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[ CAS No. 403-16-7 ] {[proInfo.proName]}

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Chemical Structure| 403-16-7

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Quality Control of [ 403-16-7 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 403-16-7 ]

CAS No. :	403-16-7	MDL No. :	MFCD00042477
Formula :	C₇H₄ClFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	PKTSBFXIHLYGEY-UHFFFAOYSA-N
M.W :	174.56	Pubchem ID :	520989
Synonyms :

Calculated chemistry of [ 403-16-7 ]

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 :	1.0
Molar Refractivity :	38.37
TPSA :	37.3 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) :	-5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.39
Log Po/w (XLOGP3) :	2.27
Log Po/w (WLOGP) :	2.6
Log Po/w (MLOGP) :	2.63
Log Po/w (SILICOS-IT) :	2.28
Consensus Log Po/w :	2.23

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.69
Solubility :	0.356 mg/ml ; 0.00204 mol/l
Class :	Soluble
Log S (Ali) :	-2.69
Solubility :	0.356 mg/ml ; 0.00204 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.66
Solubility :	0.379 mg/ml ; 0.00217 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.36

Safety of [ 403-16-7 ]

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

Application In Synthesis of [ 403-16-7 ]

* 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 [ 403-16-7 ]
Downstream synthetic route of [ 403-16-7 ]

[ 403-16-7 ] Synthesis Path-Upstream 1~9

1
[ 65055-17-6 ]
[ 403-16-7 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With hydrogenchloride In sodium hydroxide; water	2 g of 3-chloro-4-fluorobenzoyl chloride (purity 99.6percent GC [a/a]) are carefully hydrolyzed in 4 g of 50percent strength sodium hydroxide solution and 20 g of water at 60° C. The solution is then stirred for a further 2 hours at room temperature. The mixture is then adjusted to a pH of 1 using conc. hydrochloric acid, and the precipitated 3-chloro-4-fluorobenzoic acid is filtered off with suction, washed with water and dried. This gives 1.68 g of 3-chloro-4-fluorobenzoic acid in the form of a white powder. Yield: 92.8percent of theory melting point: 136° C. (lit: 136° C.)

Reference： [1] Patent: US6187952, 2001, B1,

2
[ 456-22-4 ]
[ 403-16-7 ]

Reference： [1] Journal of Organic Chemistry, 2005, vol. 70, # 4, p. 1501 - 1504

3
[ 60811-21-4 ]
[ 590-29-4 ]
[ 403-16-7 ]

Reference： [1] Journal of the American Chemical Society, 2013, vol. 135, # 8, p. 2891 - 2894

4
[ 348-51-6 ]
[ 403-16-7 ]

Reference： [1] Journal of the Chemical Society, 1963, p. 2784 - 2787

5
[ 2923-66-2 ]
[ 403-16-7 ]

Reference： [1] Journal of the Chemical Society, 1963, p. 2784 - 2787

6
[ 403-16-7 ]
[ 36556-52-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3659 - 3666

7
[ 403-16-7 ]
[ 154257-76-8 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1995, # 10, p. 1265 - 1272
[2] Journal of Medicinal Chemistry, 2006, vol. 49, # 12, p. 3659 - 3666
[3] Patent: WO2010/125102, 2010, A1, . Location in patent: Page/Page column 76

8
[ 403-16-7 ]
[ 234082-35-0 ]

Yield	Reaction Conditions	Operation in experiment
69%	With sulfuric acid In methanol for 16 h; Reflux	A round bottomed flask was charged with 3-chloro-4-fluoro-benzoic acid (2.0 g, 11.4 mmol),sulfuric acid (0.33 g, 3.4 mmol), MeOH (20 mL) and refluxed for 16 h (TLC indicatedcomplete consumption of starting material). The volatiles were removed under reducedpressure; the residue was diluted with water (15 mL) and extracted with EtOAc (3 x 50 mL).The combined organic extracts were washed with brine (50 mL), dried over Na2S04 andconcentrated in vacuo to give the crude residue which was purified by columnchromatography (100-200 silica gel, 40 g, 10percent EtOAc-hexane) to afford methyl3-chloro-4-fluoro-benzoate ( 1.5 g, 69percent) as a light yellow oil. 1H NMR [300 MHz, CDCh]: J 8.08 (dd, J = 6.9, 2.1 Hz, 1H), 7.94-7.89 (m, 1H), 7.18 (t, J =8.7 Hz, 1H), 3.90 (s, 3H).

Reference： [1] Patent: WO2018/125961, 2018, A1, . Location in patent: Page/Page column 30

9
[ 67-56-1 ]
[ 403-16-7 ]
[ 234082-35-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	Heating / reflux	Preparative Example 29.; A round bottomed flask was charged with 3-chloro-4-fluorobenzoic acid (5.0 g, 28.6 mmol), sulfuric acid (0.84 g, 8.6 mmol), and methanol (60 mL). The solution was heated at reflux overnight. The methanol was removed in vacuo. The residue was extracted with ethyl acetate (5 x), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.73 g (88percent).A round bottomed flask was charged with the ester intermediate (4.73 g, 25 mmol), potassium carbonate (3.45 g, 25 mmol), piperazine-1-carboxylic acid tert-butyl ester (5.59 g, 30 mmol) and acetonitrile (6 mL). The mixture was heated at 65⁰C overnight and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5 N HCI, 0.5 N NaOH, and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. There was obtained 4.79 g of intermediate 34 which was not purified further.

Reference： [1] Patent: WO2006/88919, 2006, A2, . Location in patent: Page/Page column 142-143
[2] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 14, p. 6724 - 6731

[ 403-16-7 ] Synthesis Path-Downstream 1~88

1
4-amino-3-(2,4-dichloro-5-fluorophenyl)-5-mercapto-1,2,4-triazol-5-thiol [ No CAS ]
[ 403-16-7 ]
6-(3-chloro-4-fluorophenyl)-3-(2,4-dichloro-5-fluorophenyl)-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole [ No CAS ]

Reference： [1]Monatshefte fur Chemie,2007,vol. 138,p. 1309 - 1316

2
[ 403-16-7 ]
2,3-dichloro-4-fluorobenzoyl chloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

3
[ 403-16-7 ]
[ 870065-86-4 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

4
[ 403-16-7 ]
[ 905600-51-3 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

5
[ 403-16-7 ]
[ 899431-55-1 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

6
[ 403-16-7 ]
[ 899431-59-5 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

7
[ 403-16-7 ]
[ 36556-52-2 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 3659 - 3666

8
[ 403-16-7 ]
2-(3'-chloro-4'-fluorobenzoyl)-1,4-benzoquinone [ No CAS ]

Reference： [1]Journal of the Indian Chemical Society,1994,vol. 71,p. 409 - 414

9
[ 403-16-7 ]
(3-Chloro-4-fluoro-phenyl)-(2,5-dihydroxy-phenyl)-methanone [ No CAS ]

Reference： [1]Journal of the Indian Chemical Society,1994,vol. 71,p. 409 - 414

10
[ 348-51-6 ]
[ 403-16-7 ]

Reference： [1]Journal of the Chemical Society,1963,p. 2784 - 2787

11
[ 1126-09-6 ]
[ 403-16-7 ]
[ 570408-12-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 48h;	Reference Example 99 To a solution of 1.15 g of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> in 20 ml of DMSO, 1.3 g of potassium carbonate and 1.4 g of isonipecotic acid ethyl ester were added, and the mixture was heated while stirring at 80 C for 2 days. EtOAc was added to the reaction solution, and the organic layer was washed with water and brine and then dried over sodium sulfate.. After the evaporation of the solvent, the obtained residue was purified by silica gel column chromatography (eluent: hexane-EtOAc = 20:1?10:1) to obtain 1.42 g of N-(4-tert-butoxycarbonyl-2-chloropheyl)isonipecotic acid ethyl ester.

Reference： [1]Patent: EP1466912,2004,A1 .Location in patent: Page 22

12
[ 403-16-7 ]
[ 65055-17-6 ]

Yield	Reaction Conditions	Operation in experiment
91%	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 45℃; for 4h;Inert atmosphere;	To a solution of 6 <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (15 g, 86.2 mmol, 1.00 equiv) in 7 dichloromethane (150 mL) under an inert atmosphere of 8 nitrogen was added 9 N,N-dimethylformamide (315 mg, 4.3 mmol, 0.05 equiv). Then 10 thionyl chloride (50.8 g, 431 mmol, 5 equiv) was added at 0 C. The reaction solution was stirred for 4 h at 45 C. The resulting mixture was concentrated under vacuum to afford 15 g (91%) of 11 3-chloro-4-fluorobenzoyl chloride as brown oil.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 18 - 25℃; for 16h;	1- [3-Chloro-4-fluorophenyl) carbony] azetidine; To a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (1.74 g, 10.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1 drop). The mixture was stirred at ambient temperature for 16 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture, which was stirred at ambient temperature for 2 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and 1N hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried (MgS04), and evaporated. The residue was crystallized from ethyl acetate/isohexane to give the title compound (1.64 g). 'H NMR 8 (CDC13) : 2.4 (m, 2H), 4.2-4. 4 (m, 4H), 7.2 (m, 1H), 7.55 (m, 1H), 7.7 (m, 1H)
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 16h;	1 -(3 -Chloro-4-fluorobenzoyl)azetidineTo a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (1.74 g, 10.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1 drop). The mixture was stirred at ambient temperature for 16 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture, which was stirred at ambient temperature for 2 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and IN hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried (MgSO4), and evaporated. The residue was crystallized from ethyl acetate / isohexane to give the title compound (1.64 g).1H NMR ? (CDCl3): 2.4 (m, 2H), 4.2-4.4 (m, 4H), 7.2 (m, IH), 7.55 (m, IH), 7.7 (m, IH).

	With thionyl chloride; N,N-dimethyl-formamide; at 60℃; for 0.5h;Inert atmosphere;	General procedure: 2-Chloro-4-fluorobenzoic acid, 2-chloro-6-fluorobenzoic acid, <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> and 4-chloro-2-fluorobenzoic acid 1(a-d) (5 g, 28.7 mmol) were converted into their respective acid chlorides 2(a-d) by reaction with thionyl chloride (4.09 g, 2.49 mL and 34 mmol) in the presence of a drop of DMF under reflux for 30 min. Completion of the reaction was indicated by the stoppage of gas evolution. Removal of excess of thionyl chloride was carried out under reduced pressure to afford dihalobenzoyl chlorides 2(a-d). Mixtures of homophthalic acid (1.3 g, 7.2 mmol) and dihalobenzoyl chlorides 2(a-d) (5.516 g, 28.7 mmol) were heated at 200 C under reflux for 4 h. The mixtures were dissolved in ethyl acetate and aqueous solution of sodium carbonate was added in order to remove the unreacted homophthalic acid. Organic layer was separated and the aqueous layer was extracted with 2× 25 mL ethyl acetate. The combined organic layers were concentrated and chromatographed on silica gel using pet ether (40-80 C fraction) as eluent which gave 3-(dihalophenyl)isocoumarins 3(a-d) as solids, which were further purified by recrystallization from methanol.
	With thionyl chloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃;Inert atmosphere;	General procedure: Under inert atmosphere, a mixture of carboxylic acid 21-31 ( Scheme 1 ) (1 equiv), thionyl chloride (1.5 equiv) and DMF (3-5 drops) in dichloromethane was stirred at rt until the complete consumption of the carboxylic acid (1H NMR control). The pale yellow solution was concentrated in vacuo to give the crude acid chloride 32-42 ( Scheme 1 ) as a yellow pale solid in quantitative yield
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 16h;	To a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (1.74 g, 10.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1 drop). The mixture was stirred at ambient temperature for 16 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture, which was stirred at ambient temperature for 2 hours. The DCM was evaporated in vacuo, and the residue partitioned between ethyl acetate (100 mL) and IN hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen . carbonate and brine, dried (MgS04), and evaporated. The residue was crystallized from ethyl acetate/ isohexane to give the title compound (1.64 g). ¹H NMR 8 (CDCl3) : 2.4 (m, 2H), 4.2-4.4 (m, 4H), 7.2 (m, 1H), 7.55 (m, 1H), 7.7 (m, 1H).

Reference： [1]Patent: US2018/79742,2018,A1 .Location in patent: Paragraph 0306; 0307
[2]Patent: WO2005/80360,2005,A1 .Location in patent: Page/Page column 95
[3]Patent: WO2007/7042,2007,A1 .Location in patent: Page/Page column 40-41
[4]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 481 - 484
[5]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245
[6]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 2307 - 2317
[7]European Journal of Medicinal Chemistry,2018,vol. 155,p. 197 - 209
[8]Patent: WO2005/121110,2005,A1 .Location in patent: Page/Page column 107

13
[ 247570-24-7 ]
[ 403-16-7 ]
C₁₈H₂₄ClFN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); water; at 20℃; for 20h;	To a solution of <strong>[403-16-7]3-chloro-4-fluoro-benzoic acid</strong> (26.9 g) and cis- (4-amino- cyclohexyl)-carbamic acid tert-butyl ester (30.0 g) in DMF (300 mL) were added Et3N (46.8 mL), HOBt-H2O (32.2 g), and EDC-HCI (29.5 g). The mixture was stirred at ambient temperature for 20 hr. To the mixture was added water (1.20 L) and the aqueous layer was extracted with CHC13 (three times). The combined organic layer was dried over MgS04, filtered, and concentrated under reduced pressure. A solution of the residue in EtOAc (650 mL) was cooled on an ice-bath and 4 M hydrogen chloride in EtOAc (325 mL) was added. The mixture was stirred at ambient temperature for 16 hr and concentrated under reduced pressure. The residue was dissolved in 1 M aqueous NaOH (300 mL) and the aqueous layer was extracted with CHCI3 (three times). The combined organic layer was dried over MgS04, filtered, concentrated under reduced pressure, and dried under reduced pressure to give N- (cis-4-amino-cyclohexyl)-3-chloro-4-fluoro- benzamide (44.4 g). ESI MS m/e 271, M (free) + IT" ; 1H NMR (300 MHz, CDCl3) 6 1. 37-1. 92 (m, 8 H), 2.94- 3.08 (m, 1 H), 4.06-4. 22 (m, l H), 6.13-6. 31 (m, 1 H), 7.19 (t, J= 8.5 Hz, 1 H), 7.61-7. 70 (m, 1 H), 7.79-7. 87 (m, 1 H).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	To a solution of ter£-butyl (c/s~4-aminocyclohexyl)carbamate (130 g) in DMF (1.3 L) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (116 g), Et3N (202 mL), HOBt-H2O (139 g), and EDC-HCl (128 g). The mixture was stirred at ambient temperature for 16 h. To the mixture was added water (3 L) 5 and the suspension was stirred at ambient temperature for 4 h. The precipitate was collected by EPO <DP n="56"/>filtration, washed with water, and dried at 800C under reduced pressure to give a brown solid (216 g). To a suspension of the above solid in EtOAc (1.3 L) was added 4 M hydrogen chloride in EtOAc (1.3 L) under 10 0C and the mixture was stirred at ambient temperature for 12 h. The precipitate was collected by filtration, washed with EtOAc, and dried at 80 0C under reduced pressure to give a pale brown solid (174 g). To the above solid was added 1 M aqueous NaOH (I L). The mixture was stirred at ambient temperature for 30 min and poured into CHCl3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give N-(c-4-aminocyclohexyl)-3-chloro-4-fluorobenzamide (145 g) as a pale brown solid. 1HNMR (300 MHz, CDCl3, delta): 1.26-1.54 (m, 4H), 1.65-1.92 (m, 6H), 2.94-3.07 (m, IH), 4.07-4.22 (m, IH), 5.98-6.17 (m, IH), 7.19 (t, J= 8.6 Hz, IH), 7.60-7.68 (m, IH), 7.83 (dd, J= 6.9, 2.3 Hz, IH); ESI MS m/z 271 (M++., 100%).

Reference： [1]Patent: WO2005/95357,2005,A2 .Location in patent: Page/Page column 127; 128
[2]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 52-53

14
[ 866648-51-3 ]
[ 403-16-7 ]
3-chloro-N-(cis-4-[6-(dimethylamino)-2-methylpyrimidin-4-yl]amino}-cyclohexyl)-4-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 12h;	To a solution of <strong>[403-16-7]3-chloro-4-fluoro-benzoic acid</strong> (192 mg) and N- (cis-4-amino- cyclohexyl)-2, N', N'-trimethyl-pyrimidine-4, 6-diamine (250 mg) in DMF (4 mL) were added Et3N (0.34 mL), HOBt-H2O (230 mg), and EDC-HCI (211 mg). The mixture was stirred at ambient temperature for 12 hr. To the mixture was added water (20 mL) and the aqueous layer was extracted wi. th CHC13 (three times). The combined organic layer was dried over MgS04, filtrated, concentrated under reduced pressure, and purified by medium- pressure liquid chromatography (NH-silica gel, 25% to 50% EtOAc in hexane) to give 3- chloro-N-(cis-4- { [6-(dimethylamino)-2-methylpyrimidin-4-yl] amino}-cyclohexyl)-4- fluorobenzamide. To a solution of the above material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.2 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated. The residue was suspended in Et2O (20 mL) and the suspension was stirred at ambient temperature for 2 hr. The precipitate was collected by filtration, washed with Et2O, and dried at 70C under reduced pressure to give 3-chloro-N-(cis-4- { [6- (dimethylamino)-2-methylpyrimidin-4-yl] amino}-cyclohexyl)-4-fluorobenzamide hydrochloride (196 mg). ESI MS m/e 406, M (free) + H+ ;'H NMR (300 MHz, CDCl3) S 1.62-2. 00 (m, 8 H), 2.49 (s, 3 H), 2.99-3. 40 (m, 6 H), 3.67-3. 79 (m, 1 H), 4.02-4. 20 (m, 1 H), 5.15 (s, 1 H), 6.59-6. 70 (m, 1 H), 7.11-7. 26 (m, 1 H), 7.67-7. 79 (m, 1 H), 7.89-8. 02 (m, 1 H), 8. 48-8. 61 (m, 1 H).

Reference： [1]Patent: WO2005/95357,2005,A2 .Location in patent: Page/Page column 118; 119

15
[ 374-01-6 ]
[ 403-16-7 ]
[ 869569-63-1 ]

Yield	Reaction Conditions	Operation in experiment
		To a 0 C solution of compound 1 (10.7 g, 61.37 mmol), (R)-1,1,1- tritluoropropanol (3.5 g, 30.68 mmol) in dimethylformamide (200 mL) was added sodium hydride( 3.7g, 92.05 mmol) portion wise over 5 minutes. After 10 min, the ice bath was removed and the reaction mixture was stirred while warming to room temperature. The reaction mixture was heated to 80 C and stirred overnight. The reaction was monitored by LC/MS. After the reaction was done it was cooled to room temperature. The reaction mixture was quenched with HCI (0.5N, 200 mL) and extracted with ethyl acetate (3 x 250 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo giving crude compound 2 (8.2 g) which was used directly in the next step without further purification. [00436] To a 0 C crude solution of compound 2 (4.1g , 15.34 mmol ). triethylamine(6.4mL, 46.02mmol) in dicholoromethane (200ml) was added pentafluorophenyl trifluoroacetate(6.35mL , 36.82 mmol) via syringe over 3 mins . After 5 mins the ice bath was removed and the reaction mixture was stirred while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by flash chromatography( silica gel, hexanes/ethyl acetate = 1:0 , 50:1) to give compound 3 (3.5 g, 50% yield).
		[00183] To a 0 C solution of compound 3.1 (10.7 g, 61.37 mmol) and (lambda)-l,l,l- trifluoropropanol (3.5 g, 30.68 mmol) in dimethylformamide (200 mL) was added sodium hydride (3.7 g, 92.05 mmol) portionwise over 5 minutes. After 10 min, the ice bath was removed <n="56"/>and the reaction mixture was stirred while warming to room temperature. The reaction mixture was heated to 80 C and stirred overnight. The reaction was monitored by LC/MS until complete. After cooling to room temperature, the reaction mixture was quenched with HCl (0.5N, 200 mL) and extracted with ethyl acetate (3 x 250 mL). The organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated in vacuo giving crude compound 3.2 (8.2 g) which was used directly in the next step without further purification.(50% yield, two steps)

Reference： [1]Patent: WO2005/107762,2005,A2 .Location in patent: Page/Page column 252-253
[2]Patent: WO2007/56056,2007,A2 .Location in patent: Page/Page column 54-55

16
[ 67-56-1 ]
[ 403-16-7 ]
[ 234082-35-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With sulfuric acid;Heating / reflux;	Preparative Example 29.; A round bottomed flask was charged with <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (5.0 g, 28.6 mmol), sulfuric acid (0.84 g, 8.6 mmol), and methanol (60 mL). The solution was heated at reflux overnight. The methanol was removed in vacuo. The residue was extracted with ethyl acetate (5 x), dried over sodium sulfate, filtered and concentrated in vacuo to yield 4.73 g (88%).A round bottomed flask was charged with the ester intermediate (4.73 g, 25 mmol), potassium carbonate (3.45 g, 25 mmol), piperazine-1-carboxylic acid tert-butyl ester (5.59 g, 30 mmol) and acetonitrile (6 mL). The mixture was heated at 650C overnight and the solvent removed in vacuo. The residue was dissolved in ethyl acetate and washed with 0.5 N HCI, 0.5 N NaOH, and brine. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. There was obtained 4.79 g of intermediate 34 which was not purified further.

Reference： [1]Patent: WO2006/88919,2006,A2 .Location in patent: Page/Page column 142-143
[2]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 6724 - 6731

17
[ 403-16-7 ]
3-Chloro-4-fluorobenzoylguanidine hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 20 3-Chloro-4-fluorobenzoylguanidine hydrochloride is obtained from <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> following the general protocol. Colorless crystals. m.p. 188-189 C.

Reference： [1]Patent: US5866610,1999,A

18
[ 403-16-7 ]
[ 161446-90-8 ]

Yield	Reaction Conditions	Operation in experiment
	With LiAlH4; In tetrahydrofuran;	Step 3: 3-Chloro-4-fluorobenzyl alcohol To a solution of LiAlH4 (2.2 g) in THF (100 mL) at 0 C. under nitrogen was added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (Aldrich; 10 g). After stirring for 1 hour at 0 C. the mixture was stirred for 1 hour at 25 C. followed by the addition of a further 1.0 g of LiAlH4. Stirring was continued for a further 12 hours at 25 C. after which time the mixture was cooled to 0 C. and quenched with H2 O. The mixture was then acidified with 1N HCl (aq) and extracted with EtOAc. After washing with NaHCO3 (aq) and drying (MgSO4), the organic solution was evaporated to give the title compound as an oil.

Reference： [1]Patent: US5314900,1994,A

19
[ 630-25-1 ]
[ 403-16-7 ]
[ 170108-04-0 ]
[ 36667-05-7 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; water;	After re-cooling to -75 C., a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (14.4 g) in dry THF was added over 1 hour, and stirring was continued overnight at -75 C. A solution of 1,2-dibromotetrachloroethane (42.77 g) in dry THF was then added over 20 minutes, stirring was continued for 2 hours at -70 C. then at room temperature for 4 hours. Water was added, the organic and aqueous phases were separated and the aqueous phase was washed with ether, then acidified with hydrochloric acid solution and extracted with dichloromethane. The dichloromethane extract was dried (arthydrous magnesium sulphate) and the solvent evaporated to give 2-bromo-3-chloro4-fluorobenzoic acid (19.54 g) as a beige solid, NMR (DMSO-D6) 7.55(t,1H), 7.75(dd,1H), 13.8(brs,1H). By proceeding in a similar manner 2,3,4-tribromobenzoic acid was prepared, NMR (DMSO-D6) 7.5(d,1H), 7.9(d,1H), 13.75(brs,1H).

Reference： [1]Patent: US5658858,1997,A

20
[ 881891-35-6 ]
[ 403-16-7 ]
3-chloro-N-(cis-4-[4-(dimethylamino)-6-methylpyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-(cz5-4-aminocyclohexyl)-N4,N4,6-trimethylpyridine-2,4-diamine (400 mg) in DMF (4 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (309 mg), Et3N (540 muL), HOBt-H2O (296 mg), and EDC-HCl (340 mg). The mixture was stirred at ambient temperature for 15 h and poured into aqueous saturated NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% to 100% EtOAc in hexane and silica gel, 3% to 10% MeOH in CHCl3). To a solution of the above purified material in EtO Ac (5 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (20 mL) was stirred at ambient temperature for 3 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3 -chloro-N-(c is-A- { [4-(dimethylamino)-6- methylpyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride (128 mg) as a white solid. 1HNMR (300 MHz, CDCl3, delta): 1.63-2.04 (m, 8H), 2.41 (s, 3H), 3.11 (s, 6H), 3.62-3.80 (m, IH), 4.02-4.23 (m, IH), 5.32 (brs, IH), 5.84 (brs, IH), 6.86-6.98 (m, IH), 7.17 (t, J= 8.6 Hz, IH), 7.70-7.80 (m, IH), 7.92-8.13 (m, 2H), 13.04 (brs, IH); ESI MS m/z 405 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 73

21
[ 881891-43-6 ]
[ 403-16-7 ]
3-chloro-N-[cis-4-([4-(dimethylamino)-5-methylpyridin-2-yl]amino}methyl)cyclohexyl]-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-[(c-4-aminocyclohexyl)methyl]-N4,N4,5-trimethylpyridine-2,4-diamine(250 mg) in DMF (3 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (200 mg), Et3N (320 muL), HOBt-H2O (218 mg), and EDC-HCl (219 mg). The mixture was stirred at ambient temperature for 12 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 14% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-N-[czs-4-([4-(dimemylamino)-5-methylpyridin-2- yl]amino}methyl)cyclohexyl]-4-fluorobenzamide hydrochloride (140 mg) as a white solid. 1HNMR (300 MHz, CDCl3, delta): 1.53-2.10 (m, 9H), 2.19 (s, 3H), 3.06 (s, 6H), 3.16-3.23 (m, 2H), 4.45-4.55 (m, IH), 5.57 (s, IH), 7.15-7.28 (m, 2H), 7.36-7.43 (m, IH), 8.10-8.16 (m, IH), 8.21 (dd, J= 7.1, 2.3 Hz, IH), 8.34-8.46 (m, IH), 12.92 (brs, IH); ESI MS m/z 419 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 76

22
[ 881891-47-0 ]
[ 403-16-7 ]
3-chioro-N-[(cis-4-[4-(dimethylamino)-5-methylpyridin-2-yl]amino}cyclohexyl)methyl]-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-[cw-4-(aminomethyl)cyclohexyl]-N4,N4,5-trimethylpyridine-2,4-diamine (250 mg) in DMF (3 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (200 mg), Et3N (320 muL), HOBt-H2O (218 mg), and EDC-HCl (219 mg). The mixture was stirred at ambient temperature for 12 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three EPO <DP n="82"/>times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 14% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-N-[(cw-4-[4-(dimethylamino)-5-methylpyridin-2- yl]amino}cyclohexyl)methyl]-4-fluorobenzamide hydrochloride (274 mg) as a white solid. 1HNMR (300 MHz, CDCl3, delta): 1.52-1.98 (m, 9H), 2.19 (s, 3H), 3.04 (s, 6H), 3.43-3.50 (m, 2H), 3.70-3.79 (m, IH), 5.65 (s, IH), 7.12-7.24 (m, 3H), 7.97-8.05 (m, IH), 8.11 (dd, J= 7.0, 2.2 Hz, IH), 8.39 (d, J= 8.4 Hz, IH), 13.15 (brs, IH); ESI MS m/z 419 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 78-79

23
[ 881891-54-9 ]
[ 403-16-7 ]
3-chloro-N-(cis-4-[4-(dimethylamino)pyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-[cis-A~ (benzylamino)cyclohexyl]-N4,N4-dimethylpyridine-2,4-diamine 5 1 -oxide (2.01 g) in MeOH (20 mL) was added 10% Pd/C (200 mg). The mixture was stirred at 50 0C under hydrogen atmosphere for 92.5 h and filtrated through a pad of celite with MeOH. The filtrate was concentrated under reduced pressure to give crude N2-(comega-4-aminocyclohexyl)-N4,N4- dimethylpyridine-2,4-diamine (1.49 g). To a solution of the above material (450 mg) and <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (402 mg) in DMF (4.5 mL) were added EDC-HCl (442 mg),10 HOBt-H2O (389 mg), and Et3N (0.64 mL). The mixture was stirred at ambient temperature for 2 days, diluted with CHCl3, and added to aqueous saturated NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSU4, filtrated, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 33% to 99% EtOAc in hexane and silica gel, 1% to 30% MeOH in CHCl3) to give 3-chloro-N-(comega-4-15 [4-(dimethylamino)pyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide. To a solution of the above material in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (0.09 mL). The mixture was stirred at ambient temperature for 4 h and concentrated under reduced pressure. The residue was suspended in Et2theta and the suspension was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give20 3-chloro-N-(cw-4-[4-(dimethylamino)pyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride (42 mg) as a pale yellow powder. 1HNMR(SOO MHz, CDCl3, delta): 1.66-2.03 (m, 8H), 3.14 (s, 6H), 3.69-3.77 (m, IH), 4.04-4.19 (m, IH),5.44 (brs5 IH), 6.09 (dd, J= 7.2, 1.9 Hz, IH), 6.80 (d, J= 8.6 Hz, IH), 7.18 (t, J= 8.6 Hz, IH), 7.39 (dd, J= 7.2, 6.0 Hz, IH), 7.69-7.77 (m, IH), 7.96 (dd, J= 7.0, 2.2 Hz, IH), 8.28 (d, J= 7.9 Hz, IH),25 13.15 (brs, IH); ESI MS m/z 87 [M (free)+-303, 100%], 391 [M (free)++l, 55%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 83

24
[ 881891-60-7 ]
[ 403-16-7 ]
3-chloro-N-(cis-4-[6-(dimethylamino)pyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N-(c/5-4-aminocyclohexyl)-N,N-dimethylpyridine-2,6-diamine (300 mg) and <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (268 mg) in DMF (3.0 mL) were added EDC-HCl (294 mg), HOBt-H2theta (259 mg), and Et3N (0.43 mL). The mixture was stirred at ambient temperature for 1 day, diluted with CHCl3, and poured into aqueous saturated NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtrated, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% EtOAc in hexane and silica gel, CHCl3 to 10% MeOH in CHCl3) to give 3-chloro-N-(cz"s-4-[6- (dimethylamino)pyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide. To a solution of the above material in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (0.38 mL). The mixture was stirred at ambient temperature for 4 h and concentrated under reduced pressure. The residue was suspended in Et2O and the suspension was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-N-(c/5-4-[6-(dimethylamino)pyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride (260 mg) as a powder.1HNMR (300 MHz5 CDCl3, delta): 1.67-1.85 (m, 2H), 1.86-2.12 (m, 6H)53.29 (s, 6H)5 3.67-3.76 (m, IH), 4.05-4.20 (m, IH), 5.74-5.82 (m, 2H), 6.68 (d, J= 8.4 Hz, IH), 7.18 (t, J= 8.6 Hz, IH), 7.48 (t, J= 8.5 Hz5 IH), 7.68-7.76 (m, IH), 7.95 (dd, J= 7.1, 2.3 Hz, IH), 9.08 (d, J= 8.2 Hz5 IH), 12.75 (brs5 IH); ESI MS m/z 391 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 85

25
[ 881891-76-5 ]
[ 403-16-7 ]
3-chloro-4-fluoro-N-[cis-4-({5-methyl-4-[methyl(2-phenylethyl)amino]pyridin-2-yl}amino)cyclohexyl]benzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-(c-4-aminocyclohexyl)-N4,5-dimethyl-N4-(2-phenylethyl)pyridine-2,4- diamine (150 mg) in DMF (2.00 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (93.0 mg), Et3N (148 muL), HOBt-H2O (101 mg), and EDC-HCl (102 mg). The mixture was stirred at ambient temperature for 14 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgStheta4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated EPO <DP n="98"/>under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-4-fluoro-N-[c-4-({5-methyl-4-[methyl(2- phenylethyl)amino]pyridin-2-yl}amino)cyclohexyl]benzamide hydrochloride (22.0 mg) as a white solid.1HNMR (300 MHz, CDCl3, delta): 1.64-1.99 (m, 8H), 2.18 (s, 3H), 2.89-2.96 (m, 2H), 3.02 (s, 3 H),3.54-3.71 (m, 3H), 4.05-4.19 (m, IH), 5.62 (s, IH), 6.77-6.86 (m, IH), 7.10-7.34 (m, 7H), 7.67-7.78(m, IH), 7.96 (dd, J= 7.1, 2.1 Hz, IH), 8.23-8.31 (m, IH), 13.25-13.32 (m, IH); ESI MS m/z 495 [M

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 94-95

26
benzyl (cis-3-aminocyclopentyl)carbamate hydrochloride [ No CAS ]
[ 403-16-7 ]
benzyl {cis-3-[(4-fluorobenzoyl)amino]cyclopentyl}carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 17h;	To a solution of benzyl (c/s-3-aminocyclopentyl)carbamate (4.50 g) in DMF (50 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (2.90 g), Et3N (2.3 mL), HOBt-H2O (3.37 g), and EDC-HCl(3.82 g). The mixture was stirred at ambient temperature for 17 h. The mixture was diluted withEtOAc and added saturated aqueous NaHCO3 (100 mL). The aqueous layer was extracted with EtOAc (three times), and the combined organic layer was washed with water and saturated aqueousNaCl. The organic layer was dried over MgStheta4, filtered, and concentrated under reduced pressure to give the title compound (6.2Og).1HNMR (OOO MHz, CDCl3, delta): 1.69-1.91 (m, 3H), 1.91-2.01 (m, 2H), 2.38-2.47 (m, IH), 3.80-3.91(m, IH), 4.40-4.49 (m, IH), 5.08-5.16 (m, 2H), 5.40 (d, J= 6.4 Hz, IH), 7.10-7.23 (m, IH), 7.28-7.42 (m, 5H), 7.74-7.85 (m, IH), 7.95-8.03 (m, IH), 8.10 (brs, IH); ESI MS m/z 413 (M÷+23, 100%).

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 101

27
[ 881890-98-8 ]
[ 403-16-7 ]
3-chloro-N-(cis-4-[4-(dimethylamino)-5-methylpyridin-2-yl]amino}cyclohexyl)-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-(cz5-4-aminocyclohexyl)-N4,N4,5-trimethylpyridine-2,4-diamine (195 mg) in DMF (3.2 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (164 mg), Et3N (260 muL), HOBt-H2O (179 mg), and EDC-HCl (180 mg). The mixture was stirred at ambient temperature for 12 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% to 67% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-N-(c-4-[4-(dimethylamino)-5-methylpyridin-2- yl]amino}cyclohexyl)-4-fluorobenzarnide hydrochloride (227 mg) as a white solid. EPO <DP n="60"/>1HNMR (300 MHz, CDCl3, delta): 1.65-2.07 (m, 8H), 2.21 (s, 3H), 3.06 (s, 6H), 3.66-3.79 (m, IH), 4.02-4.22 (m, IH), 5.66 (s, IH), 6.75-6.91 (m, IH), 7.09-7.27 (m, 2H), 7.68-7.79 (m, IH), 7.96 (d, J = 8.6 Hz, IH), 8.21-8.34 (m, IH), 13.12-13.35 (m, IH); ESI MS m/z 405 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 56-57

28
[ 881891-19-6 ]
[ 403-16-7 ]
3-chloro-N-[cis-4-({4-[ethyl(methyl)amino]-5-methylpyridin-2-yl}amino)cyclohexyl]-4-fluorobenzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of N2-(cw-4-aminocyclohexyl)-N4-ethyl-N4,5-dimethylpyridine-2,4-diamine (78.0 mg) in DMF (1 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (62.0 mg), Et3N (99.0 muL), HOBt-H2O (68.0 mg), and EDC-HCl (68.0 mg). The mixture was stirred at ambient temperature for 12 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The. combined organic layer was dried over MgStheta4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient EPO <DP n="68"/>temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-N-[cw-4-({4-[ethyl(methyl)amino]-5-methylpyridin-2- yl}amino)cyclohexyl]-4-fluorobenzamide hydrochloride (18.0 mg) as a white solid. 1HNMR (SOO MHz, CDCl3, delta): 1.27 (t, J= 7.2 Hz, 3H), 1.65-2.09 (m, 8H), 2.19 (s, 3H), 2.99 (s, 3H), 3.37 (q, J= 7.2 Hz, 2H), 3.67-3.78 (m, IH), 4.03-4.21 (m, IH), 5.69 (s, IH), 6.76-6.88 (m, IH), 7.11-7.29 (m, 2H), 7.68-7.79 (m, IH), 7.96 (dd, J= 7.0, 1.9 Hz, IH), 8.20-8.31 (m, IH), 13.24 (brs, IH); ESI MS m/z 419 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 64-65

29
C₁₆H₂₆N₄ [ No CAS ]
[ 403-16-7 ]
3-chloro-4-fluoro-N-{cis-4-[(5-methyl-4-pyrrolidin-1-ylpyridin-2-yl)amino]cyclohexyl}benzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A mixture of c-N-benzyl-N'-(5-methyl-4-pyrrolidin- 1 -ylpyridin-2-yl)cyclohexane- 1 ,4- diamine (265 mg), 10% palladium carbon (53.0 mg), and MeOH (2.6 mL) was stirred at 50 0C under hydrogen atmosphere for 24 h. The mixture was filtered through a pad of celite, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NuH-silica gel, 20% EtOAc in hexane to 5% MeOH in CHCl3) to give a pale brown oil (102 mg). To a solution of the above oil (95.0 mg) in DMF (0.5 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (72.0 mg), Et3N (116 muL), HOBt-H2O (80.0 mg), and EDC-HCl (80.0 mg). The mixture was stirred at ambient temperature for 12 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 EPO <DP n="69"/>three times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% to 100% EtOAc in hexane and silica gel, 3% to 9% MeOH in CHCI3). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-4-fluoro-N-{cw-4-[(5- methyl-4-pyrrolidin-l-ylpyridin-2-yl)amino]cyclohexyl}benzamide hydrochloride (15.0 mg) as a white solid.1HNMR (300 MHz, CDCl3, delta): 1.62-2.25 (m, 12H), 2.30 (s, 3H), 3.48-3.80 (m, 5H), 4.02-4.23 (m, IH), 5.43 (s, IH), 7.08-7.24 (m, 3H), 7.72-7.85 (m, IH), 7.87-8.08 (m, 2H), 12.72 (brs, IH); ESI MS m/z 431 [M (free)++1, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 65-66

30
[ 881891-24-3 ]
[ 403-16-7 ]
3-chloro-4-fluoro-N-{cis-4-[(5-methyl-4-morpnolin-4-ylpyridin-2-yl)amino]cyclohexyl}benzamide hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of cw-N-(5-methyl-4-morpholin-4-ylpyridin-2-yl)cyclohexane-l,4-diamine (185 mg) in DMF (2 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (132 mg), Et3N (210 muL), HOBt-H2O (144 mg), and EDC-HCl (145 mg). The mixture was stirred at ambient temperature for 12 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgSO4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 20% to 100% EtOAc in hexane and silica gel, 3% to 9% MeOH in CHCl3). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-4-fluoro- N-{comega-4-[(5-methyl-4-morpholin-4-ylpyridin-2-yl)amino]cyclohexyl}benzamide hydrochloride (166 mg) as a white solid.1HNMR (200 MHz, CDCl3, delta): 1.57-1.99 (m, 8H), 2.12 (s, 3H)52.90-3.04 (m, 4H), 3.72-3.92 (m, 5H), 4.04-4.22 (m, IH), 4.34-4.48 (m, IH), 5.89 (s, IH), 5.96-6.11 (m, IH), 7.14-7.25 (m, IH), 7.59-7.70 (m, IH), 1.16-1. %1 (m, 2H); ESI MS m/z 447 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 67

31
[ 881891-26-5 ]
[ 403-16-7 ]
3-chloro-4-fluoro-N-(cis-4-[4-(1H-imidazol-1-yl)-5-methylpyridin-2-yl]amino}cyclohexyl)benzamide dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of c/5-N-[4-(lH-imidazol-l-yl)-5-methylpyridin-2-yl]cyclohexane-l,4-diamine (80.0 mg) in DMF (2 mL) were added <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (62.0 mg), Et3N (97.0 muL), HOBt-H2O (67.0 mg), and EDC-HCl (67.0 mg). The mixture was stirred at ambient temperature for 60 h and poured into saturated aqueous NaHCO3. The aqueous layer was extracted with CHCl3 three times. The combined organic layer was dried over MgStheta4, filtered, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 25% to 100% EtOAc in hexane). To a solution of the above purified material in EtOAc (10 mL) was added 4 M hydrogen chloride in EtOAc (0.5 mL). The mixture was stirred at ambient temperature for 1 h and concentrated under reduced pressure. A suspension of the residue in Et2O (10 mL) was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et2O, and dried at 80 0C under reduced pressure to give 3-chloro-4-fluoro-N-(c-4-[4-(lH-imidazol-l-yl)-5- methylpyridin-2-yl] amino }cyclohexyl)benzamide dihydrochloride (70.0 mg) as a white solid. 1H NuMR (200 MHz, DMSO-J6, delta): 1.63-1.94 (m, 8H), 2.08 (s, 3H), 3.81-4.00 (m, 2H), 7.08 (brs, IH), 7.52 (Jt, J= 9.0 Hz, IH), 7.80-7.96 (m, 2H), 7.98-8.15 (m, 3H), 8.35-8.44 (m, IH), 9.30 (brs, IH); ESI MS m/z 428 [M (free)++l, 100%].

Reference： [1]Patent: WO2006/35967,2006,A1 .Location in patent: Page/Page column 68

32
[ 65055-17-6 ]
[ 403-16-7 ]

Yield	Reaction Conditions	Operation in experiment
92.8%	With hydrogenchloride; In sodium hydroxide; water;	2 g of 3-chloro-4-fluorobenzoyl chloride (purity 99.6% GC [a/a]) are carefully hydrolyzed in 4 g of 50% strength sodium hydroxide solution and 20 g of water at 60 C. The solution is then stirred for a further 2 hours at room temperature. The mixture is then adjusted to a pH of 1 using conc. hydrochloric acid, and the precipitated 3-chloro-4-fluorobenzoic acid is filtered off with suction, washed with water and dried. This gives 1.68 g of 3-chloro-4-fluorobenzoic acid in the form of a white powder. Yield: 92.8% of theory melting point: 136 C. (lit: 136 C.)

Reference： [1]Patent: US6187952,2001,B1

33
[ 79-37-8 ]
[ 403-16-7 ]
[ 193964-19-1 ]
[ 215605-64-4 ]

Yield	Reaction Conditions	Operation in experiment
33%		Oxalyl chloride (12.49 mL, 143 mmol) was added to a stirred suspension of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (5.00 gi 28.6 mmol) in anhydrous dichloromethane (30 mL), followed by the addition of 2 drops of DMF. The suspension was stirred at room temperature under nitrogen atmosphere for 14 h, then it was concentrated to dryness under vacuum at 50 C. To 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]-thiophene in anhydrous 1,2-dichloroethane (40 mL) was added a solution of the crude benzoyl chloride in anhydrous 1,2-dichloroethane (10 mL). The mixture was cooled to -20 C., treated with TiCl4 (7.87 mL, 71.6 mmol), which caused the mixture to form a precipitate. The resulting wet solid was sonicated in a water bath at room temperature to help the reactants to become soluble. The reaction mixture was placed in a ice bath and allowed to stir for 1.5 h, then at room temperature for 1 h. The reaction mixture was placed in an ice bath and THF (50 mL) was slowly added followed by the addition of 5N NaOH (60 mL). The solids were filtered off and and washed with EtOAc (50 mL), then the aqueous layer was extracted with EtOAc (3×50 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (60 mL×2). The combined organic layers were dried over MgSO4, filtered, concentrated, and chromatographed on silica [gradient 0-2% Et3N 18% hexanes in EtOAc] to give 8.21 g (60%) of mostly the named ketone and the isomer substituted at the six position. After recrystallization from EtOAc 4.5 g (33%) of the fluoro-ketone were obtained as a yellow solid. IR (thin film) 1651, 1607 cm-1; FDMS m/e 479 (M+,35Cl) and 481 (M+,37Cl); Anal. Calcd. for C27H23ClFNO2S: C, 67.56; H, 4.83; N, 2.92. Found: C, 67.84; H, 4.87; N, 2.83.

Reference： [1]Patent: US6350774,2002,B1 .Location in patent: Page column 29

34
[ 1027255-35-1 ]
[ 403-16-7 ]
[ 1027256-29-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 1206 - 1209

35
[ 403-16-7 ]
[ 124-40-3 ]
[ 530-62-1 ]
[ 871657-07-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (20.0 g, 115 mmol) in 100 mL THF is added carbonyldiimidazole (20.0 g, 126 mmol) and the reaction mixture is stirred at RT for 0.5 h. Then dimethylamine (1 M in THF, 171 mL) is added and the reaction mixture is stirred for another h. The reaction mixture is concentrated in vacuo, re-dissolved in DCM, washed with saturated aqueous sodium carbonate and brine and concentrated in vacuo. Yield: 20.0 g.

Reference： [1]Patent: WO2009/112565,2009,A1 .Location in patent: Page/Page column 33

36
[ 1172068-36-8 ]
[ 403-16-7 ]
[ 1196508-96-9 ]

Yield	Reaction Conditions	Operation in experiment
71%		[00473] Step A: A solution of 5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (319 mg, 1.83 mmol), BOP- Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) at room temperature was stirred for 2 hours. 3M aqueous LiOH (3 mL) was then added, and the mixture <n="153"/>was stirred for 10 minutes. Next, water (10 rnL) and DCM (10 rnL) were added, and the resulting precipitate was filtered. The solid isolated was triturated with 10:1 CH2CL:Me0H and filtered to provide N-(5-bromo-4-fluoro-lH-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4- fluorobenzamide (240 mg, 71% yield) as a solid.

Reference： [1]Patent: WO2009/140320,2009,A1 .Location in patent: Page/Page column 151-152

37
[ 1108147-58-5 ]
[ 403-16-7 ]
C₂₇H₃₅ClFN₃O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 610 - 625

38
[ 1220639-83-7 ]
[ 403-16-7 ]
[ 1220639-59-7 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 40℃; for 72h;	Example 31: Synthesis of 3-chloro-4-fluoro-N-{l- [ (2- oxo-1, 2 , 3 , 4-tetrahydroquinolin-7-yl) methyl] piperidin-4- yl}benzamide To a DMF (2.50 ttiL) solution of the compound(250 mg) obtained in Step 1-6, 3-chloro-4-fluoro benzoic acid (191 mg) , Et3N (320 muL) , HOBt*H2O (222 mg) and EDOHCl (222 mg) were added and the mixture was stirred at room temperature for three days. To the reaction mixture, a saturated aqueous NaHCO3 solution was added and the solution was extracted four times with CHCl3. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography [(silica gel 60 N, mobile phase: MeOH/CHCl3 = 0/100 to 10/90; v/v) and (Chromatorex NH, mobile phase: CHCl3) in this order] . To the residue, IPA was added at room temperature and the mixture was stirred for one hour. A precipitate was obtained by filtration and washed with IPA and hexane to obtain the titled compound (263 mg, a colorless solid) .1H NMR (600 MHz, CDCl3, delta) : 1.53-1.64 (m, 2H), 1.96-2.04 (m, 2H), 2.10-2.20 (m, 2H), 2.58-2.67 (m, 2H), 2.80-2.90 (m, 2H), 2.94 (t, J = 7.6 Hz, 2H), 3.45 (s, 2H), 3.93-4.04 (m, IH), 6.18 (tors, IH), 6.77 (s, 1 H), 6.90 (d, J = 7.3 Hz, IH), 7.10 (d, J = 7.8 Hz, IH), 7.18 (t, J = 8.7 Hz, IH), 7.67 (ddd, J = 8.6, 4.5, 2.1 Hz, IH), 7.83-7.95 (m, 2H); ESl/APCI MS m/z 416 [M+H] + .

Reference： [1]Patent: WO2010/38901,2010,A1 .Location in patent: Page/Page column 55-56

39
[ 403-16-7 ]
[ 593-51-1 ]
[ 1067637-36-8 ]

Yield	Reaction Conditions	Operation in experiment
53.0%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 23℃; for 3h;Inert atmosphere;	To a suspension of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23 C. The reaction was stirred at 23 C. for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23 C. affording a suspension. The suspension was filtered, washed with H2O (3×100 mL), and the resulting solid was dried in vacuo at 30 C. to provide 3-chloro-4-fluoro-N-methylbenzamide (14.24 g, 76 mmol, 53.0% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 2.78 (d, J=4.55 Hz, 3H) 7.53 (t, J=8.97 Hz, 1H) 7.86 (ddd, J=8.59, 4.80, 2.27 Hz, 1H) 8.04 (dd, J=7.20, 2.15 Hz, 1H) 8.51-8.65 (m, 1H). ESI-MS: m/z 188.0 (M+H)+. Mp=108.3-110.0 C.
53.0%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 23℃; for 3h;	[0593] General Procedure for coupling of amines to carboxylic acids: Synthesis of 3- chloro-4-fluoro-7V-methylbenzamide (274): To a suspension of 3 -chloro-4-fluorobenzoic acid (25.0 g, 143 mmol), methylamine hydrochloride (11.60 g, 172 mmol), M- ((ethylimino)methylene)-N3,Lambdabeta-dimethylpropane- 1,3 -diamine hydrochloride (41.2 g, 215 mmol), and l/f-benzo[<;i][l,2,3]triazol-l-ol hydrate (32.9 g, 215 mmol) in DMF (150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23 0C. The reaction was stirred at 23 0C for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23 0C affording a suspension. The suspension was filtered, washed with H2O (3 x 100 mL), and the resulting solid was dried in vacuo at 30 0C to provide the title compound as an off-white solid (14.24g, 76 mmol, 53.0 % yield). 1H NMR (400 MHz, DMSO-J6) delta ppm 2.78 (d, J=4.55 Hz, 3 H) 7.53 (t, J=8.97 Hz, 1 H) 7.86 (ddd, J=8.59, 4.80, 2.27 Hz, 1 H) 8.04 (dd, J=7.20, 2.15 Hz, 1 H) 8.51 - 8.65 (m, 1 H). ESI- MS: m/z 188.0 (M+H)+. Mp = 108.3-110.0 0C.
53%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 23℃; for 3h;	To a suspension of 3-chloro-4- fluorobenzoic acid (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), Nl-((ethylimino)methylene)-N3,N3-dimethylpropane-l,3-diamine hydrochloride (41.2 g, 215 mmol), and lH-benzo[d][l,2,3]triazol-l-ol hydrate (32.9 g, 215 mmol) in DMF(Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23 0C. The reaction was stirred at 23 0C for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23C affording a suspension. The suspension was filtered, washed with H2O (3 x 100 mL), and the resulting solid was dried in vacuo at 30 0C to provide 3-chloro-4-fluoro-N-methylbenzamide (14.24g, 76 mmol, 53.0 % yield) as an off-white solid. 1U NMR (400 MHz, DMSO-J6) delta ppm 2.78 (d, J=4.55 Hz, 3 H) 7.53 (t, J=8.97 Hz, 1 H) 7.86 (ddd, J=8.59, 4.80, 2.27 Hz, 1 H) 8.04 (dd, J=7.20, 2.15 Hz, 1 H) 8.51 - 8.65 (m, 1 H). ESI-MS: m/z 188.0 (M+H)+. Mp = 108.3- 110.0 0C.

53%

With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 23℃; for 3h;

General procedure: 3-Chloro-4-fluoro-N-methylbenzamide (5d): To a suspension of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23 C. The reaction was stirred at 23 C for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23C affording a suspension. The suspension was filtered, washed with H2O (3 x 100 mL), and the resulting solid was dried in vacuo at 30 C to provide 3-chloro-4-fluoro-N-methylbenzamide ( 14.24 g, 76 mmol, 53.0 % yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) ppm 2.78 (d, J=4.55 Hz, 3 H) 7.53 (t, J=8.97 Hz, 1 H) 7.86 (ddd, J=8.59, 4.80, 2.27 Hz, 1 H) 8.04 (dd, J=7.20, 2.15 Hz, 1 H) 8.51 - 8.65 (m, 1 H). ESI-MS: m/z 188.0 (M+H)+. Mp = 108.3-110.0 C.

Reference： [1]Patent: US2010/190763,2010,A1 .Location in patent: Page/Page column 93
[2]Patent: WO2010/111626,2010,A2 .Location in patent: Page/Page column 174
[3]Patent: WO2011/14681,2011,A1 .Location in patent: Page/Page column 111
[4]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505

40
[ 403-16-7 ]
[ 78797-58-7 ]
[ 863454-79-9 ]

Yield	Reaction Conditions	Operation in experiment
		1 - IY3 -Chloro^-fluorophenvDcarbonyll azetidine; To a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (1.74 g, 10.0 mmol) in DCM (50 mL) was added oxalyl chloride (1.05 mL, 12.0 mmol) and DMF (1 drop). The mixture was stirred at RT for 16 hours and the DCM and excess oxalyl chloride evaporated in vacuo. The residual acid chloride and azetidine hydrochloride (1.12 g, 12 mmol) were taken up in DCM (25 mL) and triethylamine (4.18 mL, 30 mmol) added to the mixture, which was stirred at RT for 2 hours. The DCM was evaporated in vacuo, and the residue partitioned EPO <DP n="45"/>between ethyl acetate (100 mL) and IN hydrochloric acid (50 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and brine, dried (MgSO4), and evaporated. The residue was crystallized from ethyl acetate and isohexane to give the title compound (1.64 g). 1R NMR delta (CDCl3): 2.4 (m, 2H), 4.2-4.4 (m, 4H), 7.2 (m, IH), 7.55 (m, IH), 7.7 (m, IH).

Reference： [1]Patent: WO2007/17649,2007,A1 .Location in patent: Page/Page column 43-44

41
4-[[[(5-methylpyridin-2-yl)methyl]amino]methyl]piperidin-4-ol trihydrochloride [ No CAS ]
[ 403-16-7 ]
[ 1250831-54-9 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7167 - 7179

42
N-(4-fluoropiperidin-4-yl)methyl-N-(5-methylpyridin-2-yl)methylamine trihydrochloride [ No CAS ]
[ 403-16-7 ]
[ 208110-64-9 ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7167 - 7179

43
[ 403-16-7 ]
(8-azabicyclo[3.2.1]octan-3-one) hydrochloride [ No CAS ]
8-(3-chloro-4-fluorobenzoyl)-8-azabicyclo[3.2.1]octan-3-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7167 - 7179

44
[ 1258304-76-5 ]
[ 403-16-7 ]
C₂₈H₃₅ClFN₃O₃ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 7675 - 7699

45
[ 1258304-99-2 ]
[ 403-16-7 ]
[ 1258305-00-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 7675 - 7699

46
[ 333411-68-0 ]
[ 403-16-7 ]
[ 1207642-86-1 ]

Yield	Reaction Conditions	Operation in experiment
62%		General procedure: The suitable acid (0.5 mmol) was dissolved in DCM (8 mL) and TBTU (193 mg, 0.6 mmol) followed by the addition of TEA (71 mg, 0.7 mmol). The resulting solution was allowed to stir for 30 min at rt and the suitable secondary amine (S5-S7) (0.5 mmol) was added to the reaction mixture. The stirring was continued for 8 h. The reaction mixture was washed with a solution of K2CO3 (25% in water, 2 × 10 mL), water (1 × 10 mL) and dried over Na2SO4. The solvent was distilled off in vacuo and the residue was crystallized from MeOH to afford the desired target compounds (12-26).

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 77 - 90

47
[ 403-16-7 ]
[ 536-90-3 ]
[ 1110780-78-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 1.5 mmol N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC·HCl) and 1 mmol 4-dimethylaminopyridine (DMAP) in 2 ml dichloromethane were added 1.5 mmol 3-substituted aniline and the solution stirred at ambient temperature for 5 min. This solution was then added to 1 mmol of substituted benzoic or nicotinic acid and the solution stirred at ambient temperature for 18 hours. The reaction mixture was filtered through a cartridge filled with 5g SCX/silica gel 2:3, pre-washed with 10 ml methanol and 20 ml dichloromethane, and the reaction product eluted with 50 ml dichloromethane. Evaporation provided the benzanilides or nicotinanilides typically as solids.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1227 - 1231

48
[ 403-16-7 ]
[ 72835-76-8 ]

Reference： [1]Patent: WO2011/23677,2011,A1

49
[ 403-16-7 ]
[ 1268675-74-6 ]

Reference： [1]Patent: WO2011/23677,2011,A1

50
[ 403-16-7 ]
[ 1268682-36-5 ]

Reference： [1]Patent: WO2011/23677,2011,A1

51
[ 403-16-7 ]
[ 1268682-34-3 ]

Reference： [1]Patent: WO2011/23677,2011,A1

52
[ 403-16-7 ]
[ 1268682-33-2 ]

Reference： [1]Patent: WO2011/23677,2011,A1

53
[ 403-16-7 ]
[ 530-62-1 ]
C₁₀H₆ClFN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran; at 20℃; for 23h;	Intermediate 7.5: 3-(3-Chloro-4-fluoro-phenyl)-3-oxo-propionic acid ethyl ester; Carbonyl-di-imidazole (62.1 g, 368 mmol) is added to an ice cooled solution of 3-chloro- 4-fluoro-benzoic acid (59 g, 331 mmol) in THF (600 ml). Stirring for 23 h at rt gives a solution of activated ester. In a separate vessel, propanediol acid 1 -ethyl ester potassium salt (54 g, 317 mmol) is suspended in THF (600 ml) and cooled in an ice bath. A THF solution of 'PrMgCI (2 M; 159 ml, 318 mmol) is added during 15 min. The mixture is stirred for 20 min at 0 0C, 90 min at rt and finally 45 min at 50 0C and then cooled again in the ice bath. Now the solution of the activated ester is added dropwise at 0-2 0C, forming a suspension which is stirred afterwards for 16 h at rt and 0.5 h at 50 C. After cooling the beige suspension in an ice-bath, 1 N HCI (600 ml) is added (pH: 6-7). The resulting red solution is stirred for 0.5 h and finally extracted with 2 portions of EtOAc (4 I). The organic layers are washed twice with H2O (3 I) and brine (1 I), dried (Na2SO4) and concentrated. Column chromatography (SiO2; EtOAc/hexane 1 :6) and stirring in heptane (0.1 I) gives the title compound, mp: 39-40 0C; ES-MS: [M+1]+ = 245/247;TLC(hexane/EtOAc 9:1): Rf = 0.26; 1H NMR (DMSO-d6) delta 8.16 (m, 1 H), 7.97 (m, 1 H), 7.59 (t, 1H), 4.22 (s, 2H), 4.10 (q, 2H), 1.16 (t, H3C).

Reference： [1]Patent: WO2011/23677,2011,A1 .Location in patent: Page/Page column 119

54
[ 403-16-7 ]
[ 325458-27-3 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 481 - 484

55
[ 1126-46-1 ]
[ 403-16-7 ]
[ 1202804-38-3 ]

Yield	Reaction Conditions	Operation in experiment
		n-Butyl lithium (2.5M solution, 5.27 mL, 13.18 mmol) was added to a stirred solution of diisopropylamine (1.93 mL, 13.75 mmol) in anhydrous THF (25 mL) at -75 C. under a nitrogen atmosphere, and maintained at -30 C. for a further 1 h to produce lithium diisopropylamide (LDA). After re-cooling to -75 C., a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (1 g, 5.73 mmol) in THF (20 mL) was added over 1 h, and stirring continued overnight at -75 C. under nitrogen. A solution of methyl 4-chlorobenzoate (1.95 g, 11.46 mmol) in THF (20 mL) was added over 10 min, stirring was continued at -70 C. for 2 h and then at RT for 4 h. Water (30 mL) was added and the aqueous layer was washed with ether (3×50 mL), acidified with 1M HCl, extracted with DCM (3×50 mL), dried over MgSO4 and concentrated in vacuo to afford a yellow solid. Partial purification was attempted with chromatography (Biotage, silica, 50% EtOAc/petrol to 20% MeOH/EtOAc). The crude product (0.60 g, 34%) was used in the next step without further purification. Rf=0.05 (50:50 EtOAc:petrol). mp=188-190 C. lambdamax (CH3OH)/nm=260. IR: 706, 749, 785, 843, 901, 958, 987, 1003, 1090, 1166, 1254, 1395, 1487, 1562, 1586, 1671, 1770, 2855, 2924, 3398 cm-1.1H NMR: (300 MHz, MeOD) delta 7.27-7.32 (dd AB, J=8.5 Hz, 2H, CC2H2C2H2C(Cl)), 7.39-7.42 (m, 1H, CHC(F)C(Cl)), 7.60-7.66 (dd AB, J=8.5 Hz, 2H, CC2H2C2H2C(Cl)), 8.17 (d, J=8.30 Hz, 1H, CHCHC(F)C(Cl), 13.60 (br s, 1H, CO2H). 13C NMR (MeOD, 75 MHz), delta 119.90, 124.16, 132.022, 132.46, 133.89, 134.91, 135.87, 139.02, 163.04, 165.05, 197.46. LCMS (DMSO): RT=3.43 min (on 5 min column), m/z=311 ES-.

Reference： [1]Patent: US2011/224274,2011,A1 .Location in patent: Page/Page column 68

56
[ 403-16-7 ]
[ 1363188-90-2 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

57
[ 403-16-7 ]
[ 1363189-06-3 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

58
[ 403-16-7 ]
[ 1363189-47-2 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

59
[ 403-16-7 ]
[ 1363189-66-5 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

60
[ 403-16-7 ]
[ 1363189-26-7 ]

Reference： [1]Journal of Fluorine Chemistry,2012,vol. 135,p. 240 - 245

61
[ 1380104-27-7 ]
[ 403-16-7 ]
[ 1380101-32-5 ]

Yield	Reaction Conditions	Operation in experiment
54%		Example 13.1: (S)-3-Chloro-N-(l-cvclopropyl-2-(pyrrolidin-l-yl)ethyl)-4-fluoro-N- methylbenzamide; 3-Chloro-4-fluorobenzoic acid (0.156 g, 0.89 mmol), TBTU (0.334 g, 1.04 mmol) and NMM (0.204 mL, 1.86 mmol) was mixed in DCM (10 mL). After 10 min at rt was (S)- l-cyclopropyl-N-methyl-2-(pyrrolidin-l-yl)ethanamine (Compound M3) (0.125 g, 0.74 mmol) added. The resultant mixture was stirred at rt for 48 h. To the mixture was 1.4 N KOH (5 mL) added. The organic phase was isolated, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (130 mg, 54%). Mixture of rotamers: NMR (600 MHz,DMSO-d6) delta 0.03, 0.16 - 0.62, 0.95, 1.50 - 1.74, 2.14 - 2.41, 2.47 - 2.51, 2.65 - 3.06, 3.84,7.29, 7.46. Total no of protons: 22. HRMS (M+H)+: calculated 325.1483; found 325.1475.

Reference： [1]Patent: WO2012/74469,2012,A1 .Location in patent: Page/Page column 109

62
[ 1380104-42-6 ]
[ 403-16-7 ]
[ 1380101-42-7 ]

Yield	Reaction Conditions	Operation in experiment
47%		Example 16.1: (S)-3-Chloro-N-(l-(3,3-difluoropiperidin-l-yl)-3-methylbutan-2-yl)-4- fluoro-N-methylbenzamide; 3-Chloro-4-fluorobenzoic acid (0.087 g, 0.50 mmol), TBTU (0.175 g, 0.54 mmol) and NMM (0.125 mL, 1.13 mmol) was mixed in DMF (2 mL). After 10 min at rt was (S)- l-(3,3-difluoropiperidin-l-yl)-N,3-dimethylbutan-2-amine (Compound S2) (0.1 g, 0.45 mmol) and additional DMF (1 mL) added. The resultant mixture was stirred at rt overnight. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCC^ (saturated, 5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (80 mg, 47%). HRMS (M+H)+: calculated 377.1607; found 377.1613.

Reference： [1]Patent: WO2012/74469,2012,A1 .Location in patent: Page/Page column 111-112

63
[ 403-16-7 ]
[ 57260-71-6 ]
[ 1279027-63-2 ]

Yield	Reaction Conditions	Operation in experiment
		3-Chloro-4-fluorobenzoic acid (1 g) was dissolved in N,N-dimethylacetamide (10 ml), and tert-butyl piperazine-1-carboxylate (1.3 g) and DIPEA (1.9 g) were added thereto, followed by stirring at 130 C. overnight. The reaction mixture was concentrated under reduced pressure, and a 1 M aqueous NaOH solution was added thereto, followed by washing with EtOAc. The pH of the aqueous layer was adjusted to around 6 to 7 by the addition of 1 M hydrochloric acid, followed by extraction with CHCl3. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH). The product was dissolved in dioxane (10 ml), and 4 M hydrogen chloride/dioxane (10 ml) was added thereto, followed by stirring at room temperature overnight. The precipitated solid was collected by filtration to obtain 3-chloro-4-piperazin-1-yl benzoic acid hydrochloride (142 mg).

Reference： [1]Patent: US2012/184520,2012,A1 .Location in patent: Page/Page column 20; 21

64
[ 403-16-7 ]
[ 348-51-6 ]

Reference： [1]Chemical Communications,2012,vol. 48,p. 8270 - 8272

65
[ 1357920-41-2 ]
[ 403-16-7 ]
[ 1357920-52-5 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 6523 - 6540

66
[ 403-16-7 ]
[ 1413285-55-8 ]

Reference： [1]Patent: WO2012/156400,2012,A1

67
[ 403-16-7 ]
[ 1413285-56-9 ]

Reference： [1]Patent: WO2012/156400,2012,A1

68
[ 403-16-7 ]
[ 1413285-57-0 ]

Reference： [1]Patent: WO2012/156400,2012,A1

69
[ 403-16-7 ]
[ 1413285-58-1 ]

Reference： [1]Patent: WO2012/156400,2012,A1

70
[ 403-16-7 ]
[ 1413285-59-2 ]

Reference： [1]Patent: WO2012/156400,2012,A1

71
[ 403-16-7 ]
[ 1413284-15-7 ]

Reference： [1]Patent: WO2012/156400,2012,A1

72
[ 18166-02-4 ]
[ 403-16-7 ]
[ 1413285-54-7 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (4.6g) in dichloromethane (100 ml) was added oxalyl chloride (2.5 ml). A drop of DMF (0.01 ml) was added and the reaction mixture was stirred at room temperature during 18 hours. The solution was then concentrated to give a colorless oil, which was diluted in toluene (20 ml). This solution was added dropwise (in approximately 20 minutes) to a mixture of trimethylsilylmethylamine (4 ml) and triethylamine (10 ml) in toluene (40ml). The solution was stirred at room temperature during 1 hour, then 200ml of ethyl acetate were added, and the resulting solution was washed twice with water (2x100ml) and brine (50ml). The organic phase was then dried over anhydrous sodium sulfate, filtered and evaporated to give the crudetitle compound as a solid(6.4 g). LCMS (Method C) RT 0.98 min, [M+H]+ 258/260. 'H-NMR (CDC13, 400 MHz): 0.00 (s, 9H), 2.81 (s, 2H), 5.90 (m, 1H), 7.05 (m, 1H), 7.49 (m, 1H), 7.70 (m, 1H)

Reference： [1]Patent: WO2012/156400,2012,A1 .Location in patent: Page/Page column 196

73
[ 403-16-7 ]
[ 1431501-12-0 ]

Reference： [1]Patent: WO2013/59648,2013,A1

74
[ 403-16-7 ]
[ 132992-43-9 ]

Yield	Reaction Conditions	Operation in experiment
78%	With sulfuric acid; nitric acid; at 20 - 100℃; for 2.5h;	A round bottom flask was charged with <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (2.50 g, 14.32 mmol) and sulfuric acid (10 ml), and nitric acid (0.91 mL, 21.48 mmol) was added slowly. The reaction mixture was stirred at rt for 30 min and then heated to 100 C and stirred at that temperature for 2h. After cooling to room temperature, the reaction mixture was poured into ice cold water and the precipitated solids were collected by filtration and washed with water and dried to afford a white powder (2.44 g, 78%).

Reference： [1]Patent: WO2013/59648,2013,A1 .Location in patent: Paragraph 0671

75
[ 403-16-7 ]
[ 1431505-19-9 ]

Reference： [1]Patent: WO2013/59648,2013,A1

76
[ 403-16-7 ]
[ 1431505-20-2 ]

Reference： [1]Patent: WO2013/59648,2013,A1

77
[ 403-16-7 ]
[ 1431505-21-3 ]

Reference： [1]Patent: WO2013/59648,2013,A1

78
[ 403-16-7 ]
[ 1431505-22-4 ]

Reference： [1]Patent: WO2013/59648,2013,A1

79
[ 403-16-7 ]
[ 1431505-23-5 ]

Reference： [1]Patent: WO2013/59648,2013,A1

80
[ 403-16-7 ]
[ 1431505-24-6 ]

Reference： [1]Patent: WO2013/59648,2013,A1

81
[ 403-16-7 ]
[ 1236119-57-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505
[2]Patent: WO2018/125961,2018,A1

82
[ 403-16-7 ]
[ 1236119-56-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505

83
[ 403-16-7 ]
[ 1236119-66-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505
[2]Patent: WO2018/125961,2018,A1

84
[ 403-16-7 ]
[ 1246085-14-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505

85
[ 403-16-7 ]
[ 1246085-26-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505

86
[ 403-16-7 ]
[ 1246085-25-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505

87
[ 403-16-7 ]
[ 1246085-31-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505

88
[ 403-16-7 ]
[ 765-30-0 ]
[ 1236119-65-5 ]

Yield	Reaction Conditions	Operation in experiment
89%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 23℃; for 3h;	General procedure: To a suspension of <strong>[403-16-7]3-chloro-4-fluorobenzoic acid</strong> (25.0 g, 143 mmol), Methylamine hydrochloride (11.60 g, 172 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (41.2 g, 215 mmol), and 1H-benzo[d][1,2,3]triazol-1-ol hydrate (32.9 g, 215 mmol) in DMF (Volume: 150 mL) was added 4-methylmorpholine (79 mL, 716 mmol) at 23 C. The reaction was stirred at 23 C for 3 hr. The reaction mixture was diluted with water (500 mL) to furnish a yellow-orange solution. The solution was stirred overnight at 23C affording a suspension. The suspension was filtered, washed with H2O (3 x 100 mL), and the resulting solid was dried in vacuo at 30 C to provide 3-chloro-4-fluoro-N-methylbenzamide ( 14.24 g, 76 mmol, 53.0 % yield) as an off-white solid.
70%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 4h;Inert atmosphere;	To a stirred solution of <strong>[403-16-7]3-chloro-4-fluoro-benzoic acid</strong> (1 g, 5.73 mmol) andcyclopropanamine (0.47 mL, 6.76 mmol) in dry DMF (10 mL), EDC.HCl (1.64 g, 8.56mmol), HOBt (1.2 g, 8.89 mmol) and NMM (3.1 mL, 28.24 mmol) were added at RT underargon atmosphere and stirred for 4 h. After completion of the reaction (monitored by TLC),the reaction mixture was diluted with cold water (25 mL) and stirred for 15 minutes. Thesolid formed was filtered off which was washed with water (50 mL) and dried under vacuumto afford 3-chloro-N-cyclopropyl-4-fluoro-benzamide (0.85 g, 70% yield) as a white solid.LCMS: m/z: 214.3 [M+Ht.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4501 - 4505
[2]Patent: WO2018/125961,2018,A1 .Location in patent: Page/Page column 35

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Ghs Precautionary Statements

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

Ghs Hazard Statements

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