Name: 154257-75-7|3-Chloro-2,4-difluorobenzoic acid|98%
Brand: Ambeed
SKU: A101830
Price: 5.0 USD
Availability: InStock
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1
[ 1583-58-0 ]
[ 154257-75-7 ]

Yield	Reaction Conditions	Operation in experiment
60%	With N,N,N,N,-tetramethylethylenediamine; hexachloroethane; sec.-butyllithium In tetrahydrofuran 1.) -90 deg C, 30 min, 2.) -78 deg C;

Reference： [1]Bennetau, Bernard; Mortier, Jacques; Moyroud, Joel; Guesnet, Jean-Luc [Journal of the Chemical Society. Perkin transactions I, 1995, # 10, p. 1265 - 1272]

2
[ 124-38-9 ]
[ 36556-37-3 ]
[ 154257-75-7 ]
[ 163656-30-2 ]

Yield	Reaction Conditions	Operation in experiment
	With n-butyllithium In tetrahydrofuran; hexane -78 deg C, 30 min; -78 to 5 deg C;

Reference： [1]Moyroud, Joel; Guesnet, Jean-Luc; Bennetau, Bernard; Mortier, Jacques [Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141]

3
[ 35227-78-2 ]
[ 154257-75-7 ]
1-(3-chloro-2,4-difluorophenyl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; thionyl chloride; sulfuric acid; water; acetic acid; N,N-dimethyl-formamide 1.) 1 h, reflux, 2.) Et₂O; 20 min, reflux, 3.) 2 h, reflux; Yield given. Multistep reaction;

Reference： [1]Moyroud, Joel; Guesnet, Jean-Luc; Bennetau, Bernard; Mortier, Jacques [Bulletin de la Societe Chimique de France, 1996, vol. 133, # 2, p. 133 - 141]

4
[ 124-38-9 ]
[ 38361-37-4 ]
[ 154257-75-7 ]

Reference： [1]Synthesis,2005,p. 617 - 621

5
[ 154257-75-7 ]
[ 1583-58-0 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide; zinc for 2h; Heating;

Reference： [1]Heiss, Christophe; Rausis, Thierry; Schlosser, Manfred [Synthesis, 2005, # 4, p. 617 - 621]

6
[ 764-93-2 ]
[ 154257-75-7 ]
3-dec-1-ynyl-2,4-difluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium 2'‐(dicyclohexylphosphaneyl)‐2,6‐diisopropyl‐[1,1'‐biphenyl]‐4‐sulfonate; dichloro bis(acetonitrile) palladium(II); caesium carbonate In water; acetonitrile at 100℃; for 12h;

Reference： [1]Anderson, Kevin W.; Buchwald, Stephen L. [Angewandte Chemie - International Edition, 2005, vol. 44, # 38, p. 6173 - 6177]

7
[ 372-18-9 ]
[ 154257-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: BuLi / hexane; tetrahydrofuran / 0.75 h / -75 °C 1.2: 74 percent / 1,1,2-trichloro-1,2,2-trifluoroethane / tetrahydrofuran; hexane / 0.75 h / -75 °C 2.1: BuLi; 2,2,6,6-tetramethylpiperidine / tetrahydrofuran; hexane / 2 h / -75 °C 2.2: 90 percent / tetrahydrofuran; hexane

Reference： [1]Heiss, Christophe; Rausis, Thierry; Schlosser, Manfred [Synthesis, 2005, # 4, p. 617 - 621]

8
[ 1435-44-5 ]
[ 154257-75-7 ]

Reference： [1]Bulletin de la Societe Chimique de France,1996,vol. 133,p. 133 - 141

9
[ 154257-75-7 ]
[ 221221-02-9 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; nitric acid; silver nitrate; acetic acid In water	P.D 5-Bromo-3-chloro-2,4-difluorobenzoic acid PRECURSOR EXAMPLE D 5-Bromo-3-chloro-2,4-difluorobenzoic acid In a mixture of 50 ml of acetic acid, 10 ml of water and 13 ml of nitric acid is dissolved 2 g (0.014 mole) of 3-chloro-2,4-difluorobenzoic acid and 3.64 ml (0.028 mole) of bromine. A solution of 3.52 g (0.0208 mole) of silver nitrate in 10 ml of water is then added slowly. After 14 hours at 20° C., the precipitate is filtered and rinsed with ether. The organic phase is washed with sodium bisulfite, then water and dried. Removal of the solvent affords the desired product.
	With bromine; nitric acid; silver nitrate; acetic acid In water at 20℃; for 14h;	EXAMPLE D EXAMPLE D 5-Bromo-3-chloro-2,4-difluorobenzoic acid EXAMPLE D 5-Bromo-3-chloro-2,4-difluorobenzoic acid In a mixture of 50 ml of acetic acid, 10 ml of water and 13 ml of nitric acid is dissolved 2 g (0.014 mole) of 3-chloro-2,4-difluorobenzoic acid and 3.64 ml (0.028 mole) of bromine.. A solution of 3.52 g (0.0208 mole) of silver nitrate in 10 ml of water is then added slowly.. After 14 hours at 20° C., the precipitate is filtered and rinsed with ether.. The organic phase is washed with sodium bisulfite, then water and dried.. Removal of the solvent affords the desired product.
	With bromine; silver nitrate In water; nitric acid; acetic acid at 20℃; for 14h;	B 5-Bromo-3-chloro-2,4-difluorobenzoic acid To a mixture of acetic acid (100 mL), water (20 mL), and nitric acid (26 [ML)] is added 3-chloro- 2,4-difluorobenzoic acid (4 g, 21 mmol) and bromine (2.2 mL, 43 mmol). A solution of silver nitrate (7.0 g 41 mmol) in water (20 [ML)] is then added slowly. After 14 hours at [20C,] the precipitate is filtered and rinsed with ether. The organic phase is washed with sodium bisulfite, water, brine, and dried over [MGS04.] Removal of the spent dessicant and concentration of the solvent affords the desired product.

Reference： [1]Current Patent Assignee: TAIGEN BIOPHARMACEUTICALS HOLDINGS LTD. - US6329391, 2001, B1
[2]Current Patent Assignee: PROCTER & GAMBLE CO - US6348624, 2002, B1 Location in patent: Page column 12
[3]Current Patent Assignee: PROCTER & GAMBLE CO - WO2004/14893, 2004, A2 Location in patent: Page 77

10
[ 154257-75-7 ]
[ 221221-03-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sulfuric acid; nitric acid for 3h;	52.A Example 52; Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a. Example 52; Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a. 3-Chloro-2,4-difluoro-benzoic acid 1a (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H2SO4 (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3×). The organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.
95%	With sulfuric acid; nitric acid for 3h;	52.A 6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid (2-hydroxy-ethoxy)-amide (10cc); Step A: 3-Chloro-2,4-difluoro-5-nitro-benzoic acid 2a 3-Chloro-2,4-difluoro-benzoic acid 1a (3.00 g, 15.6 mmol) is added to a stirred solution of concentrated H2SO4 (16 mL) and fuming nitric acid (0.85 mL, 20.3 mmol). After 3 hours a precipitate forms. The yellow slurry is poured onto ice water (100 mL). The aqueous mixture is extracted with diethyl ether (3×). The organic extracts are dried (Na2SO4) and concentrated under reduced pressure to give 3.50 g (95%) of clean desired product as a pale yellow solid.
94.6%	With sulfuric acid; nitric acid at 90℃; for 1h;	5-Nitro-2,4-difluoro-3-chlorobenzoic acid (7) A stirred solutionof 2,4-difluoro-3-chlorobenzoic acid (6) (15 g, 77.9 mmol) inconcentrated H2SO4 (98%, 49.5 g) was treated dropwise with themixture of concentrated HNO3 (65%, 9.0 g) and H2SO4 (98%,9.3 g) for 1h at 90 °C. The reaction progress was monitored by TLC(30% ethyl acetate in hexane). After completion of the reaction, thereaction mixture was cooled to room temperature and ice (12 g) wasadded. The precipitate was separated by centrifugation and driedbetween 40-45 °C for 18 h. The crude product was purified by columnchromatography using 20% ethylacetate:hexane as eluent. The solventwas removed under reduced pressure to afford a yellow solid 7 (17.5 g)in 94.6% yield.

94%	With sulfuric acid; nitric acid at 20 - 75℃;	3-Chloro-2,4-difluoro-5-nitrobenzoic acid(10) A solution of concentrated HNO3 (65%, 15.0 g) and H2SO4 (98%, 8.0 g) was added dropwise to 2,4-difluoro-3-chlorobenzoic acid (11) (15.0 g, 78.13 mmol) and concentrated H2SO4 (98%, 32.0 g) at ice-bath temperature. The temperature was kept below 20°C during the addition process. After the addition was complete, the mixture was stirred for 2 h at 70-75°C until TLC (40% ethyl acetate in hexane) showed the starting materials had disappeared. The mixture was cooled to room temperature, poured into ice-water (180 g), stirred for another 1 h at 0-5°C, filtered, and washed with water to afford a gray solid. The crude product was purified by recrystallization from hexane to afford 10 as a white solid (17.38 g, 94%); m.p. 122.3-124.1°C, (123-124°C); 17IR (KBr)/cm-1: 3269, 3055, 1692, 1533, 1322, 891; 1HNMR (300 MHz, DMSO-d6): δ = 13.67 (br s, 1 H, D2O exchangeable), 8.52-8.57 (m, 1 H); 13C NMR (75 MHz, DMSO-d6): δ = 161.9 (d, J = 3.8 Hz), 160.3 (dd, J = 268.4, 2.7 Hz), 154.4 (dd, J = 268.1, 3.7 Hz), 133.9, 127.4, 116.8 (dd, J = 12.1, 4.1 Hz), 113.2 (t, J = 22.5 Hz); HRMS (ESI): m/z [M-H]- calcd for C7HClF2NO4: 235.9562; found: 235.9559.
90%	With sulfuric acid; nitric acid In water at 0 - 20℃; for 1h;	25.1 Example 25; Step 1; 3-Chloro-2,4-difluorobenzoic acid (5.0 g, 26 mmol) was dissolved in concentrated sulfuric acid (15 ml), and fuming nitric acid (1.43 ml, 33.8 mmol) was added dropwise under ice-cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into ice water, and the mixture was stirred under ice-cooling. The precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure at 50° C. overnight to give the object compound (5.54 g, yield 90%).1H NMR (CDCl3 400 MHz) (δ) ppm: 8.78 (1H, dd, J=8.1, 7.2 Hz)
	With sulfuric acid; nitric acid	A 5-Nitro-3-chloro-2,4-difluorobenzoic acid 5-Nitro-3-chloro-2,4-difluorobenzoic acid An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to a mixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuric acid at 0° C. The suspension is then stirred at room temperature for 30 minutes and poured on ice. Filtration affords the desired product.
	With sulfuric acid; nitric acid	A 5-Nitro-3-chloro-2,4-difluorobenzoic acid 5-Nitro-3-chloro-2,4-difluorobenzoic acid An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to a mixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuric acid at 0° C. The Suspension is then stirred at room temperature for 30 minutes and poured on ice. Filtration affords the desired product.
	With sulfuric acid; nitric acid	P.E 5-Nitro-3-chloro-2,4-difluorobenzoic acid PRECURSOR EXAMPLE E 5-Nitro-3-chloro-2,4-difluorobenzoic acid An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to a mixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuric acid at 0° C. The suspension is then stirred at room temperature for 30 minutes and poured on ice. Filtration affords the desired product. The following is an example of the functionalization of a quinolone as depicted in Scheme I above.
	With sulfuric acid; nitric acid at 0 - 20℃; for 0.5h;	EXAMPLE E EXAMPLE E 5-Nitro-3-chloro-2,4-difluorobenzoic acid EXAMPLE E 5-Nitro-3-chloro-2,4-difluorobenzoic acid An amount of 1 g of 3-chloro-2,4-difluorobenzoic acid is added to a mixture of 1 ml of fuming nitric acid and 1.3 ml of sulfuiric acid at 0° C. The suspension is then stirred at room temperature for 30 minutes and poured on ice.. Filtration affords the desired product.
	With nitric acid at 0 - 20℃; for 0.5h;	D 5-Nitro-3-chloro-2, 4-difluorobenzoic acid 3-Chloro-2,4-difluorobenzoic acid (10 g, 52 mmol) is added to a mixture of fuming nitric acid (10 mL) and sulfuric acid (13 mL) at [0C.] The suspension is then stirred at room temperature for 30 minutes and poured onto ice. Filtration of the resulting solid affords the desired product.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US2004/116710, 2004, A1 Location in patent: Page 55
[2]Current Patent Assignee: ASTRAZENECA PLC - US2003/232869, 2003, A1 Location in patent: Page 61
[3]Zhou, Weiyou; Yu, Shuitao; Xia, Zhengjun; Zhang, Mingguang; Lin, Song; Chen, Zaixin [Journal of Chemical Research, 2015, vol. 39, # 5, p. 277 - 278]
[4]Zhang, Mingguang; Bi, Zhongbao; Wang, Yunyun; Zhao, Yuxun; Yang, Yang; Zhu, Yongqiang; Wang, Shifa [Journal of Chemical Research, 2021, vol. 45, # 1-2, p. 166 - 171]
[5]Current Patent Assignee: JAPAN TOBACCO INC - US2008/207618, 2008, A1 Location in patent: Page/Page column 45
[6]Current Patent Assignee: TAIGEN BIOPHARMACEUTICALS HOLDINGS LTD. - US2002/49192, 2002, A1
[7]Current Patent Assignee: TAIGEN BIOPHARMACEUTICALS HOLDINGS LTD. - US6387928, 2002, B1
[8]Current Patent Assignee: TAIGEN BIOPHARMACEUTICALS HOLDINGS LTD. - US6329391, 2001, B1
[9]Current Patent Assignee: PROCTER & GAMBLE CO - US6348624, 2002, B1 Location in patent: Page column 12
[10]Current Patent Assignee: PROCTER & GAMBLE CO - WO2004/14893, 2004, A2 Location in patent: Page 79; 80

11
[ 201849-13-0 ]
C₂ [ No CAS ]
[ 154257-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; In water;	3-Chloro-2,4-difluorobenzoic acid To a solution of 21.5 g (0.0945 mole) of 3-chloro-2.4-difluoro-bromobenzene in 220 ml of ether at -78 C. is added 59 ml of 1.6 M n-butyllithium diluted in 60 ml of ether keeping the temperature below -70 C. After 15 minutes, C2 is bubbled in the reaction keeping the temperature below -70 C. After warming to room temperature, water and hydrochloric acid are added and the organic phase separated, and dried. Removal of the solvent affords the desired product.

Reference： [1]Patent: US2002/49192,2002,A1

12
[ 201849-13-0 ]
[ 154257-75-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; CO2; In water;	3-Chloro-2,4-difluorobenzoic acid To a solution of 21.5 g (0.0945 mole) of <strong>[201849-13-0]3-chloro-2,4-difluoro-bromobenzene</strong> in 220 ml of ether at -78 C. is added 59 ml of 1.6 M n-butyllithium diluted in 60 ml of ether keeping the temperature below -70 C. After 15 minutes, CO2 is bubbled in the reaction keeping the temperature below -70 C. After warming to room temperature, water and hydrochloric acid are added and the organic phase separated, and dried. Removal of the solvent affords the desired product.
	With hydrogenchloride; n-butyllithium; CO2; In water;	3-Chloro-2,4-difluorobenzoic acid To a solution of 21.5 g (0.0945 mole) of <strong>[201849-13-0]3-chloro-2,4-difluoro-bromobenzene</strong> in 220 ml of ether at -78 C. is added 59 ml of 1.6 M n-butyllithium diluted in 60 ml of ether keeping the temperature below -70 C. After 15 minutes, CO2 is bubbled in the reaction keeping the temperature below -70 C. After warming to room temperature, water and hydrochloric acid are added and the organic phase is separated, and dried. Removal of the solvent affords the desired product.

Reference： [1]Patent: US6387928,2002,B1
[2]Patent: US6329391,2001,B1

13
[ 20485-44-3 ]
[ 67-72-1 ]
[ 1583-58-0 ]
[ 154257-75-7 ]

Yield	Reaction Conditions	Operation in experiment
40%	With hydrogenchloride; n-butyllithium In tetrahydrofuran; hexane; water	4.A EXAMPLE 4A EXAMPLE 4A (passing from VIII to VI) 2,4-Difluoro-3-chlorobenzoic acid (compound 47) 294 ml (0.471 mol) of a 1.6N solution of n-butyllithium in hexane are added dropwise and at -70° C. to a solution of 71 ml (0.471 mol) of tetramethylethylenediamine (TMEDA) in 300 ml of dry tetrahydrofuran (THF). 33.8 g (0.214 mol) of 2,4-difluorobenzoic acid, in 100 ml of dry tetrahydrofuran (THF), are added dropwise with stirring, under argon and at -70° C., to the above solution. After stirring for one hour, 111.5 g (0.471 mol) of hexachloroethane in solution in 150 ml of dry THF are run in. After two hours at -70° C., the temperature is allowed to return to 10° C. The reaction mixture is hydrolyzed with 150 ml of ice-cooled water and brought to a pH of approximately 1 by addition of 3N hydrochloric acid. The aqueous phase is extracted with ether, dried over magnesium sulphate and concentrated. The residue is recrystallized from heptane/ether. 16.5 g (yield 40%) of 2,4-difluoro-3-chlorobenzoic acid are obtained. By lithiation of the corresponding acids and then reaction with the appropriate reactant, the following acids were obtained.

Reference： [1]Current Patent Assignee: BAYER AG - US5945382, 1999, A

14
[ 154257-75-7 ]
[ 157373-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	In <i>N</i>-methyl-acetamide; toluene	M.b b b 3-Chloro-2,4-difluoro-benzoyl chloride Thionyl chloride is metered at 70° C. to a suspension of 235 g (1.22 mol) of 3-chloro-2,4-difluorobenzoic acid in 800 ml of toluene and 3 ml of dimethylformamide until a clear solution has formed and evolution of gas is no longer observed. The toluene and excess thionyl chloride are then distilled off, and the product is subsequently obtained by distillation. Yield: 256 g (99% of theory) Boiling point: 108°-110° C./22 mbar

Reference： [1]Current Patent Assignee: BAYER AG - US5457104, 1995, A

15
[ 79-37-8 ]
[ 154257-75-7 ]
[ 157373-00-7 ]

Yield	Reaction Conditions	Operation in experiment
	In dichloromethane; N,N-dimethyl-formamide	H 3-Chloro-2,4-difluorobenzoyl chloride 3-Chloro-2,4-difluorobenzoyl chloride A quantity of 6.0 g of 3-chloro-2,4-difluorobenzoic acid is suspended in 20 ml of dichloromethane. A quantity of 2.99 ml of oxalyl chloride and 2 drops of DMF are then added. The suspension is stirred at room temperature overnight and the desired product is collected after evaporation of the solvent.

Reference： [1]Current Patent Assignee: TAIGEN BIOPHARMACEUTICALS HOLDINGS LTD. - US6329391, 2001, B1

16
[ 154257-75-7 ]
[ 886501-09-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 2,4-difluoro-3-chlorobenzoic acid With dimethylsulfide borane complex In tetrahydrofuran at 0 - 20℃; for 14h; Stage #2: With water; sodium carbonate In tetrahydrofuran at 0℃;	518.1 3-Chloro-2,4-difIuorobenzoic acid (5.37 g, 27.9 mmol) was dissolved in THF (20 mL) and the solution was cooled to 0 deg. Borane methylsulfide (2.0 M in THF, 55.8 ml, 112 mmol) was added. The resulting solution was warmed to rt and stirred for 14 h. The solution was cooled in an ice bath, and 10% aqueous Na2CO3 (7 mL) was added slowly.The material was concentrated on the rotovap to a white solid. The residue was acidified with 3M aqueous HCl (30 mL), diluted with dichloromethane (50 mL), and the mixture was filtered through Celite. The layers were separated, and the organic layer was dried over sodium sulfate and concentrated. The residue was purified through silica gel (500 mL) using 30% EtOAc-hexane, to afford the title compound.

Reference： [1]Current Patent Assignee: AMGEN INC - WO2007/61670, 2007, A1 Location in patent: Page/Page column 178-179

17
[ 154257-75-7 ]
C₇H₂Cl₂F₂O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid at 20 - 200℃; for 0.175h; microwave irradiation;	10.15 Example 10; 3-chloro-5-[fethylamino)sulfonyll-2,4-difluoro-7V-[5-fl-methyl-l-phenylethyl)- l-,3i4-thiadiazol-2-yllbenzamide; Intermediate 15; 3-chloro-5-r(ethylamino)sulfonyll-2,4-difluorobenzoic acid; 3-chloro-2,4-difluorobenzoic acid (200mg) in chlorosulfonic acid (1.5 ml,22.92 mmol) was stirred at room temperature for 30 seconds, then microwaved at 200 degrees for 10 mins. The reaction mixture was cooled to room temperature and dumped on ice (8 g) slowly. Ethyl acetate (50 ml) was added and extracted twice with ethyl acetate (10 mL X2). The combined organic phase was dried over MgSOφ Ethylamine (2.5 ml) in THF (2.0 M) was added, stirred at room temperature for 10 mins and washed with 1 N HCl (10 ml). The organic phase was dried over MgSC>4 and concentrated to give crude 3-chloro-5-[(ethylamino)sulfonyl]-2,4- difluorobenzoic acid., which was carried to the next step without further purification.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/70707, 2008, A1 Location in patent: Page/Page column 37-38

18
[ 201849-13-0 ]
[ 124-38-9 ]
[ 154257-75-7 ]

Yield	Reaction Conditions	Operation in experiment
		3-Chloro-2,4-difluorobenzoic acid To a solution of 21.5 g (0.0945 mole) of 3-chloro-2.4-difluoro-bromobenzene in 220 ml of ether at -78 C. is added 59 ml of 1.6 M n-butyllithium diluted in 60 ml of ether keeping the temperature below -70 C. After 15 minutes, CO2 is bubbled in the reaction keeping the temperature below -70 C. After warming to room temperature, water and hydrochloric acid are added and the organic phase separated, and dried.. Removal of the solvent affords the desired product.
		To a solution of 3-chloro-2.4-difluoro-bromobenzene (21.5 g, 94.5 mmol) in ether (220 [ML)] at- [78C] is added a mixture of n-butyllithium (59 [ML,] [1.] 6 M in hexane, 94.4 mmol) in [ETZO] (60 [ML)] keeping the temperature [BELOW-70C.] After 15 minutes, [C02] is bubbled into the reaction mixture keeping the temperature [BELOW-70C.] After warming to room temperature, water and hydrochloric acid are added and the organic phase is separated, and dried. Removal of the solvent affords the desired product.

Reference： [1]Patent: US6348624,2002,B1 .Location in patent: Page column 10
[2]Patent: WO2004/14893,2004,A2 .Location in patent: Page 79; 80

19
[ 154257-75-7 ]
[ 1000162-62-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With N-iodo-succinimide; sulfuric acid at 0 - 20℃; for 4h;	16.1 Example 16; Step 1; 3-Chloro-2,4-difluorobenzoic acid (25 g, 130 mmol) was dissolved in concentrated sulfuric acid (250 ml), and N-iodosuccinimide (30.6 g, 136 mmol) was portionwise added over 10 min under cooling in an ice bath. After completion of the addition, the mixture was stirred at the same temperature for 30 min and at room temperature for 3.5 hr. The reaction mixture was poured into ice water (about 1000 ml) containing sodium sulfite (14.2 g, 136 mmol) and, after stirring, the precipitated solid was collected by filtration and washed with water. The obtained solid was dried under reduced pressure to give the object compound (40.4 g, yield 98%) as a white solid.1H NMR (DMSO-d6 400 MHz) (δ) ppm: 8.21-8.27 (1H, m)

Reference： [1]Current Patent Assignee: JAPAN TOBACCO INC - US2008/207618, 2008, A1 Location in patent: Page/Page column 38-39

20
[ 154257-75-7 ]
[ 36805-97-7 ]
[ 1354962-79-0 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 80℃; for 48h;	31.E Step E: Preparation of tert-butyl 3-chloro-2,4-difluorobenzoate: A 125 mL, single-neck, round-bottomed flask was charged with di-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol), 3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml). The reaction was heated to 80 °C for 48 hours. After cooling to ambient temperature, the reaction was diluted with saturated NaHCO3 and EtDAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated NaHCO3 and brine, dried, filtered and concentrated to provide the desired product as a gold oil.

Reference： [1]Current Patent Assignee: PFIZER INC - EP2090575, 2009, A1 Location in patent: Page/Page column 66

21
[ 24424-99-5 ]
[ 154257-75-7 ]
[ 1354962-79-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap; triethylamine In dichloromethane at 20℃; for 2h;	154 di-tert-butyldicarbonate (1.64 g, 7.50 mmol) was added to a 10° C. solution of 3-chloro-2,4-difluorobenzoic acid (0.963 g, 5.00 mmol), triethylamine (2.09 mL, 15.0 mmol) and 4-dimethylaminopyridine (0.220 g, 1.80 mmol) in dichloromethane (9.3 mL). The reaction mixture was stirred at room temperature for 2 hours then diluted with water and extracted two times with dichloromethane. The organic phases were combined and the solvent removed in vacuo. The product was purified by silica gel column chromatography eluting with 0-20% hexanes to ethyl acetate to afford the title compound as a colorless oil (0.554 g).1HNMR (400 MHz, DMSO): δ 1.59 (s, 9H), 7.01 (m, 1H), 7.81 (m, 1H).LCMS Rt=1.34 minutes MS m/z 249 [MH]+

Reference： [1]Current Patent Assignee: PFIZER INC - US2012/10207, 2012, A1 Location in patent: Page/Page column 54-55

22
[ 154257-75-7 ]
[ 1354962-78-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: dmap; triethylamine / dichloromethane / 2 h / 20 °C 2: potassium carbonate / dimethyl sulfoxide / 22 h / 20 - 70 °C 3: trifluoroacetic acid / 18 h

Reference： [1]Current Patent Assignee: PFIZER INC - US2012/10207, 2012, A1

23
[ 154257-75-7 ]
[ 1354960-50-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: dmap; triethylamine / dichloromethane / 2 h / 20 °C 2.1: potassium carbonate / dimethyl sulfoxide / 22 h / 20 - 70 °C 3.1: trifluoroacetic acid / 18 h 4.1: N-ethyl-N,N-diisopropylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / dichloromethane / 0.33 h 4.2: 18 h / 20 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2012/10207, 2012, A1

24
[ 154257-75-7 ]
C₁₈H₁₄Cl₂F₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: dmap; triethylamine / dichloromethane / 2 h / 20 °C 2: potassium carbonate / dimethyl sulfoxide / 22 h / 20 - 70 °C

Reference： [1]Current Patent Assignee: PFIZER INC - US2012/10207, 2012, A1

25
[ 154257-75-7 ]
C₂₉H₂₉ClFN₃O₆ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 10 steps 1.1: caesium carbonate / N,N-dimethyl-formamide / 3.5 h / 70 °C 2.1: caesium carbonate; 2-(methylsulfonyl)ethyl alcohol / N,N-dimethyl-formamide / 6.33 h / 60 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 0.5 h / 50 °C 4.1: sodium hydroxide; methanol / water; tetrahydrofuran / 0.75 h / 55 °C 5.1: triethylamine; isobutyl chloroformate / tetrahydrofuran / 0.5 h / Cooling with ice 6.1: triethylamine; methanesulfonyl chloride / tetrahydrofuran / 0.5 h / 20 °C / Cooling with ice 6.2: 0.5 h / Cooling with ice 7.1: caesium carbonate / N,N-dimethyl-formamide / 1 h / 60 °C 8.1: trifluoroacetic acid / chloroform / 0.5 h / 20 °C 9.1: oxalyl dichloride / chloroform; N,N-dimethyl-formamide / 0.5 h / 20 °C / Cooling with ice 9.2: -50 - 20 °C 10.1: triethylamine / methanol; ethanol; tetrahydrofuran / 0.33 h / 20 °C 10.2: 6 h / 80 °C