Name: 455-38-9|3-Fluorobenzoic acid|97%
Brand: Ambeed
SKU: A160641
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1
[ 352-70-5 ]
[ 455-38-9 ]

Yield	Reaction Conditions	Operation in experiment
84.7%	With copper(l) iodide; oxygen; nitric acid; at 160℃; under 11251.1 - 18751.9 Torr; for 4.7h;Autoclave;	General procedure: 2-Chloro-4-(methylsulfonyl)toluene (0.100 mol, 20.50 g), CuI (0.001 mol, 0.19 g) and 25 wt% HNO3 (12.60 g) were added in sequence to a 100 mL high pressure reaction kettle equipped with stirrer and a temperature measuring device. Oxygen gas filled the kettle until the pressure was 1.5 MPa. The reaction solution was heated to 160 C slowly (approximately 0.7 h). The autoclave pressure was raised to 2.5 MPa. The reaction was continued for 4 h with stirring at keeping 160 C (thermostated). At the conclusion of the reaction the pressure declined to 0.8 MPa and was stable (9 mol%NO2 and 5 mol% NO, gaseous species concentration determined by the concentration of NO2- and NO3- after passing the gas through NaOH solution). Thin layer chromatography (TLC) was used to determine reaction conversions in some instances. After the reaction was finished, a 25 wt% NaOH solution (0.200 mol NaOH) was added into the reaction solution and stirring was continued. After reduced pressure filtering, 36 wt% hydrochloric acid was used to adjust the pH of the filtrate to pH 2. The resulting precipitate was collected by filtration. This precipitate was added to MeOH (110 mL) containing 3.00 g of activated carbon. The mixture was heated gently to reflux temperature (60 C). The precipitate dissolved completely. Stirring was continued for 1 h. The mixture was filtered, and allowed to cool at 10 C. After 8 h at -5 C the reaction was filtered. The solid precipitate was dried at 80 C for 5 h to give 19.70 g (0.084 mol) of the product as white crystals. The yield was 84.2% and the product purity was 99.7%.

Reference： [1]Asian Journal of Chemistry,2014,vol. 26,p. 941 - 942
[2]Chemical Papers,2018,vol. 72,p. 51 - 56
[3]Bulletin of the Academy of Sciences of the USSR Division of Chemical Science,1984,vol. 33,p. 2085 - 2091
Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya,1984,p. 2284 - 2291
[4]Chemische Berichte,1936,vol. 69,p. 2799
[5]Recueil des Travaux Chimiques des Pays-Bas,1906,vol. 25,p. 332
[6]Molecular Crystals and Liquid Crystals Science and Technology, Section A: Molecular Crystals and Liquid Crystals,2000,vol. 338,p. 21 - 33

2
[ 455-38-9 ]
[ 320-98-9 ]

Yield	Reaction Conditions	Operation in experiment
97%	With sulfuric acid; nitric acid;	A. 5-Fluoro-2-Nitrobenzoic Acid Fuming nitric acid (6.0 mL) was added to concentrated sulfuric acid (60 mL) at 0 C. and stirred for several minutes. To this solution was added 3-fluorobenzoic acid (5.60 g, 40 mmol) over 30 minutes and the reaction was allowed to continue for another 6 hours in an ice bath. The reaction was poured onto cracked ice, and the precipitate was collected by filtration and dried to give 5-fluoro-2-nitrobenzoic acid (7.20 g, 97%) as a white solid.: m.p. 118-120; 1H NMR (400 MHz, DMSO-d6) delta 7.62 (dt, 1H), 7.71 (dd, 1H), 8.14 (dd, 1H); 13C NMR (100 MHz, DMSO-d6) delta 117.1, 117.4, 119.2, 119.5, 127.6, 127.7, 131.5, 131.6, 144.5, 162.9, 165.4, 165.6.
93%	With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;	a) 5-Fluoro-2-nitrobenzoic acidTo a solution of 3-fluorobenzoic acid (7.9 g, 56 mmol) in cone, sulphuric acid (50 mL) cooled to 0 0C was added fuming nitric acid (4.7 g, 67 mmol) dropwise. After the addition the solution was warmed to room temperature and stirring continued for 1 h. The solution was poured into water (750 mL) and extracted with ethyl acetate (3 x 10OmL). The combined extracts were dried (MgSO4) and concentrated in vacuo to yield 5-fluoro-2- nitrobenzoic acid as a pale yellow solid (9.6 g, 52 mmol, 93%).Data for 5-fluoro-2-nitrobenzoic acid: 1H NMR (300MHz, d6-DMSO): delta 7.66 (m, 1 H), 7.74 (m, 1 H), 8.17 (m, 1 H) ppm.
92%	With sulfuric acid; nitric acid; at 0℃; for 3h;	3-Fluorobenzoic acid (1 g, 7.13 mmol) was dissolved in concentrated H2SO4 (2 ml) by warming slightly above room temperature. The solution was cooled to 0 C. Fuming nitric acid (539 MG, 8.56 mmol) was added slowly to the solution while keeping the temperature below 0C. The solution was stirred at 0C for 3 h. The solution was poured into ice water, the solid formed were filtered, washed by cold water, and dried to yield 1.2 g (92%) of white solids. M. P. 122 C. LH NMR (DMSO-d6) : 7.60 (dt, J= 2.9, 8.5 Hz, 1H), 7.71 (DD, J= 2.9, 8.6 Hz, 1H), 8.13 (dd, J= 4. 8,8. 8 Hz, 1H). EIMS M/Z 186 (M+1).

92%	With nitric acid; In sulfuric acid; at 0 - 20℃; for 3h;	3-Fluorobenzoic acid (1 g, 7.13 mmol) was dissolved in concentrated H2SO4 (2 ml) by warming slightly above room temperature. The solution was cooled to 0 C. Fuming nitric acid (539 mg, 8.56 mmol) was added slowly to the solution while keeping the temperature below 0 C. The solution was stirred at 0 C. for 3 h. The solution was poured into ice water, the solid formed were filtered, washed by cold water, and dried to yield 1.2 g (92%) of white solids. M.P. 122 C. 1H NMR (DMSO-d6): 7.60 (dt, J=2.9, 8.5 Hz, 1H), 7.71 (dd, J=2.9, 8.6 Hz, 1H), 8.13 (dd, J=4.8, 8.8 Hz, 1H). EIMS m/z 186 (M+1).
92%	With nitric acid; In sulfuric acid; at 0 - 20℃; for 3h;Product distribution / selectivity;	3-Fluorobenzoic acid (1 g, 7.13 mmol) was dissolved in concentrated H2SO4 (2 ml) by warming slightly above room temperature. The solution was cooled to 0 C. Fuming nitric acid (539 mg, 8.56 mmol) was added slowly to the solution while keeping the temperature below 0 C. The solution was stirred at 0 C. for 3 h. The solution was poured into ice water, the solid formed were filtered, washed by cold water, and dried to yield 1.2 g (92%) of white solids. M.P. 122 C. 1H NMR (DMSO-d6): 7.60 (dt, J=2.9, 8.5 Hz, 1H), 7.71 (dd, J=2.9, 8.6 Hz, 1H), 8.13 (dd, J=4.8, 8.8 Hz, 1H). EIMS m/z 186 (M+1).
32.1 g (97.2%)	With conc. HNO3; In conc. H2 SO4;	Step 2): Conc. HNO3 (25 ml) was added dropwise to a solution of 3-fluorobenzoic acid (25 g, 178 mmol) in conc. H2 SO4 (190 ml) under cooling in an ice-bath and stirring for 30 mins. After the addition was complete, the mixture was stirred at 0 C. and at room temperature for each 30 mins. The resulting solution was poured into an ice water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4 and evaporated to give 5-fluoro-2-nitrobenzoic acid as yellow powder, 32.1 g (97.2%): mp 141-142 C.

Reference： [1]Patent: US5514676,1996,A
[2]Tetrahedron,2006,vol. 62,p. 7284 - 7292
[3]Patent: WO2006/95014,2006,A1 .Location in patent: Page/Page column 41
[4]Patent: WO2004/74218,2004,A2 .Location in patent: Page 106
[5]Patent: US2008/139551,2008,A1 .Location in patent: Page/Page column 43
[6]Patent: US2008/139551,2008,A1 .Location in patent: Page/Page column 44
[7]Tetrahedron Letters,1988,vol. 29,p. 5105 - 5108
[8]Recueil des Travaux Chimiques des Pays-Bas,1914,vol. 33,p. 336
[9]Patent: US5872115,1999,A

3
[ 455-38-9 ]
[ 1711-07-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: meta-fluorobenzoic acid With N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.0833333h; Stage #2: With oxalyl dichloride In dichloromethane at 20℃; for 12h;
87%	With thionyl chloride Heating;
65%	With thionyl chloride for 5h; Reflux;

	With phosphorus(V) chloride
	With thionyl chloride Heating;
	With thionyl chloride
	With thionyl chloride In dichloromethane for 5h; Heating;
	With thionyl chloride for 0.5h; Heating;
	With thionyl chloride for 2h; Heating;
	With thionyl chloride for 12h; Heating;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
	With oxalyl dichloride; N-ethyl-N,N-diisopropylamine; N,N-dimethyl-formamide In dichloromethane; N,N-dimethyl-formamide at 20℃; for 1h;
	With oxalyl dichloride; N,N-dimethyl-formamide In 1,2-dichloro-ethane at 20℃; for 2h;
	With thionyl chloride In toluene	1 Preparation of 3-Fluorobenzoyl Chloride EXAMPLE 1 STR5 Preparation of 3-Fluorobenzoyl Chloride A 100-mL, three-necked, round-bottomed flask, equipped with a reflux condenser, thermometer, nitrogen bubbler and magnetic stirring bar is charged sequentially with thionyl chloride (52.7 mmol, 6.28 g), toluene (40 mL), 3-fluorobenzoic acid (7.02 g, 50.1 mmol) and a catalytic amount of dimethylaminopyridine (DMAP). The funnel used for addition of the above reagents is rinsed with toluene (10 mL) which is also added to the reaction mixture. The reaction mixture is slowly heated to 60°-70° C. with stirring. The progress of the reaction is followed by gas chromatography wherein several drops of the reaction mixture are added to methanol to produce the methyl ester of the acid chloride. The methanol solution is allowed to stand for about 5 minutes at room temperature prior to GC analysis (GC analysis utilizes a Hewlett Packard 5890 Series II gas chromatograph on a 30 m*0.25 mm DB-5 capillary column; 60° C. for 5 minutes to 275° C. at a rate of 20° C./minute.; Rt for methyl ester of 3-fluorobenzoic acid is 10.3 minutes, Rt for 3-fluorobenzoic acid is 11.4 minutes). After approximately 4-6 hours the reaction is cooled to room temperature when the ratio of methyl ester to acid is greater than 95 to 5. The resulting title compound in solution can be used directly in the following designated reactions.
	With thionyl chloride for 8h; Heating;
	With thionyl chloride at 70 - 80℃; for 1h;
	With thionyl chloride
	With thionyl chloride In N,N-dimethyl-formamide
	With oxalyl dichloride; N,N-dimethyl-formamide In tetrahydrofuran for 1h; Inert atmosphere;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃;
	With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 1h; Inert atmosphere;
	With thionyl chloride Reflux;
	With thionyl chloride for 2h; Reflux;
	With thionyl chloride at 20℃;
	With bis(trichloromethyl) carbonate; N,N-dimethyl-formamide In dichloromethane at 40℃; for 3h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 5h; Reflux;
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide at 60℃; for 3h; Inert atmosphere; Schlenk technique;
	With thionyl chloride at 60 - 80℃;
	With thionyl chloride for 5h; Reflux;	General procedure: Compounds 6a-t were synthesized from substituted benzoic acid via six steps according to the literature method as described. Various substituted benzoic acids 1a-t were treated with SOCl2 to give compounds 2a-t, which were reacted with CH3OH and EtN3 in CH2Cl2 at 0 to afford compounds 3a-t. Compounds 4a-t were prepared by the reaction of compounds 3a-t, hydrazine hydrate in CH3OH under reflux condition about 5h. Subsequently, compounds 5a-t were obtained by reaction of compounds 4a-t with CS2 and KOH in CH3OH. Compounds 6a-t were obtained by the cyclization reaction of compounds 5a-t in the presence of HCl at 0-5°C.
	With thionyl chloride; N,N-dimethyl-formamide In toluene at 80℃; for 3h;
	With thionyl chloride at 80℃; for 4h;
	With thionyl chloride
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 3h; Inert atmosphere;
	With thionyl chloride for 2h; Reflux;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 12h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 3h; Inert atmosphere;
	With thionyl chloride In dichloromethane; toluene at 110℃; for 5h;	12 4.2. General procedure for the synthesis of piperazines 2, 4a-k and 10a-f General procedure: 4.2.1. Method i Benzoic acid (1 mmol) was reacted with a solution of thionyl chloride in CH2Cl2 (1 M, 6 mL) in refluxing toluene (3 mL) for 5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The obtained benzoyl chloride was dissolved in dry CH2Cl2 (5 mL), and the resultant solution was cooled to 0 C. To this solution, TEA (4.4 mmol, 0.444 g), 1-(9H-fluoren-9-yl)-piperazine (3) (1.1 mmol, 0.275 g) or 1-(diphenylmethyl)-piperazine (9) (1.1 mmol, 0.277 g) in dry CH2Cl2 (5 mL) was added dropwise. After the addition, the reaction mixture was stirred for 16 h at room temperature. Subsequently, the solution was washed with aqueous HCl (10%, v/v, 3 15 mL), a saturated NaHCO3 solution(1 15 mL), and aqueous NaCl (5%, w/v, 1 15 mL). Finally, the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent was evaporated under reduce pressure. When necessary, the products were purified using silica gel chromatography with CH2Cl2/methanol (20:5, v/v) as the mobile phase. This protocol was used for the synthesis of 9H-fluoren-9-yl-piperazines 2, 4a, 4c-e, 4h-i and 1-(diphenylmethyl)-piperazines 10a-b and 10d-e. The crystal used for the data collection was obtained by recrystallization of compound 4d from hexane followed by slow evaporation at room temperature.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere;
	With thionyl chloride
	With thionyl chloride In dichloromethane; toluene for 5h; Reflux;	4.2.1. Method i General procedure: Benzoic acid (1 mmol) was reacted with a solution of thionyl chloride in CH2Cl2 (1 M, 6 mL) in refluxing toluene (3 mL) for 5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The obtained benzoyl chloride was dissolved in dry CH2Cl2 (5 mL), and the resultant solution was cooled to 0 °C. To this solution, TEA (4.4 mmol, 0.444 g), 1-(9H-fluoren-9-yl)-piperazine (3) (1.1 mmol, 0.275 g) or 1-(diphenylmethyl)-piperazine (9) (1.1 mmol, 0.277 g) in dry CH2Cl2 (5 mL) was added dropwise. After the addition, the reaction mixture was stirred for 16 h at room temperature. Subsequently, the solution was washed with aqueous HCl (10%, v/v, 3 x 15 mL), a saturated NaHCO3 solution (1 x 15 mL), and aqueous NaCl (5%, w/v, 1 x 15 mL). Finally, the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent was evaporated under reduce pressure. When necessary, the products were purified using silica gel chromatography with CH2Cl2/methanol (20:5, v/v) as the mobile phase. This protocol was used for the synthesis of 9H-fluoren-9-yl-piperazines 2, 4a, 4c-e, 4h-i and 1-(diphenylmethyl)-piperazines 10a-b and 10d-e. The crystal used for the data collection was obtained by recrystallization of compound 4d from hexane followed by slow evaporation at room temperature.
	With thionyl chloride at 65℃; for 1h;	35.A Part A. N-(4-bromopyridin-2-yl)-3 -fluorobenzamide A solution of 3-fluorobenzoic acid (100 mg, 0.714 mmol) in sulfurous dichloride (255 mg, 2.141 mmol) was heated at 65 °C for 1 h, then concentrated under reduced pressure in a N2 atmosphere to afford 3-fluorobenzoyl chloride as an oil, which was kept under N2 until needed. In separate single neck round bottom flask 4-bromopyridin-2-amine (149 mg, 0.864 mmol) was taken up in DCM (4 mL). To this stirred solution at room temperature, was added DIEA (0.125 mL, 0.714 mmol). The solution was then cooled to 0 °C and a solution of the 3-fluorobenzoyl chloride in DCM (1 mL) was added dropwise. The reaction mixture was then allowed to stir at room temperature for 7 h. The reaction mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (3 x 3 mL). The combined organic layers were washed with water (10 mL), dried over Na2S04 and evaporated under reduced pressure to afford N-(3-bromophenyl)-3 -fluorobenzamide ( 30 mg, 0.078 mmol, 11% yield). The crude product was taken into the next step without purification. LCMS (ESI) m/e 295.0[(M+H)+, calcd for Ci2H9BrFN20, 294.98]; LC/MS retention time (method E): tR = 1.94 min.
	With thionyl chloride In toluene for 3h; Reflux;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 5h; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide In N,N-dimethyl-formamide; toluene at 80℃; for 3h;
	With thionyl chloride for 2h; Reflux;	2.1.1. Synthesis of substituted benzohydrazide. (4a-4g) General procedure: Substituted benzoic acid (1.0 mmol) was dissolved in thionylchloride and refluxed for 2 h, then the solvent was removed underreduced pressure to obtain the white solid. The white solid in methanol was added concentrated sulfuric acid (1 mL) and themixture was refluxed for 4 h, the solvent was removed to obtaincrude solid. The crude solid was extracted with ethyl acetate andwater. The solvents were evaporated to afford the pure product.Finally, the pure product was dissolved in ethanol, and the hydrazinehydrate was added. The mixture was refluxed for 9 h, and thesolvent was removed
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 1h; Reflux;
	With thionyl chloride at 60℃; for 6h; Inert atmosphere;
	With oxalyl dichloride
	With thionyl chloride In toluene for 3h; Reflux;	General synthetic procedure for compounds 3a-3t General procedure: A solution of thionyl chloride (25 mmol) was addeddropwisely to 1 (20 mmol) in toluene(15 mL). The mixture was heated to reflux for 3 h. Excess thionyl chloride wasremoved in vacuo. The remained mixture was added dropwise to ammonia waterbelow 10 °C, then stirred at 10 °C for 1 h. The intermediate 3 was obtained as white solid by filtration.
	With thionyl chloride; N,N-dimethyl-formamide for 5h; Reflux;
	With thionyl chloride for 4h; Reflux;	3 3-fluorobenzoyl chloride (M3) synthesis To 5mL thionyl chloride was added slowly 3-fluorobenzoic acid in a flask, set a reflux condenser and drying tube on the upper end of the flask. Gradually warmed at reflux for 4 hours, cooled, residual thionyl chloride is removed by pressure distillation, the residual liquid which is 3-pyridinecarbonyl chloride.
	With thionyl chloride for 2h; Reflux;
	With thionyl chloride In toluene for 2h; Reflux;	4.1. General procedure for morpholine amides General procedure: To the carboxylic acid (4.98 mmol), PhMe (25 mL) was added followed by SOCl2 (1.1 mL, 14.92 mmol). The suspension was heated to reflux for 2 h before the solvent was removed under reduced pressure. The mixture was dissolved in dry DCM (10 mL) before K2CO3 (1.5 g, 10.85 mmol) was added and morpholine amine (1.5 mL) was added drop wise at 0 °C. The cooling bath was removed after 30 min and stirring was continued at rt overnight. The mixture was filtered, the solvent evaporated and the crude material was purified by column chromatography.
	With thionyl chloride
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0℃; for 5h; Inert atmosphere; Schlenk technique;
	With trichlorophosphate In 1,2-dichloro-ethane for 3h; Reflux;	General procedure: Aralkanoic acid chlorides 2 were synthesized by the reaction ofaralkanoic acids 1 (1 mmol) in the presence of 1,2edichloroethane(12 mL) solvent and phosphorous oxychloride (0.4 mL) as chlorinatingagent under reflux for 3 h. Then, the resulting solution wascooled to room temperature, and the solvent was removed underreduced pressure to afford aralkanoic acid chlorides 2, which wasdirectly used in the next step without further purification. Aralkanoicacid chlorides 2 was dissolved in acetonitrile (80 mL), addeddrop wise to a solution containing hydrazine hydrate (1 mmol), TEA(0.5 mL) and acetonitrile (20 mL) and allowed to reflux for 3 h withmonitoring by TLC. After consumption of the starting material, thereaction mixture was cooled to room temperature. Evaporation ofthe solvent under reduced pressure yielded crude substituted aromaticacid hydrazides 3 as a white solid on cooling, which waspurified by column chromatography and crystallized on methanol.
	With thionyl chloride at 80℃;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃; for 5h; Inert atmosphere; Schlenk technique;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h;	General Procedure for the Preparation of Starting Materials General procedure: To a 100 mL three-necked flask, acid (20 mmol), DMF (3 drops), and anhydrous CH2Cl2 (30 mL)were added. Oxalyl chloride (40 mmol, 2 equiv) was added dropwise at 0°C resulting in vigorousbubbling. The mixture was stirred for 3 h at room temperature, and the solvent was then removedin vacuo. The resulting acid chloride was used immediately without further purification. The acidcholoride was then re-dissolved in 25 mL dry CH2Cl2 and added dropwise to a 30 mL dry CH2Cl2solution containing amine (24 mmol) and Et3N (30 mmol) at 0 °C. After stirring for 6h at roomtemperature, the resulting mixture was washed with brine, dried over Na2SO4, filtered andconcentrated under reduced pressure. The residue was purified by flash chromatography to give thedesired product.
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane at 55℃; for 5h;
	With thionyl chloride In 1,2-dimethoxyethane at 50℃; for 18h;	3-Fluorobenzoic acid (54.4 g, 0.39 mol) was suspended in DME (150 mL), thionyl chloride (98.4g, 0.83 mol, 2.1 eq) and DMF (1 mL). The reaction mixture was stirred at 50 °C for 18 h. The reaction was quenched with ammonia solution (35% aq., 500 g) and the volatile components were removed by evaporation. The crude solid was suspended in ethylacetate and heated under reflux for 2 h with vigorous agitation. The mixture was filtered hot to remove the inorganics and the volume was reduced to approximately 150 mL. Hexane (150 mL) was added and the resulting precipitate was collected by filtration and washed with ethylacetate :hexane (1:4) (46.4 g, 86%): m.p. 133-134 °C.
	With thionyl chloride for 2h; Reflux;
	Stage #1: meta-fluorobenzoic acid With N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.0833333h; Stage #2: With phosgene In dichloromethane at 20℃; for 12h;
	With thionyl chloride at 85℃; for 3h; Inert atmosphere;
	With thionyl chloride; N,N-dimethyl-formamide In toluene at 70℃; Inert atmosphere;	Preparation of Aromatic Anhydrides; General Procedure General procedure: Step 1 In a three-necked 100 mL flask under N2-atmosphere, the corresponding benzoic acid (32 mmol) was suspended in anhydrous toluene (21 mL, 1.5 M). A few drops of anhydrous DMF (126 μL, 1.6 mmol, 0.05 equiv) and SOCl2 (3.0 mL, 41.5 mmol, 1.3 equiv) were added atr.t. sequentially. The mixture was heated to 70 °C and stirred at this temperature for 1 hour, then cooled to r.t. and the excess SOCl2 was purged from the system by flushing with N2 for 15 min. The solution of the benzoyl chloride was used without purification in the next step. Step 2 In a three-necked flask under N2-atmosphere, the corresponding benzoic acid (32 mmol, 1.0 equiv) was suspended in anhydrous toluene (21 mL, 1.5 M). Anhydrous pyridine (3.1 mL, 38.3 mmol, 1.2 equiv) was added to the mixture and the resulting solution was cooled to0 °C. A solution of the corresponding benzoyl chloride from Step 1 was added at such rate that the temperature was kept under 20 °C, while a white precipitate formed. The resulting suspension was heated at reflux for 2 h then cooled to r.t. The precipitate (Pyr·HCl) was filtered, washed with toluene, and the filtrate was evaporated. The residue was dissolved in CH2Cl2 (100 mL), washed with 10% HCl (10 mL) then washed with cc. NaHCO3 (3 × 10 mL) and brine (10 mL). The organic layer was dried over Na2SO4, filtered and evaporated to dryness. Pure anhydrides were obtained in 91-98% yield; NMR data were consistent with the reported values.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 5h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 2h; Reflux;
	With thionyl chloride Reflux;	1.5 Synthesis of intermediate 6 General procedure: The corresponding acid compound 5 (10 mmol) was completely dissolved in 30 mL of SOCl2. The reaction was stirred at reflux temperature for 12 h. The mixture was evaporated under vacuum, the residue was dissolved in 10 mL of dry DCM and used in next step without purification.
	With oxalyl dichloride
	With thionyl chloride In Carbon tetrachloride; N,N-dimethyl-formamide for 5h; Reflux;	In the next stage to p-fluorobenzoic acid (4.96 g) in CCL4 (25ml) fresh SOCl2 (4ml) and DMFA (0.05 ml) in CCl4 (25 ml)were added. The mixture was refluxed during 5 hoursuntil the end of release of gaseous products. The solvent and excess of SOCl2 were removed in vacuum. Obtained oil (5.6 g ,97 % of theoretical yield) , without additionalpurification, was dissolved in cold DCM (20 mL). This solution was added dropwise to cold suspension of AlCl3 (5 g) and thioanisole (4.38 g ,35 mmol) in of DCM (30 mL).The mixture was refluxed during 4 hours until the end of emission of HCl. Obtained product was carefully hydrolyzed by 5 % HCl, then extracted by CH2Cl2, (330 mL) anddried over Na2SO4. After removing of the solvent the residue was recrystallized from n-hexane to purify the product from traces of thioanisole. Yield: 6.48 g (75 %), colorlesscrystals, mp. 107-108 °C.
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2h;
	With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide
	Stage #1: meta-fluorobenzoic acid With N,N-dimethyl-formamide In dichloromethane at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: With oxalyl dichloride In dichloromethane Inert atmosphere;
	With thionyl chloride for 24h; Inert atmosphere; Reflux;	4.1. General Procedures for The synthesis of Benzoyl Chloride and 2-Phenylacetyl Chloride Derivatives (1-12) General procedure: Benzoic acid derivatives (1-6) and 2-phenylacetic acid derivatives (7-12) (6-10 mmol, 0.5 g) werereacted with thionyl chloride (68.9 mmol, 5 mL) under nitrogen atmosphere for 24 h to aord thecorresponding benzoyl chloride or 2-phenylacetyl chloride derivatives. The mixture was maintainedfor 15 min. at room temperature and then concentrated under vacuum to give the corresponding crudearoyl chloride derivatives, which were immediately used in the next reaction.
	With oxalyl dichloride; N,N-dimethyl-formamide In toluene at 20℃; for 2h;
	With oxalyl dichloride at 0 - 20℃;	2.1 General procedure for the preparation of benzamides 1a-1ac ^1-2 General procedure: Acid chloride (20 mol) was prepared from the corresponding carboxylic acid and oxalyl chloride. Acid chloride was added to a solution of 2,3,4,5,6-pentafluoroaniline (22 mmol) in toluene (50 mL). The reaction mixture was stirred for 24 h under reflux. After cooling to room temperature, the precipitate was filtered off, washed with water, and recrystallized from toluene or ethyl acetate/hexane to give the products 1 (the crude mixture was sometimes purified by flash chromatography if necessary).
	With oxalyl dichloride
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 1h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 4h; Reflux;	General procedure: The synthesis method of compound 3 was as follows [33]: To a coldsolution of a catalytic amount of DMF in anhydrous benzoic acid(1.0 mmol, 1 equiv) in anhydrous DCM (25 mL) was added thionyl chloride (1.5 mmol, 1.5 equiv) dropwise. The reaction mixture wasrefluxed for 4 h. The solvent was removed under reduced pressure. Theacid chloride residue was added to a solution of thiosemicarbazone(1.5 mmol, 1.5 equiv) in pyridine (25 mL), and then stirred at roomtemperature for 16 h. Pyridine was removed under reduced pressure.The crude residue was dissolved in an aqueous solution (25 mL), sodiumhydroxide (1.5 mmol, 1.5 equiv) was added, and the resultingmixture was reacted at reflux at 100 °C for 3 h. After the reaction wascompleted, the mixture was cooled to room temperature and neutralizedwith 10% HCl. The precipitate was filtered, washed with water,and dried to obtain the compound
	With oxalyl dichloride In dichloromethane
	With thionyl chloride In dichloromethane; N,N-dimethyl-formamide for 3h; Reflux; Further stages;	9.1 20(S)-Ginsengdiol-12β-hydroxy-3β-yl-[5-[3-fluoro-phenyl]-4H-[1,2,4]triazol-3-yl ]-Thioacetate (B6). Step 1: Add 3-fluorobenzoic acid to 15 mL of dry dichloromethane solution, add excess thionyl chloride, and add 5 drops of dimethylformamide (DMF). The reaction was refluxed for 3h, and the solvent was removed under reduced pressure. Add 20mL pyridine solution to dissolve, add thiosemicarbazide to it, react at room temperature for 17h, remove the pyridine solution under reduced pressure to obtain crude product, add sodium hydroxide aqueous solution, reflux reaction at 100 for 3h, cool, adjust pH value, filter to precipitate precipitate, wash and dry , To obtain the triazole intermediate.
	With thionyl chloride for 5h; Reflux;
	With phosgene In dichloromethane Reflux;
	With thionyl chloride for 2h; Reflux;	Preparation of the title compounds 4a-4n General procedure: The aromatic acid (1.2 mmol) was dissolved in SOCl2 (4 mL)and refluxed for about 2 h. SOCl2 was distilled off in vacuoto obtain the intermediates 3a-3n.[18] A solution of 3a-3n in CH2Cl2 (5 mL) was added dropwise to a mixture of 2(1.0 mmol) and triethyl amine (1.0 mmol) in CH2Cl2(15 mL). After the reaction was completed (monitored byTLC), the mixture was diluted with water, the organic layer was dried over anhydrous sodium sulfate, filtered, distilledoff in vacuo, and petroleum ether was added to residue. Thecrude products were recrystallized with isopropanol toafford the target compounds 4a-4n. The SupplementalMaterials contains sample 1H and 13C NMR and high resolutionmass spectra of the products 4 (Supplementary material Figures S1-S46).
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 1h; Inert atmosphere;
	With thionyl chloride In toluene at 80℃; for 3h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; Inert atmosphere;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere;
	With oxalyl dichloride In dichloromethane at 0 - 20℃; for 5h; Inert atmosphere;
	With thionyl chloride for 2h; Reflux;	General procedure for preparation of the target compounds 4a-4o General procedure: Substituted benzoic acid (2.40 mmol) was added in SOCl2 (4 mL) and refuxed for about 2 h. SOCl2 was distilled of under vacuum to obtain intermediates 3. Then, a solution of intermediate 3 in CH2Cl2 (5 mL) was added dropwise to a mixture of the intermediate 2 (0.946 g, 2.00 mmol) and trimethylamine (TEA) (0.202 g, 2.00 mmol) in 15 mL CH2Cl2. After the reaction was completed (monitored by TLC), the mixture was diluted with water (20 mL). After that, the organic layer was dried over anhydrous sodium sulfate and fltered, and the fltrates were distilled of under vacuum. The crude products were recrystallized with isopropanol to afford the target compounds 4a-4o.
	With thionyl chloride; N,N-dimethyl-formamide In tetrahydrofuran at 65℃; for 1h;	3.2 (2) Synthesis of 2-(3-fluoro)benzamido-4,5,6,7-tetrahydrobenzo(b)thiophene-3-carboxylic acid ethyl ester derivatives Weigh 1.5 eq of 3-fluorobenzoic acid, add tetrahydrofuran, 10 eq of thionyl chloride and 1 drop of N,N-dimethylformamide, and stir at room temperature. The solution is colorless and transparent. The temperature was raised to 65°C, and the mixture was stirred for 1 hour until the reaction was completed as detected by TLC. The reaction solution was concentrated under reduced pressure to obtain the benzoyl chloride derivative, which was used for later use.
	With thionyl chloride at 90℃;	2.10. General Procedure for the Preparation of Compoundsb General procedure: A selected arylcarboxylic acid (10 mmol) was solved inSOCl2 (50 mL), which was heated to 90 °C and stirred for 1-2 h until the reaction was completed. The crude product (a1-a30) was furnished after the removal of SOCl2 under reducedpressure [64-65]. To the resulting residue, 50 mL of toluenewas added and stirred for 30 min at room temperature. Thiourea(40 mmol) was subsequently added, and the reactionsolution was heated to 100 °C for 1.5-2 h [66, 67]. At the endof the reaction (monitored by TLC), the solvent was removedunder vacuum, and excess saturated NaHCO3 solutionwas added. The resulted mixture was extracted withethyl acetate, dried over MgSO4, filtered, and concentratedunder vacuum. The residue was purified by a silica gel columnusing ethyl acetate and petroleum ether as eluent to affordthe desired compound (b1-b30) as a white powder
	With thionyl chloride; N,N-dimethyl-formamide In dichloromethane for 5h; Inert atmosphere; Schlenk technique; Reflux;
	With thionyl chloride at 90℃;	2.10. General Procedure for the Preparation of Compoundsb General procedure: A selected arylcarboxylic acid (10 mmol) was solved inSOCl2 (50 mL), which was heated to 90 °C and stirred for 1-2 h until the reaction was completed. The crude product (a1-a30) was furnished after the removal of SOCl2 under reducedpressure [64-65]. To the resulting residue, 50 mL of toluenewas added and stirred for 30 min at room temperature. Thiourea(40 mmol) was subsequently added, and the reactionsolution was heated to 100 °C for 1.5-2 h [66, 67]. At the endof the reaction (monitored by TLC), the solvent was removedunder vacuum, and excess saturated NaHCO3 solutionwas added. The resulted mixture was extracted withethyl acetate, dried over MgSO4, filtered, and concentratedunder vacuum. The residue was purified by a silica gel columnusing ethyl acetate and petroleum ether as eluent to affordthe desired compound (b1-b30) as a white powder
	With thionyl chloride Reflux;
	With N,N-dimethyl-formamide In tetrahydrofuran
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 3h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 0 - 20℃; for 2.58333h;	A dried round-bottom flask was charged with the acid (4.5 mmol), DCM (15 mL), and 2 drops of DMF. Then, oxalyl chloride (0.60 mL, 6.9 mmol) was added dropwise within 5 min at 0 °C. The resulting mixture was stirred at rt. for 3.5 h and concentrated underreduced pressure. The residue was dissolved in EA (40 mL) and K2CO3 (1.24 g, 9.0mmol), MeONH2 .HCl (458 mg, 5.4 mmol) and water (20 mL) were added sequentially.The resulting mixture was stirred for 20 h at rt. and extracted with EA (50 mL × 2). Theorganic layer was washed with saturated aqueous NaHCO3 (15 mL × 2), brine (15 mL× 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure.The crude product was recrystallized (EA) to afford the product. In the case of oil, thecrude product was purified by silica gel column chromatography, using EA/PE as theeluent

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4
[ 186581-53-3 ]
[ 455-38-9 ]
[ 455-68-5 ]

Yield	Reaction Conditions	Operation in experiment
		REFERENCE EXAMPLE 67 Methyl m-fluorobenzoate (67) STR86 To an ice-cooled and stirred solution of m-fluorobenzoic acid (8.0 g, 57 mmol) in 50 ml of ether was added an excess solution of diazomethane in ether. After concentration, the residue was distilled under reduced pressure to give a colorless transparent oil of methyl m-fluorobenzoate (7.4 g, 48.1 mmol, yield 84.4percent, b.p. 80°-82° C./16 mmHg), which was assigned the structure by the following data: IR(Liquid film method): 2990, 2950, 2840, 1725, 1610, 1590, 1425, 1330, 1295, 1260, 1165, 1130, 1085, 1070, 970, 915, 840, 815, 770, 750, 690, 660 cm-1. NMR(90 MHz, CDCl3, delta): 3.92(3H, s), 7.1-7.9(4H, m).

Reference： [1]Magnetic Resonance in Chemistry,1989,vol. 27,p. 585 - 591
[2]Patent: US4775692,1988,A
[3]Organic and Biomolecular Chemistry,2017,vol. 15,p. 5033 - 5040

5
[ 455-37-8 ]
[ 455-38-9 ]

Reference： [1]Journal of Organic Chemistry,1989,vol. 54,p. 4443 - 4448

6
[ 456-48-4 ]
[ 455-38-9 ]

Yield	Reaction Conditions	Operation in experiment
98.9%	With potassium ferrate(VI) In neat (no solvent) for 2h; Milling;
98%	With oxygen; copper(II) acetate monohydrate; cobalt(II) diacetate tetrahydrate In water at 70℃; for 12h;	9 Example 9 Preparation of m-fluorobenzoic acid by oxidation of m-fluorobenzaldehyde Under atmospheric pressure oxygen, water (2 mL), m-fluorobenzaldehyde (1 mmol), Cu(OAc)2·H2O (0.003 mmol, 0.3% mole fraction) and Co(OAc)2·4H2O (0.003mmol, 0.3% mole fraction) was added to a 15mL glass reaction tube, and an oxygen balloon was connected.The reaction tube was placed in an oil bath heated to 70°C in advance to stir the reaction for 12 hours. After the reaction was completed, the temperature was lowered, the crude product solid was centrifuged, and then ultrasonically washed with 3 mL of water, centrifuged, and dried to constant weight to obtain the target product. The separation yield was 98 %.
95%	With oxygen; Langlois reagent In acetonitrile at 25℃; for 12h; Irradiation; Green chemistry;

94%	With dihydrogen peroxide In tetrahydrofuran for 8h; Heating;
90%	With tert.-butylhydroperoxide; potassium <i>tert</i>-butylate In water at 60℃; for 5h;	4.1.1 Typical experimental procedure for oxidation of aldehydes to carboxylic acids (2a-q) General procedure: In a 25mL round-bottom flask, t-BuOK (0.5mmol) was dissolved in water (1mL), and an aldehyde (0.5mmol) was added. Subsequently, aq 70% TBHP (1mmol) was slowly added to this flask. The resulting slurry was stirred at 60°C or (optional) 25°C for 5h or 40h. After completion of reaction this slurry was cooled to room temperature. The slurry was then acidified with 2M hydrochloric acid until the aqueous layer was strongly acidic by pH paper. This on simple filtration resulted in pure carboxylic acids.
86%	With sodium perborate In acetic acid at 45 - 50℃;
71%	With [2,2]bipyridinyl; water; oxygen; sodium hydroxide at 50℃; for 10h; Sealed tube;	3.4. General Procedure for the Oxidation of Aldehyde 1 General procedure: Aldehyde 1 (0.2 mmol), Ag/C3N4 (10 mol%), NaOH (1 equiv), H2O (1 mL) were added into a 10 mL sealed tube under O2 (1 atm). The mixture was stirred at 50o C for 10 h. Then the reaction was stopped and 1M dilute hydrochloric acid was added to adjust the pH value to 3. The mixture was extracted with ethyl acetate (3 × 3 mL). The combined organic phase was dried with Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography (5:1 hexanes and ethyl acetate).
59%
57%	With potassium permanganate; disodium hydrogenphosphate In methanol; water at 20℃; for 0.5h;	17.1 Step 1 To a purple solution of KMn04 (4.0 g, 25.0 mmol) and Na2HP04 (6.7 g, 25 mmol) in H20 (100 mL) was added a solution of 3-fluorobenzaldehyde (3.1 g, 25 mmol) in MeOH (100 mL) in a dropwise manner at rt. The reaction mixture was stirred for about 30 min until a brown suspension formed. The resulting suspension was filtered through a pad of Celite, and the filtrate was concentrated via rotovap and was diluted with H20 (100 mL). The diluted filtrate was acidified with IN HC1 until pH reached 3-4. The resulting precipitate was filtered and dried in vacuo at 76 °C overnight to give 3-fluorobenzoic acid (2.0 g, 57%) as a white solid.
	With perchloric acid; N-bromobenzamide; water In acetic acid at 19.9℃; ΔH^, ΔS^, other temp.;
	With mercury(I) acetate; sulfuric acid; bromate In water; acetic acid at 35℃; investigation of effect of substrate concentration, <H(+)>, solvent composition, mercuric acetate, temperature; ΔH(excit), ΔS(excit), ΔG(excit);
	With perchloric acid; mercury(II) diacetate; N-bromoacetamide In acetic acid at 24.9℃; other temperatures, ΔG(excit.), ΔH(excit.), ΔS(excit.);
	With perchloric acid; bis(2,2'-bipyridyl) copper(II) permanganate In water; acetic acid at 14.9℃; other temperatures; ΔH, ΔS, ΔG; kinetics and mechanism of the oxidation of monosubstituted benzaldehydes by bis(2,2'-bipyridyl)copper(II) permanganate (BBCP); formation and decomposition of benzaldehyde-BBCP complexes;
	With rat hepatic microsomal aldehyde dehydrogenase; NAD In phosphate buffer; N,N-dimethyl-formamide at 37℃;
	With ((2,2'-(ethane-1,2-diylbis[(nitrilo-κN)methylidyne])bis(phenolato-κO))(2-))oxomanganese(1+) hexafluorophosphate In acetonitrile at 14.85℃;
	With HABR In water; acetic acid at 14.85 - 44.85℃;
	With pyridinium hydrobromide perbromide In water; acetic acid at 44.85℃;
	With benzyltrimethylammonium tribromide; potassium bromide In water; acetic acid at 44.85℃; for 10h;
	With benzyltrimethylammonium chlorobromate In water; acetic acid at 24.84℃;
	With tetra-N-butylammonium tribromide; acetic acid at 14.84℃;
	With 2,2'-bipyridinium chlorochromate In dimethyl sulfoxide at 24.84℃;
	With morpholinium chlorochromate In dimethyl sulfoxide at 44.84℃;
	With aryl-alcohol oxidase, FAD containing, from Pleurotus eryngii; oxygen at 24℃; for 3h; aq. phosphate buffer; Enzymatic reaction;
	With tetraethylammonium chlorochromate(VI) In dimethyl sulfoxide at 24.84℃;
	Multi-step reaction with 2 steps 1: potassium cyanide; potassium iodide / 24 h / 75 - 80 °C 2: sodium hydroxide / water / 20 °C
	With potassium permanganate In water; acetonitrile
	Stage #1: 3-Fluorobenzaldehyde With bis(pyridine)silver(I) permanganate; acetic acid In water at 24.84℃; for 10h; Darkness; Stage #2: With hydrogenchloride
	With 1,4-dithio-D,L-threitol; recombinant aldehyde dehydrogenase from bovine lens; water‐forming NADH oxidase from Streptococcus mutans; NAD In aq. phosphate buffer at 40℃; for 4h; Green chemistry; Enzymatic reaction; chemoselective reaction;
	With oxygen; C₆₆H₄₈N₈Pd In chloroform Irradiation;

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[2]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN111116348, 2020, A Location in patent: Paragraph 0028-0029
[3]Fu, Hua; Liu, Can; Liu, Yong; Yang, Haijun; Zhu, Xianjin [Green Chemistry, 2020, vol. 22, # 13, p. 4357 - 4363]
[4]Choi, Joong-Kwon; Chang, Young-Kil; Hong, Sung Yeap [Tetrahedron Letters, 1988, vol. 29, # 16, p. 1967 - 1970]
[5]Shaikh, Tanveer Mahammadali; Hong, Fung-E [Tetrahedron, 2013, vol. 69, # 42, p. 8929 - 8935]
[6]McKillop, Alexander; Kemp, Duncan [Tetrahedron, 1989, vol. 45, # 11, p. 3299 - 3306]
[7]Wu, Chaolong; Yao, Xiaoquan; Yu, Min; Zhou, Li; Zhu, Li [Letters in Organic Chemistry, 2021, vol. 18, # 3, p. 167 - 175]
[8]Bankston, Donald [Synthesis, 2004, # 2, p. 283 - 289]
[9]Current Patent Assignee: THE ROSKAMP INST - WO2020/154420, 2020, A2 Location in patent: Page/Page column 43
[10]Banerji, Kalyan K. [Journal of Organic Chemistry, 1986, vol. 51, # 25, p. 4764 - 4767]
[11]Anandan, S.; Gopalan, R. [Journal of the Indian Chemical Society, 1985, vol. 62, # 3, p. 216 - 218]
[12]Gupta, Anita; Mathur, Sandhya; Banerji, Kalyan K. [Journal of Chemical Research, Miniprint, 1988, # 1, p. 201 - 223]
[13]Mohnot, Kavita; Sharma, Pradeep K.; Banerji, Kalyan K. [Journal of Organic Chemistry, 1996, vol. 61, # 4, p. 1310 - 1314]
[14]Martini, Robert; Murray, Michael [Chemical Research in Toxicology, 1996, vol. 9, # 1, p. 268 - 276]
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[22]Location in patent: experimental part Sharma, Pradeep K. [Journal of the Indian Chemical Society, 2008, vol. 85, # 12, p. 1281 - 1288]
[23]Location in patent: experimental part Choudhary, Anurag; Malani; Agarwal; Sharma; Sharma, Vinita [Journal of the Indian Chemical Society, 2009, vol. 86, # 9, p. 927 - 935]
[24]Location in patent: scheme or table Ferreira, Patricia; Hernandez-Ortega, Aitor; Herguedas, Beatriz; Rencoret, Jorge; Gutierrez, Ana; Martinez, Maria Jesus; Jimenez-Barbero, Jesus; Medina, Milagros; Martinez, Angel T. [Biochemical Journal, 2010, vol. 425, # 3, p. 585 - 593]
[25]Location in patent: experimental part Gehlot; Prasadrao; Sharma [Asian Journal of Chemistry, 2011, vol. 23, # 3, p. 1173 - 1178]
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7
[ 455-38-9 ]
[ 102940-86-3 ]

Yield	Reaction Conditions	Operation in experiment
74%		A solution of 3-fluorobenzoic acid (4.02 g, 28.71 mmol) in 20 mL of THF was added dropwise to a suspension of TMEDA (10.00 mL, 66. 3 mmol) and 1.3M sec-BuLi (48 mL, 62.4 mmol) in 50 mL of THF at -90 C. The mixture was stirred at -90 C for 35 min. The mixture was warmed to -78 C when a solution of hexachloroethane (27.0 g, 113.9 mmol) in 50 mL of THF was added. After 20 h, the reaction was quenched with water and diluted with diethyl ether. The bilayer was adjusted to pH ~1-2 with conc. HCl. The organic layer was washed with water, brine, dried and concentrated to give 30.4g crude as a tan solid, which was washed with hexane to give 3.728g (74 %) of the desired product 1a (light tan solid). MS (m/z) 175.2 (M+H).
74%		Example 1; N-r4-chloro-2-hvdroxy-3-(piperazine-l-sulfonyl)phenyll-N'-(2-chloro-3-fluorophenyl)urea hydrochloride; Ia) 2-chloro-3-fluorobenzoic acid; A solution of 3-fluorobenzoic acid (4.02 g, 28.71 mmol) in 20 mL of THF was added dropwise to a suspension of tetramethylenediamine (TMEDA) (10.0OmL, 66.3mmol) and 1.3M sec-BuLi (48mL, 62.4mmol) in 50 mL of THF at -9O0C. The mixture was stirred at -9O0C for 35min. The mixture was warmed to -780C when a solution of hexachloroethane (27.Og, 113.9mmol) in 50 mL of THF was added. After 20 h, the reaction was quenched with water and diluted with diethyl ether. The bilayer was adjusted to pH ~l-2 with cone, hydrochloric acid (HCl). The organic layer was washed with water, brine, dried and concentrated to give 30.4g crude as a tan solid, which was washed with hexane to give 3.728g (74%) of the desired product Ia (light tan solid). MS (m/z) 175.2 (M+H).
74%		A solution of 3-fluorobenzoic acid (4.02 g, 28.71 mmol) in 20 mL of THF was added dropwise to a suspension of tetramethylenediamine (TMEDA) (10.0OmL, 66.3mmol) and 1.3M sec-BuLi (48mL, 62.4mmol) in 50 mL of THF at -900C. The mixture was stirred at -900C for 35min. The mixture was warmed to -78C when a solution of hexachloroethane (27.Og, 113.9mmol) in 50 mL of THF was added. After 20 h, the reaction was quenched with water and diluted with diethyl ether. The bilayer was adjusted to pH ~l-2 with cone. HCl. The organic layer was washed with water, brine, dried and concentrated to give 30.4g crude as a tan solid, which was washed with hexane to give 3.728g (74%) of the desired product Ia (light tan solid). MS (m/z) 175.2 (M+H).

60%		A solution of 3-fluorobenzoic acid (6, 4.02 g, 1.0 equiv.) in 20 mL of THF was added dropwise to a suspension of TMEDA (10.0 mL, 2.3 equiv.) and 1.5 mol/L n-BuLi (42.1 mL, 2.2 equiv.) in 50 mL of THF at -78C. The mixture was stirred at -78C for 30 min, and then a solution of hexachloroethane (2.72 g, 4.0 equiv.) in 50 mL of THF was added. After 12 h, the reaction was quenched with water and diluted with diethyl ether. The bilayer was adjusted to pH 1-2 with conc. hydrochloric acid. The organic layer was washed with water, brine, dried and concentrated to give crude as a tan solid, which was washed with hexane to give of the desired product 7 (3.0 g) in 60% yield.
		Example 1Ia) 2-chloro-3-fluorobenzoic acid A solution of 3-fluorobenzoic acid (4.02 g, 28.71 mmol) in 20 mL of THF was added dropwise to a suspensition of TMEDA (lO.OOmL, 66.3mmol) and 1.3M sec -BuLi (48mL, 62.4mmol) in 50 mL of THF at -9O0C. The mixture was stirred at -90C for 35min. The mixture was warmed to -78C when a solution of hexachloroethane (27.Og, 113.9mmol) in 50 mL of THF was added. After 20 hours, the reaction was quenched with water and diluted with diethyl ether. The bilayer was adjusted to pH ~l-2 with cone. HCl. The organic layer was washed with water, brine, dried and concentrated to give 30.4g crude as a tan solid, which was washed with hexane to give the desired product 3.728g as a light tan solid. MS (m/z) 175.2 (M+).

Reference： [1]Patent: WO2004/39775,2004,A2 .Location in patent: Page 12
[2]Patent: WO2009/39091,2009,A1 .Location in patent: Page/Page column 13
[3]Patent: WO2007/150015,2007,A2 .Location in patent: Page/Page column 5
[4]Journal of the Chemical Society. Perkin transactions I,1995,p. 1265 - 1272
[5]Bulletin de la Societe Chimique de France,1996,vol. 133,p. 133 - 141
[6]Chinese Chemical Letters,2014,vol. 25,p. 667 - 669
[7]Tetrahedron Letters,1995,vol. 36,p. 881 - 884
[8]Patent: WO2006/43950,2006,A1 .Location in patent: Page/Page column 12

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[ 455-38-9 ]
[ 132715-69-6 ]

Reference： [1]Bulletin de la Societe Chimique de France,1996,vol. 133,p. 133 - 141
[2]Journal of the Chemical Society. Perkin transactions I,1995,p. 1265 - 1272
[3]Tetrahedron Letters,1995,vol. 36,p. 881 - 884

9
[ 602-94-8 ]
[ 455-38-9 ]
[ 652-18-6 ]
[ 455-40-3 ]
[ 65-85-0 ]

Reference： [1]Tetrahedron Letters,1995,vol. 36,p. 4655 - 4658
[2]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361

10
[ 455-38-9 ]
[ 74-88-4 ]
[ 699-90-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1995,p. 1265 - 1272

11
[ 67-56-1 ]
[ 1073-06-9 ]
[ 201230-82-2 ]
[ 455-38-9 ]
[ 455-68-5 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 8336 - 8340

12
[ 1073-06-9 ]
[ 201230-82-2 ]
[ 455-38-9 ]
[ 455-68-5 ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 8336 - 8340

13
[ 67-56-1 ]
[ 455-38-9 ]
[ 455-68-5 ]

Yield	Reaction Conditions	Operation in experiment
83%	With 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione; at 70℃; for 20h;	General procedure: The mixture of carboxylic acid, alcohol, and 1,3-dibromo-5,5-dimethylhydantoin was stirredin a 25 mL reactor tube at 70 C for 2-40 h. After reaction completion, the mixture was cooled toroom temperature and the alcohol was evaporated under reduced pressure. The isolation procedurewas as follows, except where noted dierently in the Supporting Information. The residue wasdissolved in 10 mL ethyl acetate and washed with a mixture of 1 mL saturated NaHCO3(aq), 1 mLsaturated Na2S2O3(aq), and 10 mL distilled water, and the water phase was extracted with ethyl acetate(2 10 mL). The organic layers were combined, dried over Na2SO4, and the solvent was evaporatedunder reduced pressure
70%	With N-Bromosuccinimide; at 70℃; for 20h;	General procedure: The mixture of carboxylic acid, alcohol and N-bromosuccinimide was stirred in a 25 mL reactortube at 70 C for 2-40 h. After the completion of the reaction, the mixture was cooled to roomtemperature and alcohol was evaporated under reduced pressure. The isolation procedure was as follows, except where noted differently in Section 3.2.6. The residue was dissolved in ethyl acetate andconsecutively washed with 10 mL of 10% Na2S2O3 (aq), 5 mL of saturated NaHCO3 (aq) and 10 mL ofdistilled water. The water phase was extracted with ethyl acetate (3Chi5 mL). The organic layers were combined, dried over Na2SO4 and the solvent was evaporated under reduced pressure.
	With thionyl chloride; at 20℃;	General procedure: Different substituted carboxylic acids (20 mmol) (A) were stirred with thionyl chloride (100 mmol) in dry methanol (75 ml) or 5-6 h to synthesize corresponding methyl esters (B) (Scheme1). After extraction of esters in chloroform, solvent was evaporated and esters (66 mmol) were refluxed with hydrazine hydrate(330 mmol) in ethanol (75 ml) for 4-5 h. A solid was obtained upon removal of the solvent by rotary evaporation. The resulting solid was washed with hexane to afford hydrazide ligand (C). The spectral and analytical data are given below.

With sulfuric acid; for 12h;Reflux;

General procedure: A mixture of 2-fluorobenzoic acid (5a)(1 g, 7.13mmol) in MeOH (20 mL) was stirred for a fewminutes. Concentrated H2SO4 (1 mL) was added, and themixture was refluxed for 12 h. The reaction was monitoredby TLC using -hexane, with ethyl acetate as a developingsystem.CH2Cl2 (30 mL) was then added, and the mixture wasextracted with distilled H2O (3 × 20 mL).The organic phasewas separated, dried on anhydrous Na2SO4, and evaporatedunder vacuum to afford corresponding ester 6a in almostquantitative yield in oil form (1.09 g).

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