyldimethylsilyloxy)ethanol (19) (640 mg), 2-Chloro-4-fluorophenol (696 mg) and triphenylphosphine (1246 mg) in dichloro- methane (10 ml.) was added a solution of (E)-bis(4-chlorobenzyl) diazene-1 ,2-dicarbox- ylate in dichloromethane (20 ml.) dropwise. The mixture was stirred at 45 °C overnight before being filtered and the filtrate was applied to a silica column and eluted with 10 to 100% ether in heptane. The product containing fractions were concentrated to afford the title compound (835 mg) as a white solid.

Reference： [1]Current Patent Assignee: MERCK & CO INC - WO2011/76723, 2011, A1 Location in patent: Page/Page column 32-33

37
[ 590-92-1 ]
[ 1996-41-4 ]
3-<2-Chlor-4-fluorphenoxy>-propionsaeure [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 310 - 317

38
[ 1996-41-4 ]
[ 84478-75-1 ]

Reference： [1]Patent: WO2013/36232,2013,A2
[2]Organic Process Research and Development,2014,vol. 18,p. 122 - 134
[3]Patent: WO2008/133753,2008,A2

39
[ 1996-41-4 ]
[ 1455096-45-3 ]
4-(2-chloro-4-fluorophenoxy)-2-[(2,5-dimethoxybenzyl)(ethoxycarbonylmethyl)amino]methyl}benzoic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With 2,2,6,6-tetramethylheptane-3,5-dione; caesium carbonate; copper(l) chloride In 1-methyl-pyrrolidin-2-one at 130℃; for 24h; Inert atmosphere;	97.a 4-(2-Chloro-4-fluorophenoxy)-2-[(2,5-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]-methyl}- benzoic acid ethyl ester To a mixture of 4-bromo-2- [(2,5-dimethoxy-benzyl)-ethoxycarbonylmethyl-amino]- methyl} -benzoic acid ethyl ester (3.44 g, 6.96 mmol) and 2-chloro-4-fluorophenol (2.04 g, 13.9 mmol) in NMP (6.8 mL) was added CS2CO3 (4.53 g, 13.9 mmol). The resultant mixture was degassed and re-filled with N2 gas prior to the addition of 2,2,6,6-tetramethyl-heptane-3,5-dione (128 mg, 0.70 mmol) and Cu(I)Cl (344 mg, 3.48 mmol). It was de-gassed and filled with N2 gas again. The resultant mixture was heated in a 130 °C oil bath for 24 h. Reaction mixture was filteredthrough a pad of celite and washed with EtOAc until no UV active spot was detected from the filtrate. Filtrate was washed with 1 N HC1 (100 mL and 50 mL), water and brine. It was dried over MgSO/t, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with CH2CI2, to provide the title compound 2.07 g (3.70 mmol) in 44% yield. lH NMR (200 MHz) in CDC13, δ ppm: 7.80 (d, J = 8.4 Hz, 1 H), 7.38 (d, J = 2.6 Hz, 1 H), 7.20 (m, 1 H), 7.03 (m, 3 H), 6.73 (dd, J = 8.4, 2.6 Hz, 1 H), 6.38 (m, 2 H), 4.29 (q, J = 7.2 Hz, 2 H), 4.18 (s, 2 H), 4.1 1 (q, J = 7.0 Hz, 2 H), 3.79 (s, 3 H), 3.72 (s, 3 H), 3.70 (s, 2 H), 3.28 (s, 2 H), 1.4-1.2 (m, 6 H).

Reference： [1]Current Patent Assignee: FIBROGEN, INC. - WO2013/134660, 2013, A1 Location in patent: Paragraph 0375

40
[ 1996-41-4 ]
[ 119817-95-7 ]
[ 1430546-24-9 ]

Yield	Reaction Conditions	Operation in experiment
75%	With caesium carbonate In N,N-dimethyl-formamide at 130℃; for 0.333333h; Microwave irradiation;	Typical Procedure for the Synthesis of (R)-4-benzyl-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-ones General procedure: The solutionof aryl substituted 2-chlorophenols (2.40 mmol), (S)-Nbenzyl-2-chloropropanamide (0.49 g, 2.40 mmol), Cs2CO3(2.40 g, 7.36 mmol) in dry DMF was placed into microwave oven (KMIC-1.5kW) and irradiated at 130 °C (or heated conventionally at 130 °C) for the period listed in Table 1. The solvent was evaporated under reduced pressure. The residue was poured into water and was then extracted by ethyl acetate. The combined organic layers were dried over anhydrous MgSO4. The solvent was removed under vacuum to obtain the crude product which was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate.

Reference： [1]Meng, Li-Juan; Zuo, Hua; Vijaykumar; Dupati, Gautam; Choi, Kyung-Min; Jang, Kiwan; Yoon, Yong-Jin; Shin, Dong-Soo [Bulletin of the Korean Chemical Society, 2013, vol. 34, # 2, p. 585 - 589]

41
[ 1996-41-4 ]
[ 1620847-91-7 ]
[ 1620847-14-4 ]

Yield	Reaction Conditions	Operation in experiment
27%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1h;	25 Preparation of 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (109) Example 25 Preparation of 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (109) Cs2CO3 (244.4 mg, 0.75 mmol) was added to a solution of 4-chloro-2,5-difluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (71.2 mg, 0.25 mmol) and 2-chloro-4-fluorophenol (109.9 mg, 0.75 mmol) in DMF (2 mL) and the reaction was stirred at 100° C. for 1 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 4-chloro-2-(2-chloro-4-fluorophenoxy)-5-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (109) (22.8 mg, 27%). ESI-MS m/z calc. 410.00, found 411.2 (M+1)+; Retention time: 1.76 minutes (3 minutes run).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2014/213616, 2014, A1 Location in patent: Paragraph 0766; 0767

42
[ 1996-41-4 ]
[ 62257-16-3 ]
[ 84478-72-8 ]

Reference： [1]Organic Process Research and Development,2014,vol. 18,p. 122 - 134
[2]Organic Process Research and Development,2014,vol. 18,p. 122 - 134

43
[ 1996-41-4 ]
[ 1621108-97-1 ]
C₂₃H₁₅ClFN₃O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 1h;	3 00624] To methyl 5-(2-chloroquinoline-3-carboxamido)picolinate (52.26 mg, 0.15 mmol), 2- chloro-4-fluorophenol (21.98 mg, 0.15 mg), potassium carbonate (62.19 mg, 0.45 mmol) and 1- methylpyrrolidin-2-one (1 mL) were added and the reactions were stirred at 100 °C for 1 hour. 2M lithium hydroxide (75 0.45 mmol) and methanol were added and the reaction stirred at 50° C for 2 hours. The reaction was filtered and (75 mmol) of 2M lithium hydroxide were added and stirring was continued for an additional 2 hours. The reaction was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HC1 as a modifier to yield of 5-(2-(2-chloro-4-fluorophenoxy)quinoline-3- carboxamido)picolinic acid hydrochloric acid (79) (4.2 mg, 6%). ESI-MS m/z calc. 437.06, found 338.4 (M+l)+ )+; Retention time: 1.49 minutes (3 minutes run).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2014/120815, 2014, A1 Location in patent: Paragraph 00624

44
[ 1996-41-4 ]
[ 1621060-60-3 ]
C₂₁H₁₃ClF₄N₂O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 100℃; for 0.833333h;	Example 1 Preparation of 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinic acid (65) General procedure: Example 1 Preparation of 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinic acid (65) [embedded image] A solution of 2-fluoro-5-(trifluoromethyl)benzoyl chloride (2.98 mL, 19.72 mmol) in dichloromethane (22.3 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (3.0 g, 19.72 mmol), pyridine (4.80 mL, 59.16 mmol) and dichloromethane (89.4 mL) at 0° C. The mixture was removed from the ice bath after 1.5 hours and was stirred at room temperature for 0.5 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The layers were separated and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration rinsing with hexanes to yield methyl 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (5.16 g, 76%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) - 11.18 (s, 1H), 8.95 (d, J=2.5 Hz, 1H), 8.38 (dd, J=8.6, 2.5 Hz, 1H), 8.16 (dd, J=6.1, 2.4 Hz, 1H), 8.13 (d, J=8.6 Hz, 1H), 8.09-7.98 (m, 1H), 7.67 (t, J=9.2 Hz, 1H), 3.88 (s, 3H) ppm. ESI-MS m/z calc. 342.06. found 343.2 (M+1)+. Retention time: 1.54 minutes (3 minutes run).To 5-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylate (51.3 mg, 0.15 mmol) in N-methylpyrrolidinone (1 mL) was added 2,4-dimethoxyphenol (23.1 mg, 0.45 mmol), cesium carbonate (146.6 mg, 0.45 mmol) and the mixture was heated at 100° C. for 50 minutes to yield methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate that was taken into the next step without further purification.Sodium hydroxide (150 -L, 3M) and methanol (150 -L) were added to the methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate prepared in the previous step, and the reaction was stirred at 50° C. from 3 hours. The reaction mixture was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HCl as a modifier to yield 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinic acid hydrochloric acid (65) (37.3 mg, 49%). 1H NMR (400 MHz, DMSO-d6) - 10.97 (s, 1H), 8.97 (d, J=2.5 Hz, 1H), 8.35 (dd, J=8.8, 2.5 Hz, 1H), 8.09 (d, J=8.6 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.78 (dd, J=8.9, 2.4 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 6.92-6.69 (m, 2H), 6.61 (dd, J=8.8, 2.8 Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H) ppm. ESI-MS m/z calc. 462.10. found 463.5 (M+1)+. Retention time: 1.81 minutes (3 minutes run). The following compounds were prepared using a procedure similar to the one described above for compound 65 from the following alcohols.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - US2014/221435, 2014, A1 Location in patent: Paragraph 0577-0581

45
[ 1996-41-4 ]
[ 60611-24-7 ]
[ 1621060-65-8 ]

Yield	Reaction Conditions	Operation in experiment
79%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	Example 5 Preparation of 5-(2-(2-chloro-4-fluorophenoxy)-6-(trifluoromethyl)benzamido)picolinic acid (74) [embedded image] To a solution of 2-chloro-4-fluoro-phenol (20.97 g, 143.10 mmol) and <strong>[60611-24-7]2-fluoro-6-(trifluoromethyl)benzaldehyde</strong> (25 g, 130.1 mmol) in DMF (125.0 mL) was added Cs2CO3 (46.62 g, 143.1 mmol) and the reaction mixture was stirred at 100 C. for 1 hour. The reaction mixture was poured into water (500 ml) and extracted with ethyl acetate (3150 ml). The organics were combined, washed with water, brine (2), dried over Na2SO4, filtered and evaporated to give a red oil which solidified after standing over night. The material was then triturated with hot hexanes and cooled to 25 C. The slurry was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off white solid. 1H NMR (400 MHz, DMSO) - 10.61 (s, 1H), 7.84-7.70 (m, 2H), 7.66 (d, J=7.9 Hz, 1H), 7.47 (dd, J=9.0, 5.3 Hz, 1H), 7.42-7.32 (m, 1H), 7.12 (d, J=8.3 Hz, 1H) ppm.To a solution of 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (31 g, 97.29 mmol) in tBuOH (155.0 mL), water (100.8 mL), CH3CN (155.0 mL) and 2-methyl-2-butene (51.45 mL, 486.4 mmol) was added sodium dihydrogen phosphate (35.02 g, 291.9 mmol) and the mixture was cooled to 0 C. Sodium chlorite (26.40 g, 291.9 mmol) was added in one portion and the mixture was stirred at 25 C. for 1 hour. The pH of the reaction was adjusted to 2-3 with 1N HCl and the layers were separated. The aqueous layer was extracted with EtOAc (3). All the organic layers were combined, and solid sodium sulfite (-5 g) was added followed by brine (50 ml) and 1N NaOH (10 ml) and the mixture was shaken until the yellow color disappeared. The layers were separated and the organic was washed with brine, dried over Na2SO4, filtered through a short plug of silica and evaporated to dryness to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (40 g, 98%) as an oil that was used in the next step without further purification. ESI-MS m/z calc. 334.00. found 335.1 (M+1)+. Retention time: 1.58 minutes (3 minutes run).A solution of 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoic acid (33.46 mg, 0.10 mmol), ethyl 5-aminopyridine-2-carboxylate (19.94 mg, 0.12 mmol), HATU (41.83 mg, 0.11 mmol) and N-methylmorpholine (21.99 -L, 0.20 mmol) was stirred at 100 C. for 8 hours. NaH (16.00 mg, 0.40 mmol) was added and the mixture was stirred at 100 C. for 10 min. The mixture was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in Water (1-99%) and HCl as a modifier, to give 5-[[2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzoyl]amino]pyridine-2-carboxylic acid (74) (2.52 mg, 5%) as a white solid. ESI-MS m/z calc. 454.03. found 455.3 (M+1)+. Retention time: 1.42 minutes (3 minutes run).
79%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	To a solution of 2-chloro-4-fluoro-phenol (21 g, 143.1 mmol) and 2- fluoro-6-(trifluoromethyl)benzaldehyde (25 g, 130.1 mmol) in DMF (125.0 mL) was added CS2CO3 (46.6 g, 143.1 mmol) and the reaction mixture was stirred at 100 C for 1 hour. The mixture was poured into water (500 ml) and extracted with ethyl acetate (3 x 150 ml). The organics were combined, washed with water, brine (2x), dried over Na2S04, filtered and evaporated to give a red oil that solidified after standing over night. The material was then triturated with hot hexanes and cooled to 25 C. The slurry was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluoro-phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta 10.61 (s, 1H), 7.84 - 7.70 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.47 (dd, J = 9.0, 5.3 Hz, 1H), 7.42 - 7.32 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H) ppm.
79%	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 1h;	To a solution of 2-chloro-4-fluoro-phenol (20.97 g, 143.1 mmol) and 2-fluoro-6- (trifluoromethyl)benzaldehyde (25.0 g, 130.1 mmol) in DMF (125 mL) was added cesium carbonate (46.6 g, 143.1 mmol) and the reaction mixture was stirred at 100 C for 1 hour. The reaction mixture was poured in to water (500 ml) and extracted with ethyl actetate (3 x 150 ml). Organics were combined, washed with water, brine (2x), dried over sodium sulfate and evaporated to give a red oil which solidified after standing over night. The material was then triturated with hot hexanes and cooled to room temperature. The slurry was filtered and washed with cold hexanes to give 2-(2-chloro-4-fluoro- phenoxy)-6-(trifluoromethyl)benzaldehyde (32.7 g, 79%) as an off-white solid. NMR (400 MHz, DMSO-d6) delta 10.61 (s, 1H), 7.84 - 7.70 (m, 2H), 7.66 (d, J = 7.9 Hz, 1H), 7.47 (dd, J = 9.0, 5.3 Hz, 1H), 7.42 - 7.32 (m, 1H), 7.12 (d, J = 8.3 Hz, 1H) ppm.

Reference： [1]Patent: US2014/221435,2014,A1 .Location in patent: Paragraph 0594-0597
[2]Patent: WO2015/10065,2015,A1 .Location in patent: Paragraph 00252
[3]Patent: WO2019/14352,2019,A1 .Location in patent: Paragraph 001799; 001800; 001829; 001830

46
[ 115812-96-9 ]
[ 1996-41-4 ]
4-(2-chloro-4-fluorophenoxy)-3-nitropyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With copper(l) iodide; potassium carbonate In N,N-dimethyl-formamide at 20 - 110℃; for 3.5h;	229.A Step A: 4-(2-Chloro-4-fluorophenoxy)-3-nitropyridine Step A: 4-(2-Chloro-4-fluorophenoxy)-3-nitropyridine Potassium carbonate (1.1 16 g, 8.45 mmol) and copper (I) iodide (0.0167 g, 0.088 mmol) were added to a stirred solution of 4-fluoro-3-nitropyridine (1.0 g, 7.04 mmol) and 2-chloro-4- fluorophenol (1.13 g, 7.74 mmol) in DMF (10 ml) at ambient temperature. The reaction was stirred for 0.5 h, heated at 1 10 °C for 3 h then cooled to ambient temperature. The mixture was diluted with water (20 ml), extracted with ethyl acetate (2 x 40 ml), washed with brine (20 ml) and dried (Na2S04). The organic layer was filtered and concentrated under reduced pressure to yield the crude product, which was purified by column chromatography (silica gel, eluting with 10 % ethyl acetate/hexane) to afford the title compound (1.5 g, 79%) as brown solid. LC-MS: m/z = 269.2 [M+H] +.

Reference： [1]Current Patent Assignee: AMPLA PHARMACEUTICALS - WO2014/199164, 2014, A1 Location in patent: Page/Page column 89

47
[ 1996-41-4 ]
[ 117752-04-2 ]
2-(2-chloro-4-fluorophenoxy)-6-methylbenzaldehyde [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1h;	25 EXAMPLE 25 Preparation of 2-(2-chloro-4-fluorophenoxy)-6-methyl-N-(3-sulfamoylphenyl)benzamide (38) To a solution of 2-fluoro-6-methyl-benzaldehyde (1.1 g, 7.75 mmol) and 2-chloro-4-fluoro-phenol (817.7 μ, 7.75 mmol) in DMF (9.2 mL) was added cesium carbonate (2.5 g, 7.75 mmol) and the mixture was heated at 100 °C for 1 hour. The mixture was cooled to room temperature before it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-100%) to yield 2-(2-chloro-4-fiuoro-phenoxy)-6-methyl-benzaldehyde (1.05 g, 51%). ESI- MS m/z calc. 264.03, found 265.1 (M+l)+; Retention time: 2.02 minutes (3 minutes run).
51%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1h;	216.1 Step 1: 2- -chloro-4-fluoro-phenoxy)-6-methyl-benzaldehyde To a solution of 2-fluoro-6-methyl-benzaldehyde (1.07 g, 7.746 mmol) and 2-chloro-4- fluoro-phenol (approximately 1.135 g, 817.7 μ, 7.746 mmol) in DMF (9.169 inL) was added cesium carbonate (approximately 2.524 g, 7.746 mmol), and the mixture was heated at 100 °C for 1 hour. The mixture was cooled to room temperature before it was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate (3x). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using a gradient of ethyl acetate in hexanes (0-100%) to yield 2-(2-chloro-4- fluoro-phenoxy)-6-methyl-benzaldehyde (1.05 g, 51%). ESI-MS m/z calc. 264.03534, found 265.1 (M+l)+; Retention time (Method B): 2.02 minutes (3 min run).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/10065, 2015, A1 Location in patent: Paragraph 00261
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2019/14352, 2019, A1 Location in patent: Paragraph 001854; 001855

48
[ 1996-41-4 ]
4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide [ No CAS ]
4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1h;	33 EXAMPLE 33 Preparation of 4-chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (8) To a solution of 4-chloro-2-fluoro-N-(3-sulfamoylphenyl)benzamide (39.4 mg, 0.12 mmol) and 2-chloro-4-fluorophenol (52.8 mg, 0.36 mmol) in DMF (0.8 mL) was added cesium carbonate (117.3 mg, 0.36 mmol) and the reaction was heated at 100 °C for 1 hour. The reaction was filtered and purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water containing HC1 as a modifier to yield 4- chloro-2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)benzamide (8) (1.7 mg, 3%). ESI-MS m/z calc. 454.00, found 455.3 (M+l)+; Retention time: 1.73 minutes (3 minutes run).

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/10065, 2015, A1 Location in patent: Paragraph 00274

49
[ 1996-41-4 ]
5-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide [ No CAS ]
2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 4h;	31 EXAMPLE 31 Preparation of 2-(2-chloro-4-fluorophenoxy)-5-cyano-N-(3-sulfamoylphenyl)benzamide (11) To a solution of 5-cyano-2-fluoro-N-(3-sulfamoylphenyl)benzamide (31.9 mg, 0.10 mmol) and 2-chloro-4-fluorophenol (44.0 mg, 0.30 mmol) in NMP (0.5 mL) was added Cs2C03 (97.7 mg, 0.30 mmol) and the mixture was stirred at 90 °C for 4 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) using HCl as a modifier to yield 2-(2-chloro-4-fluoro-phenoxy)-5-cyano-N- (3-sulfamoylphenyl)benzamide (11) (5.8 mg, 13%). ESI-MS m/z calc. 445.03, found 446.1 (M+l)+; Retention time: 1.57 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.33 (s, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.81 (d, J = 6.9 Hz, 1H), 7.69 (dd, J = 8.3, 2.8 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.48 (dd, J = 9.1, 5.2 Hz, 1H), 7.44 - 7.34 (m, 3H), 6.88 (d, J = 8.7 Hz, 1H) ppm.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/10065, 2015, A1 Location in patent: Paragraph 00271

50
[ 1996-41-4 ]
5-(difluoromethyl)-2-fluoro-N-(3-sulfamoylphenyl)benzamide [ No CAS ]
2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3-sulfamoylphenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With caesium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 2h;	34 EXAMPLE 34 Preparation of 2-(2-chloro-4-fluorophenoxy)-5-(difluoromethyl)-N-(3- sulfamoylphenyl)benzamide (40) 5-(Difluoromethyl)-2-fluoro-N-(3-sulfamoylphenyl)benzamide (75 mg, 0.22 mmol), 2-chloro-4-fluoro-phenol (95.7 mg, 0.65 mmol) and cesium carbonate (212.9 mg, 0.65 mmol) in NMP (0.75 mL) was stirred at 90 °C for 2 hours. The reaction mixture was diluted with MeOH, filtered and purification by reverse phase HPLC using a gradient of acetonitrile in water (1-99%) and HCl as a modifier gave 2-(2-chloro-4-fluorophenoxy)-5- (difluoromethyl)-N-(3-sulfamoylphenyl)benzamide (40) (56 mg, 53%) as a white solid. ESI- MS m/z calc. 470.03, found 471.3 (M+l)+; Retention time: 1.63 minutes (3 minute run). 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 8.32 (s, 1H), 7.87 (s, 1H), 7.85 - 7.78 (m, 1H), 7.72 - 7.64 (m, 2H), 7.60 - 7.53 (m, 2H), 7.39 (s br, 3H), 7.35 (d, J = 8.1 Hz, 1H), 7.10 (t, J = 55.8 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H) ppm.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/10065, 2015, A1 Location in patent: Paragraph 00276

51
[ 1996-41-4 ]
2-fluoro-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide [ No CAS ]
2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With caesium carbonate In N,N-dimethyl-formamide at 100℃; for 1.25h;	28 EXAMPLE 28 Preparation of 2-(2-chloro-4-fluorophenoxy)-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide (26) A mixture of 2-fluoro-N-(3-sulfamoylphenyl)-5- (trifluoromethyl)benzamide (15 g, 41.40 mmol), 2-chloro-4-fluoro-phenol (17.35 g, 118.4 mmol), cesium carbonate (40.47 g, 124.20 mmol) and DMF (375.0 mL) was heated at 100 °C for 1 hour and 15 minutes. The mixture was cooled to room temperature and filtered using ethyl acetate. Water was added to the filtrate. The layers were separated and the aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organics were washed with saturated aqueous solution of NH4C1, water and brine. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified silica gel chromatography utilizing a gradient of ethyl acetate in dichloromethane (0- 10%). The fractions containing the desired product were concentrated and the resulting solid slurried in ether and hexanes and filtered. The solvent was evaporated under reduced pressure to yield 2-(2-chloro-4-fluoro-phenoxy)-N-(3-sulfamoylphenyl)-5-(trifluoromethyl)benzamide (26) (10.35 g, 50%) as a light pink solid. ESI-MS m/z calc. 488.02, found 489.2 (M+l)+; Retention time: 2.03 minutes (3 minutes run). 1H NMR (400 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.37 - 8.27 (m, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.92 - 7.74 (m, 2H), 7.69 (dd, J = 8.4, 3.0 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.50 - 7.28 (m, 4H), 6.92 (d, J = 8.7 Hz, 1H) ppm.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2015/10065, 2015, A1 Location in patent: Paragraph 00266

52
[ 1996-41-4 ]
4-chloro-7-(2-(piperidin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline [ No CAS ]
4-(2-chloro-4-fluorophenoxy)-7-(2-(piperidin-1-yl)ethoxy)-5-((tetrahydro-2H-pyran-4-yl)oxy)quinazoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With sodium hydride In N,N-dimethyl-formamide at 100℃; for 2h;	1 Synthesis of 4-(2-chloro-4-fluorophenoxy)-7-(2-(piperidin-1 -yl)ethoxy)-5-((tetrahyd ro-2H-pyran-4-yl)oxy)q uinazoli ne To a mixture of 4-chloro-7-(2-(piperidin-1 -yl)ethoxy)-5-((tetrahydro-2H- pyran-4-yl)oxy)quinazoline (15 mg, 0.038 mmol) and 2-chloro-4-fluorophenol (12 pL, 0.12 mmol) in 0.5 mL of N,N-dimethylformamide was added sodium hydride (7.6 mg, 0.19 mmol). The mixture was heated at 100 00 for 2 h, and the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography developed with 0.5:5:94.5 NH4OH:methanol:dichloromethane to afford the title compound as a white solid in 74% yield (14 mg). 1H NMR (300 MHz, 0D013): 8.54 (5, 1 H), 7.29-7.21 (m, 2H), 7.12-7.05 (m, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 6.63 (d, J = 2.4 Hz, 1 H), 4.83-4.73 (m, 1 H), 4.28 (t, J = 6.3 Hz, 2H), 4.02-3.93 (m, 2H), 3.70-3.60 (m, 2H),2.87 (t, J= 6.3 Hz, 2H), 2.57 (m, 4H), 2.13-1.99 (m, 2H), 1.99--i .86 (m, 2H),1.70-1.57 (m, 4H), 1.53-1.41 (m, 2H); MS (ES+): m/z502.4 and 504.4 (M + 1).

Reference： [1]Current Patent Assignee: SIGNALCHEM LIFESCIENCES - WO2015/77375, 2015, A1 Location in patent: Paragraph 0187

53
[ 1996-41-4 ]
6-(6-bromopyridin-2-yl)-3-((2-chlorophenyl)thio)-6-(thiophen-3-yl)piperidine-2,4-dione [ No CAS ]
6-[6-(2-chloro-4-fluoro-phenoxy)-2-pyridyl]-3-(2-chlorophenyl)sulfanyl-6-(3-thienyl)piperidine-2,4-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate In 1,4-dioxane at 120℃; for 3h; Inert atmosphere;	3.A Example 3 6-[6-(2-chloro-4-fluoro-phenoxy)-2-pyridyl]-3-(2-chlorophenyl)sulfanyl-6-(3-thienyl)piperidi ne-2,4-dione Example 3 6-[6-(2-chloro-4-fluoro-phenoxy)-2-pyridyl]-3-(2-chlorophenyl)sulfanyl-6-(3-thienyl)piperidi ne-2,4-dione Step A: 6'-Bromo-5-(2-chloro-phenylsulfanyl)-4-hydroxy-2-thiophen-3-yl-2,3- dihydro-lH-[2,2']bipyridinyl-6-one (500 mg, 1 mmol), 2-chloro-4-fluoro-phenol (178 mg, 1.2 mmol), 2-(dimethylamino)acetic acid hydrochloride (28 mg, 0.2 mmol), Cul (39 mg, 0.2 mmol) and Cs2C03 (0.99 g, 3 mmol) were combined. Dioxane (5 ml) was added, the mixture was stirred at 120 °C for 3 h under nitrogen atmosphere. After the suspension was cooled to ambient temperature, EtOAc (20mL) was added, and the mixture was filtered over Celite. The resulting solution was washed three times with brine, dried anhydrous Na2S04, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by preparative HPLC (formic acid) to give the product (mixture of diastereoisomers, 230 mg, 41%, 10 mg was delivered) as white solid. The mixture of diastereoisomers (220 mg) was purified by SFC (neutral) to give the isomers (stereoisomer 1, 80 mg and stereoisomer 2, 128 mg) as white solid. Mixture of diastereoisomers: 'H NMR (400MHZ, (CD3)2SO) δ 7.93 (dd, J= 8.0, 8.0 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.44 (dd, J= 4.8, 2.1 Hz, 1H), 7.37 (d, J= 7.6 Hz, 1H), 7.30 - 7.23 (m, 3H), 7.18 (dd, J= 2.8, 1.2 Hz, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.91 (dd, J= 4.2, 1.2 Hz, 1H), 6.78 - 6.74 (m, 1H), 5.88 (dd, J= 7.6, 1.2 Hz, 1H), 3.37 (d, J = 16.4 Hz, 1H), 3.13 (d, J= 16.4 Hz, 1H). LCMS M+l = 558.7. Stereoisomer 1 : NMR (400MHz, CD3OD) δ 7.88 (dd, J= 8.0, 8.0 Hz, 1H), 7.36 (dd, J= 3.9, 2.4 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.22 (dd, J= 8.0, 1.2 Hz, 1H), 7.19 - 7.09 (m, 3H), 7.07 (d, J= 8.2 Hz, 1H), 6.96 (dd, J= 3.9, 0.9 Hz, 1H), 6.94 (dd, J= 8.0, 1.2 Hz, 1H), 6.81 - 6.74 (m, 1H), 5.88 (dd, J= 8.4, 1.2 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.20 (d, J= 16.4 Hz, 1H). LCMS M+l = 558.7. Stereoisomer 2: NMR (400MHz, CD3OD) δ 7.89 (dd, J= 8.0, 8.0 Hz, 1H), 7.36 (dd, J= 3.9, 2.4 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.22 (dd, J= 8.0, 1.2 Hz, 1H), 7.19 - 7.09 (m, 3H), 7.07 (d, J= 8.2 Hz, 1H), 6.96 (dd, J= 3.9, 0.9 Hz, 1H), 6.94 (dd, J= 8.0, 1.2 Hz, 1H), 6.81 - 6.74 (m, 1H), 5.97 (dd, J= 8.4, 1.2 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.20 (d, J= 16.4 Hz, 1H). LCMS M+l = 558.8
41%	With copper(l) iodide; N,N-dimethylglycine hydrochoride; caesium carbonate In 1,4-dioxane at 120℃; for 3h; Inert atmosphere;	3.A Step A: 6'-Bromo-5-(2-chloro-phenylsulfanyl)-4-hydroxy-2-thiophen-3-yl-2,3- dihydro-lH-[2,2']bipyridinyl-6-one (500 mg, 1 mmol), 2-chloro-4-fluoro-phenol (178 mg, 1.2 mmol), 2-(dimethylamino)acetic acid hydrochloride (28 mg, 0.2 mmol), Cul (39 mg, 0.2 mmol) and Cs2C03 (0.99 g, 3 mmol) were combined. Dioxane (5 ml) was added, the mixture was stirred at 120 °C for 3 h under nitrogen atmosphere. After the suspension was cooled to ambient temperature, EtOAc (20mL) was added, and the mixture was filtered over Celite. The resulting solution was washed three times with brine, dried anhydrous Na2S04, filtered, and the solvent evaporated under reduced pressure. The crude residue was purified by preparative HPLC (formic acid) to give the product (mixture of diastereoisomers, 230 mg, 41 %, 10 mg was delivered) as white solid. The mixture of diastereoisomers (220 mg) was purified by SFC (neutral) to give the isomers (stereoisomer 1 , 80 mg and stereoisomer 2, 128 mg) as white solid. Mixture of diastereoisomers: lH NMR (400MHz, (CD3)2SO) δ 7.93 (dd, / = 8.0, 8.0 Hz, 1H), 7.60 - 7.53 (m, 1H), 7.44 (dd, / = 4.8, 2.1 Hz, 1H), 7.37 (d, = 7.6 Hz, 1H), 7.30 - 7.23 (m, 3H), 7.18 (dd, / = 2.8, 1.2 Hz, 1H), 7.04 (d, = 8.4 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.91 (dd, J = 4.2, 1.2 Hz, 1H), 6.78 - 6.74 (m, 1H), 5.88 (dd, = 7.6, 1.2 Hz, 1H), 3.37 (d, = 16.4 Hz, 1H), 3.13 (d, = 16.4 Hz, 1H). LCMS M+l = 558.7. Stereoisomer 1 : lU NMR (400MHz, CD3OD) δ 7.88 (dd, = 8.0, 8.0 Hz, 1H), 7.36 (dd, = 3.9, 2.4 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.22 (dd, = 8.0, 1.2 Hz, 1H), 7.19 - 7.09 (m, 3H), 7.07 (d, = 8.2 Hz, 1H), 6.96 (dd, = 3.9, 0.9 Hz, 1H), 6.94 (dd, = 8.0, 1.2 Hz, 1H), 6.81 - 6.74 (m, 1H), 5.88 (dd, = 8.4, 1.2 Hz, 1H), 3.48 (d, = 16.4 Hz, 1H), 3.20 (d, = 16.4 Hz, 1H). LCMS M+l = 558.7. Stereoisomer 2: lU NMR (400MHz, CD3OD) δ 7.89 (dd, = 8.0, 8.0 Hz, 1H), 7.36 (dd, = 3.9, 2.4 Hz, 1H), 7.35 - 7.32 (m, 2H), 7.22 (dd, = 8.0, 1.2 Hz, 1H), 7.19 - 7.09 (m, 3H), 7.07 (d, = 8.2 Hz, 1H), 6.96 (dd, = 3.9, 0.9 Hz, 1H), 6.94 (dd, = 8.0, 1.2 Hz, 1H), 6.81 - 6.74 (m, 1H), 5.97 (dd, = 8.4, 1.2 Hz, 1H), 3.48 (d, J = 16.4 Hz, 1H), 3.20 (d, = 16.4 Hz, 1H). LCMS M+l = 558.8.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/142903, 2015, A2 Location in patent: Page/Page column 74
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2015/140133, 2015, A1 Location in patent: Page/Page column 85; 86

54
[ 1996-41-4 ]
[ 148254-32-4 ]

Reference： [1]Patent: US2016/24110,2016,A1
[2]Patent: JP2016/56157,2016,A
[3]Patent: JP2016/60742,2016,A

55
[ 1996-41-4 ]
[ 146447-18-9 ]

Reference： [1]Patent: US2016/24110,2016,A1
[2]Patent: JP2016/56157,2016,A
[3]Patent: JP2016/60742,2016,A

56
[ 1996-41-4 ]
[ 501-65-5 ]
(Z)-[1-(2-chloro-4-fluorophenoxy)ethene-1,2-diyl]dibenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With [{Au(IPr)}2(μ-OH)][BF4] In toluene at 110℃; for 6h; regioselective reaction;	(Z)-[1-(2-Chloro-4-fluorophenoxy)ethene-1,2-diyl]dibenzene (3ak) According to the general procedure for hydrophenoxylation, a crudeproduct, which was prepared from diphenylacetylene (1a) (89.0 mg,0.50 mmol), 2-chloro-4-fluorophenol (2k) (81.0 mg, 0.55 mmol) and[{Au(IPr)}2(μ-OH)][BF4] (6.5 mg, 5 μmol, 1.0 mol %) in toluene (1 mL) at110 °C for 6 h, was purified by column chromatography on silica gel (nhexane/EtOAc = 95/5) to give 3ak (143 mg, 88%, average of two runs)as a white solid whose NMR data were consistent to those reported in the literature [3].

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

57
[ 942152-80-9 ]
[ 1996-41-4 ]
7-(2-chloro-4-fluorophenoxy)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.3%	With copper(l) iodide; dimethylaminoacetic acid; caesium carbonate In dimethyl sulfoxide at 140℃; for 20h; Inert atmosphere;	28.1 Step 1) 7 - (2-chloro-4-fluorophenoxy) - 4-hydroxy-1-methyl-2-oxo -1,2-dihydro-quinoline-3-carboxylic acid methyl ester Under nitrogen, 7-bromo-4-hydroxy-1-methyl-2-oxo -1,2-dihydro-quinoline-3-carboxylic acid methyl ester (1.00g, 3 . 20mmol), 2-chloro-4-fluoro-phenol (0.60 ml, 5 . 50mmol), cuprous iodide (130 mg, 0 . 683mmol), N, N-dimethyl glycine (100 mg, 0 . 970mmol), cesium carbonate (2.60g, 7 . 98mmol) and dimethyl sulfoxide (100 ml) were added sequentially into the container.The reaction mixture was heated to 140 °C and stirred for 20 hours. Cooling to room temperature, using 1M to pH=4 dilute hydrochloric acid, ethyl acetate (50 ml × 2) extraction. Combined with the phase, with water (50 ml × 2), saturated salt water (50 ml) to wash, dry anhydrous sodium sulfate. Filtering, distilling off the solvent under reduced pressure, the crude product purification column chromatography (petroleum ether/ethyl acetate (v/v)=4/1) to get a white solid (730 mg, 60.3%).

Reference： [1]Current Patent Assignee: SHENZHEN DONGYANGGUANG INDUSTRIAL DEVELOPMENT CO LTD - CN105384687, 2016, A Location in patent: Paragraph 0588; 0589; 0590; 0591; 0592

58
[ 1996-41-4 ]
[ 123855-51-6 ]
tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 20℃; for 18h;
3.81 g	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 35℃; for 18h;	1.A A) tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.50 g), 2-chloro-4-fluorophenol (1.49 mL) and tri-n-butylphosphine (3.47 mL) in THF (50 mL) was added ADDP (3.52 g) at 0° C., and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was passed through a pad of silica gel/NH silica gel, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (3.81 g). 1H NMR (300 MHz, CDCl3) δ 1.21-1.38 (2H, m), 1.42-1.51 (9H, m), 1.78-2.11 (3H, m), 2.64-2.85 (2H, m), 3.75-3.97 (2H, m), 4.04-4.37 (2H, m), 6.80-7.00 (2H, m), 7.05-7.16 (1H, m).
3.81 g	With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine In tetrahydrofuran at 0 - 35℃; for 18h;	26.A A) tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carboxylate To a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.50 g), 2-chloro-4-fluorophenol (1.49mL) and tributylphosphine (3.47 mL) in THF (50 mL) was added ADDP (3.52 g) at 0°C, and the reaction mixture wasstirred at room temperature for 18 hr. The reaction mixture was passed through silica gel/NH silica gel pad, and thefiltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethylacetate/hexane) to give the title compound (3.81 g).1H NMR (300 MHz, CDCl3) δ 1.21-1.38 (2H, m), 1.42-1.51 (9H, m), 1.78-2.11 (3H, m), 2.64-2.85 (2H, m), 3.75-3.97 (2H,m), 4.04-4.37 (2H, m), 6.80-7.00 (2H, m), 7.05-7.16 (1H, m).

3.81 g

With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine at 0 - 35℃; for 18h;

1.F F) tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)piperidine-1-carboxylate To a solution of 39 tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (2.50 g), 40 2-chloro-4-fluorophenol (1.49 mL) and 41 tri-n-butylphosphine (3.47 mL) in 8 THF (50 mL) was added ADDP (3.52 g) at 0°C, and the reaction mixture was stirred at room temperature for 18 hr. The reaction mixture was passed through silica gel/NH silica gel pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the 42 title compound (3.81 g). 1H NMR (300 MHz, CDCl3) δ 1.21-1.38 (2H, m), 1.42-1.51 (9H, m), 1.78-2.11 (3H, m), 2.64-2.85 (2H, m), 3.75-3.97 (2H, m), 4.04-4.37 (2H, m), 6.80-7.00 (2H, m), 7.05-7.16 (1H, m).

Reference： [1]Ikeda, Shuhei; Sugiyama, Hideyuki; Tokuhara, Hidekazu; Murakami, Masataka; Nakamura, Minoru; Oguro, Yuya; Aida, Jumpei; Morishita, Nao; Sogabe, Satoshi; Dougan, Douglas R.; Gay, Sean C.; Qin, Ling; Arimura, Naoto; Takahashi, Yasuko; Sasaki, Masako; Kamada, Yusuke; Aoyama, Kazunobu; Kimoto, Kouya; Kamata, Makoto [Journal of Medicinal Chemistry, 2021, vol. 64, # 15, p. 11014 - 11044]
[2]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - US2017/283406, 2017, A1 Location in patent: Paragraph 0672; 0673
[3]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP3279191, 2018, A1 Location in patent: Paragraph 0353; 0365
[4]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP3438109, 2019, A1 Location in patent: Paragraph 0302; 0315

59
[ 1996-41-4 ]
[ 105-39-5 ]
[ 1716-85-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 12h;	1 Example 1 Dissolve 14.6g of 2-chloro-4-fluorophenol 1-1 in 200ml of N, N-dimethylformamide,Add 14.7g ethyl chloroacetate and 27.6g potassium carbonate respectively. The reaction system was heated to 50 ° C and stirred for 12 hours. TLC followed the reaction. After the reaction was completed, the reaction system was added to 400 mL of ice water. The aqueous phase was extracted twice with 400 mL of ethyl acetate, and the organic phases were combined. The organic phase was washed 3 times with 400 mL of saturated brine, and then dried over anhydrous sodium sulfate. After spin-drying the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain 20.2 g of light yellow oily substance 2. The yield was 87.0%.
	With potassium carbonate In acetonitrile for 2h; Reflux;	General procedure for intermediates 14 General procedure: Intermediates 14 were prepared by following the knownprocedure [22, 29, 30]. The mixture of ethyl 2-chloroacetate(1 mmol), substituted phenols (1 mmol), and K2CO3(1.2 mmol) in acetonitrile was stirred in refluxing for 2 h(the course of the reactions was monitored by TLC)

Reference： [1]Current Patent Assignee: LIAOCHENG UNIVERSITY - CN111072615, 2020, A Location in patent: Paragraph 0020-0021
[2]Wang, Yanyan; Lu, Xiumian; Shi, Jun; Xu, Jiahong; Wang, Fenghua; Yang, Xiao; Yu, Gang; Liu, Zhiqian; Li, Chuanhui; Dai, Ali; Zhao, Yonghui; Wu, Jian [Monatshefte fur Chemie, 2018, vol. 149, # 3, p. 611 - 623]

60
[ 1996-41-4 ]
[ 768-60-5 ]
4-fluoro-2-(5-fluoro-2-(4-methoxyphenyl)benzofuran-3-yl)phenol [ No CAS ]
[ 65540-47-8 ]

Yield	Reaction Conditions	Operation in experiment
1: 51% 2: 15%	Stage #1: 2-chloro-4-fluorophenol With dichloro bis(acetonitrile) palladium(II); Cy-DHTP*HBF₄; tert.-butyl lithium In 1,4-dioxane at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 4-methoxyphenylacetylen In 1,4-dioxane for 25h; Reflux; Inert atmosphere;	Typical experimental procedure for the synthesis of 2,3-disubstituted benzofurans (Table 1, Entry 11). 1,4-Dioxane (1.0 mL) was added to PdCl2(CH3CN)2 (7.7 mg, 0.03 mmol), 1b·HBF4 (32.7 mg, 0.06 mmol), t-BuOLi (160 mg, 2.0 mmol), and 2-chloro-4-fluorophenol (147.3 mg, 1.0 mmol) in a two-neck flask under argon. The reaction mixture was stirred at rt for 20 min, after which time 4-ethynylanisole (66.3 mg, 0.50 mmol) was added. The reaction mixture was then stirred at reflux for 25 h. The resulting suspension was quenched with saturated NH4Cl (6 mL) at rt and extracted using ethyl acetate (3 × 20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentrated in vacuo, and the resulting residue was purified by preparative TLC (PTLC) (SiO2, hexane/dichloromethane= 2/1 (twice)) to give 3j (89.3 mg, 51%) as a brown oil.

Reference： [1]Yamaguchi, Miyuki; Ozawa, Hayato; Katsumata, Haruka; Akiyama, Tomoyo; Manabe, Kei [Tetrahedron Letters, 2018, vol. 59, # 33, p. 3175 - 3178]

61
[ 765-03-7 ]
[ 1996-41-4 ]
[ 1234862-03-3 ]
2-(2-decyl-5-fluorobenzofuran-3-yl)-4-fluorophenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 76% 2: 9%	Stage #1: 2-chloro-4-fluorophenol With dichloro bis(acetonitrile) palladium(II); Cy-DHTP*HBF₄; tert.-butyl lithium In 1,4-dioxane at 20℃; for 0.333333h; Inert atmosphere; Stage #2: 1-dodecyne In 1,4-dioxane for 25h; Reflux; Inert atmosphere;	Typical experimental procedure for the synthesis of 2,3-disubstituted benzofurans (Table 1, Entry 11). 1,4-Dioxane (1.0 mL) was added to PdCl2(CH3CN)2 (7.6 mg, 0.03 mmol), 1b·HBF4 (32.6 mg, 0.06 mmol), t-BuOLi (160mg, 2.0 mmol), and 2-chloro-4-fluorophenol (146.9 mg, 1.0 mmol) in a two-neck flask under argon. The reaction mixture was stirred at rt for 20 min, after which time dodec-1-yne (82.6 mg, 0.50 mmol) was added. The reaction mixture was then stirred at reflux for 25 h. The resulting suspension was quenched with saturated NH4Cl (6 mL) at rt and extracted using ethyl acetate (3 × 20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentratedin vacuo, and the resulting residue was purified by preparative TLC (PTLC) (SiO2, hexane/dichloromethane = 2/1(twice)) to give 3k (146.9 mg, 76%) as a pale yellow oil.

Reference： [1]Yamaguchi, Miyuki; Ozawa, Hayato; Katsumata, Haruka; Akiyama, Tomoyo; Manabe, Kei [Tetrahedron Letters, 2018, vol. 59, # 33, p. 3175 - 3178]

62
[ 1996-41-4 ]
[ 445-27-2 ]
C₁₄H₁₀ClFO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 100℃;	5 In a 100 mL round bottom flask, 4 mmol of the compound represented by formula (D) (for specific substituents, see Table 2) and 6 mmol of the compound represented by formula (E) (for specific substituents, see Table 2)And 8 mmol of anhydrous potassium carbonate, 10 mL of DMF was added, and the temperature was raised to 100 ° C.TLC monitors the reaction of the raw materials after the reaction is complete and stops the reaction. After adding 50 mL of ether, washing twice with 30 mL of 2M NaOH and then once with 50 mL of saturated brineThe solvent was removed under reduced pressure to obtain a compound represented by the formula (F).
	With potassium carbonate In N,N-dimethyl-formamide Reflux;

Reference： [1]Current Patent Assignee: UNIV CENTRAL CHINA NORMAL - CN110357857, 2019, A Location in patent: Paragraph 0138-0140
[2]Li, Hua; Gao, Meng-Qi; Chen, Yan; Wang, Yu-Xia; Zhu, Xiao-Lei; Yang, Guang-Fu [Journal of Agricultural and Food Chemistry, 2020, vol. 68, # 47, p. 14001 - 14008]

63
[ 1996-41-4 ]
(S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin-1-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate [ No CAS ]
(S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4-fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-1-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 16h;	187.1 Stepl To a solution of (S)-isopropyl 2-(5-(2-bromoethoxy)-4'-(4,4-dimethylpiperidin- l-yl)-6'-methyl-[2,3'-bipyridin]-5'-yl)-2-(tert-butoxy)acetate (40 mg, 0.069 mmol) in DMF (5 mL) was added CS2CO3 (45.2 mg, 0.139 mmol) and a solution of 2-chloro-4-fluorophenol (15.25 mg, 0.104 mmol) in DMF (1 mF). The mixture was stirred at 90 °C for 16 h, cooled and pH was adjusted to about 7 with acetic acid. The mixture was filtered and the filtrate was purified by Prep-HPFC to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-4- fluorophenoxy)ethoxy)-4'-(4,4-dimethylpiperidin-l-yl)-6'-methyl-[2,3'-bipyridin]-5'- yl)acetate (40 mg, 0.059 mmol, 85 % yield). FCMS (M + H) = 642.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/244066, 2019, A2 Location in patent: Page/Page column 151

64
[ 1996-41-4 ]
[ 96628-67-0 ]
tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.5%	Stage #1: 2-chloro-4-fluorophenol With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: 2-(tert-butoxycarbonylamino)ethyl methanesulfonate In N,N-dimethyl-formamide at 100℃; for 16h;	226.2; 227.1; 305.1; 321.1; 326.1 Step 2 To a stirred solution of 2-chloro-4-fluorophenol (1 g, 6.82 mmoL) in DMF (15 mL) was added CS2CO3 (4.45 g, 13.65 mmoL) in one-portion at 20 °C. The reaction mixture was stirred at 20 °C for 0.5 h. Then 2-((tert-butoxycarbonyl)amino)ethyl methanesulfonate (1.633 g, 6.82 mmoL) was added and heated up to 100 °C for 16 h. LCMS showed most of the starting material was consumed. The reaction mixture was filtered, the filter cake was washed with ethyl acetate (10 ml x 2), the filtrate was diluted with water (200 ml) and ethyl acetate (100 ml), separated and the organic phase was washed by with brine (200 ml x 3), dried over anhydrous NaiSCri, filtered and concentrated to give a yellow oil. The crude product was purified by silical gel chromatography (5%~l0% ethyl acetate/petroleum ether) to give tert-butyl (2-(2-chloro-4-fluorophenoxy)ethyl)carbamate (800 mg, 2.76 mmoL, (1024) 40.5 % yield). LCMS (M + H) = 312 & 314, Retention time (0.1% TFA): 1.639 min.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/244066, 2019, A2 Location in patent: Page/Page column 185; 187; 309; 331; 336

65
[ 1996-41-4 ]
[ 540-51-2 ]
[ 4033-60-7 ]

Yield	Reaction Conditions	Operation in experiment
80%	With sodium hydroxide In water at 90℃; for 16h;	166.1; 195.1 Step 1 To a mixture of 2-chloro-4-fluorophenol (1 g, 6.82 mmol) in water (11 mL) was added 2-bromoethanol (1.279 g, 10.24 mmol), NaOH (0.409 g, 10.24 mmol) and stirred at 90 °C for 16 hours. The solution was cooled to room temperature and extracted with DCM (3 x 20 mL). The combined organic layers were dried over anhydrous NaiSOr and concentrated to give a yellow crude product. The crude product was purified by silica gel chromatography (using 12 g, eluting with 15% ethyl acetate to 17% ethyl acetate in petroleum ether) to give the desired product 2-(2-chloro-4-fluorophenoxy)ethanol (1.12 g, 5.42 mmol, 80 % yield) as a colorless oil. LCMS [M + H] = 190.9.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2019/244066, 2019, A2 Location in patent: Page/Page column 132; 133; 157

66
[ 614730-89-1 ]
[ 1996-41-4 ]
tert-butyl 4-[(2-chloro-4-fluorophenoxy)methyl]-4-methylpiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
35.5%	With caesium carbonate In N,N-dimethyl-formamide at 15 - 90℃; for 16h; Inert atmosphere;	b Step b) tert-Butyl 4-[(2-chloro-4-fluoro-phenoxy)methylJ-4-methyl-piperidine-1-carboxylate To a solution of tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine- 1 -carboxylate (450mg, 1.46 mmol) in DMF (5 mL) was added Cs2CO3 (620 mg, 1.9 mmol) and 2-chloro-4-fluorophenol (0.14 mL, 1.46 mmol) at 15 °C. The mixture was heated to 90 °C and stirred for 16h. The reaction solution was diluted by EtOAc (10 mL), washed twice with brine (10 mL each),and dried over Na2504. The organic layer was concentrated under vacuum to give the crude product (0.7 g) as light yellow oil. The crude product was purified by prep-HPLC and dried by lyophilization to give the desired compound as colorless solid (186 mg, 0.520 mmol, 35.5% yield). MS (ESI): m/z =302 [M-56+H]t
35.5%	With caesium carbonate In N,N-dimethyl-formamide at 15 - 90℃; for 16h;	b Step b) tert-Butyl 4- [(2-chloro-4-fluoro-phenoxy) methyl] -4-methyl-piperidine- 1-carboxy late To a solution of tert-butyl 4-methyl-4-(methylsulfonyloxymethyl)piperidine-l-carboxylate (450 mg, 1.46 mmol) in DMF (5 mL) was added CS2CO3 (620 mg, 1.9 mmol) and 2-chloro-4- fluorophenol (0.14 mL, 1.46 mmol) at 15 °C. The mixture was heated to 90 °C and stirred for 16 h. The reaction solution was diluted by EtOAc (10 mL), washed twice with brine (10 mL each), and dried over Na2S04. The organic layer was concentrated under vacuum to give the crude product (0.7 g) as light yellow oil. The crude product was purified by prep-HPLC and dried by lyophilization to give the desired compound as colorless solid (186 mg, 0.520 mmol, 35.5% yield). MS (ESI): m/z =302 [M-56+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/35425, 2020, A1 Location in patent: Page/Page column 64; 160
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2020/35424, 2020, A1 Location in patent: Page/Page column 168; 169

67
[ 614729-58-7 ]
[ 1996-41-4 ]
tert-butyl 4-[(2-chloro-4-fluorophenoxy)methyl]-4-fluoropiperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61.5%	With caesium carbonate In N,N-dimethyl-formamide at 0 - 85℃; for 16h; Inert atmosphere;	b Step b) tert-Butyl 4-[(2-chloro-4-fluoro-phenoxy)methylJ-4-fluoro-piperidine-1-carboxylate To a solution of tert-butyl 4-fluoro-4-(methylsulfonyloxymethyl)piperidine-1-carboxylate (383 mg, 1.23 mmol) in DMF (4 mL) was added Cs2CO3 (601 mg, 1.85 mmol), 2-chloro-4- fluorophenol (0.13 mL, 1.35 mmol) and 2-chloro-4-fluorophenol (0.13 mL, 1.35 mmol) at 15°C. The mixture was heated to 85 °C and stirred for 16 h. The mixture was extracted three times with EtOAc (5 mL each) at 15 °C, the combined organic layers washed three times with brine (5mL each), dried over Na2504, filtered and evaporated. The crude product was purified by preparative HPLC and dried by lyophilization to give the desired compound as light yellow oil (275 mg, 0.760 mmol, 61.5%). MS (ESI): mlz = 306 [M-56+H].
61.5%	With caesium carbonate In N,N-dimethyl-formamide at 15 - 85℃; for 16h;	b Step b) tert-Butyl 4-[(2-chloro-4-fluoro-phenoxy)methyl]-4-fluoro-piperidine-l-carboxylate To a solution of tert-butyl 4-fluoro-4-(methylsulfonyloxymethyl)piperidine-l-carboxylate (383 mg, 1.23 mmol) in DMF (4 mL) was added CS2CO3 (601 mg, 1.85 mmol), 2-chloro-4- fluorophenol (0.13 mL, 1.35 mmol) and 2-chloro-4-fluorophenol (0.13 mL, 1.35 mmol) at 15 °C. The mixture was heated to 85 °C and stirred for 16 h. The mixture was extracted three times with EtOAc (5 mL each) at 15 °C, the combined organic layers washed three times with brine (5 mL each), dried over Na?S04, filtered and evaporated. The crude product was purified by preparative HPLC and dried by lyophilization to give the desired compound as light yellow oil (275 mg, 0.760 mmol, 61.5%). MS (ESI): m/z = 306 [M-56+H]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/35425, 2020, A1 Location in patent: Page/Page column 64; 161
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2020/35424, 2020, A1 Location in patent: Page/Page column 169

68
[ 1065608-51-6 ]
[ 1996-41-4 ]
tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)azepane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.1%	Stage #1: tert-butyl 4-(hydroxymethyl)azepane-1-carboxylate; 2-chloro-4-fluorophenol With triphenylphosphine In tetrahydrofuran at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: With diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃;	b Step a) tert-butyl 4- ((2 -chloro-4-fluorophenoxy) met hy 1) azepane-1-carboxylate In a 25m1 four-necked sulphonation flask under argon, tert-butyl 4-(hydroxymethyl)azepane- 1- carboxylate (480 mg, 2.09 mmol) was dissolved in THF (10 ml). Subsequently, 2-chloro-4- fluorophenol (337 mg, 251 i.il, 2.3 mmol) and triphenylphosphine (604 mg, 2.3 mmol) wereadded and the clear solution was stirred for 5 mm at rt. The mixture was cooled to 0°C and DEAD (401 mg, 365 pi, 2.3 mmol) was added in portions over 10mm. The mixture was stirred for 1 hr at 0°C, then overnight at rt. The mixture was taken up into EtOAc (50 ml), washed with water (2x25 ml), organic phase washed with 1M NaOH (3x25 ml), brine (20 ml), dried with Na2504, filtered and concentrated in vacuo. Residue was disolved in n-Heptane/diethyletherand the mixture stirred for 30 mm, the TPPO precipitate filtered and the crude concentrated in vacuo. The crude material was adsorbed on Isolute and purified by flash column chromatography (0 - 30% EtOAc/Heptane) over silica gel (50 g) to afford the desired product (630 mg, 1.76 mmol, 84.1%) as a yellow oil. LC-MS (ESI): m/z: 302.1 [M-56+H]+
84.1%	With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; Inert atmosphere;	a Step a) tert-butyl 4-((2-chloro-4-fluorophenoxy)methyl)azepane-l-carboxylate In a 25ml four-necked sulphonation flask under argon, tert-butyl 4-(hydroxymethyl)azepane-l- carboxylate (480 mg, 2.09 mmol) was dissolved in THF (10 ml). Subsequently, 2-chloro-4- fluorophenol (337 mg, 251 m, 2.3 mmol) and triphenylphosphine (604 mg, 2.3 mmol) were added and the clear solution was stirred for 5 min at rt.. The mixture was cooled to 0°C and DEAD (401 mg, 365 m, 2.3 mmol) was added in portions over lOmin. The mixture was stirred for 1 hr at 0°C, then overnight at rt. The mixture was taken up into EtOAc (50 ml), washed with water (2x25 ml), organic phase washed with 1M NaOH (3x25 ml), brine (20 ml), dried with Na2S04, filtered and concentrated in vacuo. Residue was disolved in n- Heptane/ diethyl ether and the mixture stirred for 30 min, the TPPO precipitate filtered and the crude concentrated in vacuo. The crude material was adsorbed on Isolute and purified by flash column (1178) chromatography (0 - 30% EtOAc/Heptane) over silica gel (50 g) to afford the desired product (630 mg, 1.76 mmol, 84.1%) as a yellow oil. LC-MS (ESI): m/z: 302.1 [M-56+H]+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/35425, 2020, A1 Location in patent: Page/Page column 64; 213
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2020/35424, 2020, A1 Location in patent: Page/Page column 221

69
[ 1996-41-4 ]
tert-butyl 4-chloro-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate [ No CAS ]
tert-butyl 4-(2-chloro-4-fluorophenoxy)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78.6%	With potassium carbonate In N,N-dimethyl-formamide at 25 - 70℃; for 1h;	6 Tert-Butyl 4-(2-chloro-4-fluorophenoxy)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate Tert-Butyl 4-(2-chloro-4-fluorophenoxy)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate To a solution of tert-butyl 4-chloro-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.1 g, 3.877 mmol, 1 equiv.) and 2-chloro-4-fluorophenol (0.85 g, 5.800 mmol, 1.50 equiv.) in DMF (15 mL, 193.826 mmol, 50.00 equiv.) was added K2CO3 (1.07 g, 7.753 mmol, 2 equiv.) at 25° C. The mixture was stirred at 70° C. for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1 to 5/1) to afford tert-butyl 4-(2-chloro-4-fluorophenoxy)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.2 g, 78.60%) as a yellow solid.
78.6%	With potassium carbonate In N,N-dimethyl-formamide at 70℃;	6 Tert-Butyl 4-(2-chloro-4-fluorophenoxy)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d] pyrimidine- 7-carboxylate To a solution of tert-butyl 4-chloro-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (1.1 g, 3.877 mmol, 1 equiv.) and 2-chloro-4-fluorophenol (0.85 g, 5.800 mmol, 1.50 equiv.) in DMF (15 mL, 193.826 mmol, 50.00 equiv.) was added K2CO3 (1.07 g, 7.753 mmol, 2 equiv.) at 25°C. The mixture was stirred at 70°C for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10/1 to 5/1) to afford tert-butyl 4-(2-chloro-4- fluorophenoxy)-6-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1.2 g, 78.60%) as a yellow solid.

Reference： [1]Current Patent Assignee: GOLDFINCH BIO INC - US2020/102301, 2020, A1 Location in patent: Paragraph 0191; 0198
[2]Current Patent Assignee: GOLDFINCH BIO INC - WO2020/191056, 2020, A1 Location in patent: Page/Page column 64; 65; 67

70
[ 1996-41-4 ]
[ 916420-27-4 ]
tert-butyl 2-chloro-4-(2-chloro-4-fluorophenoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.78%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 0.5h; Inert atmosphere;	8 Example 8. Example 8. Synthesis of Compound 112 Tert-butyl 2-chloro-4-(2-chloro-4-fluorophenoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate To a stirred mixture of tert-butyl 2,4-dichloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (800 mg, 2.630 mmol, 1 equiv.) and 2-chloro-4-fluorophenol (578.16 mg, 3.945 mmol, 1.50 equiv.) in DMF (15 mL) was added K2CO3 (726.99 mg, 5.260 mmol, 2.00 equiv.) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for 0.5 hours at 70° C. under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3200 mL). The combined organic layers were washed with brine (2100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (30/1 to 10/1) to afford tert-butyl 2-chloro-4-(2-chloro-4-fluorophenoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1 g, 91.78%) as a yellow oil.
91.78%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 0.5h; Inert atmosphere;	8 Tert-butyl 2-chloro-4-(2-chloro-4-fluorophenoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine- 7-carboxylate To a stirred mixture of tert-butyl 2,4-dichloro-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (800 mg, 2.630 mmol, 1 equiv.) and 2-chloro-4-fluorophenol (578.16 mg, 3.945 mmol, 1.50 equiv.) in DMF (15 mL) was added K2CO3 (726.99 mg, 5.260 mmol, 2.00 equiv.) in portions at rt under nitrogen atmosphere. The resulting mixture was stirred for 0.5 hours at 70°C under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to rt. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (30/1 to 10/1) to afford tert-butyl 2-chloro-4-(2-chloro- 4-fluorophenoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (1 g, 91.78%) as a yellow oil.

Reference： [1]Current Patent Assignee: GOLDFINCH BIO INC - US2020/102301, 2020, A1 Location in patent: Paragraph 0209-0210
[2]Current Patent Assignee: GOLDFINCH BIO INC - WO2020/191056, 2020, A1 Location in patent: Page/Page column 71; 72

71
[ 1996-41-4 ]
4-chloro-8-methyl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-7-carboxylic acid tert-butyl ester [ No CAS ]
tert-butyl 4-(2-chloro-4-fluorophenoxy)-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.05%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 1h; Inert atmosphere;	4 Tert-butyl 4-(2-chloro-4-fluorophenoxy)-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate Tert-butyl 4-(2-chloro-4-fluorophenoxy)-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate To a stirred solution of tert-butyl 4-chloro-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (4 g, 14.096 mmol, 1 equiv.) and 2-chloro-4-fluorophenol (2.07 g, 14.096 mmol, 1 equiv.) in DMF (50 mL) was added K2CO3 (3.90 g, 28.193 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The mixture was stirred at 70 for 1 h. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford tert-butyl 4-(2-chloro-4-fluorophenoxy)-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carboxylate (4 g, 72.05%) as a white solid.
72.05%	With potassium carbonate In N,N-dimethyl-formamide at 70℃; Inert atmosphere;	4 Tert-butyl 4-(2-chloro-4-fluorophenoxy)-8-methyl-5H,6H,7H,8H-pyrido[3,4-d] pyrimidine- 7-carboxylate To a stirred solution of tert-butyl 4-chloro-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (4 g, 14.096 mmol, 1 equiv.) and 2-chloro-4-fluorophenol (2.07 g, 14.096 mmol, 1 equiv.) in DMF (50 mL) was added K2CO3 (3.90 g, 28.193 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The mixture was stirred at 70 for lh. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1 : 1) to afford tert- butyl 4-(2-chloro-4-fluorophenoxy)-8-methyl-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7- carboxylate (4 g, 72.05%) as a white solid.

Reference： [1]Current Patent Assignee: GOLDFINCH BIO INC - US2020/102301, 2020, A1 Location in patent: Paragraph 0173; 0181
[2]Current Patent Assignee: GOLDFINCH BIO INC - WO2020/191056, 2020, A1 Location in patent: Page/Page column 59; 61

72
[ 1996-41-4 ]
[ 143360-89-8 ]
4-fluoro-2-(2-phenyl-1H-indol-3-yl)phenol [ No CAS ]
4-fluoro-2-(2-phenyl-1H-indol-3-yl)phenyl 2,2,2-trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1: 31% 2: 14%	Stage #1: o-(phenylethynyl)trifluoroacetanilide With dichloro bis(acetonitrile) palladium(II); Cy-DHTP*HBF₄; lithium tert-butoxide In 5,5-dimethyl-1,3-cyclohexadiene at 20℃; for 0.666667h; Inert atmosphere; Stage #2: 2-chloro-4-fluorophenol In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 24h; Inert atmosphere;	Typical experimental procedure for the synthesis of 2,3-disubstituted benzofurans General procedure: Xylene (2.0 mL) was added to PdCl2(CH3CN)2 (3.9 mg, 0.015 mmol), 1·HBF4 (16.4 mg, 0.03 mmol), t-BuOLi (60.0 mg,0.75 mmol), and 4 (72.3 mg, 0.25 mmol) in a two-neck flask under argon. The reaction mixture was stirred at rt for 40 min, after which time 2-chlorophenol (32.1 mg, 0.25 mmol) was added. The reaction mixture was then stirred at 140 °C for 24 h. The resulting suspension was quenched with saturated NH4Cl (5 mL) at rt and extracted using ethyl acetate (3 ×20 mL). The combined organic layers were then dried over anhydrous Na2SO4 and concentrated in vacuo, and the resulting residue was purified by preparative TLC (PTLC) (SiO2, hexane/chloroform = 1/2) to give 5b (22 mg, 31%) as a yellow oil.

Reference： [1]Yamaguchi, Miyuki; Ogihara, Kota; Konishi, Hideyuki; Manabe, Kei [Tetrahedron Letters, 2020, vol. 61, # 21]

73
[ 1996-41-4 ]
3-chloro-5-fluoro-2-hydroxybenzenesulfonyl chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With chlorosulfonic acid at 0 - 20℃; for 2h;	122 Synthesis of compound 122.1. Into a 250 mL 3-necked round-bottom flask were added 2-chloro-4-fluorophenol (1 g, 6.82 mmol, 1 equiv) and sulfonoperoxoyl chloride (954.1 mg, 8.19 mmol, 1.2 equiv) at 0 C. The resulting mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of water/ice (10 mL). The resulting mixture was extracted with EtOAc (2 x 15 mL). The combined organic layers were concentrated under reduced pressure. This resulted in 1.02 g (61%) of 122.1 as a brown solid. (ES, m/z): [M-H]- 242.9.

Reference： [1]Current Patent Assignee: NIMBUS ARTEMIS - WO2020/97408, 2020, A1 Location in patent: Paragraph 00449

74
[ 1996-41-4 ]
[ 1147557-97-8 ]
tert-butyl 6-(2-chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.3%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 24h; Inert atmosphere;	Step a) tert-Butyl 6-(2-chloro-4-fluorophenoxy)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 2-chloro-4-fluorophenol (756 mg, 562 pL, 5.16 mmol, CAS RN 1996-41-4), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1000 mg, 4.69 mmol, CAS RN 1147557-97-8) and triphenylphosphine (1.48 g, 5.63 mmol, CAS RN 603-35-0) in THF (23.4 mL) was added DIAD (1.14 g, 1.09 mL, 5.63 mmol, CAS RN 2446-83-5) dropwise at 0 °C and the reaction was stirred at RT for 18 h. Triphenylphosphine (738 mg, 2.81 mmol), followed by DIAD (569 mg, 547 pL, 2.81 mmol) were added and the reaction was stirred at RT for 6 h. The reaction mixture was poured into sat. aq. NaHCCb solution (50 mL) and EtOAc (30 mL) was added. The phases were separated and the aq. phase was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give an orange oil. The crude product was immobilized on Isolute and purified by column chromatography (40 gr, 0 to 30 % EtOAc in heptane) to afford the title compound as a yellow solid (1.51 g, 4.19 mmol, 89.3%). MS (ESI): m/z = 286.2 [M-56+H]+.
89%	With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at 0 - 20℃; for 24h; Inert atmosphere;	1 Step 1: tert-Butyl 6-(2-chloro-4-fluoro-phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of 2-chloro-4-fluorophenol (756 mg, 0.56 mL, 5.16 mmol, 1.1 equiv; CAS RN 1996-41-4), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (1.0 g, 4.69 mmol, 1.0 equiv; CAS RN 1147557-97-8) and triphenylphosphine (1.48 g, 5.63 mmol, 1.2 equiv) in THF (23.4 mL) was added DIAD (1.09 mL, 5.63 mmol, 1.2 equiv; CAS N 2446-83-5) dropwise at 0 °C and the reaction was stirred at RT for 18 h. Another batch of triphenylphosphine (738 mg, 2.81 mmol, 0.6 equiv), followed by DIAD (0.55 mL, 2.81 mmol, 0.6 equiv) were added and the reaction was stirred at RT for 6 h. The reaction mixture was poured into sat. aqueous NaHCO3 solution (50 mL) and ethyl acetate (30 mL) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a sat. aqueous NaCl solution, dried over Na2SO4, filtered and concentrated. The crude orange oil was immobilized on Isolute and purified by silica gel chromatography using a MPLC system eluting with a gradient of n-heptane : ethyl acetate (100 : 0 to 70 : 30) to yield the title compound as a yellow solid (1.50 g, 89 %). MS (ESI): m/z = 286.2 [M+2H-tBu]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/104494, 2020, A1 Location in patent: Page/Page column 80; 111
[2]Current Patent Assignee: ROCHE HOLDING AG - WO2022/49134, 2022, A1 Location in patent: Page/Page column 91; 173-174

75
[ 1996-41-4 ]
[ 108-24-7 ]
[ 445-38-5 ]

Yield	Reaction Conditions	Operation in experiment
65.62%	Stage #1: 2-chloro-4-fluorophenol; acetic anhydride With sulfuric acid at 20℃; for 2h; Stage #2: With aluminum (III) chloride at 120℃; for 8h;	1 Step 1: Preparation of l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone A solution of 2-chloro-4-fluorophenol (4.5 g, 30.71 mmol, CAS registry number: 1996-41- 4, Vendor: Bide Pharmatech, Catalog number: BD19192), acetic anhydride (4.7 g, 46.06 mmol) and sulfuric acid (1.51 g, 15.35 mmol) was stirred at room temperature for 2 hours. After completion, the reaction mixture was diluted with water (50 mL). The aqueous layer was extracted by EtOAc (50 mL) twice, and the combined organic layer was concentrated in vacuo. Then, aluminum chloride (6.1 g, 46.06 mmol) was added to the resulting residue and stirred at 120 °C for 8 hours. The reaction mixture was diluted with water (150 mL), and the aqueous layer was extracted by EtOAc (100 mL) twice. The combined organic layer was concentrated in vacuo to give the crude product. The crude product was purified by flash column (eluting with EtOAc : PE = 3% to 10%) to give l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone (3.8 g, yield: 65.62%) as a light yellow solid. MS obsd. (ESI+) [(M-H) ]: 187.0.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2020/120528, 2020, A1 Location in patent: Page/Page column 54

76
[ 1996-41-4 ]
methyl 6-tert-butyl-4-chloro-2-methyl-pyridine-3-carboxylate [ No CAS ]
6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: 2-chloro-4-fluorophenol; methyl 6-tert-butyl-4-chloro-2-methyl-pyridine-3-carboxylate With caesium carbonate In acetonitrile at 20℃; for 4h; Stage #2: With water; lithium hydroxide In ethanol at 20℃; for 72h;	156.3 Step 3: 6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylic acid A solution of methyl 6-tert-butyl-4-chloro-2-methyl-pyridine-3-carboxylate (350 mg, 1.45 mmol) in acetonitrile (3 mL) was treated with Cs2CO3 (600 mg, 1.84 mmol) and 2-chloro-4-fluoro- phenol (170 µL, 1.56 mmol) and stirred at room temperature for 4 hours. Aqueous LiOH (3.5 mL of 2 M, 7 mmol) and ethanol (3 mL) were added and the mixture stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate and washed with 2 M aqueous NaOH. The organic layer was dried over MgSO4, filtered and concentrated to provide crude methyl 6-tert-butyl-4-(2-chloro-4-fluoro- phenoxy)-2-methyl-pyridine-3-carboxylate. Aqueous LiOH (3.5 mL of 2 M, 7 mmol) and ethanol (3 mL) were added and the mixture stirred to afford the hydrolyzed ester. The mixture was acidified with 2 M aqueous HCl (6 mL) and extracted into ethyl acetate. The organic layer was separated, dried over MgSO4 and concentrated to provide 6-tert-butyl-4-(2-chloro-4-fluoro-phenoxy)-2-methyl-pyridine-3-carboxylic acid (350 mg, 72%). ESI-MS m/z calc.337.09, no ionization observed; LC/MS retention time (Method F): 0.59 minutes.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2020/146682, 2020, A1 Location in patent: Paragraph 00878

77
[ 1996-41-4 ]
6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid [ No CAS ]
6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: 2-chloro-4-fluorophenol; 6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid With caesium carbonate In toluene for 0.166667h; Inert atmosphere; Stage #2: With copper(l) iodide In toluene at 125℃; for 4h; Inert atmosphere;	174.1 Step 1: 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid A mixture of 6-bromo-2-fluoro-3-methoxy-4-(trifluoromethyl)benzoic acid (220 mg, 0.694 mmol), 2-chloro-4-fluoro-phenol (80 µL, 0.74 mmol) and Cs2CO3 (340 mg, 1.044 mmol) in toluene (1 mL) was bubbled with nitrogen for 10 minutes, then copper (I) iodide (50 mg, 0.2625 mmol) was added. The mixture was heated at 125 C with vigorous stirring for 4 hours under nitrogen. The mixture was cooled to room temperature and acidified with 1 M aqueous HCl (15 mL), filtered and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% ethyl acetate/heptane) to provide 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-methoxy-4- (trifluoromethyl)benzoic acid (120 mg, 43%). ESI-MS m/z calc.382.00, found 380.8 (M-1)-; LC/MS retention time (Method F): 0.74 minutes.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2020/146682, 2020, A1 Location in patent: Paragraph 00925

78
[ 1996-41-4 ]
tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate [ No CAS ]
tert-butyl 2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 1h;	38.1 Step 1: tert-butyl 2-bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate A stirring mixture of tert-butyl 2-bromo-6-fluoro-3-(trifluoromethyl)benzoate (1.0 g, 2.91 mmol), 2-chloro-4-fluoro-phenol (493 mg, 3.364 mmol), K2CO3 (800 mg, 5.788 mmol), and DMSO (4 mL) was heated at 100 °C for 1 hour. The reaction mixture was cooled to RT and was then directly purified by silica gel column chromatography using a gradient of EtOAc in hexanes to give tert-butyl 2- bromo-6-(2-chloro-4-fluoro-phenoxy)-3-(trifluoromethyl)benzoate (1.3 g, 95%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) d 7.84 (d, J = 8.9 Hz, 1H), 7.72 (dd, J = 8.4, 2.9 Hz, 1H), 7.52 - 7.23 (m, 2H), 6.92 (d, J = 8.9 Hz, 1H), 1.53 (s, 9H) ppm.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2020/146682, 2020, A1 Location in patent: Paragraph 00479

79
[ 1996-41-4 ]
6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid [ No CAS ]
6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With copper(l) iodide; caesium carbonate In toluene at 100℃; for 2h; Inert atmosphere;	157.1 Step 1: 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid A mixture of 6-bromo-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid (3.0 g, 9.5 mmol, see US 2019/0016671, Example 129, Step 3, which is incorporated by reference), 2-chloro-4- fluoro-phenol (1.57 g, 1.17 mL, 10.7 mmol), Cs2CO3 (3.37 g, 10.3 mmol) and copper iodide (395 mg, 2.07 mmol) was flushed with nitrogen before adding in toluene (60 mL). The mixture was stirred at 100 °C under nitrogen for 2 hours. The cooled mixture was acidified with 1 M aqueous HCl, then diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 × 60 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (0-60% ethyl acetate/heptane) provided 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-4-methoxy-3-(trifluoromethyl)benzoic acid (2.94 g, 81%). 1H NMR (400 MHz, CDCl3) d 7.30 - 7.27 (m, 1H), 7.17 (dd, J = 9.0, 5.0 Hz, 1H), 7.07 (ddd, J = 9.0, 7.4, 3.0 Hz, 1H), 5.97 (s, 1H), 3.72 (s, 3H) ppm. ESI-MS m/z calc.382.00, LC/MS retention time (Method F): 0.96 minutes.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2020/146682, 2020, A1 Location in patent: Paragraph 00881

80
[ 1996-41-4 ]
6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid [ No CAS ]
6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 2-chloro-4-fluorophenol; 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid With caesium carbonate In toluene for 0.166667h; Inert atmosphere; Stage #2: With copper(l) iodide In toluene at 100℃; for 1h; Inert atmosphere;	29.1 Step 1: 6-(2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid A solution of 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (5 g, 17.42 mmol), 2- chloro-4-fluoro-phenol (3.0 g, 20.47 mmol), Cs2CO3 (11.4 g, 34.99 mmol) in toluene (100 mL) was degassed with N2 for 10 minutes, then CuI (664 mg, 3.486 mmol) was added. The reaction was flushed with N2 then heated at 100 C with vigorous stirring for 1 h. The mixture was allowed to cool then diluted with ethyl acetate and water. The water layer was acidified with HCl (26 mL of 1 M, 26.00 mmol) and the product extracted with ethyl acetate. The organic layer was concentrated under vacuo and the residue was purified by silica gel column chromatography using a MeOH/DCM eluent to provide 6- (2-chloro-4-fluoro-phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (5.1 g, 80%) as a white solid. ESI- MS m/z calc.351.99255, found 353.0 (M+1)+; Retention time (Method B): 1.66 minutes. 1H NMR (400 MHz, DMSO-d6) d 14.19 (s, 1H), 7.89 - 7.58 (m, 2H), 7.59 - 7.22 (m, 2H), 6.69 (d, J = 8.9 Hz, 1H) ppm.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2020/146682, 2020, A1 Location in patent: Paragraph 00436

81
[ 1996-41-4 ]
tert-butyl 6-methanesulfonyloxymethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]
tert-butyl (1R,5S,6r)-6-[(2-chloro-4-fluoro-phenoxy)methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43.4%	With caesium carbonate In N,N-dimethyl-formamide at 15 - 85℃; for 16h;	a a) tert-butyl (lR,5S,6r)-6-[(2-chloro-4-fluoro-phenoxy)methyl]-3-azabicyclo[3.1.0]hexane-3- carboxylate To a solution of tert-butyl (lR,5S,6r)-6-(methylsulfonyloxymethyl)-3-azabicyclo[3.1.0]hexane- 3-carboxylate (CAS 958633-11-9, 294 mg, 1.01 mmol) in DMF (3 mL) was added cesium carbonate (493.16 mg, 1.51 mmol), 2-chloro-4-fluorophenol (0.11 mL, 1.11 mmol) at 15 °C. The mixture was heated to 85 °C and stirred for 16 hrs. The mixture was quenched with water (5 mL) at 0 °C, then extracted three times with EtOAc (5 mL) and dried over Na2S04. The organic layers were combined and concentrated in vacuo to obtained crude product as a yellow oil. The crude product was purified by Prep-HPLC and dried by lyophilization to obtain the desired product tert-butyl (lR,5S,6r)-6-[(2-chloro-4-fluoro-phenoxy)methyl]-3-azabicyclo[3.1.0]hexane- 3-carboxylate (150 mg, 0.440 mmol, 43.4% yield) as a light yellow oil. LC-MS (ESI): m/z = 286.0 [M-56+H+]+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2021/48036, 2021, A1 Location in patent: Page/Page column 55

82
[ 1996-41-4 ]
[ 637301-16-7 ]
tert-butyl 8-((2-chloro-4-fluorophenoxy)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
26.3%	With di-isopropyl azodicarboxylate; triphenylphosphine In dichloromethane at 20℃; for 19h;	a a) tert-butyl 8-((2-chloro-4-fluorophenoxy)methyl)-3-azabicyclo[3.2.1 ] octane-3 -carboxylate To a solution of 2-chloro-4-fluorophenol (65.6 mg, 48.8 pi, 448 pmol), tert-butyl 8- (hydroxymethyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (108 mg, 448 pmol) and triphenylphosphine (117 mg, 448 pmol) in DCM (2.24 ml) was added DIAD (99.5 mg, 95.7 pi, 492 pmol) dropwise and the reaction was stirred for 19 h at rt. The reaction mixture was quenched by addition of sat. aq. NaHCCb solution. The phases were separated and the aq. phase was extracted with DCM three times. The combined organic layers were dried over sodium sulfate and concentrated to dryness to afford a brown oil. The crude was immobilized on Isolute and purified by column chromatography (SiCh, 0 - 30 % EtOAc in heptane) to afford tert- butyl 8-((2-chloro-4-fluorophenoxy)methyl)-3-azabicyclo[3.2.1] octane-3 -carboxylate (45.9 mg, 26.3 %) as a yellow oil. LC-MS (ESI): m/z = 314.2 [M-56+H+]+

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2021/48036, 2021, A1 Location in patent: Page/Page column 55-56

83
[ 1996-41-4 ]
[ 27542-85-4 ]
(E)-2-chloro-4-fluorophenyl 3-(4-acetoxyphenyl)acrylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane	14 At 0°C, take 4-hydroxycinnamic acid (300mg, 1.83mmol) and DMAP (22mg, 0.18mmol) into 1.5mL pyridine solution,Add acetic anhydride (0.22mL, 2.28mmol) and stir for 2 hours.Put ice cubes in the reaction system,Adjust to pH=2 by 2N HCl,Extract with EA/THF=3:1 (3×20mL),The organic phases were combined and washed with saturated aqueous NaCl solution (2×20 mL),After filtration, it was dried with anhydrous Na2SO4.After the filtrate is concentrated,Weigh the concentrate (373mg, 1.83mmol),2-chloro-4-fluorophenol (175.9mg, 1.2mmol),EDCI (460mg, 2.4mmol),DMAP (7.4mg, 0.06mmol) is dissolved in 8mL dichloromethane solution,Add triethylamine (0.33mL, 2.4mmol) under stirring,Stir overnight.The reaction was quenched with saturated aqueous NaHCO3 (20 mL),CH2Cl2 (3×20mL) extraction,The organic phases were combined and washed with saturated aqueous NaCl solution (2×20 mL),After filtration, it was dried with anhydrous Na2SO4.After the filtrate is concentrated,Separation and purification by column chromatography,The eluent is EtOAc:petroleum ether=1:12,To obtain a white powder compound,The yield was 86%.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃;	4.1.1 A general method for synthesis of compounds 1-5, 6a-6f and 7a-7f General procedure: To a stirred solution of cinnamic acid (1.5 mmol) in 8 mL dichloromethane solution was added alcohol or phenol (1 mmol), EDCI (2 mmol) and DMAP (0.05 mmol) at 0 °C. The triethylamine (2 mmol) was added to the previous liquor and the reaction was warmed to room temperature and stirred mechanically overnight. After that, the reaction mixture was quenched with saturated aqueous NaHCO3 solution (20 mL) and extracted with CH2Cl2 (3×20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (2×20 mL) and dried over anhydrous Na2SO4, then filtrated and evaporated the solvent under vacuum. The residue was subjected to silica gel column chromatography for purification using EtOAc/petroleum ether (1:6) as eluent to give compound 1-5 and 6a-6f as white foam (80-87% yield). To a stirred 6a-6f (0.4 mmol) and K2CO3 (0.12 mmol) were put into 2.5 mL methanol and 2.5 mL THF for 2 h. The reaction was acidified with 2 N HCl to pH 1. The resultant mixture was extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated aqueous NaCl solution (2×20 mL) and dried over anhydrous Na2SO4, then filtrated and evaporated the solvent under vacuum. The residue was subjected to silica gel column chromatography for purification using EtOAc/petroleum ether (1:3) as eluent to give compound 7a-7f as white foam (60-76% yield).

Reference： [1]Current Patent Assignee: QINGDAO UNIVERSITY - CN112624927, 2021, A Location in patent: Paragraph 0125; 0126; 0127; 0128; 0129; 0130; 0131; 0132
[2]Lv, Mengqi; Wu, Han; Qu, Yaxuan; Wu, Siyi; Wang, Junxia; Wang, Congcong; Luan, Yepeng; Zhang, Zhongyin [Bioorganic Chemistry, 2021, vol. 114]

84
[ 2170-05-0 ]
[ 1996-41-4 ]
tetraphenylantimony 2-chloro-4-fluorophenoxide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	In octane; benzene at 20℃;	Synthesis of tetraphenylantimony 2,5-difluorophenoxide(I). General procedure: A solution of pentaphenylantimony(100 mg, 0.197 mmol) and 2,4-difluorophenol(26 mg, 0.197 mmol) in a benzene-octane (5 : 1vol/vol) mixture was kept at 20°C to the completeremoval of solvents.

Reference： [1]Efremov, A. N.; Sharutin, V. V.; Sharutina, O. K. [Russian Journal of Coordination Chemistry, 2021, vol. 47, # 6, p. 393 - 398][Koord. Khim., 2021, vol. 47, # 6, p. 356 - 362]

85
[ 1996-41-4 ]
[ 1053656-57-7 ]
C₁₈H₁₉ClFN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃;	1.5.1. Tert-butyl4-(2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate. General procedure: To a solution of 2-(trifluoromethyl)phenol (90 mg, 0.56 mmol) in ACN, DBU (113 mg, 0.74 mmol) was added. Next, tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 11 (100 mg, 0.37 mmol) was added and the resulting mixture was stirred at 80 overnight. Upon completion, the mixture was concentrated under vacuum. The crude product was purified by flash chromatography to give the product (111 mg, 76%).
	With 1,8-diazabicyclo[5.4.0]undec-7-ene In acetonitrile at 80℃;	1.5.1. Tert-butyl4-(2-(trifluoromethyl)phenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate. General procedure: To a solution of 2-(trifluoromethyl)phenol (90 mg, 0.56 mmol) in ACN, DBU (113 mg, 0.74 mmol) was added. Next, tert-butyl 4-chloro-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate 11 (100 mg, 0.37 mmol) was added and the resulting mixture was stirred at 80 overnight. Upon completion, the mixture was concentrated under vacuum. The crude product was purified by flash chromatography to give the product (111 mg, 76%).

Reference： [1]Cao, Zhengyu; Chen, Lili; Jiang, Shan; Liu, Mengru; Shen, Jianhua; Tian, Hongtao; Wang, Kai; Zhang, Zhuang [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]
[2]Cao, Zhengyu; Chen, Lili; Jiang, Shan; Liu, Mengru; Shen, Jianhua; Tian, Hongtao; Wang, Kai; Zhang, Zhuang [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]

86
[ 1996-41-4 ]
C₈H₆ClFO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
7 g	With triethylamine In dichloromethane at 0℃;	7.1 (1) Synthesis of compound 2: 6 g of compound 1 and triethylamine (4.97 g, 1.2 eq) were dissolved in dichloromethane in a 100 mL three-neck flask, and acetyl chloride (3.86 g, 1.2 eq) was slowly added at 0 °C. The reaction was monitored by TLC until it was completed. Extracted with water and ethyl acetate, dried over anhydrous sodium sulfate, evaporated, and purified by column chromatography to obtain 7 g of compound 2. GC-MS [M] was 188.

Reference： [1]Current Patent Assignee: TYK MEDICINES - EP3967696, 2022, A1 Location in patent: Paragraph 0126-0127

87
[ 1851-22-5 ]
[ 1996-41-4 ]
3-(2-chloro-4-fluorophenoxy)-2(1H)-pyridinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: Cs₂CO₃ 2: acetic anhydride; triethylamine

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2022/106273, 2022, A1

88
[ 1851-22-5 ]
[ 1996-41-4 ]
[ 944744-93-8 ]

Yield	Reaction Conditions	Operation in experiment
	With Cs₂CO₃	17 Example 18 Preparation of 3-(2-chloro-4-fluorophenoxy)pyridine-N-oxide Example 18 2-Chloro-4-fluorophenol 1.5 g, 3-chloropyridine-N-oxide 1.6 g, cesium carbonate 4.9 g and dimethylformamide 10 mL were mixed at room temperature, and the mixture was heated to 140° C. and stirred for 20 hours. The resulting reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with chloroform 50 mL. The resulting organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 3-(2-chloro-4-fluorophenoxy)pyridine-N-oxide 1.2 g.

Reference： [1]Current Patent Assignee: Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - US2022/106273, 2022, A1

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CAS No. :	1996-41-4	MDL No. :	MFCD00002168
Formula :	C₆H₄ClFO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IGYXYGDEYHNFFT-UHFFFAOYSA-N
M.W :	146.55	Pubchem ID :	74814
Synonyms :

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

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

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

[ CAS No. 1996-41-4 ] {[proInfo.proName]}

Quality Control of [ 1996-41-4 ]

Related Doc. of [ 1996-41-4 ]

Product Details of [ 1996-41-4 ]

Safety of [ 1996-41-4 ]

Application In Synthesis of [ 1996-41-4 ]

[ 1996-41-4 ] Synthesis Path-Upstream 1~12

[ 1996-41-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 1996-41-4 ]

Fluorinated Building Blocks

Aryls

Chlorides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

[ CAS No. 1996-41-4 ] {[proInfo.proName]}

Quality Control of [ 1996-41-4 ]

Related Doc. of [ 1996-41-4 ]

Product Details of [ 1996-41-4 ]

Safety of [ 1996-41-4 ]

Application In Synthesis of [ 1996-41-4 ]

[ 1996-41-4 ] Synthesis Path-Upstream 1~12

[ 1996-41-4 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 1996-41-4 ]

Fluorinated Building Blocks

Aryls

Chlorides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 1996-41-4 ]