[ CAS No. 321-14-2 ] {[proInfo.proName]}

Name: 321-14-2|5-Chloro-2-hydroxybenzoic acid|98%
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Quality Control of [ 321-14-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 321-14-2 ]

Product Details of [ 321-14-2 ]

CAS No. :	321-14-2	MDL No. :	MFCD00002457
Formula :	C₇H₅ClO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NKBASRXWGAGQDP-UHFFFAOYSA-N
M.W :	172.57	Pubchem ID :	9447
Synonyms :

Calculated chemistry of [ 321-14-2 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	40.43
TPSA :	57.53 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.16 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.09
Log Po/w (XLOGP3) :	3.09
Log Po/w (WLOGP) :	1.74
Log Po/w (MLOGP) :	1.59
Log Po/w (SILICOS-IT) :	1.38
Consensus Log Po/w :	1.78

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.19
Solubility :	0.11 mg/ml ; 0.000639 mol/l
Class :	Soluble
Log S (Ali) :	-3.97
Solubility :	0.0187 mg/ml ; 0.000108 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.81
Solubility :	2.69 mg/ml ; 0.0156 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.18

Safety of [ 321-14-2 ]

Signal Word:	Danger	Class:	6.1
Precautionary Statements:	P264-P270-P301+P310+P330-P405-P501	UN#:	2811
Hazard Statements:	H301	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 321-14-2 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 321-14-2 ]
Downstream synthetic route of [ 321-14-2 ]

[ 321-14-2 ] Synthesis Path-Upstream 1~6

1
[ 321-14-2 ]
[ 37551-43-2 ]

Yield	Reaction Conditions	Operation in experiment
84.6%	With sodium hydroxide; sulfuric acid; hydroxylamine sulfate In methanol; water	EXAMPLE 1 5-Chlorosalicylhydroxamic Acid 50 ml. of concentrated sulfuric acid is added dropwise to a stirred slurry of 200 gm. of 5-chlorosalicylic acid in 400 ml. of methanol. The reaction temperature rises to approximately 35° C. The mixture is heated at reflux with the exclusion of moisture for about 20 hours. The methyl ester separates as an oil and is combined in one portion with 144 gm. of hydroxylamine sulfate in 600 ml. of water at room temperature and rinsed in with methanol. The mixture is stirred and 468 gm. of 50percent w/w sodium hydroxide is dripped in while the reaction temperature is maintained at a temperature range of from about 25° to 35° C. After addition of the alkali is completed, 750 ml. of water is added to dissolve the solids while heating to a temperature of about 50° C. The clear solution obtained is allowed to cool to room temperature and neutralized with 140 gm of concentrated sulfuric acid while the temperature is maintained below about 40° C. The precipitate obtained is diluted with 200 ml. of water, filtered, washed with water and dried at a temperature of about 100° C. The 5-chlorosalicylhydroxamic acid obtained has a m.p. 218°-220° C., and weighs 182 gm. representing a yield of 84.6percent.
84.6%	With sodium hydroxide; sulfuric acid; hydroxylamine sulfate In methanol; water	EXAMPLE 1 5-CHLOROSALICYLHYDROXAMIC ACID 50 ml. of concentrated sulfuric acid is added dropwise to a stirred slurry of 200 gm. of 5-chlorosalicylic acid in 400 ml. of methanol. The reaction temperature rises to approximately 35° C. The mixture is heated at reflux with the exclusion of moisture for about 20 hours. The methyl ester separates as an oil and is combined in one portion with 144 gm. of hydroxylamine sulfate in 600 ml. of water at room temperature and rinsed in with methanol. The mixture is stirred and 468 gm. of 50percent w/w sodium hydroxide is dripped in while the reaction temperature is maintained at a temperature range of from about 25° to 35° C. After addition of the alkali is completed, 750 ml. of water is added to dissolve the solids while heating to a temperature of about 50° C. The clear solution obtained is allowed to cool to room temperature and neutralized with 140 gm. of concentrated sulfuric acid while the temperature is maintained below about 40° C. The precipitate obtained is diluted with 200 ml. of water, filtered, washed with water and dried at a temperature of about 100° C. The 5-chlorosalicylhydroxamic acid obtained has a m.p. 218°-220° C., and weighs 182 gm. representing a yield of 84.6percent.

Reference： [1] Patent: US4224323, 1980, A,
[2] Patent: US4224443, 1980, A,
[3] Inorganic Chemistry, 2013, vol. 52, # 19, p. 10747 - 10755

2
[ 321-14-2 ]
[ 1570-64-5 ]

Reference： [1] Chemical and Pharmaceutical Bulletin, 1979, vol. 27, p. 816 - 820

3
[ 321-14-2 ]
[ 77-78-1 ]
[ 3438-16-2 ]

Reference： [1] Journal of Organic Chemistry, 1959, vol. 24, p. 1759,1762
[2] Patent: CN105461549, 2016, A, . Location in patent: Paragraph 0012; 0013
[3] Patent: CN106699717, 2017, A, . Location in patent: Paragraph 0032-0034
[4] RSC Advances, 2017, vol. 7, # 61, p. 38171 - 38178

4
[ 321-14-2 ]
[ 74-88-4 ]
[ 3438-16-2 ]

Reference： [1] Patent: US4474792, 1984, A,

5
[ 321-14-2 ]
[ 121-87-9 ]
[ 50-65-7 ]

Yield	Reaction Conditions	Operation in experiment
68.7%	With phosphorus trichloride In chlorobenzene at 135℃; for 3 h;	In 135 °C, to the 5- chlorine salicylic acid (3.44g, 20 . 0mmol) and 2-chloro-4-nitroaniline (3.44g, 20 . 0mmol) dissolved in chlorobenzene mixing solution of adding dropwise PCl₃(2.4g, 17 . 5mmol) dissolved in a chlorobenzene solution. 3 hours later, the reaction solution is cooled to the room temperature. Filtering and collecting the resulting solid, wash, then from ethyl acetate (or acetone) recrystallization to obtain a white solid (6.8g, 68.7percent) shaped N-(2-chloro-4-nitro-phenyl) - 5-chloro-2-hydroxy-benzamide.

Reference： [1] Patent: CN105566147, 2016, A, . Location in patent: Paragraph 0063; 0064; 0065
[2] Patent: CN106431949, 2017, A, . Location in patent: Paragraph 0013; 0014; 0015

6
[ 321-14-2 ]
[ 328-74-5 ]
[ 978-62-1 ]

Yield	Reaction Conditions	Operation in experiment
85.5%	With phosphorus trichloride In toluene for 3 h; Heating / reflux	A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
62%	With phosphorus trichloride In chlorobenzeneMicrowave irradiation	General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl₃) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30–60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41–83percent.
57%	With trichlorophosphate In toluene for 6 h; Inert atmosphere; Reflux	To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent). m.p: 172-173° C.; ¹H-NMR (300 MHz, DMSO-d⁶): δ 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).

28%	With pyridine; phosphorus trichloride In toluene for 12 h; Inert atmosphere; Reflux	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley’s Carousel reaction tube (modified from Itai et al.²⁰). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6–7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO₄), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
28%	With pyridine; phosphorus trichloride In tolueneInert atmosphere; Reflux	Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley’s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO₄) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 ^oC. ¹H NMR (DMSO-d₆) δ 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J₁=8.7Hz, J₂=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H).

Reference： [1] Patent: EP1352650, 2003, A1,
[2] Patent: EP1512397, 2005, A1, . Location in patent: Page/Page column 77
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 4, p. 1524 - 1532
[4] Patent: US2014/221411, 2014, A1, . Location in patent: Paragraph 0192; 0193
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 114 - 126
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1748 - 1751
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8375 - 8391,17
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8375 - 8391

[ 321-14-2 ] Synthesis Path-Downstream 1~88

1
[ 67-56-1 ]
[ 321-14-2 ]
[ 4068-78-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With sulfuric acid; for 120h;Inert atmosphere; Reflux;	Concentrated sulfuric acid (20 ml_) was added to a suspension of 5-chlorosalicylic acid (50 g, 290 mmol) in methanol (500 ml_), and the mixture was refluxed for five days. The reaction was concentrated under reduced pressure and the residue was dissolved in Et2O (500 ml_). The resulting mixture was poured into a saturated aqueous solution of NaHCO3 (400 ml_) cooled to 0 0C, and the layers were separated. The aqueous layer was extracted with Et2O (2 x 400 ml_) and the combined organic layers were washed with a saturated aqueous solution of NaHCO3 and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a white solid. Yield: 49.5 g, 265 mmol, 91 %.
91%	With sulfuric acid; for 120h;Reflux;	Step 1. Synthesis of methyl 5-chloro-2-hydroxybenzoate. Concentrated sulfuric acid (20 mL) was added to a suspension of 5-chlorosalicylic acid (50 g, 290 mmol) in methanol (500 mL), and the mixture was refluxed for five days. The reaction was concentrated under reduced pressure and the residue was dissolved in Et20 (500 mL). The resulting mixture was poured into a saturated aqueous solution of NaHC03 (400 mL) cooled to 0 C, and the layers were separated. The aqueous layer was extracted with Et20 (2 x 400 mL) and the combined organic layers were washed with a saturated aqueous solution of NaHC03 and brine. The organic layer was dried (Na2S04) and concentrated under reduced pressure to afford the title compound as a white solid. Yield: 49.5 g, 265 mmol, 91 %.
90%	With thionyl chloride; at 60℃; for 48h;	5-Chloro-2-hydroxybenzoic acid (1.73 g, 0.010 mol) and its derivative were dissolved in 30 mL of methanol, and a catalytic amount of thionyl chloride was added under ice bath, and stirred at 60 C for 48 h; The progress of the reaction was checked by thin layer chromatography. After completion of the reaction, the methanol was evaporated to dryness under reduced pressure, dissolved in dichloromethane, and extracted with aqueous sodium carbonate, and then dichloromethane was evaporated under reduced pressure to give 5-chloro-2-hydroxybenzoic acid. Ester (9), yield 90%.

89%	With sulfuric acid; for 1h;Reflux;	5-Chlorosalicylic acid (1 g) was dissolved in methanol (15 mL) and concentrated H2SO4 (approximately 20 muL) was added, which was evaporated after 1 h reflux. The residue dissolved in ethylacetate was washed with 5% NaHCO3 and subsequently dried over anhydrous Na2SO4, which was subjected to flash evaporation to obtain MCSA. Yield: 0.96 g (89%); mp: 46 C; IR (Nujol): 1682 (CO) cm-1; 1H NMR (DMSO-d6): delta = 3.86 (s, 3H, CH3), 7.01 (d, J = 8.8 Hz, 1H, H-3), 7.53 (dd, J = 8.4, 2.7 Hz, 1H, H-4), 7.69 (d, J = 2.4 Hz, 1H, H-6); C8H7O3Cl1 (186.59) calcd: C, 51.49; H, 3.78; found: C, 51.82; H, 3.72.
87%	With sulfuric acid; for 18h;Inert atmosphere; Reflux;	General procedure: Method A: The corresponding carboxylic acid (28.96 mmol) wasdissolved in MeOH (60 mL) and H2SO4 (98%, 2 mL) was addeddropwise to the solution. The reaction mixture was heated under reflux for 18hours, subsequently it was cooled to 25 C and the solvent was removed undervacuum. The residue was diluted with water (50 mL), thereafter K2CO3was added until pH = 5-6, and the aqueous solution wasextracted with DCM (3 x 30 mL). Finally, the combined organic phases were driedover Na2SO4 and concentrated under vacuum to afford thedesired compound with enough purity to be usedin the next reaction without further purification.
79%	With sulfuric acid;Inert atmosphere; Reflux;	5-chloro-2-hydroxybenzoic acid (1.0 g, 5.79 mmol) in methanol (15 ml) solution ofWas added dropwise concentrated sulfuric acid (200 mul). Under an argon atmosphere, and stirred under reflux conditions overnight. After completion of the reaction, concentrated to dryness. Saturated brine, saturated aqueous sodium hydrogen carbonate solution was added, followed by extraction with ethyl acetate. Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. To give the title compound (850 mg, 79%).
	With thionyl chloride; at 15 - 20℃;Heating / reflux;	Example 1; Synthesis of methyl 5-chlorosalicylate; To 750 ml methanol (MeOH) is added thionyl chloride (165.0 ml, 269.11 g, 2.26 mol, 1.3 eq) dropwise maintaining the temperature within the range from (+15)-(+20) 0C. After the addition is complete, the solution is treated with 5-chlorosalicylic acid (300 g, 1.74 mol, 1.0 eq) and heated at reflux overnight and a small amount of thionyl chloride (16.5 ml, 26.91 g, 226.13 mmol, 0.13 eq) is added to reach full conversion and stirred further at reflux <n="13"/>temperature for an hour. The cooled reaction mixture is concentrated under vacuum to give a beige solid.
	With acetyl chloride; at 90℃; for 72h;	A solution of 5-chlorosalicylic acid (75. Og, 0.44mol) in MeOH (250ml) was treated portionwise with acetyl chloride (5ml, 70mmol) and heated at 90C for 3 d. The reaction mixture was chilled to -18C and the resulting precipitate collected by filtration. Further purification by trituration with 1 : 1 ethenPE ether gave the title compound; (71.99g, 038mmol)NMR (CDC13) delta 10.70 (IH, s), 7.82 (IH, d, J2.8), 7.42 (IH, dd, J 8.8, 2.8), 6.95 (IH, d, J 8.8)
	With sulfuric acid; for 12h;Reflux;	Preparation of methyl 5-chlo -2-hydroxybenzoateTo a solution of 5-chloro salicylic acid (13..0 g, 0.07 mol) in methanol was added few drops of cone. sulphuric acid and the reaction mass was refluxed for 12 hours. Methanol was removed under vaccum, quenched in water and extracted with DCM. The organic layer was washed with NaHC03 solution, dried over anhydrous sodium sulphate and concentrated to afford 7.50 g of desired product. 1HNMR (CDC13): delta 3.96 ((s, 3H), 6.88 (d, J = 9.0 Hz, 1H), 7.53 (dd, J = 2.4 Hz, 2.7 Hz, 1H), 7.96 (s, 1H).
	With thionyl chloride; for 7h;Cooling with ice; Reflux;	0.86 g (5 mmol, 1.0 eq) 5-chloro-salicylic acid (compound 1a) was dissolved in 7 ml methanol. To the mixture was added 0.90 g(7 mmol, 1.4 eq) thionyl chloride under the condition of ice bath. After the reaction was refluxed for 7.0 hours, it is cooled to room temperature. The methanol was removed to obtain 0.90 g pale yellow oily crude product (compound 2b), which was used without purification in the next step directly. According to this method, compound 2c to 2f were obtained from 4-chloro-salicylate (compound 1b), 5- nitro-salicylic acid (compound 1c), 4- bromo acid (compound 1d) and 5-methoxy-salicylic acid (compound 1e).
	With thionyl chloride; at 0 - 65℃; for 48.16h;	General procedure: Methyl 4-bromosalicylate (1 mol) was dissolved in methanol(25 mL), and thionyl chloride was added dropwise under ice-cooling,after 10 min, The mixture was stirred at 65 C for 48 h. and monitoredby TLC. After the reaction was completed, excess methanol was evaporated,the residue was extracted with ethyl acetate and aqueous sodiumcarbonate, and the organic phase was added to anhydrous sodiumsulfate and concentrated to obtain intermediate 6a.The compounds 6b-6h were prepared analogously.

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[11]Patent: JP2016/124812,2016,A .Location in patent: Paragraph 0311
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2
[ 13589-72-5 ]
[ 321-14-2 ]

Reference： [1]Chemische Berichte,1904,vol. 37,p. 4027

3
[ 321-14-2 ]
[ 106-47-8 ]
[ 1147-98-4 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus trichloride; In chlorobenzene; for 0.333333h;Microwave irradiation;	General procedure: A mixture of substituted salicylic acid 1 (0.1 mol), appropriate amine 2 (0.1 mol) and phosphorus trichloride (0.05 mol) in chlorobenzene (250 ml) was stirred under microwave irradiation in the microwave reactor (400 W input power) for 20 min. Reaction mixture was then left in the fridge overnight. The precipitate was collected by filtration and recrystallized from ethanol to give salicylamide in sufficient purity.
	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Inert atmosphere; Reflux;	General procedure: Anilide synthesis. General method. To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv), the aniline derivative (1 equiv), and dry xylenes(stored over 3A molecular sieves, 40 mL per gram of 5-chloro-2-hydroxybenzoic acid) under an Argon atmosphere. The mixture was heated to reflux, and PCl3 (0.4 equiv) was added rapidly via syringe. The mixture was heated at reflux for 1 h and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 h. Saturated sodium bicarbonate was added to a final pH of 3-4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95% by LC. Additional experimental procedures and analytical data are provided in Supplemental data.

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4
[ 69-72-7 ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]American Chemical Journal,1879,vol. 1,p. 176
Chemische Berichte,1880,vol. 13,p. 34
[2]Journal of Physical Chemistry,1980,vol. 84,p. 629 - 631
[3]American Chemical Journal,1890,vol. 12,p. 505
[4]Journal fur praktische Chemie (Leipzig 1954),1876,vol. <2> 13,p. 427

5
[ 69-72-7 ]
[ 321-14-2 ]
[ 1829-32-9 ]

Reference： [1]Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,1928,vol. 60,p. 161
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[3]Journal of the Chemical Society. Perkin transactions II,1988,p. 385 - 392
[4]Journal of Physical Chemistry,1980,vol. 84,p. 629 - 631
[5]Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,1928,vol. 60,p. 161
Chemisches Zentralblatt,1928,vol. 99,p. 767

6
[ 50-79-3 ]
[ 321-14-2 ]

Reference： [1]Synthetic Communications,2003,vol. 33,p. 1783 - 1787
[2]Synthetic Communications,2002,vol. 32,p. 2055 - 2059
[3]Recueil des Travaux Chimiques des Pays-Bas,1931,vol. 50,p. 753,779
[4]Journal of the Chemical Society,1952,p. 4368,4371

7
[ 2832-19-1 ]
[ 321-14-2 ]
5-Chloro-3-[(2-chloro-acetylamino)-methyl]-2-hydroxy-benzoic acid [ No CAS ]

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

8
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]Australian Journal of Chemistry,1984,vol. 37,p. 73 - 86

9
[ 2051-59-4 ]
potassium hydroxide [ No CAS ]
[ 321-14-2 ]

Reference： [1]Justus Liebigs Annalen der Chemie,1870,vol. 154,p. 85

10
[ 7647-18-9 ]
[ 69-72-7 ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]Journal fur praktische Chemie (Leipzig 1954),1876,vol. <2> 13,p. 427

11
[ 7647-01-0 ]
[ 7732-18-5 ]
[ 7722-84-1 ]
[ 69-72-7 ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]Bulletin de la Societe Chimique de France,1927,vol. <4> 41,p. 1363

12
[ 64-17-5 ]
[ 7782-50-5 ]
[ 69-72-7 ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]American Chemical Journal,1890,vol. 12,p. 505

13
[ 7782-50-5 ]
[ 64-19-7 ]
[ 69-72-7 ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]Chemische Berichte,1878,vol. 11,p. 1225

14
[ 7782-50-5 ]
[ 69-72-7 ]
CS₂ [ No CAS ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]American Chemical Journal,1890,vol. 12,p. 505

15
[ 7664-93-9 ]
[ 13589-72-5 ]
[ 321-14-2 ]

Reference： [1]Chemische Berichte,1904,vol. 37,p. 4027

16
dipotassium salicylate [ No CAS ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]Chemische Berichte,1911,vol. 44,p. 427

17
monopotassium salicylate [ No CAS ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]American Chemical Journal,1890,vol. 12,p. 505

18
[ 7732-18-5 ]
[ 578-36-9 ]
[ 7782-50-5 ]
[ 321-14-2 ]
[ 320-72-9 ]

Reference： [1]American Chemical Journal,vol. 12,p. 505

19
[ 54-21-7 ]
[ 7782-50-5 ]
natrium carbonate [ No CAS ]
[ 321-14-2 ]
[ 1829-32-9 ]

Reference： [1]Zhurnal Russkago Fiziko-Khimicheskago Obshchestva,vol. 60,p. 159,162
Chemisches Zentralblatt,1928,vol. 99,p. 767

20
[ 535-80-8 ]
[ 321-14-2 ]
[ 1829-32-9 ]

Reference： [1]Chemical Communications,2005,p. 5301 - 5303
[2]Chemistry - A European Journal,2009,vol. 15,p. 13171 - 13180

21
[ 321-14-2 ]
[ 33228-45-4 ]
5-chloro-N-(4-hexyl-phenyl)-2-hydroxy-benzamide [ No CAS ]

Reference： [1]Archiv der Pharmazie,2006,vol. 339,p. 616 - 620

22
[ 321-14-2 ]
[ 2696-84-6 ]
5-chloro-2-hydroxy-N-(4-propyl-phenyl)-benzamide [ No CAS ]

Reference： [1]Archiv der Pharmazie,2006,vol. 339,p. 616 - 620

23
[ 321-14-2 ]
[ 159323-96-3 ]

Reference： [1]Journal of Organic Chemistry,1994,vol. 59,p. 4297 - 4303
[2]Journal of Organic Chemistry,2015,vol. 80,p. 11818 - 11848

24
[ 321-14-2 ]
[ 30431-54-0 ]

Reference： [1]Australian Journal of Chemistry,1984,vol. 37,p. 73 - 86

25
[ 321-14-2 ]
[ 328-74-5 ]
[ 978-62-1 ]

Yield	Reaction Conditions	Operation in experiment
85.5%		Example 51 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Comopund No. 50). Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 85.5percent. 1H-NMR(DMSO-d6): delta 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
85.5%	With phosphorus trichloride; In toluene; for 3.0h;Heating / reflux;	A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): delta 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
62%	With phosphorus trichloride; In chlorobenzene;Microwave irradiation;	General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30?60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41?83percent.

57%	With trichlorophosphate; In toluene; for 6.0h;Inert atmosphere; Reflux;	To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent). m.p: 172-173° C.; 1H-NMR (300 MHz, DMSO-d6): delta 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).
28%	With pyridine; phosphorus trichloride; In toluene; for 12.0h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
28%	With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;	Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 oC. 1H NMR (DMSO-d6) delta 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J1=8.7Hz, J2=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H).

Reference： [1]Patent: EP1352650,2003,A1
[2]Patent: EP1512397,2005,A1 .Location in patent: Page/Page column 77
[3]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 1524 - 1532
[4]Patent: US2014/221411,2014,A1 .Location in patent: Paragraph 0192; 0193
[5]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126
[6]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751
[7]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17

26
[ 321-14-2 ]
[ 349-58-6 ]
C₁₅H₇ClF₆O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13.9%	With trichlorophosphate; In xylene; at 140℃; for 2h;	A mixture of 5-chlorosalicylic acid(172.6mg, 1mmol), 3,5-bis(trifluoromethyl)phenol(152 muL, 1mmol), phosphorus oxychloride(40 muL, 0.43mmol) and xylene(3mL) was stirred at 140°C for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1-->5:1) to give the title compound(53.6mg, 13.9percent) as a white crystal.1H-NMR(CDCl3): delta 7.04(1H, d, J=9.0Hz), 7.54(1H, dd, J=9.0, 2.7Hz), 7.75(2H, s), 7.86(1H, s), 8.02(1H, d, J=2.7Hz), 10.09(1H, s).
13.9%	With trichlorophosphate; In xylene; at 140℃; for 2h;	A mixture of 5-chlorosalicylic acid(172.6mg, 1mmol), 3,5-bis(trifluoromethyl)phenol(152 muL, 1mmol), phosphorus oxychloride(40 muL, 0.43mmol) and xylene(3mL) was stirred at 140°C for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1-->5:1) to give the title compound(53.6mg, 13.9percent) as a white crystal.1H-NMR(CDCl3): delta 7.04(1H, d, J=9.0Hz), 7.54(1H, dd, J=9.0, 2.7Hz), 7.75(2H, s), 7.86(1H, s), 8.02(1H, d, J=2.7Hz), 10.09(1H, s).
13.9%	With trichlorophosphate; In xylene; at 140℃; for 2h;	A mixture of 5-chlorosalicylic acid(172.6mg, 1mmol), 3,5-bis(trifluoromethyl)phenol(152 muL, 1mmol), phosphorus oxychloride(40 muL, 0.43mmol) and xylene(3mL) was stirred at 140°C for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1-->5:1) to give the title compound(53.6mg, 13.9percent) as a white crystal.1H-NMR(CDCl3): delta 7.44(1H, d, J=9.0Hz), 7.54(1H, dd, J=9.0, 2.7Hz), 7.75(2H, s), 7.86(1H, s), 8.02(1H, d, J=2.7Hz), 10.09(1H, s).

13.9%

With trichlorophosphate; In xylene; at 140℃; for 2h;

A mixture of 5-chlorosalicylic acid(172.6mg, 1mmol), 3,5-bis(trifluoromethyl)phenol(152 muL, 1mmol), phosphorus oxychloride(40 muL, 0.43mmol) and xylene(3mL) was stirred at 140°C for 2 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=10:1-->5:1) to give the title compound(53.6mg, 13.9percent) as a white crystal.1H-NMR(CDCl3): delta 7.04(1H, d, J=9.0Hz), 7.54(1H, dd, J=9.0, 2.7Hz), 7.75(2H, s), 7.86(1H, s), 8.02(1H, d, J=2.7Hz), 10.09(1H, s).

Reference： [1]Patent: EP1510207,2005,A1 .Location in patent: Page/Page column 165
[2]Patent: EP1514544,2005,A1 .Location in patent: Page/Page column 169
[3]Patent: EP1512396,2005,A1 .Location in patent: Page/Page column 163-164
[4]Patent: EP1510210,2005,A1 .Location in patent: Page/Page column 165-166

27
[ 321-14-2 ]
[ 367-71-5 ]
[ 634189-16-5 ]

Yield	Reaction Conditions	Operation in experiment
6.9%	With phosphorus trichloride; In toluene; for 4.5h;Heating / reflux;	Phosphorus trichloride(44 mu L, 0.5mmol) was added to a mixture of 5-chlorosalicylic acid(173mg, 1mmol), <strong>[367-71-5]2,4-bis(trifluoromethyl)aniline</strong>(229mg, 1mmol) and toluene(5mL), and the mixture was refluxed for 4.5 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1) to give the title compound(26.3mg, 6.9%) as a white powder.1H-NMR(CDCl3):delta 7.03(1H, dd, J=8.7, 0.6Hz), 7.43-7.48(2H, m), 7.91(1H, d, J=9.0Hz), 7.96(1H, s), 8.42(1H, s), 8.49(1H, d, J=8.7Hz), 11.26(1H, s).

Reference： [1],2020,vol. 14,p. 371 - 393
[2]ChemMedChem,2019
[3]Patent: EP1535609,2005,A1 .Location in patent: Page/Page column 126

28
[ 321-14-2 ]
[ 107045-28-3 ]
[ 868636-85-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;	To a stirred solution of 5-chloro-2-hydroxybenzoic acid (0.57 g, 3.3 mmol) and <strong>[107045-28-3]tert-butyl 4-(aminomethyl)benzoate</strong> (0.72 g, 3.5 mmol) in dichloromethane (5 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.95 g, 5.0 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (0.76 g, 5.0 mmol), and triethylamine (0.46 mL, 3.3 mmol). After being stirred overnight, the reaction mixture was poured into sodium bicarbonate aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL*2). The combined organic layers were washed with brine (50 mL), dried (magnesium sulfate), and evaporated. The residue was purified by flush column chromatography on silica gel eluding with hexane/ethyl acetate (10/1) to afford 0.57 g (48%) of the title compound as white solids: 1H-NMR (CDCl3) delta 12.12 (1H, s), 7.99 (2H, d, J=7.9 Hz), 7.47-7.30 (4H, m), 6.97 (1H, d, J=8.4 Hz), 6.67-6.52 (1H, m), 4.68 (2H, d, J=5.7 Hz), 1.59 (9H, s).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane;	To a stirred solution of 5-chloro-2-hydroxybenzoic acid (0.57 g, 3.3 mmol) and tert-butyl 4- (aminomethyl)benzoate (0.72 g, 3.5 mmol) in dichloromethane (5 mL) were successively added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.95 g, 5.0 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (0.76 g, 5.0 mmol), and triethylamine (0.46 mL, 3.3 mmol). After being stirred overnight, the reaction mixture was poured into sodium bicarbonate aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 mL x 2). The combined organic layers were washed with brine (50 mL), dried (magnesium sulfate), and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (10/1) to afford 0.57 g (48%) of the title compound as white solids: (at)H-NMR (CDC13) 8 12.12 (1 H, s), 7.99 (2H, d, J = 7.9 Hz), 7.47-7.30 (4H, m), 6.97 (1 H, d, J = 8.4 Hz), 6.67-6.52 (1 H, m), 4.68 (2H, d, J = 5.7 Hz), 1.59 (9H, s).

Reference： [1]Patent: US2005/250818,2005,A1 .Location in patent: Page/Page column 18
[2]Patent: WO2005/102389,2005,A2 .Location in patent: Page/Page column 211-212

29
[ 321-14-2 ]
[ 4068-78-4 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	With sulfuric acid; In methanol;	a. Methyl 5-chloro-2-hydroxybenzoate (2c) A mixture of 5-chloro-2-hydroxybenzoic acid (100g, 0.57 mol), 20 ml of conc. H2SO4 and 200 ml of dry methanol was heated under reflux for 22 hours. An additional 5 ml of conc. H2SO4 was then added and the solution heated for an additional 24 hours. The solvent was evaporated under reduced pressure and the resulting residue poured into aqueous saturated Na2CO3 and then extracted with CH2Cl2 (2 x 400 ml). The organic layers were combined, dried over anhydrous Na2SO4,and evaporated to give the desired compound as a white solid (100.5 g, 94.8% yield), mp 44-46C. IR (nujol) 1680 (ester) cmmin1. NMR (CDCl3) delta 10.60 (s, 1H, OH), 7.73 (d, 1H, JBC=3 Hz HC), 7.33 (d of d, 1H, JAB=9 Hz, HB), 6.87 (d, 1H, HA), and 3.92 (s, 3H, CH3).
74%	With thionyl chloride; In methanol; ethyl acetate;	(205-1) Under nitrogen atmosphere, a solution of 5-chlorosalicylic acid (5.00 g) in MeOH (100 mL) was cooled to 0 C., and thereto was added dropwise SOCl2 (3.20 mL). After the addition, the mixture was stirred at 60 C. for 10 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed twice with water, washed with a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=5/1) to give methyl 5-chloro-2-hydroxybenzoate (4.03 g, 74%). 1H NMR (CDCl3, 400 MHz) delta 10.68 (s, 1H), 7.81 (d, 1H, J=2.7 Hz), 7.40 (dd, 1H, J=2.7, 8.9 Hz), 6.94 (d, 1H, J=8.9 Hz), 3.96 (s, 3H).
74%	With thionyl chloride; In methanol; ethyl acetate;	(205-1) Under nitrogen atmosphere, a solution of 5-chlorosalicylic acid (5.00 g) in MeOH (100 mL) was cooled to 0C, and thereto was added dropwise SOCl2 (3.20 mL). After the addition, the mixture was stirred at 60C for 10 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate, washed twice with water, washed with a saturated brine, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate = 5/1) to give methyl 5-chloro-2-hydroxybenzoate (4.03 g, 74 %). 1H NMR (CDCl3, 400MHz) delta 10.68 (s, 1H), 7.81 (d, 1H, J=2.7Hz), 7.40 (dd, 1H, J=2.7, 8.9Hz), 6.94 (d, 1H, J=8.9Hz), 3.96 (s, 3H).

	With thionyl chloride; In methanol; water;	EXAMPLE 1 Methyl 5-chlorosalicylate Thionyl chloride (900 g, 7.56 mol) is added dropwise to methanol (1977 g, 61.72 mol) at 20 C. over a period of 1.5 hours, maintaining the temperature between 15-25 C. with an ice bath. The cooling bath is removed and 5-chlorosalicylic acid (1000 g, 5.8 mol) added in one portion, then slowly heated to reflux. On completion of the reaction the solution is cooled to -5 C. for 1 hour. The methyl 5-chlorosalicylate is filtered, washed with cold methanol (150 ml) and dionized water (2*1 L). The solid is dried under house vacuum at 30 C. for 24 hours to give methyl 5-chlorosalicylate; m.p. 44-46 C.
		Methyl 5-chloro-2-hydroxybenzoate Following the procedure described for Phenol 1 but substituting 5-chloro-2-hydroxybenzoic acid (Aldrich) for 2-hydroxyphenylacetic acid as starting material, the title compound was obtained as a solid.
	With thionyl chloride; In methanol;	EXAMPLE 1 METHYL 5-CHLOROSALICYLATE To a cold solution of 100 ml methanol is slowly added 100 ml thionyl chloride followed by 30 g of 5-chlorosalicylic acid. This is then refluxed overnight, the solvent removed and the residue dissolved in ether. The ether is washed with a sodium bicarbonate solution, water, dried over magnesium sulfate and evaporated to dryness to obtain methyl 5-chlorosalicylate which is used directly in the next step.
	With sulfuric acid; In methanol;	Example III (S)-N-[3-(1-azabicyclo[2.2.2]octyl)]-5-chloro-2-(2-?18[F]fluoroethoxy)-3-iodobenzamide. (Radioactive analog of 18 (TDP 1056) from Table I). 5-Chlorosalicylic acid was treated with one equivalent of 18M sulfuric acid in refluxing methanol for 20 h to give methyl 5-chlorosalicylate.
	With sulfuric acid; In methanol;	a. Methyl 5-chlorosalicylate 5-Chlorosalicylic acid (5 kg.) dissolved in methanol (50 l.) and concentrated sulfuric acid (2 l.), was heated under reflux for 24 hours. The product crystallized when the solution was cooled in a dry ice/acetone mixture, and the solid when collected gave the ester (5 kg., 92%) sufficiently pure to use in the next step. Recrystallization give pure ester m.p. 45-47.

Reference： [1]Patent: EP234872,1991,B1
[2]Patent: US2003/181496,2003,A1
[3]Patent: EP1479384,2004,A1
[4]Patent: US5288731,1994,A
[5]Patent: US5314900,1994,A
[6]Patent: US4863921,1989,A
[7]Patent: US5723103,1998,A
[8]Patent: US3965173,1976,A

30
[ 58929-72-9 ]
[ 321-14-2 ]
[ 521065-04-3 ]

Yield	Reaction Conditions	Operation in experiment
93%	With potassium carbonate; In ethyl acetate; acetonitrile;	Example 65 6-[5-CHLORO-2-(2-METHOXY-ETHOXY)-PHENYL]-N-(4-CHLORO-PHENYL)[1,3,5]TRIAZINE-2,4-DIAMINE A mixture of 5-chlorosalicylic acid (5.0 g, 29.0 mmol), potassium carbonate (10.8 g, 78.1 mmol), acetonitrile (100 ml), and 2-bromoethylmethyl ether (6.8 ml, 72.3 mmol) was heated under reflux for 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml). The solution was washed with aqueous sodium hydroxide solution (1 M, 2*50 ml), washed with water (50 ml), dried over sodium sulfate, and concentrated under reduced pressure to provide 5-chloro-2-(2-methoxyethoxy)benzoic acid 2-methoxyethyl ester (7.83 g, 93% yield).

Reference： [1]Patent: US2003/153570,2003,A1

31
conc. H₂ SO₄ [ No CAS ]
[ 321-14-2 ]
[ 4068-78-4 ]

Yield	Reaction Conditions	Operation in experiment
94.8%	In methanol;	a. Methyl 5-chloro-2-hydroxybenzoate (2c) A mixture of 5-chloro-2-hydroxybenzoic acid (100 g, 0.57 mol), 20 ml of conc. H2 SO4 and 200 ml of dry methanol was heated under reflux for 22 hours. An additional 5 ml of conc. H2 SO4 was then added and the solution heated for an additional 24 hours. The solvent was evaporated under reduced pressure and the resulting residue poured into aqueous saturated Na2 CO3 and then extracted with CH2 Cl2 (2*400 ml). The organic layers were combined, dried over anhydrous Na2 SO4, and evaporated to give the desired compound as a white solid (100.5 g, 94.8% yield), mp 44-46 C. IR (nujol) 1680 (ester) cm-1. NMR (CDCl3) delta 10.60 (s, 1H, OH), 7.73 (d, 1H, JBC =3 Hz HC), 7.33 (d of d, 1H, JAB =9 Hz, HB), 6.87 (d, 1H, HA), and 3.92 (s, 3H, CH3).

Reference： [1]Patent: US4888353,1989,A

32
[ 321-14-2 ]
[ 116233-17-1 ]
5-Chloro-2-hydroxy-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.5%		Example 165 5-Chloro-2-hydroxy-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)benzamide (Comopund No. 164). Using 5-chlorosalicylic acid and <strong>[116233-17-1]2-amino-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalene</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 77.5%. 1H-NMR(DMSO-d6): delta 1.23(6H, s), 1.24(6H, s), 1.64(4H, s), 2.19(3H, s), 7.13(1H, d, J=9.0Hz) 7.20(1H, s), 7.49(1H, dd, J=8.7, 2.7Hz), 7.67(1H, s), 8.04(1H, d, J=2.7Hz), 10.23(1H, s), 12.26(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

33
[ 321-14-2 ]
[ 2380-36-1 ]
N-{3,5-bis[(1,1-dimethyl)ethyl] phenyl}-5-chloro-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34.1%		Example 163 N-{3,5-Bis[(1,1-dimethyl)ethyl]phenyl}-5-chloro-2-hydroxybenzamide (Comopund No. 162). Using 5-chlorosalicylic acid and 3,5-bis[(1,1-dimethyl)ethyl]aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 34.1%. 1H-NMR(CDCl3): delta 1.26(18H, s), 6.99(1H, d, J=8.7Hz), 7.29(1H, t, J=1.8Hz), 7.39(1H, dd, J=9.0, 2.4Hz), 7.41(2H, d, J=1.5Hz), 7.51(1H, d, J=2.1Hz), 7.81(1H, brs), 12.01(1H, s).
	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Patent: EP1352650,2003,A1
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

34
[ 321-14-2 ]
[ 393-15-7 ]
5-chloro-2-hydroxy-N-[4-methoxy-3-(trifluoromethyl)phenyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79.1%		Example 121 5-Chloro-2-hydroxy-N- [4-methoxy-3-(trifluoromethyl)phenyl]benzamide (Comopund No. 121). Using 5-chlorosalicylic acid and <strong>[393-15-7]4-methoxy-3-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 79.1%. 1H-NMR(DMSO-d6): delta 7.02(1H, d, J=9.0Hz), 7.30(1H, d, J=9.0Hz) 7.48(1H, dd, J=9.0, 3.0Hz), 7.92(1H, dd, J=9.0, 2.4Hz), 7.96(1H, d, J=2.7Hz), 8.04(1H, d, J=2.4Hz), 10.47(1H, s), 11.78(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

35
[ 321-14-2 ]
[ 3535-88-4 ]
5-chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.5%		Example 161 5-Chloro-N-[5-(1,1-dimethyl)ethyl-2-methoxyphenyl]-2-hydroxybenzamide (Comopund No. 160). Using 5-chlorosalicylic acid and 5-[(1,1-dimethyl)ethyl]-2-methoxyaniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 89.5%. 1H-NMR(DMSO-d6): δ 1.28(9H, s), 3.33(3H, s), 7.01(1H, d, J=8.7Hz), 7.05(1H, d, J=9.0Hz), 7.11(1H, dd, J=8.7, 2.4Hz), 7.47(1H, dd, J=9.0, 3.0Hz), 7.99(1H, d, J=3.0Hz), 8.49(1H, d, J=2.4Hz), 10.78(1H, s), 12.03(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

36
[ 321-14-2 ]
[ 328-93-8 ]
[ 439144-65-7 ]

Yield	Reaction Conditions	Operation in experiment
29%	With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;	General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent).
3.6%		Example 100 N-[2,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Comopund No. 100). Using 5-chlorosalicylic acid and <strong>[328-93-8]2,5-bis(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 3.6percent. 1H-NMR(CDCl3): delta 7.03(1H, d, J=8.7Hz), 7.43-7.48(2H, m), 6.61(1H, d, J=8.1Hz), 7.85(1H, d, J=8.4Hz), 8.36(1H, brs), 8.60(1H, s), 11.31(1H, s).
	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]ChemMedChem,2019
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751
[3]Patent: EP1352650,2003,A1
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

37
[ 535-52-4 ]
[ 321-14-2 ]
5-chloro-N-(2-fluoro-5-(trifluoromethyl)phenyl)-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.9%		Example 112 5-Chloro-N-[2-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide (Comopund No. 112). Using 5-chlorosalicylic acid and <strong>[535-52-4]2-fluoro-5-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 77.9%. 1H-NMR(DMSO-d6): delta 7.07(1H, d, J=9.0Hz), 7.52(1H, dd, J=9.0, 2.7Hz), 7.58-7.61(2H, m), 7.95(1H, d, J=2.7Hz), 8.71(1H, d, J=7.5Hz), 10.90(1H, s), 12.23(1H, s).
38%	With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;	General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Patent: EP1352650,2003,A1
[2]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751
[3]ChemMedChem,2019
[4]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

38
[ 5734-64-5 ]
[ 321-14-2 ]
5-Chloro-N-(6-chloro-4-methoxypyrimidin-2-yl)-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
2.2%		Example 43 5-Chloro-N-(6-chloro-4-methoxypyrimidin-2-yl)-2-hydroxybenzamide (Comopund No. 43). Using 5-chlorosalicylic acid and 2-amino-6-chloro-4-methoxypyrimidine as the raw materials, the same operation as the example 16 gave the title compound. Yield: 2.2%, white solid. 1H-NMR(DMSO-d6): delta 3.86(3H, s), 6.85(1H, s), 7.01(1H, d, J=9.0Hz) 7.47(1H, dd, J=9.0, 3.0Hz), 7.81(1H, d, J=3.0Hz), 11.08(1H s), 11.65(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

39
[ 321-14-2 ]
[ 445-03-4 ]
N-[4-chloro-2-(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21.5%		Example 105 5-Chloro-N-[4-chloro-2-(trifluoromethyl)phenyl]-2-hydroxybenzamide (Comopund No. 105). Using 5-chlorosalicylic acid and <strong>[445-03-4]4-chloro-2-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 21.5percent. 1H-NMR(DMSO-d6): delta 7.07(1H, d, J=8.7Hz), 7.52(1H, dd, J=8.7, 2.7Hz), 7.80-7.85(2H, m), 7.97(1H, d, J=2.7Hz), 8.26(1H, d, J=8.4Hz), 10.80(1H, s), 12.26(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

40
[ 321-14-2 ]
[ 454-67-1 ]
5-chloro-N-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.0%		Example 110 5-Chloro-N-[3-fluoro-5-(trifluoromethyl)phenyl]-2-hydroxybenzamide (Comopund No. 110). Using 5-chlorosalicylic acid and <strong>[454-67-1]3-fluoro-5-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 62.0%. 1H-NMR(DMSO-d6): delta 7.04(1H, d, J=8.7Hz), 7.42(1H, d, J=8.4Hz), 7.48(1H, dd, J=9.0, 3.0Hz), 7.85(1H, d, J=2.4Hz), 7.94(1H, dd, J=11.4, 2.1Hz), 7.99(1H, s), 10.73(1H, s), 11.46(1H, s).

Reference： [1]Patent: EP1352650,2003,A1

41
[ 321-14-2 ]
[ 37551-43-2 ]

Yield	Reaction Conditions	Operation in experiment
84.6%	With sodium hydroxide; sulfuric acid; hydroxylamine sulfate; In methanol; water;	EXAMPLE 1 5-Chlorosalicylhydroxamic Acid 50 ml. of concentrated sulfuric acid is added dropwise to a stirred slurry of 200 gm. of 5-chlorosalicylic acid in 400 ml. of methanol. The reaction temperature rises to approximately 35 C. The mixture is heated at reflux with the exclusion of moisture for about 20 hours. The methyl ester separates as an oil and is combined in one portion with 144 gm. of hydroxylamine sulfate in 600 ml. of water at room temperature and rinsed in with methanol. The mixture is stirred and 468 gm. of 50% w/w sodium hydroxide is dripped in while the reaction temperature is maintained at a temperature range of from about 25 to 35 C. After addition of the alkali is completed, 750 ml. of water is added to dissolve the solids while heating to a temperature of about 50 C. The clear solution obtained is allowed to cool to room temperature and neutralized with 140 gm of concentrated sulfuric acid while the temperature is maintained below about 40 C. The precipitate obtained is diluted with 200 ml. of water, filtered, washed with water and dried at a temperature of about 100 C. The 5-chlorosalicylhydroxamic acid obtained has a m.p. 218-220 C., and weighs 182 gm. representing a yield of 84.6%.
84.6%	With sodium hydroxide; sulfuric acid; hydroxylamine sulfate; In methanol; water;	EXAMPLE 1 5-CHLOROSALICYLHYDROXAMIC ACID 50 ml. of concentrated sulfuric acid is added dropwise to a stirred slurry of 200 gm. of 5-chlorosalicylic acid in 400 ml. of methanol. The reaction temperature rises to approximately 35 C. The mixture is heated at reflux with the exclusion of moisture for about 20 hours. The methyl ester separates as an oil and is combined in one portion with 144 gm. of hydroxylamine sulfate in 600 ml. of water at room temperature and rinsed in with methanol. The mixture is stirred and 468 gm. of 50% w/w sodium hydroxide is dripped in while the reaction temperature is maintained at a temperature range of from about 25 to 35 C. After addition of the alkali is completed, 750 ml. of water is added to dissolve the solids while heating to a temperature of about 50 C. The clear solution obtained is allowed to cool to room temperature and neutralized with 140 gm. of concentrated sulfuric acid while the temperature is maintained below about 40 C. The precipitate obtained is diluted with 200 ml. of water, filtered, washed with water and dried at a temperature of about 100 C. The 5-chlorosalicylhydroxamic acid obtained has a m.p. 218-220 C., and weighs 182 gm. representing a yield of 84.6%.

Reference： [1]Patent: US4224323,1980,A
[2]Patent: US4224443,1980,A
[3]Inorganic Chemistry,2013,vol. 52,p. 10747 - 10755

42
[ 321-14-2 ]
[ 54396-44-0 ]
5-chloro-2-hydroxy-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
14.5%		Example 118 5-Chloro-2-hydroxy-N-[2-methyl-3-(trifluoromethyl)phenyl]benzamide (Comopund No. 118). Using 5-chlorosalicylic acid and <strong>[54396-44-0]2-methyl-3-(trifluoromethyl)aniline</strong> as the raw materials, the same operation as the example 16 gave the title compound. Yield: 14.5percent. 1H-NMR(DMSO-d6): delta 2.36(3H, d, J=1.2Hz), 7.05(1H, d, J=8.7Hz), 7.46(1H, t, J=8.1Hz), 7.50(1H, dd, J=8.7, 2.7Hz), 7.60(1H, d, J=7.2Hz), 7.99(1H, d, J=7.2Hz), 8.00(1H, d, J=2.4Hz), 10.43(1H, s), 12.08(1H, s).
	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Patent: EP1352650,2003,A1
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

43
[ 321-14-2 ]
[ 7149-75-9 ]
[ 860001-25-8 ]

Reference： [1]Journal of Medicinal Chemistry,2007,vol. 50,p. 6177 - 6188

44
[ 321-14-2 ]
[ 93246-53-8 ]
[ 1000048-16-7 ]

Yield	Reaction Conditions	Operation in experiment
49%	With phosphorus trichloride; In toluene; for 1.5h;Heating / reflux;	Example 1 Preparation of 5-chloro-N-(3-fluoro-4-morpholinophenyl)-2-hydroxybenzamide (Compound No. 1) A mixture of 5-chlorosalicylic acid (0.30 g, 1.738 mmol), 3-fluoro-4-morpholinoaniline (compound of Reference Example 74; 0.34 g, 1.738 mmol), phosphorus trichloride (0.08 ml, 0.869 mmol) and toluene (6 ml) was refluxed for 1.5 hours. The reaction mixture was cooled to the room temperature, and extracted with ethyl acetate after addition of water. The ethyl acetate layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was washed with diisopropyl ether to give the title compound (0.30 g, 49%) as a colorless crystal. 1H-NMR (DMSO-d6) delta: 2.98 (4H, t, J=4.5 Hz), 3.74 (4H, t, J=4.5 Hz), 7.02 (1H, d, J=9.0 Hz), 7.05 (1H, t, J=9.0 Hz), 7.40 (1H, dd, J=9.0, 2.0 Hz), 7.45 (1H, dd, J=9.0, 2.5 Hz), 7.64 (1H, dd, J=15.0, 2.0 Hz), 7.91 (1H, d, J=2.5 Hz), 10.49 (1H, brs), 11.83 (1H, brs).

Reference： [1]Patent: US2008/227784,2008,A1 .Location in patent: Page/Page column 62

45
[ 321-14-2 ]
[ 15411-43-5 ]
[ 1187819-28-8 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17

46
[ 321-14-2 ]
[ 5369-19-7 ]
[ 634186-63-3 ]

Yield	Reaction Conditions	Operation in experiment
89.9%	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane;Reflux;	Example 5 N-(3-tert-butylphenyl)-5-chloro-2-hydroxybenzamide (3i) Using the method described for compound 3a, 5-chlorosalicylic acid (2.04 g, 11.82 mmol) reacted with <strong>[5369-19-7]3-tert-butylaniline</strong> (1.76 g, 11.82 mmol) and 2M PCl3 in CH2Cl2 (2.336 mL, 4.73 mmol) in xylenes (30 mL). At completion of reaction, the hot xylenes solvent was decanted, cooled to room temperature, and then diluted with hexanes (30 mL). This was stored at 4° C. for 30 hours during which time an off-white crystalline solid separated. The product was recrystallized from EtOAc/hexanes to give a mixture of the title compound (89.9percent and an unidentified impurity (10.1percent). 1H NMR of the major component (400 MHz, DMSO-d6) delta 1.280 (S, 9H), 7.172 (dq, J=8.0, 0.8 Hz, 1H), 7.283 (dd, J=8.0, 0.8 Hz, 1H), 7.455 (dd, J=8.8, 2.6 Hz-, 1H), 7.560 (dd, J=8.0, 0.8 Hz, 1H), 7.679 (M, 1H), 7.982 (d, J=2.6 Hz, 1H), 10.345 (S, 1H), 11.903 (S, 1H). HPLC TR 3.095 min; m/z 303.95 [M+H]+; m/z- =301.85[M-H]-; (EM 303.10).

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17
[2]Patent: US2013/324555,2013,A1 .Location in patent: Paragraph 0086

47
[ 21739-93-5 ]
[ 321-14-2 ]

Reference： [1]Chemistry - A European Journal,2010,vol. 16,p. 2366 - 2370

48
[ 321-14-2 ]
[ 769-21-1 ]

Reference： [1]Patent: WO2011/48525,2011,A1
[2]Patent: WO2011/48525,2011,A1

49
[ 321-14-2 ]
[ 75-36-5 ]
[ 4068-78-4 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 90℃; for 72h;	Methyl 5-chlorosalicylate (14)A solution of 5-chlorosalicylic acid (75. Og, 0.44mol) in MeOH (250ml) was treated portionwise with acetyl chloride (5ml, 70mmol) and heated at 90C for 3 d. The reaction mixture was chilled to 18C and the resulting precipitate collected by filtration. Further purification by trituration with 1 : 1 ether:PE ether gave the title compound (71.99g, 0.38mol).NMR (CDCI3) delta 10.70 (IH, s), 7.82 (IH, d, J2.8), 7.42 (IH, dd, J 8.8, 2.8), 6.95 (IH, d, J 8.8)

Reference： [1]Patent: WO2011/151651,2011,A1 .Location in patent: Page/Page column 58

50
[ 321-14-2 ]
[ 68-35-9 ]
[ 1369701-09-6 ]

Yield	Reaction Conditions	Operation in experiment
63%	With phosphorus trichloride; In chlorobenzene; toluene; for 0.5h;Microwave irradiation; Reflux;	General procedure: 5-Chlorosalicylic acid or 3-chlorobenzoic acid (in the case of 1e) and appropriate sulfonamide (both 1.5 mmol) were suspended in 15 mL of the mixture of toluene and chlorobenzene (1:1), PCl3 (0.75 mmol) was added in one portion by micropipette. The reaction was carried out with vigorous stirring in a microwave reactor (550 W) for 30 min to reflux. Then the reaction mixture was filtered while hot, let stand at room temperature and then at +4 C for 12 h. The crude product was filtered off and recrystallized from boiling ethanol to obtain a pure product.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 50,p. 433 - 440

51
[ 321-14-2 ]
[ 53312-79-1 ]
[ 1401460-87-4 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17

52
[ 321-14-2 ]
[ 77123-60-5 ]
5-chloro-N-(3-cyano-4-fluorophenyl)-2-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17

53
[ 321-14-2 ]
[ 41406-00-2 ]
[ 634186-04-2 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17
[2]Medicinal Chemistry Research,2019,vol. 28,p. 387 - 393

54
[ 321-14-2 ]
[ 22236-08-4 ]
[ 1401460-90-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 8375 - 8391,17

55
[ 321-14-2 ]
[ 85068-29-7 ]
[ 648923-55-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 4h;	To a solution of 5-chlorosalicylic acid (690 mg, 4 mmol), N,N-dimethylaminopyridine (49mg, 0.4 mmol) in dry dichloromethane (12 ml) were added EDCI (1.2g, 8 mmol), and (3,5-bis(trifluoromethyl)benzylamine (973 mg, 4 mmol) at room temperature then the mixture was stirred for 4 h. The reaction mixture was poured into diluted hydrochloric acid and extracted with dichloromethane. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel(ethyl acetate : n - hexane: =1:10) to give the title compound(609mg , 61%). KRT1231 (815mg, 41%) as a white solid. mp=125 - 127 oC. 1H NMR(DMSO-d6) delta 12.09(s, 1H), 9.41(dd, J1=5.9Hz, J2=5.9Hz, 1H), 8.05(s, 2H), 8.01(s, 1H), 7.89(d, J=2.7Hz, 1H), 7.44(dd, J1=8.8Hz, J2=2.6Hz, 1H), 6.97(d, J=8.8Hz, 1H), 4.68(d, J=5.8Hz, 2H).
55%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 3h;	1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a mixture of 5-chlorosalicylic acid (690 mg, 4 mmol, 1.0 equiv), 3,5-bis(trifluoromethyl)benzylamine (973 mg, 4 mmol, 1.0 equiv), 4-dimethylaminopyridine (50 mg, 0.4 mmol, 0.1 equiv) and DCM (12 mL, 0.3 M), and the mixture was stirred at room temperature (3 h). The reaction mixture was poured into dilute HCl (50 mL) and extracted with DCM (70 mL). After the organic layer was washed with water and brine, dried (MgSO4), and concentrated under vacuum, the crude product was purified by column chromatography (1:4 EtOAc:Hex) to give product 23 (245 mg, 55%). White solid. Mp 125-127 C. 1H NMR (300 MHz, DMSO-d6): delta 4.68 (d, J = 5.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 1H), 7.44 (dd, J1 = 8.8, J2 = 2.6 Hz, 1H), 7.89 (d, J = 2.7 Hz, 1H), 8.01 (s, 1H), 8.05(s, 2H), 9.41(dd, J1 = 5.9 Hz, J2 = 5.9 Hz, 1H), 12.09 (s, 1H). HRMS (APCI), m/z calcd for C16H10ClF6NO2: 396.0226, found 396.0229.
38%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;Inert atmosphere;	To 12 ml and of dichloromethane were added 5-chlorosalicylic acid (690 mg, 4 mmol), 3,5-bis(trifluoromethyl)aniline (972 mg, 4 mmol), EDCI (1.2 g, 8 mmol), and DMAP (49 mg, 0.4 mmol) in the presence of argon gas, followed by stirring for 12 hours at room temperature. The mixture was concentrated under reduced pressure, and then dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography (developing solvent: hexane/ethylacetate=1/10) to give 609 mg of the target compound (yield: 38%). m.p: 125-127 C.; 1H-NMR (300 MHz, DMSO-d6) delta 4.68 (d, J=5.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.6 Hz, 1H), 7.89 (d, J=2.7 Hz, 1H), 8.03 (d, J=10.9 Hz, 3H), 9.41 (t, J=5.8 Hz, 1H), 12.09 (s, 1H).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126
[3]Patent: US2014/221411,2014,A1 .Location in patent: Paragraph 0281-0283

56
[ 321-14-2 ]
[ 4273-98-7 ]
[ 1417658-16-2 ]

Yield	Reaction Conditions	Operation in experiment
24%	With pyridine; phosphorus trichloride; In toluene; for 12.0h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

57
[ 321-14-2 ]
[ 4519-40-8 ]
[ 1284390-00-6 ]

Yield	Reaction Conditions	Operation in experiment
58%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

58
[ 321-14-2 ]
[ 393-39-5 ]
[ 634185-66-3 ]

Yield	Reaction Conditions	Operation in experiment
6%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]ChemMedChem,2019
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

59
[ 321-14-2 ]
[ 39885-50-2 ]
[ 934192-70-8 ]

Yield	Reaction Conditions	Operation in experiment
43%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Inert atmosphere; Reflux;	General procedure: Anilide synthesis. General method. To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv), the aniline derivative (1 equiv), and dry xylenes(stored over 3A molecular sieves, 40 mL per gram of 5-chloro-2-hydroxybenzoic acid) under an Argon atmosphere. The mixture was heated to reflux, and PCl3 (0.4 equiv) was added rapidly via syringe. The mixture was heated at reflux for 1 h and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 h. Saturated sodium bicarbonate was added to a final pH of 3?4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95percent by LC. Additional experimental procedures and analytical data are provided in Supplemental data.
	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Molecular sieve; Inert atmosphere; Reflux;	General procedure: Example 4. Anilide Synthesis (0233) (0234) General Method: (0235) To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv.), the aniline derivative (1 equiv.), and dry xylenes (stored over 3 A molecular sieves, 40 mL per gram of 5-chloro-2-hydroxybenzoic acid) under an atmosphere of argon. The mixture was heated to reflux, and PCl3 (0.4 equiv.) was added rapidly via syringe. The mixture was heated at reflux for 1 hour and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 hour. Saturated sodium bicarbonate was added to a final pH of 3-4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95percent by LC. HPLC/MS was accomplished using an Agilent spectrometer ?6310 Ion trap. Mass ions (m/z) detected in positive ionization mode are M+; in negative ionization mode, mass ions (m/z) are M?.

With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane; for 5h;Reflux;

Both compounds were synthesized using a one-step reaction. For the synthesis of Compound 7, commercially- available 5-chlorosalicylic acid was coupled with [39885-50-2]2-chloro-4-trifluoromethyl aniline using a 2 M solution of phosphorus trichloride in dichloromethane. Xylene was used as the solvent for the reaction and the reaction mixture was refluxed for 5 hours (or until the reactants disappeared). The hot solution was transferred and brought to room temperature for the product to precipitate out of the solution. The precipitate was then re-dissolved in ethyl acetate and recrystallized to obtain the pure Compound 7.

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126
[2]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5829 - 5838
[3]Patent: US2017/190675,2017,A1 .Location in patent: Paragraph 0233-0236
[4]Patent: WO2018/136650,2018,A1 .Location in patent: Paragraph 0251

60
[ 321-14-2 ]
[ 452-83-5 ]
[ 1417658-22-0 ]

Yield	Reaction Conditions	Operation in experiment
26%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

61
[ 321-14-2 ]
[ 433-94-3 ]
[ 2965-99-3 ]

Yield	Reaction Conditions	Operation in experiment
9%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

62
[ 321-14-2 ]
[ 393-36-2 ]
[ 1426396-71-5 ]

Yield	Reaction Conditions	Operation in experiment
26%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

63
[ 321-14-2 ]
[ 654-70-6 ]
[ 634185-61-8 ]

Yield	Reaction Conditions	Operation in experiment
16%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

64
[ 321-14-2 ]
[ 35944-64-0 ]
[ 96279-53-7 ]

Yield	Reaction Conditions	Operation in experiment
14%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

65
[ 203302-95-8 ]
[ 321-14-2 ]
[ 1417658-25-3 ]

Yield	Reaction Conditions	Operation in experiment
32%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

66
[ 321-14-2 ]
[ 367-34-0 ]
[ 1417658-27-5 ]

Yield	Reaction Conditions	Operation in experiment
10%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

67
[ 321-14-2 ]
[ 3862-73-5 ]
[ 1039811-86-3 ]

Yield	Reaction Conditions	Operation in experiment
16%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

68
[ 321-14-2 ]
[ 98446-49-2 ]
[ 1417658-28-6 ]

Yield	Reaction Conditions	Operation in experiment
43%	With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;	General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 114 - 126

69
[ 321-14-2 ]
[ 349-55-3 ]
5-chloro-2-hydroxy-N-(3-methoxy-5-(trifluoromethyl)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
49%	With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;	General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751

70
[ 321-14-2 ]
[ 393-36-2 ]
[ 634185-62-9 ]

Yield	Reaction Conditions	Operation in experiment
26%	With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;	General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751

71
[ 268733-18-2 ]
[ 321-14-2 ]
[ 1426396-73-7 ]

Yield	Reaction Conditions	Operation in experiment
20%	With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;	General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1748 - 1751

72
[ 321-14-2 ]
[ 74-88-4 ]
[ 4068-78-4 ]

Reference： [1]Organic Letters,2013,vol. 15,p. 2574 - 2577
[2]Organic Letters,2015,vol. 17,p. 4550 - 4553

73
[ 69-72-7 ]
[ 321-14-2 ]
[ 320-72-9 ]
[ 1829-32-9 ]

Reference： [1]Magnetic Resonance in Chemistry,2014,vol. 52,p. 310 - 317

74
[ 2033-24-1 ]
[ 321-14-2 ]
[ 883-92-1 ]

Yield	Reaction Conditions	Operation in experiment
	In water at 50℃; for 0.5h; Sonication;

Reference： [1]Kanchithalaivan, Selvaraj; Sumesh, Remani Vasudevan; Kumar, Raju Ranjith [ACS Combinatorial Science, 2014, vol. 16, # 10, p. 566 - 572]

75
[ 21803-75-8 ]
[ 321-14-2 ]
[ 17209-16-4 ]

Yield	Reaction Conditions	Operation in experiment
21%	With trichlorophosphate; In 5,5-dimethyl-1,3-cyclohexadiene; for 17.5h;Reflux;	To a mixture of 5-chloro-2-hydroxybenzoic acid (0.35g, 0.002 mol) and 4-amino-3- chlorobenzonitrile (0.3 lg, 0.002 mol) in xylenes (10 mL) at ambient temperature was added phosphorous oxychloride (0.068g, 0.56 mmol) in one portion. The mixture was refluxed for 17.5 h. The mixture was cooled to ambient temperature and the resulting orange solid was filtered and washed several times with hexanes to give 265 mg of crude product. The orange solid was placed in hot acetic acid (45 mL) and an insoluble orange solid (B) was filtered off. The filtrate was allowed to cool to ambient temperature and stand for 3 days. The resulting light orange solid (A) was filtered and washed with hexanes. After air drying both solids, B amounted to 33.8 mg and A amounted to 92.8 mg. Total yield was 126.6 mg (21% yield) of 5-chloro-N-(2-chloro-4-cyanophenyl)-2-hydroxybenzamide. Both solids gave similar MS and NMR results. The following MS and NMR results are for A. MS: m/z 305 (MH"). 1H NMR (500 MHz, DMSO~d6): delta 7.097 (d, 1H), 7.538 (dd, 1H), 7.884 (dd, 1H), 7.967 (d, 1H), 8.190 (d, 1H), 8.714 (d, 1H), 11.220 (s, 1H), 12.450 (s, 1H).

Reference： [1]Patent: WO2014/165816,2014,A1 .Location in patent: Page/Page column 71-72

76
[ 321-14-2 ]
[ 69409-98-9 ]
5-chloro-N-(2-fluoro-4-(trifluoromethyl)phenyl)-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Inert atmosphere; Reflux;	General procedure: Anilide synthesis. General method. To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv), the aniline derivative (1 equiv), and dry xylenes(stored over 3A molecular sieves, 40 mL per gram of 5-chloro-2-hydroxybenzoic acid) under an Argon atmosphere. The mixture was heated to reflux, and PCl3 (0.4 equiv) was added rapidly via syringe. The mixture was heated at reflux for 1 h and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 h. Saturated sodium bicarbonate was added to a final pH of 3-4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95% by LC. Additional experimental procedures and analytical data are provided in Supplemental data.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5829 - 5838

77
[ 321-14-2 ]
[ 22864-65-9 ]
5-chloro-2-hydroxy-N-methyl-N-(4-(trifluoromethyl)phenyl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Inert atmosphere; Reflux;	General procedure: Anilide synthesis. General method. To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv), the aniline derivative (1 equiv), and dry xylenes(stored over 3A molecular sieves, 40 mL per gram of 5-chloro-2-hydroxybenzoic acid) under an Argon atmosphere. The mixture was heated to reflux, and PCl3 (0.4 equiv) was added rapidly via syringe. The mixture was heated at reflux for 1 h and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 h. Saturated sodium bicarbonate was added to a final pH of 3-4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95% by LC. Additional experimental procedures and analytical data are provided in Supplemental data.

Reference： [1]Bioorganic and Medicinal Chemistry,2015,vol. 23,p. 5829 - 5838

78
[ 29608-05-7 ]
[ 321-14-2 ]
5-chloro-2-hydroxy-N-(4-(piperidin-1-ylmethyl)phenyl)benzamide [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 283 - 288

79
[ 321-14-2 ]
[ 121-87-9 ]
[ 50-65-7 ]

Yield	Reaction Conditions	Operation in experiment
68.7%	With phosphorus trichloride; In chlorobenzene; at 135℃; for 3h;	In 135 C, to the 5- chlorine salicylic acid (3.44g, 20 . 0mmol) and 2-chloro-4-nitroaniline (3.44g, 20 . 0mmol) dissolved in chlorobenzene mixing solution of adding dropwise PCl3(2.4g, 17 . 5mmol) dissolved in a chlorobenzene solution. 3 hours later, the reaction solution is cooled to the room temperature. Filtering and collecting the resulting solid, wash, then from ethyl acetate (or acetone) recrystallization to obtain a white solid (6.8g, 68.7%) shaped N-(2-chloro-4-nitro-phenyl) - 5-chloro-2-hydroxy-benzamide.
	With thionyl chloride; In 5,5-dimethyl-1,3-cyclohexadiene; at 78℃; for 6.1h;Reflux;	5-chloro-salicylic acid, o-chloro-p-nitroaniline, xylene = 14%: 15.5%: 59.5% 5-chloro-salicylic acid, o-chloronitroaniline, xylene Into the chemical reactor for the first reaction, The temperature of the mixture was raised to 78 C while stirring, Open the exhaust gas absorption system, In the 3.1 hours of time to the chemical reactor by adding a weight ratio of 11% thionyl chloride, After dripping, Heated to reflux and heat for 3 hours, And then cooled to 30 C to obtain a solid-liquid mixture. The solid-liquid mixture is fed into a filter, Filter out the liquid fraction, The solid portion is fed to a centrifugal separator to further separate the liquid portion, The resulting solid is the crude of the nicotinamide intermediate. The crude product of nicotinamide intermediate is fed into the recrystallization kettle for the second reaction, adding the same amount of ethanol as the first reaction and the same amount of xylene, Heated to reflux for 0.9 hours, And then cooled to 20 C to obtain a solid-liquid mixture, The solid-liquid mixture was then sent to a centrifugal centrifuge to obtain a solid by centrifugation, and the solid was sent to a drying machine to dry, That is, products, The yield of the final product, niclosamide intermediate, is greater than 80% and the purity is greater than 95.0%.

Reference： [1]Patent: CN105566147,2016,A .Location in patent: Paragraph 0063; 0064; 0065
[2]Patent: CN106431949,2017,A .Location in patent: Paragraph 0013; 0014; 0015
[3]Medicinal Chemistry Research,2019,vol. 28,p. 387 - 393

80
[ 19798-77-7 ]
[ 321-14-2 ]
5-chloro-N-(2-chloropyridine-4-yl)-2-hydroxybenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With phosphorus trichloride; In 5,5-dimethyl-1,3-cyclohexadiene; for 1h;Molecular sieve; Inert atmosphere; Reflux;	Example 1. Comp [00153] General method: To a 100 mL flask equipped with a reflux condenser was added 5-chloro-2-hydroxybenzoic acid (1 equiv.), the aminoheteroaryl derivative NH2-Q (1 equiv.), and dry xylenes (stored over 3A molecular sieves, 40 mL per gram of 5-chloro-2- hydroxybenzoic acid) under an atmosphere of argon. The mixture was heated to reflux, and PCI3 (0.4 equiv.) was added rapidly via syringe. The mixture was heated at reflux for 1 hour and cooled to room temperature. Water (40 mL per gram of 5-chloro-2-hydroxybenzoic acid) was added and the resultant heterogeneous mixture stirred rapidly for 1 hour. Saturated sodium bicarbonate was added to a final pH of 3-4, and the mixture stirred rapidly overnight. The solids were filtered and washed sequentially with water, toluene and hexane. Samples were analyzed by NMR, HPLC/mass spectrometry and TLC. Purification by crystallization or column chromatography on silica gel was performed when purity was less than 95% by LC. HPLC/MS was accomplished using an Agilent spectrometer - 6310 Ion trap. Mass ions (m/z) detected in positive ionization mode are M+ ; in negative ionization mode, mass ions (m/z) are M-.

Reference： [1]Patent: WO2016/210247,2016,A1 .Location in patent: Paragraph 00153-00154

81
[ 5910-89-4 ]
[ 321-14-2 ]
C₇H₅ClO₃*C₆H₈N₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	In methanol; water; for 0.25h;	A solution of 5-CHBA (0.0345g, 0.20mmol) and 2,3-DMP (44muL, 0.4mmol) was prepared in water-methanol solution (1:1=v/v, 10mL). Then the solution was strongly stirred for 15min and kept at 25C. The colorless block crystals were gained in 69% yield after two weeks. m. p: 159C. Anal. Calcd (%) for C13H13ClN2O3 (1): C, 55.61; H, 4.63; N, 9.98; found: C, 54.85; H, 4.99; N, 9.87. IR (KBr pellet, cm-1): 3435 (m), 3055 (m), 2392 (m), 1922 (m), 1663 (s), 1598 (m), 1485 (s), 1474 (s), 1408 (s), 1362 (m), 1328 (m), 1292 (m), 1231 (s), 1175 (s), 1107 (m), 977 (m), 914 (m), 876 (m), 839 (m), 804 (m), 704 (s), 648 (s), 616 (m), 541 (m), 454 (w), 441 (m)

Reference： [1]Journal of Molecular Structure,2018,vol. 1165,p. 106 - 119

82
[ 321-14-2 ]
[ 978-62-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2307 - 2315

83
[ 321-14-2 ]
[ 50-65-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2019,vol. 29,p. 2307 - 2315

84
[ 321-14-2 ]
[ 1940-29-0 ]
N-(4-bromo-3,5-dichlorophenyl)-5-chloro-2-hydroxybenzamide [ No CAS ]

Reference： [1]ChemMedChem,2019

85
[ 321-14-2 ]
[ 65896-11-9 ]
N-(2-bromo-6-fluorophenyl)-5-chloro-2-hydroxybenzamide [ No CAS ]

Reference： [1]ChemMedChem,2020,vol. 15,p. 210 - 218

86
[ 321-14-2 ]
[ 121-01-7 ]
5-chloro-2-hydroxy-N-(4-nitro-2-(trifluoromethyl)phenyl) benzamide [ No CAS ]

Reference： [1],2020,vol. 14,p. 371 - 393

87
[ 321-14-2 ]
[ 27298-99-3 ]
(R)-5-chloro-N-(1-(4-chlorophenyl)ethyl)-2-hydroxybenzamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2020,vol. 63,p. 3142 - 3160

88
[ 7749-47-5 ]
[ 321-14-2 ]
C₇H₅ClO₃*C₆H₉N₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; for 0.5h;Heating;	General procedure: The title salts were synthesized by the reaction of 1:1 stoichiometricmixtures of 2-amino-4-methoxy-6-methylpyrimidine(34.79 mg, 0.25 mmol) with 4-aminosalicylic acid (38.28 mg,0.25 mmol) or 5-chlorosalicylic acid (43.14 mg, 0.25 mmol) inhot methanol solution (20 ml), after warming over a water bathfor 30 min. The solutions were cooled and kept at roomtemperature.Within a few days, block-shaped brown crystals ofsalt I and colourless needle-shaped crystals of salt II wereobtained by slow evaporation at room temperature. Bothcrystals were suitable for single-crystal X-ray structure analysis

Reference： [1]Acta Crystallographica Section C: Structural Chemistry,2022,vol. 78,p. 181 - 191

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P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
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P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
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P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
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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
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H271	May cause fire or explosion; strong oxidizer
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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
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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. 321-14-2 ] {[proInfo.proName]}

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[ 321-14-2 ] Synthesis Path-Upstream 1~6

[ 321-14-2 ] Synthesis Path-Downstream 1~88

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Aryls

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Carboxylic Acids

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