Name: 105184-38-1|3,5-Difluorophenylacetic acid|98%
Brand: Ambeed
SKU: A114463
Price: 5.0 USD
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1
[ 64-17-5 ]
[ 105184-38-1 ]
[ 139368-37-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In dichloromethane; at 0 - 20℃; for 22h;	10 ml of ethanol and 354 mg (2.90 mmol) of 4-(dimethylamino)pyridine were added to dichloromethane (100 ml) solution of 5.0 g (29.0 mmol) of <strong>[105184-38-1](3,5-difluorophenyl)acetic acid</strong>. After cooling with ice, 6.68 g (34.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added thereto, and stirred for 22 hours with graduallywarming up to room temperature. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and 1 N hydrochloric acid were added to the residue. The organic layer separated was washed with aqueous saturated sodium bicarbonate solution and brine, and dried over anhydrous magnesium sulfate. After filtrating and concentrating under reduced pressure, 27.3 g (quantitative) of the entitled compound was obtained as a pale yellow oil. MS(FAB)m/z:201(M+).1H-NMR(CDCl3)delta: 1.27(3H, t, J=7.1Hz), 3.59(2H, s), 4.17(2H, q, J=7.1H), 6.67-6.87(3H, m).
	With sulfuric acid; for 2h;Heating / reflux;	Preparation 2.2; Ethyl 2-(3,5-difluorophenyl)-3-hydroxy-2-propenoate (III); A) Ethyl 3,5-difluorophenylacetate; 5 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> are dissolved in 50 ml of ethanol and 3 ml of concentrated H2SO4, and the mixture is heated at reflux for two hours. The mixture is evaporated to dryness, neutralization is then carried out with a saturated K2CO3 solution, extraction is then carried out with AcOEt and the organic phase is evaporated to produce 5.0 g of the expected compound in the form of a colourless liquid. NMR CDCl3 (200 MHz): 1.27 ppm:t:3H; 3.59 ppm:s:2H; 4.18 ppm:q:2H; 6.68-6.85 ppm:unresolved peak:3H.
	With hydrogenchloride; In water; for 18h;Reflux;	General procedure: To a stirred solution of carboxylic acid 11j-r (1 mmol) in EtOH(3 mL) was added conc. HCl (1 drop), and the resulting mixturewas refluxed for 18 h. After cooling, the solvent was removed, andthen the residue was added sat. NaHCO3 aq., and the aqueous mixturewas extracted with CH2Cl2. The organic extracts were driedover Na2SO4, and the solvent was removed to afford the correspondingethyl ester, which was used for the next reaction withoutfurther purification. To a stirred solution of ethyl ester (1 mmol),obtained above, in EtOH (0.5 mL) was added hydrazine monohydrate(0.05 mL, 1 mmol), and the resulting mixture was refluxedfor 18 h. The solvent was removed to give the corresponding acylhydrazide, which was used for the next reaction without furtherpurification. To a stirred solution of acylhydrazide, obtained above,in CH2Cl2 (1 mL) was added a solution of isothiocyanate 8a-h or10c, i (1 mmol) in CH2Cl2 (5 mL), and the resulting mixture was stirredat room temperature for 18 h. The insoluble solid was correctedby filtration, and dried to give acyl hydrazino thiourea 13A-U.

Reference： [1]Patent: EP1479681,2004,A1 .Location in patent: Page 113
[2]Journal of Medicinal Chemistry,1994,vol. 37,p. 113 - 124
[3]Patent: US2005/288318,2005,A1 .Location in patent: Page/Page column 9
[4]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3736 - 3745

2
[ 105184-38-1 ]
[ 157033-24-4 ]

Yield	Reaction Conditions	Operation in experiment
	With (COCl)2; In dichloromethane; N,N-dimethyl-formamide; toluene;	EXAMPLE 10 N-[4-(3'-Cyano-biphenyl-4-yl)-1-cyclopropylmethyl-piperidin-4-ylmethyl]-2-(3.5-difluoro-phenyl)-acetamide: To a stirred solution of <strong>[105184-38-1]3,5-difluorophenyl acetic acid</strong> (0,172 g, 1 mmol) in CH2Cl2 (1 mL) at room temperature under Ar was added (COCl)2 (0.175 mL, 2 mmol, 2 eq.) followed by DMF (0.01 mL, catalyst). The resulting mixture was stirred at room temperature for 16 h. The mixture was concentrated by rotary evaporation and the resulting oil was evaporated from CH2Cl2 (25 mL) and toluene (15 mL) and dried under high vacuum for 1 h to give (3,5-difluoro-phenyl)-acetyl chloride as a pale yellow oil.
	In N-methyl-acetamide; oxalyl dichloride; 1,2-dichloro-ethane;	19.3 cm3 of oxalyl chloride and then a few drops of dimethylformamide are successively added to a solution of 25 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> in 350 cm3 of 1,2-dichloroethane at a temperature in the region of 20 C., after stirring for 3 hours at a temperature in the region of 20 C., 30 cm3 of oxalyl chloride and a then few drops of dimethylformamide are again successively added. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40 C. 27.6 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> chloride are thus obtained in the form of a yellow oil.
	With thionyl chloride;	EXAMPLE 3 (R)-5,7-Difluoro-1,2,3,4-tetrahydro-2-hydroxynaphthalene The following is the preparation of a compound of Formula 6 in which t is 2 and R1 is fluoro at the 5- and 7-position. A mixture <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (100 g, 0.58 mmol) and thionyl chloride (13.7 M, 100 mL, 1.37 mol) was stirred for 15 hours at room temperature. Evaporation gave 3,5-difluorophenylacetyl chloride as an oily residue.

	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0℃; for 3h;	Acid Chloride Preparation 3,5-Difluorophenylacetic acid (30 g, 0.174 mol) (Aldrich) was dissolved in dichloromethane and this solution was cooled to 0C. DMF (0.5 mL, catalytic) was added followed by the dropwise addition of oxalyl chloride (18 mL, 0.20 mol) over a 5 minute period. The reaction was stirred for 3 h and then rotoevaporated at reduced pressure to give an oil which was placed on a high vacuum pump for 1 h to afford 3,5-difluorophenylacetyl chloride as a thin yellow oil. Other acid chlorides can be prepared in a similar manner.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere;	(3,5-Difluorophenyl)-acetyl chloride; 3,5-Difluorophenylacetic acid (47.5 g, 273 mmol) was dissolved in dry DCM(30OmL) followed by addition of oxalyl chloride (26.2 mL, 301 mmol). A nitrogen atmosphere was established and dry dimethylformamide (few drops) was added. The mixture was stirred overnight at rt followed by evaporation in vacuo to yield the crude title compound (52.0 g, 100%).
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere;	3,5-Difluorophenylacetic acid (47.5 g, 273 mmol) was dissolved in dry DCM (300 ml_) followed by addition of oxalyl chloride (26.2 ml_, 301 mmol). A nitrogen atmosphere was established and dry DMF (few drops) was added. The mixture was stirred overnight at RT followed by evaporation in vacuo to yield the crude title compound (52.0 g, 100%). The product was used without further purification.
	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃;Inert atmosphere;	(3,5-Difluorophenyl)-acetyl chloride (Intermediate compound)3,5-Difluorophenylacetic acid (47.5 g, 273 mmol) was dissolved in dry DCM (300 ml_) followed by addition of oxalyl chloride (26.2 ml_, 301 mmol). A nitrogen atmosphere was established and dry DMF (few drops) was added. The mixture was stirred overnight at RT followed by evaporation in vacuo to yield the crude title compound (52.0 g, 100%). The product was used without further purification.
	With oxalyl dichloride; In dichloromethane; N,N-dimethyl-formamide; at 20℃; for 24h;	General procedure: To the various carboxylic acids (obtained from ASDI, Inc., 0.076 mmol, 1 equiv.) was added dry DCM (0.5 mL), oxalyl chloride (0.076 mmol, 1 equiv.), and then 2 drops of DMF. The reactions were placed in the shaker and reacted overnight at ambient temperature for 24 h. A solution of the hydrochloride salt of 3 (0.048 mmol, 1 equiv.) in 1.5 mL of DMF was added, followed by DIEA (0.240 mmol, 5 equiv.). The vials were agitated in the shaker for 24 h at ambient temperature. The solvent was removed in a Genevac HT24 centrifugal evaporator, and the crude intermediates were carried forward without purification. To each of the above crude products was added 10% TEA in MeOH (2 mL). The reaction vials were then placed in the shaker at 33 C overnight, and the solvent was evaporated. All the crude products were purified via preparative HPLC to >95% purity, and the desired products in the yields as described below.
	With oxalyl dichloride; In dichloromethane; at 20℃; for 2h;	To a solution of <strong>[105184-38-1]2-<strong>[105184-38-1](3,5-difluorophenyl)acetic acid</strong></strong> (5.0 g, 29 mmol) in DCM (50 mL) was added oxalyl chloride (17 mL, 2M solution in DCM, 35 mmol) and the mixture was stirred at room temperature for 2 h. The solvent was removed on a rotary evaporator and the residue was dissolved in DCM (50 mL). To this solution was added 1,4-dimethoxybenzene (6.0 g, 44 mmol) followed by aluminum chloride (5.8 g, 44 mmol) and the resulting darkorange solution stirred for 2 h. The reaction mixture was quenched with ice-water and extracted with DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel (0-50% EtOAc/heptane) to obtain the desired product (5.0 g, 59%). ?H NMR (400 MHz, Chloroformd) oe 7.28 -7.18 (m, 1H), 7.05 (dd, J= 9.0, 3.2 Hz, 1H), 6.92 (d, J= 9.0 Hz, 1H), 6.82- 6.65(m, 3H), 4.29 (s, 2H), 3.89 (s, 3H), 3.78 (s, 3H).
	With thionyl chloride; for 15h;	5,7-Difluoro-2-tetralone. SOCl2 (100 mL) was added in one portion to <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (100 g, 0.58 mol) and after stirring for 15 h, the volatiles were evaporated under reduced pressure. The resulting oily acid chloride was dissolved in CH2Cl2 (200 mL) and added dropwise to a mechanically stirred suspension of AlCl3 (154 g, 1.16 mol) in CH2Cl2 (1.0 L). The stirred suspension was cooled to an internal temperature of -65 C in a dry ice/acetone bath, and the acid chloride solution was added at such a rate in order to maintain an internal temperature <-60 C. After the addition was complete, ethylene gas was bubbled through the reaction mixture at a rapid rate for 10 min at -65 C. The reaction mixture was allowed to warm to 0 C over 2 h with stirring, and was then cooled to -10 C and treated with H2O (500 mL) initially dropwise, followed by rapid addition. The organic layer was separated, washed with brine (100 mL) and dried over MgSO4. Evaporation under reduced pressure gave a dark oily residue which was distilled in vacuo on a Kugelrohr collecting material boiling between 90-110 C (1.0 to 0.7 mm Hg). The distillate was redistilled at 100-105 C (0.3 mm Hg) to give the product as a white solid, (73.6 g, 0.40 mol; 70%): mp 46 C; IR (KBr) 1705 cm-1; 1H NMR (CDCl3) delta 2.55 (t, J =7.5 Hz, 2H), 3.10 (t, J = 7.5 Hz, 2H), 3.58 (s, 2H), 6.70 (m, 2H); MS m/z 182 (M+). Anal. Calcd for C10H8F2O: C, 65.93; H, 4.42. Found: C, 65.54; H, 4.42.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; for 1h;	Method C 2-(3,5-Difluoro-phenyl)-lambda/-(4-oxo-2-pyrrolidin-1 -yl-4/-/-quinazolin-3-yl)-acetamide (Compound CD3,5-Difluorophenylacetic acid (0.227 g, 1.30 mmol) was dissolved in DCM (5 ml_), followed by addition of oxalyl chloride (137 mul_, 1.56 mmol) and 2 drops of dry DMF. After 1 hour gas evolution had stopped and pyridine (106 mul_, 1.30 mmol) was added, followed by addition of 3-amino-2-pyrrolidin-1 -yl-3H-quinazolin-4-one. After stirring at RT for 5 minutes additional pyridine (212 mul_, 2.60 mmol) was added. The reaction mixture was stirred overnight at RT. The mixture was diluted with EtOAc (20 ml_), washed with 1 M HCI (20 ml_), dried (MgSO4) and evaporated in vacuo. The crude product was subjected to column chromatography (EtOAc/Heptane) giving the title compound (0.073 g, 15%). LC-ESI-HRMS of [M+H]+ shows 385,1485 Da. CaIc. 385,147607 Da.
2.1 kg	With oxalyl dichloride; In dichloromethane; at 20℃;Cooling with ice; Large scale;	S1: 1.72 kg of raw material I (1 equivalent) of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong>, its structural formula is: dissolved in 17L (10 volumes) of methylene chloride, and the resulting solution A is subjected to an ice-water bath, while To solution A, 2.5 kg of oxalyl chloride (2 equivalents) was added dropwise, and then stirred overnight at room temperature, and the resulting product concentrated oil pump was vacuum dried to obtain 2.1 kg of intermediate II as acid chloride, the structural formula of which was:

Reference： [1]Tetrahedron,1999,vol. 55,p. 6001 - 6018
[2]Patent: US2003/13720,2003,A1
[3]Patent: US2001/27193,2001,A1
[4]Patent: US5538988,1996,A
[5]Patent: EP951466,2009,B1 .Location in patent: Page/Page column 63
[6]Patent: EP1191008,2002,A1 .Location in patent: Page 68
[7]Patent: WO2010/94645,2010,A1 .Location in patent: Page/Page column 28
[8]Patent: WO2010/105960,2010,A1 .Location in patent: Page/Page column 23
[9]Patent: WO2010/122064,2010,A1 .Location in patent: Page/Page column 30
[10]European Journal of Medicinal Chemistry,2013,vol. 62,p. 777 - 784
[11]Journal of Medicinal Chemistry,2013,vol. 56,p. 3068 - 3077
[12]Patent: WO2016/97073,2016,A1 .Location in patent: Page/Page column 177; 178
[13]European Journal of Medicinal Chemistry,2017,vol. 130,p. 73 - 85
[14]Patent: EP2182804,2017,B1 .Location in patent: Paragraph 0130
[15]Patent: WO2008/142140,2008,A2 .Location in patent: Page/Page column 38
[16]Organic Letters,2018,vol. 20,p. 7239 - 7244
[17]Patent: CN111018663,2020,A .Location in patent: Paragraph 0012-0013; 0019
[18]Biomolecules,2020,vol. 10

3
[ 105184-38-1 ]
[ 82004-77-1 ]
[ 64-19-7 ]
[ 158922-07-7 ]
N-Fmoc-β-methyl-L-Trp [ No CAS ]
6-amino-2-[2-({1-[(3,5-difluoro-phenyl)-acetyl]-piperidine-3-carbonyl}-amino)-3-(1<i>H</i>-indol-3-yl)-butyrylamino]-hexanoic acid <i>tert</i>-butyl ester; compound with acetic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multistep reaction;

Reference： [1]Zhou, Changyou; Guo, Liangqin; Morriello, Greg; Pasternak, Alex; Pan, Yanping; Rohrer, Susan P.; Birzin, Elizebeth T.; Huskey, Su-Er Wu; Jacks, Tom; Schleim, Klaus D.; Cheng, Kang; Schaeffer, James M.; Patchett, Arthur A.; Yang, Lihu [Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 3, p. 415 - 417]

4
[ 105184-38-1 ]
[ 467223-90-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	With borane-THF;	The synthesis of 2- (3, 5-Difluorophenyl)-1-oxiranylethanol (67) followed that reported in Kurihara, M. et al. Tetrahedron Left. 1999,40, 3183-3184 for the synthesis of 2-phenyl-1-oxiranylethanol. 2-(3, 5-Difluorophenyl)-1-oxiranylethanol : Rf = 0.42 (30% EtOAc/hexanes); retention time (min) = 1.350 (method [1] ) ; MS (ESI) 242.3 (84), 201.3 (26), 183.3 (100). The synthesis of 2- [2- (3, 5-Difluorophenyl)-1-methoxyethyl] oxirane (68) followed the method of Boeckman, R. K. Jr.; Liu, X. Synthesis 2002,2138-2142. 2- (3, 5-Difluorophenyl)-1-oxiranylethanol (67) (411 mg, 2.05 mmol) was combined with silver (l) oxide (1.934 g, 8.34 mmol) in iodomethane (5.2 mL, 83.3 mmol), and heated to gentle reflux (45 C bath) for 20 h. The mixture was then diluted with diethyl ether, filtered through diatomaceous earth, and the filtrate concentrated under reduced pressure to give 68. Flash chromatography (10% EtOAc/hexanes elution) afforded 273 mg (63%) of the product as an oil : Rf = 0.26 (10% EtOAc/hexanes); retention time (min) = 1.895 (major), 1.951 (minor), method [1] ; MS (ESI) 256.3 (100), 237.3 (22), 215.3 (26).
		Step 1. 2-(3,5-difluorophenyl)ethan-1-ol <strong>[105184-38-1]2-<strong>[105184-38-1](3,5-difluorophenyl)acetic acid</strong></strong> (250 mg, 1.45 mmol) was dissolved in 10 ml of THF and cooled to 0 C. 1M Borane THF complex solution (2.18 ml, 2.18 mmol) was then added dropwise over 15 mins. The reaction was then allowed to warm to room temperature overnight and then quenched with water at 0 C. The reaction mixture was diluted with EtOAc and washed with water, brine, dried (MgSO4), and concentrated. The crude residue was concentrated in vacuo to give the title compound as a clear oil which was used without further purification. 1H NMR (CHCl3, 400 MHz) delta 6.68 (m, 2H), 6.55 (m, 1H), 3.75 (t, J=6.5 Hz, 2H), 2.74 (t, J=6.5 Hz, 2H).
		A stirred solution of 10.0 grams (0.058 mole) of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> in 100 mL of THF was cooled to about 5 &deg C, and 80 mL of a 1.0M solution of borane-THF complex (in 80 mL of THF) was added dropwise, while maintaining the reaction mixture temperature between about 5 &deg C and about 10 &deg C. Upon completion of addition, the reaction mixture was stirred as it warmed to ambient temperature. After this time the reaction mixture was treated with a solution of 7.5 grams of sodium hydroxide in 100 mL of water. The mixture was extracted with two 200 mL portions of diethyl ether, and the combined extracts were dried with magnesium sulfate. The mixture was filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of methylene chloride and diethyl ether. The fractions containing product were combined and concentrated under reduced pressure, yielding 8.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure. Step B Synthesis of tri(l-methylethyl)silyl 2- (3,5-difluorophenyl)ethyl ether as an intermediate A solution of 8.3 grams (0.052 mole) of 2- (3,5-difluorophenyl)ethanol 8.9 grams (0.130 mole) of imidazole in about 100 mL of methylene chloride was stirred, and a solution of 13.9 mL (0.065 mole) of triisopropylsilyl chloride in about 25 mL of methylene chloride was added dropwise. Upon completion of addition, the reaction mixture stirred at ambient temperature for about 18 hours. After this time the reaction mixture was diluted with about 200 mL of water, the organic layer was separated, and the aqueous layer was extracted with one 150 mL portion of methylene chloride. The methylene chloride extract was combined with the organic layer, and filtering it through a silicone-coated filter paper dried the combination. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of methylene chloride and petroleum ether. The fractions containing product were combined and concentrated under reduced pressure, yielding 15.8 grams of the subject compound. The NMR spectrum was consistent with the proposed structure. Step C Synthesis of 2,6-difluoro-4-[2-[tri(l-methylethyl)silyloxy]ethyl]benz- aldehyde as an intermediate A stirred solution of 3.0 grams (0.0095 mole) of tri(1-methylethyl)silyl 2- (3,5-difluorophenyl) ethyl ether in 50 mL of THF was cooled to about-78 &deg C, and 4.0 mL of 2.5M solution of n-butyllithium (0.0100 mole-in hexane) was added dropwise during a 15 minute period while maintaining the reaction mixture temperature at about-75 &deg C. Upon completion of addition, the cold reaction mixture was stirred for about 30 minutes and a solution of 1.4 grams (0.0190 mole) of DMF in 25 mL of THF was added dropwise. Upon completion of addition, stirring of the reaction mixture was continued at about-75 &degC for 1.5 hours. The reaction mixture was then treated with a dilute aqueous ammonium chloride solution, and extracted with two 200 mL portions of diethyl ether. The combined extracts were washed with one 75 mL portion of aqueous 10% lithium chloride, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of methylene chloride and petroleum ether. The fractions containing product were combined and concentrated under reduced pressure, yielding 1.6 grams of the subject compound. The NMR spectrum was consistent with the proposed structure. Step D Synthesis of tri(l-methylethyl)silyl 2-[3,5-difluoro-4-(ethoxyimino- methyl) phenyl]ethyl ether as an intermediate A solution of 1.2 grams (0.0035 mole) of 2,6-difluoro-4-[2-[tri(l- methylethyl) silyloxy]ethyl]benzaldehyde and 0.56 gram (0.0058 mole) of 0- ethylhydroxylamine hydrochloride in 30 mL of acetonitrile was stirred, and 0.59 gram (0.0058 mole) of triethylamine was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was diluted with about 70 mL of water and extracted with two 75 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of methylene chloride and petroleum ether. The fractions containing product were combined and concentrated under reduced pressure, yielding 1.2 grams of the subject compound. The NMR spectrum was consistent with the proposed structure. Step E Synthesis of 2-[3,5-difluoro-4-(ethoxyiminomethyl)phenyl]ethanol as an intermediate A solution of 0.95 gram (0.0025 mole) of tri(1-methylethyl)silyl 2-[3,5- difluoro-4-(ethoxyiminomethyl)phenyl]ethyl ether in 25 mL of THF was stirred, and 3.7 mL (0.0...

Reference： [1]Patent: WO2005/87751,2005,A2 .Location in patent: Page/Page column 237
[2]Journal of Medicinal Chemistry,2002,vol. 45,p. 4321 - 4335
[3]Patent: US2018/169078,2018,A1
[4]Journal of Enzyme Inhibition and Medicinal Chemistry,2018,vol. 33,p. 1460 - 1471
[5]Patent: WO2005/108374,2005,A1 .Location in patent: Page/Page column 34-37

5
[ 105184-38-1 ]
[ 327052-53-9 ]
[ 208255-80-5 ]

Reference： [1]Organic and Biomolecular Chemistry,2005,vol. 3,p. 2450 - 2457
[2]Australian Journal of Chemistry,2005,vol. 58,p. 585 - 594
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 1983 - 1985

6
[ 74-85-1 ]
[ 105184-38-1 ]
[ 172366-38-0 ]

Yield	Reaction Conditions	Operation in experiment
80%		(1) Dissolve 100 grams of 3,5-difluorophenylacetic acid 1 in 500 mL of dichloromethane,Add 50 grams of thionyl chloride under stirring, and then increase the temperature to 40~50,After keeping this temperature for 4 hours, the reaction is completed by HPLC and TLC.Cool down, concentrate, add dichloromethane to dilute and store temporarily, as the prepared acid chloride;Add 500 mL of dichloromethane to another reaction flask,Then add 150g aluminum trichloride,Then add the previously prepared acid chloride dropwise to the reaction system,After the addition is complete, ethylene gas is introduced into the system,When the reaction of the raw materials is complete, add 500 mL of purified water to the system to quench the reaction.After quenching, the system is separated and the organic phase is concentrated.Intermediate 2 was obtained by column chromatography with a yield of 80%;
	aluminium trichloride; In dichloromethane;	(Example 4) Synthesis of 6,8-difluoro-2-propyl-7-(3,4,5-trifluorophenyl)-9,10-dihydrophenanthrene Following conversion of (3,5-difluorophenyl)-acetic acid to an acid chloride with thionyl chloride, subsequent reaction with ethylene gas at -10C using methylene chloride as the solvent and in the presence of aluminum chloride yielded 5,7-difluoro-3,4-dihydro-1H-naphthalen-2-one.
	aluminium trichloride; In dichloromethane;	Following conversion of (3,5-difluorophenyl)-acetic acid to an acid chloride with thionyl chloride, subsequent reaction with ethylene gas at -10C using methylene chloride as the solvent and in the presence of aluminum chloride yielded 5,7-difluoro-3,4-dihydro-1H-naphthalen-2-one.

Reference： [1]Patent: CN113527108,2021,A .Location in patent: Paragraph 0012; 0033; 0035-0036
[2]Molecular Crystals and Liquid Crystals,2004,vol. 411,p. 155/[1197]-161/[1203]
[3]Patent: EP1201632,2002,A1
[4]Patent: EP1201632,2002,A1

7
[ 857079-31-3 ]
[ 105184-38-1 ]
[ 924369-63-1 ]

Yield	Reaction Conditions	Operation in experiment
58%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 55℃; for 18h;	To a solution of methyl N-[(4'-amino-l,r-biphenyl-4-yl)surfonyl]-N-methyl-L-valinate (80 mg, 0.21mmol) in dichloromethane (3 mL) was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (73 mg, 0.42 mmol), 4-dimethylaminopyridine (52 mg, 0.42 mmol), and l-(3-dimethylaminopropyl)-3- ethylcarbodmide hydrochloride (81 mg, 0.42 mmol). The mixture was heated at 550C for 18 h. The mixture was allowed to cool to ambient temperature and was diluted with methylene chloride. The organic mixture was washed with IN aqueous hydrochloric acid solution and brine then concentrated to dryness under reduced pressure. The residue was suspended in ether, and the solid was collected by filtration. The solid was washed with ether and dried under high vacuum to afford methyl Nu-[(4'- [(3,5-difluorophenyl)acetyl]arnino}-l,r-biphenyl-4-yl)surfonyl]-N-methyl-L-valinate (65 mg, 58%). 1H NMR (400 MHz, CD3OD) delta 0.90 (d, 3 H), 0.97 (d, 3 H), 2.08 (m, 1 H), 2.88 (s, 3 H), 3.35 (s, 3 H), 3.72 (s, 2 H), 4.05 (d, 1 H), 6.82 (t, 1 H), 6.96 (d, 2 H), 7.61 (d, 2 H), 7.68 (d, 2 H), 7.74 (d, 2 H), 7.78 (d, 2 H); LC-MS m/z 531.2 (MH+), retention time 3.62 min.

Reference： [1]Patent: WO2007/16538,2007,A2 .Location in patent: Page/Page column 33

8
[ 680231-01-0 ]
[ 105184-38-1 ]
[ 680228-25-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 1h;	Example 37. (25)-2-r(3.,5-Difluorophenyl)acetvnamino-N-r(3j?.6.<?.7R)-4-methyl-5-oxo-3,7- diphenyI-l,4-oxazepan-6-yI1-2-phenylacetamide (37)To a solution of (25)-2-amino-iV-[(3i?,65',7i?)-4-methyl-5-oxo-3,7-diphenyl-l,4-oxazepan- 6-yl]-2-?henylacetamide (37b) (42 mg, 0.098 mmol) in DCM (5 mL) at 0 0C under N2 was added the <strong>[105184-38-1](3,5-difluorophenyl)acetic acid</strong> (17 mg, 0.098 mmol), HOBt-hydrate (33 mg, 0.215 mmol), EDACHCl (28 mg, 0.147 mmol) and NMM (18 ?L, 0.147mmol). The reaction mixture was stirred 1 h at 00C, concentrated in vacuo and partitioned between 0.25N HCl (10ml) and EtOAc (10 mL). The organic phase was collected and consecutively washed with 0.25N HCl, water, saturated NaHCO3, and brine, dried and the solvent removed in vacuo to yield an oil. After filtering thru a small plug of silica (CHCl3) the title compound (37) was obtained (35 mg, 61%) as a white solid. 1H NMR (300 MHz, CDCl3) 62.67 (s, 3H), 3.49 (s, 2H), 3.97 (dd, IH), 4.34 (t, IH), 4.80 (d, IH), 5.01 (d, IH), 5.21 (dd, IH), 5.46 (t, IH), 6.48 (d, IH), 6.7-6.8 (m, 3H), 7.02 (m, 2H), 7.2-7.3 (m, 10.5H), 7.40 (m, 3.5H). MS APCI, m/z = 584(M+1). LC/MS: 2.51 min.

Reference： [1]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 99

9
[ 2491-20-5 ]
[ 105184-38-1 ]
[ 680230-04-0 ]

Yield	Reaction Conditions	Operation in experiment
88%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	To a stirred solution of 3, 5-<strong>[105184-38-1]difluorophenylacetic acid</strong> (6.02 g, 34.97 [MMOL),] L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in dichloromethane (200 mL) under nitrogen at [0C] was added NMM (8.84g, 87.39 mmol) and EDAC-HCl (7.38 g, [38.] 49 [MMOL).] The mixture was allowed to warm gradually to ambient temperature and stir overnight. The reaction was diluted with ethyl acetate and extracted sequentially with aqueous sodium bicarbonate, IN aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1 : [1] [(V/V)] hexanes: ethyl acetate to afford [N [ (3,] 5- difluorophenyl) acetyl] -L-alanine methyl ester (7.91 g, 88% yield) as a white [SOLID. LH NMR] (300 MHz, [CDC13)] [6] 1.39 (d, 3H, [J= 7.] 0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, 1H), 6.02 (br [1H),] 6.67-6. 87 (m, 3H). MS APCI, m/z = 258 (M+1). LC/MS: 1.68 min. Lithium hydroxide (1.40 g, 33.33 mmol) in water (60 mL) was added dropwise to a solution of N [ (3, 5-difluorophenyl) acetyl] -L-alanine methyl ester (7.79 g, 30.28 mmol) in 1,4-dioxane (150 mL). After 2h the solvent was evaporated. The residue was dissolved in water and the solution extracted with diethyl ether. The aqueous phase was acidified with IN aqueous HCl and extracted with ethyl acetate three times. The combined ethyl acetate extracts were dried, filtered and evaporated to afford the title compound (7.16 g, 97% yield) as a white [SOLID. LH] NMR (300 MHz, d6-DMSO) 5 1.28 (d, 3H, J= 7.4 Hz), 3.51 (s, 2H), 4.20 (m, 1H), 6.93-7. 12 (m, 3H), 8.44 (d, 1H, J= 7.0 Hz), 12.46 (br, 1H). HPLC Method A: 2.12 min.
88%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 25℃; for 12h;	e. JV-r(3,5-DifluorophenvI)acetyl1-L-aIanine (Ie)To a stirred solution of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (6.02 g, 34.97 mmol), L-alanine methyl ester hydrochloride (4.88 g, 34.96 mmol) and HOBt (5.20 g, 38.48 mmol) in DCM (200 mL) under nitrogen at 0 0C was added NMM (8.84g, 87.39 mmol) and EDAC-HCl (7.38 g, 38.49 mmol). The mixture was allowed to warm to 25 0C and to stir for -12 h. The reaction was diluted with EtOAc and extracted sequentially with aqueous sodium bicarbonate, IN aqueous HCl and brine. The organic phase was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexanes-EtOAc to afford N- [(3,5- difluorophenyl)acetyl]-L-alanine methyl ester (7.91 g, 88% yield) as a white solid. 1H NMR (300 MHz, CDCl3) ? 1.39 (d, 3H, J= 7.0 Hz), 3.54 (s, 2H), 3.75 (s, 3H), 4.59 (m, IH), 6.02 (br IH), 6.67-6.87 (m, 3H). MS APCI, m/z = 258 (M+l). LC/MS: 1.68 min.
82%	With dmap; diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 14h;Inert atmosphere;	General procedure: Procedure A: A solution of a phenylacetic acid (3.7 mmol), DMAP (5.55 mmol) and DCC (5.55 mmol) in THF (40-70 ml) was stirred at room temperature (rt) for 30 min. The hydrochloride salt of the carboxy protected aminoacid (3.7 mmol) was added and the solution was stirred for 48 h at rt. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. The methyl ester (1eq) was dissolved in methanol. A solution of NaOH (1N, 17 ml) was added and the reaction mixture was stirred for 1 h at rt. H2O was added and methanol only was evaporated under reduced pressure. The pH was reduced to 2 using HCl solution 1N. The crude material was extracted with ethyl acetate and the organic phase was dried with Na2SO4 anhydrous. The solvent was removed in vacuo to afford 4 without any further purification. Procedure B: A solution of phenylacetic acid (6 mmol), the hydrochloride salt of the carboxy protected aminoacid (6 mmol), DMAP (3 mmol) and DCI (10 mmol) in (50-80 ml) was stirred at r.t. for 14 h. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. Treatment with NaOH as reported in procedure A.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 35-36
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 55
[3]ARKIVOC,2010,vol. 2010,p. 145 - 151
[4]European Journal of Medicinal Chemistry,2012,vol. 47,p. 239 - 254

10
2-amino-1-(5-amino-3-phenyl-pyrazole-1-yl)-pentan-1-one di-HCI salt [ No CAS ]
[ 105184-38-1 ]
[ 681488-41-5 ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃; for 2h;	160 mg (0.62 mmol, 1.0 Eq. ) of the title compound of Step C [(2-AMINO-1- (5-AMINO-3-] [PHENYL-PYRAZOLE-1-YL)-PENTAN-1-ONE] Di-HCI) was combined in a flask with 128 mg (0.74 mmol, 1.2 Eq. ) of 3, 5-Difluoro-phenyl acetic acid, 0.31 mL (2.2 mmol, 3.0 Eq. ) of triethylamine, 267 mg (0.62 mmol, 1.0 Eq. ) of HBTU and 10 mL of anhydrous dichloromethane. After 2 hours of room temperature stirring MS and TLC indicated reaction completion. Desired product was confirmed by [H'NMR] and LC/MS.

Reference： [1]Patent: WO2004/33434,2004,A1 .Location in patent: Page 36

11
[ 680231-37-2 ]
[ 105184-38-1 ]
[ 680229-50-9 ]
(2S)-2-[(3,5-difluorophenyl)acethyl]amino-N-[(2S,3R)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-2-phenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To a stirred solution of (2S)-2-amino-N-[(2, 3-cis)-4-oxo-2-phenyl-2, 3,4, 5-tetrahydro- [1,] 5-benzoxazepin-3-yl] -2-phenylacetamide 58b (108 mg, 0. [279MMOL)] in dichloromethane (3mL) under nitrogen was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (58 mg, 0.336 [MMOL),] HOBt (50 mg, 0.370 mmol), NMM (42 mg, 0.416 mmol) and [EDAC-HCL] (71 mg, 0.370 mmol). The mixture was stirred overnight at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, IN aqueous [HCL,] and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 100: 1 (v/v) chloroform: methanol to afford the title compound as a 1: 1 mixture with (2S)-2- [ (3, 5- difluorophenyl) acetyl] [AMINO-N-[(2S, 3R)-4-OXO-2-PHENYL-2,] 3,4, [5-TETRAHYDRO-1,] 5- benzoxazepin-3-yl] -2-phenylacetamide (110 mg, 73%) as a white [SOLID. LH NMR] (300 MHz, [CDC13)] [83.] 47 (s, 1H), 3.56 (s, 1H), 5.07 (m, 1H), 5.45 (d, 0.5H, 7.0 Hz), 5. [56] (d, 0.5H, 7.0 Hz), 5.71 (d, 0.5H, 7.0 Hz), 5.82 (d, 0.5H, 7.0 Hz), 6.52 (m, 1H), 6.72 [(M,] [2H),] 6.80-7. 09 (m, 4H), 7.11-7. 40 (m, 12H), 7.65 (s, 0.5H), 8.29 (s, 0.5H). MS APCI, [M/Z=] 542 [(M+1).] LC/MS: 2. [58] min.
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 58. (2S)-2-r(3,5-Difluorophenyl)acetynamino-N-r(2Jg,35)-4-oxo-2-phenyl-2.3,4,5- tetrahydro-l,5-benzoxazepin-3-yll-2-phenyIacetamide (58)To a stirred solution of (25)-2-amino-N-[(2,3-cw)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-l,5- benzoxazepin-3-yl]-2-phenylacetamide (58b) (108 mg, 0.279 mmol) in DCM (3 mL) under nitrogen was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (58 mg, 0.336 mmol), HOBt (50 mg, 0.370 mmol), NMM (42 mg, 0.416 mmol) and EDAC-HCl (71 mg, 0.370 mmol). The mixture was stirred for -12 h at ambient temperature then evaporated. The residue was dissolved in EtOAc and extracted in succession with saturated sodium bicarbonate, IN aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 100:1 (v/v) CHCl3: methanol to afford the title compound as a 1:1 mixture with (260-2-[(3,5-difluorophenyl)acetyl]amino-N-[(25,3i?)-4-oxo-2- phenyl-2,3,4,5-tetrahydro-l,5-benzoxazepin-3-yl]-2-phenylacetamide (110 mg, 73%) as a white solid. 1H NMR (300 MHz, CDCl3) 53.47 (s, IH), 3.56 (s, IH), 5.07 (m, IH), 5.45 (d, 0.5H, 7.0 Hz), 5.56 (d, 0.5H, 7.0 Hz), 5.71 (d, 0.5H, 7.0 Hz), 5.82 (d, 0.5H, 7.0 Hz), 6.52 (m, IH), 6.72 (m, 2H), 6.80-7.09 (m, 4H), 7.11-7.40 (m, 12H), 7.65 (s, 0.5H), 8.29 (s, 0.5H). MS APCI, m/z = 542 (M+l). LC/MS: 2.58 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 100
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 121

12
(2S)-2-amino-N-[(3R,6R,7S)-4-methyl-5-oxo-3,7-diphenyl-1,4-oxazepan-6-yl]-2-phenylacetamide [ No CAS ]
[ 105184-38-1 ]
[ 680228-25-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0℃; for 1h;	To a solution of [(2S)-2-AMINO-N-[ (3R, 6S, 7R)-4-METHYL-5-OXO-3, 7-DIPHENYL-1,] 4- oxazepan-6-yl]-2-phenylacetamide (37b) (42 mg, 0.098 mmol) in dichloromethane (5ml) at [0C] under N2 was added the (3,5-difluorophenyl) acetic acid (17 mg, 0.098 mmol), HOBt- hydrate (33 mg, 0.215 mmol), EDAC. HCI (28 mg, 0.147 mmol) and NMM (18 [I1L,] 0. [147MMOL).] The reaction mixture was stirred 1 h at [0C,] concentrated in vacuo and partitioned between 0.25N HCl [(10ML)] and ethyl acetate (10ml). The organic phase was collected and consecutively washed with 0.25N HCl (2x), water, saturated [NAHCO3,] and brine, dried and the solvent removed in vacuo to yield an oil. After filtering thru a small plug of silica (chloroform) the title compound [(37)] was obtained [(35] mg, [61%)] as a white [SOLID. 1H] NMR (300 MHz, [CDC13)] [82.] 67 (s, 3H), 3.49 (s, 2H), 3.97 (dd, 1H), 4.34 (t, 1H), 4.80 (d, 1H), 5.01 (d, [1H),] 5.21 (dd, [1H),] 5.46 (t, 1H), 6.48 (d, 1H), 6.7-6. 8 (m, 3H), 7.02 (m, 2H), 7.2-7. 3 (m, 10.5H), 7.40 (m, 3. [5H).] MS APCI, [M/Z =] 584 [(M+1).] LC/MS: 2.51 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 78

13
[ 680231-24-7 ]
[ 105184-38-1 ]
(2S)-2-[2-(3,5-difluoro-phenyl)-acetylamino]-N-((6S,7S)-5-oxo-7-phenyl-[1,4]thiazepan-6-yl)-2-phenyl-acetamide [ No CAS ]
[ 680229-42-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To a stirred solution of [(22-2-AMINO-N-[(6, 7-CIS)-5-OXO-7-PHENYL-1,] 4-thiazepan-6-yl] - 2-phenylacetamide [(OB)] (82 mg, 0.230 mmol) in dichloromethane (4 mL) was added 3,5- <strong>[105184-38-1]difluorophenylacetic acid</strong> (52 mg, 0.302 mmol), HOBt (41 mg, 0.304 mmol), NMM (40 mg, 0.396 mmol) and EDAC-HC1 (58 mg, 0.303 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with a gradient from 50% ethyl acetate: 50% hexanes to 100% ethyl acetate to afford the title compound in a 1: [1] mixture with the 6S, 7S diastereomer (86 mg, 73%) as a white [SOLID.'H] NMR (300 MHz, CDC) [82.] 72 (m, 1H), 2.98 (m, 0.5H), 3.14 (m, [0.] 5H), 3.53 (s, 1H), 3.54 (s, 1H), 3.55-3. 90 (m, 2H), 3.97 (d, 0.5H, J= 3.5 Hz), 4.33 (d, [0.] 5H, [J=] 3.5 Hz), 2.26 (m, 1H), 5.48 (d, [0.] 5H, J= 7.0 Hz), 5.70 (d, [0.] 5H, J= 7.0 Hz), 6.28 (br t, [0.] 5H), 6.64-6. 87 (m, 4.5H), 6.90-7. 05 (m, 1.5H), 7.11 (m, 1H), 7.18-7. 36 (m, 8.5H). MS APCI, m/z= 510 [(M+1).] [LC/MS] : 2.57 min.
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 50. (25)-2-[(3,5-Difluorophenyl)acetvnam?no-?-r(6R JJg)-5-oxo-7-phenyl-l,4- thiazepan-6-vH-2-phen?lacetamide (50)To a stirred solution of (25)-2-amino-N-[(6,7-c?)-5-oxo-7 -phenyl- l,4-thiazepan-6-yl]-2- phenylacetamide (50b) (82 mg, 0.230 mmol) in DCM (4 mL) was added 3,5- <strong>[105184-38-1]difluorophenylacetic acid</strong> (52 mg, 0.302 mmol), HOBt (41 mg, 0.304 mmol), NMM (40 mg, 0.396 mmol) and EDAC-HCl (58 mg, 0.303 mmol). The mixture was stirred at ambient temperature under nitrogen for -12 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with a gradient from 50% EtOAc: 50% hexanes to 100% EtOAc to afford the title compound in a 1:1 mixture with the 6S,7$ diastereomer (86 mg, 73%) as a white solid. 1H NMR (300 MHz, CDCl3) 52.72 (m, IH), 2.98 (m, 0.5H), 3.14 (m, 0.5H), 3.53 (s, IH), 3.54 (s, IH), 3.55-3.90 (m, 2H), 3.97 (d, 0.5H, J= 3.5 Hz), 4.33 (d, 0.5H, J= 3.5 Hz), 2.26 (m, IH), 5.48 (d, 0.5H, J= 7.0 Hz), 5.70 (d, 0.5H, J= 7.0 Hz), 6.28 (br t, 0.5H),6.64-6.87 (m, 4.5H), 6.90-7.05 (m, 1.5H), 7.11 (m, IH), 7.18-7.36 (m, 8.5H). MS APCI, m/z= 510 (M+l). LC/MS: 2.57 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 91-92
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 112

14
[ 680231-26-9 ]
[ 105184-38-1 ]
[ 680229-44-1 ]
N₂-[(3,5-difluorophenyl)acetyl]-N₁-[(6S,7S)-5-oxo-7-phenyl-1,4-thiazepan-6-yl]-L-leucinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To a stirred solution [OF NI-[(6, 7-CIS)-5-OXO-7-PHENYL-1,] 4-thiazepan-6-yl] -L- leucinamide 52b (67 mg, 0.200 mmol) in dichloromethane (4 mL) was added 3,5- <strong>[105184-38-1]difluorophenylacetic acid</strong> (52 mg, 0.302 mmol), HOBt (41 mg, 0.304 mmol), NMM (40 mg, 0.396 mmol) and EDAC-HCl (58 mg, 0.303 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with a gradient from 50% ethyl acetate: [50%] hexanes to 100% ethyl acetate to afford the title compound in a 1: 1 mixture with the 6S, 7S diastereomer (76 mg, 0.155 mmol, 77%) as a white [SOLID. 1H] NMR (300 MHz, [CDC13)] [50.] 74-0.89 (m, 6H), 1.32 (m, 3H), 2.75 (m, 1H), 3.00 (m, 1H), 3.49 (s, 1H), 3.51 (s, 1H), [3.. 63-3.] 89 (m, 2H), 4.24 (d, [0.] [5H,] 4. [1] Hz), 4.31 (d, 0.5H, J= 4.1 Hz), 4.59 (m, [0.] 5H), 4.70 (m, 0.5H), 5.13 (m, 0.5H), 5.32 (m, 0.5H), 6.05 [(BR D,] 0.5H), 6.17 [(BR D,] 0.5H), 6.54 (m, 0.5H), 6.66-6. [88] (m, 3H), 6.95 (m, 0.5H), 7.12-7. 30 (m, [5.] [5H),] [7.] 36 (br d, 0.5H). MS APCI, m/z= 490 [(M+1).] LC/MS: 2. [56 MIN.]
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 52. N2-r(3<5-Difluorophenyl)acetvn-NJ-r(6J?JJg)-5-oxo-7-phenyl-1.4-thiazepan-6- vIl-L-leucinamide (52)To a stirred solution of ^-[(?J-ci^-S-oxo^-phenyl-l^-thiazepan-?-ylJ-L-leucinamide (52b) (67 mg, 0.200 mmol) in DCM (4 mL) was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (52 mg, 0.302 mmol), HOBt (41 mg, 0.304 mmol), NMM (40 mg, 0.396 mmol) and EDAC-HCl (58 mg, 0.303 mmol). The mixture was stirred at ambient temperature under nitrogen for -12 h. The solvent was evaporated and the residue was purified by flash chromatography on silica gel eluting with a gradient from 50% EtOAc: 50% hexanes to.100% EtOAc to afford the title compound in a 1:1 mixture with the 6S,7S diastereomer (76 mg, 0.155 mmol, 77%) as a white solid. 1H NMR (300 MHz, CDCl3) ?O.74-0.89 (m, 6H), 1.32 (m, 3H), 2.75 (m, IH), 3.00 (m, IH), 3.49 (s, IH), 3.51 (s, IH), 3.63-3.89 (m, 2H), 4.24 (d, 0.5H, 4.1 Hz), 4.31 (d, 0.5H, J= 4.1 Hz), 4.59 (m, 0.5H), 4.70 (m, 0.5H), 5.13 (m, 0.5H), 5.32 (m, 0.5H), 6.05 (br d, 0.5H), 6.17 (br d,0.5H), 6.54 (m, 0.5H), 6.66-6.88 (m, 3H), 6.95 (m, 0.5H), 7.12-7.30 (m, 5.5H), 7.36 (br d, 0.5H). MS APCI, m/z= 490 (M+l). LC/MS: 2.56 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 93
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 114

15
[ 680231-39-4 ]
[ 105184-38-1 ]
[ 680229-52-1 ]
(2S)-2-cyclohexyl-2-[(3,5-difluorophenyl)acetyl]amino-N-[(2S,3R)-4oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	To a stirred solution of [(2S)-2-AMINO-N-[(2,] 3-cis) -4-oxo-2-phenyl-2,3, 4,5-tetrahydro- [1,] [5-BENZOXAZEPIN-3-YL]-2-CYCLOHEXYLACETAMIDE] [(60B)] (137 mg, 0.350mmol), 3,5- <strong>[105184-38-1]difluorophenylacetic acid</strong> (67 mg, 0. [389] mmol), HOBt (59 mg, 0.437 mmol) and NMM (45 mg, 0.455 mmol) in dichloromethane [(5ML)] under nitrogen at [0C] was added EDAC-HC1 (83 mg, 0.432 mmol). The mixture was kept at [0C] for 30 min. then stirred overnight at ambient temperature. The reaction was diluted with ethyl acetate and extracted in succession with saturated sodium bicarbonate, IN aqueous HC1, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1: 1 (v/v) hexane: ethyl acetate to afford the title compound as a 1 : 1 mixture with the [2S,] 3R diastereomer (110 mg, 57%) as a white [SOLID. LH] NMR (300 MHz, DMSO-d6) [50.] 72-1.22 (m, 5H), 1.29-1. 70 (m, 5H), 3.27 (s, 2H), 3.52 (m, 1H), 4.13 (m, 0.5H), 4.28 (m, 0.5H), 4.98 (m, 0.5H), 5.08 (m, 0.5H), 5.58 (m, 1H), 6.87-7. 56 (m, [13H),] 8.03 [(BR D,] 0.5H), 8.17 (br d, 0.5H), 10.26 (s, 0.5H), 10.30 (s, 0.5H). MS APCI, m/z = 548 [(M+1).] LC/MS: 2.49 min.
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 12.5h;	Example 60. (25)-2-CvcIohexyl-2-r(3,5-difluorophenyl)acetv?amino-N-r(2ig<3lS)-4-oxo-2- phenyl-2,3,4,5-tetrahydro-l,5-benzoxazepin-3-vnacetamide (60)To a stirred solution of (2S)-2-amino-N-[(2,3-cis)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-l,5- benzoxazepin-3-yl]-2-cyclohexylacetamide (60b) (137 mg, O.350mmol), 3,5- <strong>[105184-38-1]difluorophenylacetic acid</strong> (67 mg, 0.389 mmol), HOBt (59 mg, 0.437 mmol) and NMM (45 mg, 0.455 mmol) in DCM (5mL) under nitrogen at 0 0C was added EDAC-HCl (83 mg, 0.432 mmol). The mixture was kept at 00C for 30 min. then stirred for -12 h at ambient temperature. The reaction was diluted with EtOAc and extracted in succession with saturated sodium bicarbonate, IN aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1:1 (v/v) hexane-EtOAc to afford the title compound as a 1:1 mixture with the 2S,3i? diastereomer (110 mg, 57%) as a white solid. 1H NMR (300 MHz, DMSO-d6) ?O.72-1.22 (m, 5H), 1.29-1.70 (m, 5H), 3.27 (s, 2H), 3.52 (m, IH), 4.13 (m, 0.5H), 4.28 (m, 0.5H), 4.98 (m, 0.5H), 5.08 (m, 0.5H), 5.58 (m, IH), 6.87-7.56 (m, 13H), 8.03 (br d, 0.5H), 8.17 (br d, 0.5H), 10.26 (s, 0.5H), 10.30 (s, 0.5H). MS APCI, m/z = 548 (M+l). LC/MS: 2.49 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 102
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 123

16
[ 680231-41-8 ]
[ 105184-38-1 ]
3-cyclohexyl-N₂-[(3,5-difluorophenyl)acetyl]-N₁-[(6S,7S)-5-oxo-7-phenyl-1,4-thiazepan-6-yl]-L-alaninamide [ No CAS ]
[ 680229-54-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To [A] stirred solution [OF 3-CYCLOHEXYL-N-[(6, 7-CIS)-5-OXO-7-PHENYL-1,] 4-thiazepan-6- [ YL] -L-ALANINAMIDE (62B) (115 MG, 0.306 MMOL) IN DICHLOROMETHANE (6 ML) WAS ADDED 3,5-] <strong>[105184-38-1]difluorophenylacetic acid</strong> (56 mg, 0.325 mmol), HOBt (50 mg, 0.370 mmol), NMM (37 mg, 0.366 mmol) and EDAC-HCl (70 mg, 0.365 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated, the residue dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, IN aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1: 1 (v/v) dichloromethane: ethyl acetate to afford the title compound in a 1: 1 mixture with the 6S, 7S diastereomer (45 mg, [28%)] as a white solid. TLC Rf= 0.27 (1: 1 dichloromethane: ethyl [ACETATE).'H] NMR (300 MHz, [CDC13)] [80.] 84 (m, 3H), 1.00-1. 44 (m, 6H), 1.48-1. 70 (m, 4H), 2.80 (m, 1H), 3.07 (m, 1H), 3.50 (m, 2H), 3.80 (m, 2H), 4.33 (d, [1H,] J= 4.4 Hz), 4.41 (m, [1H),] 5.32 (m, [1H),] 5.81 (d, [1H,] J= 7.9 Hz), 6.23 (br t, [1H),] 6.68-6. 87 (m, 3H), 7.04, d, J= 6.1 Hz), 7.27 (s, 5H). MS APCI, [M/Z=] 530 [(M+1).] LC/MS: 2.55 min.
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 62. 3-CvcIohexyI-iV2-r(3.5-difluorophenvI)acetvn-N/-rf6R.7J?)-5-oxo-7-phenv?-1.4- thiazepan-6-yIl -L-alaninamide (62)To a stirred solution of 3-cyclohexyl-iV7-[(6,7-ci5)-5-oxo-7-phenyl-l,4-thiazepan-6-yl]-L- alaninamide (62b) (115 mg, 0.306 mmol) in DCM (6 niL) was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (56 mg, 0.325 mmol), HOBt (50 mg, 0.370 mmol), NMM (37 mg, 0.366 mmol) and EDAC- HCl (70 mg, 0.365 mmol). The mixture was stirred at ambient temperature under nitrogen for -12 h. The solvent was evaporated, the residue dissolved in EtOAc and extracted in succession with saturated sodium bicarbonate, IN aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 1 : 1 (v/v) DCM-EtOAc to afford the title compound in a 1 : 1 mixture with the 6S,7S diastereomer (45 mg, 28%) as a white solid. TLC Rf= 0.27 (1:1 DCM : EtOAc). 1H NMR (300 MHz, CDCl3) ??.84 (m, 3H), 1.00-1.44 (m, 6H), 1.48-1.70 (m, 4H), 2.80 (m, IH), 3.07 (m, IH), 3.50 (m, 2H), 3.80 (m, 2H), 4.33 (d, IH, J= 4.4 Hz), 4.41 (m, IH), 5.32 (m, IH), 5.81 (d, IH, J= 7.9 Hz), 6.23 (br t, IH), 6.68-6.87 (m, 3H), 7.04, d, J= 6.1 Hz), 7.27 (s, 5H). MS APCI, m/z= 530 (M+l). LC/MS: 2.55 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 103-104
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 125

17
[ 680231-53-2 ]
[ 105184-38-1 ]
[ 680228-53-9 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 5h;	To a stirred solution of (2S)-2-amino-2-(4-fluorophenyl)-N-[(2R,3S)-4-oxo-2-phenyl- 2,3, 4, [5-TETRAHYDRO-1,] 5-benzoxazepin-3-yl] acetamide [65B] (81 mg, 0.199 mmol) in dichloromethane (2mL) under nitrogen was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (40 mg, 0.232 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HC1 (50 mg, 0.261 mmol). The mixture was stirred 5h at ambient temperature then evaporated. The residue was dissolved in ethyl acetate and extracted in succession with saturated sodium bicarbonate, IN aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6: 1 [(V/V)] dichloromethane: ethyl acetate (TLC Rf= 0.42) to afford the title compound (85 mg, 76%) as a white [SOLID. 1H] NMR (300 MHz, CDC13) [83.] 54 (s, 2H), 5.08 (t, [1H,] J= 7.0 Hz), 5.19 (d, 1H, [J= 6. 5 HZ),] 5.79 (d, 1H, [J= 7. 0 HZ),] 6.16 [(BR D, 1H, J= 6. 5 HZ),] 6.62 (br d, 1H, J= 7.0 Hz), 6.66-6. 86 (m, 3H), 6.87-7. 04 (m, 3H), 7.08-7. 39 (m, lOH), 7.50 (br s, 1H). MS APCI, [M/Z = 560 (M+1).] LC/MS: 2.61 min.
76%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 5h;	Example 65. (25)-2-r(3,5-Difluorophenyl)acetvnam?no-2-(4-fluorophenvI)-N-r(2Jg,35)-4-oxo- 2-phenyl-2,3A5-tetrahydro-1.5-benzoxazepin-3-yl1acetamide (65)To a stirred solution of (25)-2-amino-2-(4-fluorophenyl)-N-[(2/?,35)-4-oxo-2-phenyl- 2,3,4,5-tetrahydro-l,5-benzoxazepin-3-yl]acetamide (65b) (81 mg, 0.199 mmol) in DCM (2 mL) under nitrogen was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (40 mg, 0.232 mmol), HOBt (35 mg, 0.259 mmol), NMM (30 mg, 0.297 mmol) and EDAC-HCl (50 mg, 0.261 mmol). The mixture was stirred 5 h at ambient temperature then evaporated. The residue was dissolved in EtOAc and extracted in succession with saturated sodium bicarbonate, IN aqueous HCl, and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 6: 1 (v/v) DCM-EtOAc (TLC Rf= 0.42) to afford the title compound (85 mg, 76%) as a white solid. 1H NMR (300 MHz, CDCl3) 53.54 (s, 2H), 5.08 (t, IH, J= 7.0 Hz), 5.19 (d, IH, J= 6.5 Hz), 5.79 (d, IH, J= 7.0 Hz), 6.16 (br d, IH, J= 6.5 Hz), 6.62 (br d, IH, J= 7.0 Hz), 6.66-6.86 (m, 3H), 6.87-7.04 (m, 3H), 7.08-7.39 (m, 10H), 7.50 (br s, IH). MS APCI, m/z = 560 (M+ 1). LC/MS: 2.61 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 110-111
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 132

18
[ 680230-18-6 ]
[ 105184-38-1 ]
N₂-[(3,5-difluoro-phenyl)-acetyl]-N₁-((2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl)-L-alaninamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	To a stirred solution [OF NL-[(2R, 35)-4-OXO-2-PHENYL-2,] 3,4, [5-TETRAHYDRO-1,] 5- [ BENZOXAZEPIN-3-YL] -L-ALANINAMIDE (6G) (765 MG, 2.351 MMOL) IN DICHLOROMETHANE (10 ML)] was added <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (450 mg, 2.614 mmol), HOBt (441 mg, 3.265 mmol), NMM (330 mg, 3.267 mmol) and EDAC-HC1 (626 mg, 3.265 mmol). The mixture was stirred at ambient temperature under nitrogen overnight. The solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated and then washed in succession with IN aqueous HCl and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 2: 1 (v/v) ethyl acetate: hexanes to afford the title compound (968 mg, 86 %) as a white solid. TLC Rf= 0.30 (2: 1 ethyl acetate: [HEXANES). LH] NMR (300 MHz, DMSO-d6) [61.] 11 (d, 3H, J= 7.0 Hz), 3.46 (q AB, 2H, J= 14.4 Hz), 4.24 (m, [1H),] 4.95 (m, 1H), 5.61 (d, 1H, J= 6.6 Hz), 6.94 (m, 2H), 7.02-7. 29 (m, [5H),] 7.32-7. 40, (m, 6H), 8.32 (m, 1H), 10.29 (br, 1H). MS APCI, [M/Z] = 480 [(M+1).] LC/MS: 2.31 min.
86%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	Example 6. A^-r(3,5-D?fluorophenyl)acetyll-A^/-r(2J?.35)-4-oxo-2-phenyl-2.3.4.5-tetrahvdro- l,5-benzoxazepin-3-y?-L-aIaninamide (6)To a stirred solution of iVi-[(2i?,35')-4-oxo-2-phenyl-2,3,4,5-tetrahydro-l,5-benzoxazepin- 3-yl]-L-alaninamide (6g) (765 mg, 2.351 mmol) in DCM (10 mL) was added 3,5- <strong>[105184-38-1]difluorophenylacetic acid</strong> (450 mg, 2.614 mmol), HOBt (441 mg, 3.265 mmol), NMM (330 mg, 3.267 mmol) and EDAC-HCl (626 mg, 3.265 mmol). The mixture was stirred at ambient temperature under nitrogen for -12 h. The solvent was evaporated and the residue partitioned between EtOAc and saturated aqueous sodium bicarbonate. The organic phase was separated and then washed in succession with IN aqueous HCl and brine. The organic solution was dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel elutingwith 2:1 (v/v) EtOAc-hexanes to afford the title compound (968 mg, 86 0Io) as a white solid. TLC Rf= 0.30 (2:1 EtOAc-hexanes). 1H NMR (300 MHz, DMSO-d6) ?l.l 1 (d, 3H, J= 7.0 Hz), 3.46 (q AB, 2H, J= 14.4 Hz), 4.24 (m, IH), 4.95 (m, IH), 5.61 (d, IH, J= 6.6 Hz), 6.94 (m, 2H), 7.02- 7.29 (m, 5H), 7.32-7.40, (m, 6H), 8.32 (m, IH), 10.29 (br, IH). MS APCI, m/z = 480 (M+l). LC/MS: 2.31 min.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 41
[2]Patent: WO2007/104933,2007,A1 .Location in patent: Page/Page column 60-61

19
[ 5680-80-8 ]
[ 105184-38-1 ]
[ 680230-09-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃; for 3h;	To an ice cooled solution of 3, 5-<strong>[105184-38-1]difluorophenylacetic acid</strong> (2.16 g) in anhydrous dichloromethane (100 mL) under nitrogen was added HOBt-hydrate (4.23 g), [EDAC-XC1] (3.6 g), and NMM (2.2 mL). The reaction mixture was stirred at [0C] under nitrogen for 15 min and L-serine methyl ester-HCl (1.96g) was added followed by NMM (1. [38] mL). The reaction was stirred at [0C] for 1 H and RT for 2 H. The reaction mixture was concentrated in vacuo and partitioned between water (100 mL) and ethyl acetate (125 mL). The organic phase was collected and consecutively washed with water, dilute aqueous sodium bicarbonate, brine, dried, filtered and the solvent removed in vacuo to yield a white solid. Trituration with CHCl3 afforded pure title compound (1.8g). The impure filtrate was subjected to flash chromatography (20% acetone/CHCl3) to afford additional title compound (800 mg, total yield [76%). 1H NMR] (300 MHz, d6-DMSO) [83.] 57 (d, 2H), 3.62 (s, 3H), 3.7 (m, 1H), 4.35, (m, [1H),] 5.1 (bs, 1H), 7.00 (d, 2H), 7.09 (t, 1H), 8.53, (d, 1H). MS APCI, [M/Z = 274 (M+1).] LC/MS: 1.34 min. b.

Reference： [1]Patent: WO2004/31154,2004,A1 .Location in patent: Page 39

20
[ 56558-30-6 ]
[ 105184-38-1 ]
[ 681143-31-7 ]

Yield	Reaction Conditions	Operation in experiment
36%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine; In dichloromethane; at 20℃;	[1.] Og [(7.] 8 mmol, 1.0 Eq. ) of the title compound of Step A was combined in a flask at room temperature with 1.62g (9.4 [MMOL,] 1.2 Eq. ) of (3, 5-Difluoro-phenyl)-acetic acid, 4. 1g [(9.] 4 mmol, 1.0 Eq. ) of HBTU, 2.6 mL (18.7 mmol, 3.0 Eq. ) of triethylamine, and 40 mL of dichloromethane. After stirring overnight at room temperature MS and TLC indicated reaction completion. Solution was extracted successively with [1 N HCI,] water, saturated sodium bicarbonate, water, and brine. This was dried over sodium sulfate and the solvent removed. The oil obtained was purified by flash chromatography using 4: 1 Hexane: Ethyl Acetate as eluent. 800 mg (36%) of the desired product was obtained. (MS: 286.2 [[P+1]/284.] 1 [[P-1])] [(RF=0.] 70 on silica TLC with 1: 1 Hexane/Ethyl Acetate) (H'NMR in [CDCI3] : 0.84, 3H t, (J=339 Hz), 1.27, 2H m, (J= 510 Hz), 1.60, 1H m, (J=641.855), 1.773, 1H m, (J=708.639 Hz), 3.70, 3H s, (J=1478 Hz), 4.57, 1H m, (J=1828 Hz), 5.91, 1H brd d, (J=2362 Hz), 6.69, 1H m, (J=2677 Hz), 6.78, 2H m, (J=2712 Hz))

Reference： [1]Patent: WO2004/33434,2004,A1 .Location in patent: Page 34

21
C₁₆H₃₁N₃O₃Si [ No CAS ]
[ 105184-38-1 ]
[ 794565-36-9 ]

Yield	Reaction Conditions	Operation in experiment
		Carboxylic acid (0.5 MMOL) was dissolved in 4.0 mL of anhydrous DMF under N2 at rt. DIISOPROPYLETHYLAMINE (0.9 MMOL) was added, followed by EDCI (0.6 MMOL) and HOBt (0.6 MMOL) and the resultant solution was stirred for 10 minutes. Intermediate 100 (0.5 MMOL) was then added in solution with 1.0 mL anhydrous DICHLOROMETHANE and the reaction was stirred for 16 h. The solution was then diluted with 100 mL EtOAc and washed with 50 mL portions of H20 and aqueous saturated sodium chloride. The organics were then dried over NA2SO4, filtered and concentrated under reduced pressure. The crude products were purified through flash chromatography on silica gel to give the desired intermediates (Table 6)

Reference： [1]Patent: WO2004/99200,2004,A1 .Location in patent: Page 43

22
[ 845897-08-7 ]
[ 105184-38-1 ]
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃;	A mixture of 3,5-di-fluoro-phenyl acetic acid (51.6 mg, 0.3 mmol), 2-amino-pentanoic acid (5-tert-butyl-[1,3,4]thiadiazol-2-yl)-amide (88 mg, 0.3 mmol), HBOT (43 mg, 0.315 mmol), EDC HCl (69 mg, 0.36 mmol.) and triethylamine (0.17 ml) in methylene chloride was stirred at room temperature until product formation or disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was separated, washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound as a cude oil. The oil was purified by Shimadzu HPLC to provide the title compound as a white solid (56 mg), LC-MS M+1=411.2, 1 H NMR(CDCL3) 8.7 (d,1 H,NH), 6.73(m,2H), 6.6(m,1 H), 4.7(m,1H), 3.5(Abq, 2H), 1.6-1.9(m,2H), 1.3-1.6(m,2H), 1.5(s,9H), 0.92(t,3H) ppm.

Reference： [1]Patent: US2005/43372,2005,A1 .Location in patent: Page/Page column 16

23
[ 67-56-1 ]
[ 105184-38-1 ]
[ 210530-70-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With thionyl chloride; at 0℃;Reflux;	3,5-Difluorophenylacetic acid (75 g,0.44 mol) was dissolved in methanol (600 mL) and the resulting solution was cooled to 0 0C with stirring. Thionyl chloride (95 mL, 1.31 mol) was added dropwise over 30 min. The reaction mixture was then warmed to reflux temperature and stirred for 3 h. The reaction mixture was then concentrated in vacuo. The residue was taken up in toluene and concentrated in vacuo again. This residue was taken up in ether and the resulting solution was washed three times with a saturated NaHCtheta3 solution, dried over MgSO4 and filtered. Solvent was removed in vacuo to afford the title product (80.9 g, 99% yield): 1H NMR (CDCl3, 300 MHz): 6.81 (dt, 2H, J = 8, 1), 6.72 (td, IH, J = 8, 1), 3.71 (s, 3H), 3.60 (s, 2H); HRMS (ES ): Calcd for C9H7F2O2 (M+ - H): 185.0414, Found: 185.0420.
89%		A solution of <strong>[105184-38-1]2-<strong>[105184-38-1](3,5-difluorophenyl)acetic acid</strong></strong> (10 g, 58 mmol) in anhydrous methanol (100 mL) was stirred at ambient temperature as concentrated sulfuric acid (0.50 mL, 9.4 mmol) was added. After stirring for 4 hours, the reaction mixture was cooled in ice and 10% aqueous NaHCO3 solution (50 mL) and solid NaHCO3 (10 g) were carefully added. The mixture was stirred for another 1 hour at ambient temperature. The methanol solvent was removed in vacuo. The residue was extracted with EtOAc (200 mL) and the organic phase was washed with water (3 x 20 mL), brine, dried over Na2504, filtered and concentrated in vacuo to afford methyl 2-(3,5-difluorophenyl)acetate as a colorless liquid (9.6 g, 89% yield). 1H NMR (500 MHz, chlorofonn-d) oe (ppm) 6.84 (dd, 1 H), 6.75 (tt, 2 H), 3.74 (s, 3 H), 3.63 (s,2H).
	With hydrogenchloride; In 1,4-dioxane; for 6h;Heating / reflux;	A solution of 5.0 g (29.1 mmol) of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> and a solution of 20 ML (80 mmol) of HCl in dioxane (4M) in 60 mL of methanol was heated at reflux for 6H. After cooling, the solution was concentrated and the residue poured into 200 mL of ether/ethyl acetate (1/1). The organic layer was washed with 20 mL of water, dried over Na2S04 and concentrated to afford the title compound.

	With boron trifluoride diethyl etherate; at 50℃; for 1h;	The starting aldehyde was prepared as follows: A solution of 5.3 g of 3,5-difluorophenyl-acetic acid in 40 ml of MeOH and 3 ml of BF3.Et2O was warmed to 50 C. for 1 h. The solution was evaporated, the residue partitioned between Et2O and aqueous NaHCO3, No. the organic layer was washed with water, dried and evaporated. The remaining methylester (5.6 g) was dissolved in 240 ml of dry toluene, cooled to -78 C. and treated with 45 ml of a 1M solution of diisobutylaluminum hydride in CH2Cl2 and stirring was continued at -78 C. No. for 1 h. The mixture was quenched with 30 ml of MeOH and 100 ml of a 50% aqueous solution of sodium-potassium tartrate and extracted with Et2O. The organic layer was washed with brine, dried and evaporated to give 4.5 g of (3,5-difluoro-phenyl)-acetaldehyde.
	With hydrogenchloride; In 1,4-dioxane; for 6h;Heating / reflux;	A solution of 5.0 g (29.1 mmol) of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> and a solution of 20 mL (80 mmol) of HCl in dioxane (4M) in 60 mL CH3OH was heated at reflux for 6 h. After cooling, the solution was concentrated and the residue poured into 200 mL of ether/ethyl acetate (1/1). The organic layer was washed with 20 mL of water, dried over Na2SO4 and concentrated to afford the title compound.

Reference： [1]Patent: WO2009/137657,2009,A1 .Location in patent: Page/Page column 23
[2]Patent: WO2018/89330,2018,A2 .Location in patent: Page/Page column 00262
[3]Patent: WO2005/809,2005,A1 .Location in patent: Page 85
[4]Patent: US2005/107341,2005,A1 .Location in patent: Page/Page column 8
[5]Patent: US2007/123505,2007,A1 .Location in patent: Page/Page column 49
[6]Bioorganic and Medicinal Chemistry Letters,2012,vol. 22,p. 1130 - 1135

24
[ 105184-38-1 ]
[ 797784-29-3 ]

Yield	Reaction Conditions	Operation in experiment
13%		A mixture of (3, 5- difluorophenyl) acetic acid (3 g, 17. 4 mmol) and thionyl chloride were heated at 81oC for 2 hours. The solution was cooled to room temperature and concentrated in vacuo to clear oil. The oil was coevaporated once with toluene, dissolved in dichloromethane (20 ML) and added dropwise to a cold (0oC) solution of hyrdazine (13. 7 ML, 435 mmol) in dichloromethane (100 mL). This solution was stirred for 30 minutes, diluted with water and extracted with dichloromethane. The combined organics were concentrated IRA vacuo to yield 2- (3, 5-difluorophenyl) acetic hydrazide (409. 3 mg, 13 %) as a white SOLID. 1H NMR (DMSO) : 8 9. 24 (s, 1 H), 7. 09 (m, 1 H), 6. 97 (dd, J = 8. 4, 2. 0 Hz, 2 H), 4. 25 (s, 2 H), 3. 39 (s, 2 H) ; MS ONLY 187 (M+1).

Reference： [1]Patent: WO2004/101512,2004,A2 .Location in patent: Page 91
[2]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3736 - 3745

25
[ 105184-38-1 ]
[ 15028-39-4 ]
N-(3,5-difluorophenylacetyl)-L-phenylglycine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;	Example 75 Synthesis of N-(3,5-difluorophenylacetyl)-L-phenylglycine methyl ester Following General Procedure F above, and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and L-phenylglycine methyl ester hydrochloride (Bachem), the title compound was prepared. NMR data was as follows: 1H-nmr (CDCl3): delta =7.4-7.3 (m, 5H), 6.9-6.7 (m, 3H), 6.55 (d 1H, 7.1 Hz), 5.56 (d 1H 7 Hz), 3.72 (s 3H), 3.57 (s 2H) 13C-nmr (CDCl3): delta = 197.6, 177.6, 171.8, 169.3, 136.7, 129.6, 129.3, 127.8, 113.0, 112.9, 112.7, 111.4, 103.8, 103.5, 65.1, 57.2, 53.5, 45.1, 43.3, 43.3 C17H15NO3F2 (MW = 319.31, Mass Spectroscopy (MH +320)). GENERAL PROCEDURE FEDC Coupling of Acid and Amine The acid derivative was dissolved in methylene chloride. The amine (1 eq.), N-methylmorpholine (5 eq.), and hydroxybenzotriazole monohydrate (1.2 eq.) were added in sequence. The reaction was cooled to about 0C and then 1.2 eq. of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added. The solution was allowed to stir overnight and come to room temperature under N2. pressure. The reaction mix was worked up by washing the solution with saturated, aqueous Na2CO3, 0.1M citric acid, and brine before drying with Na2SO4 and removal of solvents to yield crude product. Pure products were obtained by flash chromatography in an appropriate solvent.

Reference： [1]Patent: EP951464,2005,B1 .Location in patent: Page/Page column 48; 28

26
[ 17344-99-9 ]
[ 105184-38-1 ]
N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example B64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine Ethyl Ester Following General Procedure BG and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95 C. The reaction was monitored by tlc on silica gel (Rf 0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane. NMR data was as follows: 1H-nmr (DMSO-d6): delta=1.30 (d, 3H); 3.52 (s, 2H).
		Example B64 Synthesis of N-[(3,5-Difluorophenyl)acetyl]alanine Ethyl Ester Following General Procedure BG and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95 C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane. NMR data was as follows: 1H-nmr (DMSO-d6): delta=1.30 (d, 3H); 3.52 (s, 2H). C13H15NO3F2 (MW=271.26, Mass Spectroscopy (MH+271)).
		Example 64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester Following General Procedure G and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95 C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane. NMR data was as follows: 1 H-nmr (DMSO-d6): delta=1.30 (d, 3H); 3.52 (s, 2H).

		EXAMPLE A64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester Following General Procedure G' and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95 C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane. NMR data was as follows: 1H-nmr (DMSO-d6): delta=1.30 (d, 3H); 3.52 (s, 2H).
		EXAMPLE A64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine Ethyl Ester Following General Procedure G' and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95 C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane. NMR data was as follows: 1H-nmr (DMSO-d6): delta=1.30 (d, 3H); 3.52 (s, 2H).
		Example A64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester Following General Procedure G' and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95 C. The reaction was monitored by tlc on silica gel (Rf=0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1 -chlorobutane. NMR data was as follows: 1H-nmr (DMSO-d6): delta=1.30 (d, 3H); 3.52 (s, 2H).
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In tetrahydrofuran; at 20℃; for 4 - 17h;	Example 64 Synthesis of N-[(3,5-difluorophenyl)acetyl]alanine ethyl ester Following General Procedure G and using <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (Aldrich) and alanine ethyl ester (Aldrich), the title compound was prepared as a solid with a melting point of 93-95C. The reaction was monitored by tlc on silica gel (Rf = 0.8 in EtOAC) and purification was by chromatography on silica gel using EtOAc as the eluant followed by recrystallization from 1-chlorobutane. NMR data was as follows: 1H-nmr (DMSO-d6): delta = 1.30 (d, 3H); 3.52 (s, 2H). C13H15NO3F2 (MW = 271.26, Mass Spectroscopy (MH+ 271)). GENERAL PROCEDURE GEDC Coupling of Acid and Amine A round bottom flask was charged with carboxylic acid (1.0 eq.), hydroxybenzotriazole hydrate (1.1 eq.) and amine (1.0 eq.) in THF under nitrogen atmosphere. An appropriate amount (1.1 eq. for free amines and 2.2 eq. for hydrochloride amine salts) of base, such as Hunig's base was added to the well stirred mixture followed by EDC (1.1 eq.). After stirring from 4 to 17 hours at room temperature the solvent was removed at reduced pressure, the residue taken up in EtOAc (or similar solvent)/water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, 1N HCl, brine and dried over anhydrous sodium sulfate. In some cases, the isolated product was analytically pure at this stage while, in other cases, purification via chromatography and/or recrystallization was required prior to biological evaluation

Reference： [1]Patent: US2002/45747,2002,A1
[2]Patent: US6506782,2003,B1
[3]Patent: US6117901,2000,A
[4]Patent: US6191166,2001,B1
[5]Patent: US6207710,2001,B1
[6]Patent: US6211235,2001,B1
[7]Patent: EP951464,2005,B1 .Location in patent: Page/Page column 45; 28

27
[ 105184-38-1 ]
[ 5557-81-3 ]
[ 649736-97-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	A solution of 1.72 g of 3,5-difluorophenyl-acetic acid in 50 ml of dimethylformamide at 0° C. is admixed with 1.01 g of N-methylmorpholine, 5.72 g of PyBOP, 2.15 g of <strong>[5557-81-3](S)-alanine benzyl ester hydrochloride</strong> and 1.01 g of N-methylmorpholine. The mixture is allowed to return to ambient temperature and is stirred for 18 h. The reaction medium is evaporated and the residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution, a solution of potassium hydrogen sulfate (1M) and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate. The residue is chromatographed on a silica gel column, eluding with a 7:3 (v/v) petroleum ether/ethyl acetate mixture, to give 1.9 g of a white solid. NMR 300 MHz (CDC13) delta ppm: 1.40 (d, 3H); 3.54 (s, 2H); 4.62 (m, 1H); 5.18 (m, 2H); 6.10 (d, 1H); 6.73 (t, 2H); 6.80 (d, 1H); 7.32 (m, 5H). A solution of 1.9 g of N-3,5-difluorophenylacetyl-(S)-alanine benzyl ester in 80 ml of absolute ethanol is admixed with 300 mg of 10percent palladium on carbon. The reaction medium is hydrogenated at atmospheric pressure and at ambient temperature for 8 h. The reaction medium is filtered on paper, washed with absolute ethanol and then evaporated. This gives 1.37 g of a white solid. NMR 300 MHz (CDC13) delta ppm: 1.36 (d, 3H); 3.48 (s, 2H); 3.70 (s, 1H); 4.40 (m, 1H); 6.65 (t, 2H); 6.70 (d, 1H); 6.95 (d, 1H).

Reference： [1]Patent: US2005/182104,2005,A1 .Location in patent: Page/Page column 7

28
[ 649737-42-8 ]
[ 105184-38-1 ]
methyl 2-[2-[2-(3,5-difluorophenyl)acetyl-amino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	EXAMPLE 23 Methyl 2-[2-[2-(3,5-difluorophenyl)acetyl-amino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate (compound 59) A solution of 0.21 g of methyl 2-[2-[2-(3,5-difluorophenyl)-2-hydroxyacetylamino]-(2S)-(3-methoxypropionyl)amino]-5-(1-methylethyl)thiazole-4-carboxylate, obtained in Example 22, in 30 ml of dimethylformamide at 0 C. is admixed with 0.09 g of N-methylmorpholine, 0.42 g of PyBOP and then 0.14 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong>. The reaction is allowed to return to ambient temperature and the mixture is stirred for 18 h. The reaction medium is evaporated. The residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution, twice with water, once with 1M aqueous solution of potassium hydrogen sulfate and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and then concentrated. The residue is chromatographed on a silica column, eluding with a 1:1 (v/v) petroleum ether/ethyl acetate mixture to give 0.12 g of a white solid. LC/MS: MH+=456.

Reference： [1]Patent: US2005/182104,2005,A1 .Location in patent: Page/Page column 15

29
[ 649737-02-0 ]
[ 105184-38-1 ]
methyl 2-[2-[2-(3,5-difluorophenyl)acetyl-amino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	EXAMPLE 5.2 Methyl 2-[2-[2-(3,5-difluorophenyl)acetyl-amino]-(2S)-pentanoylaminol-5-(1-methylethyl)thiazole-4-carboxylate A solution of 0.7 g of methyl 2-(2-amino-(2S)-pentanoylamino)-5-(1-methylethyl)thiazole-4-carboxylate, obtained in step 5.1 of Example 5, in 30 ml of dimethylformamide at 0 C. is admixed with 0.255 g of N-methylmorpholine, 1.30 g of PyBOP and then 0.43 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong>. The reaction is allowed to return to ambient temperature and the mixture is stirred for 18 h. The reaction medium is evaporated. The residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution, twice with water, once with a 1M aqueous solution of potassium hydrogen sulfate and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and then concentrated. The residue is chromatographed on a silica column, eluding with a 1:1 (v/v) petroleum ether/ethyl acetate mixture, to give 0.7 g of a white solid. LC/MS: MH+=454.

Reference： [1]Patent: US2005/182104,2005,A1 .Location in patent: Page/Page column 8

30
[ 649737-16-6 ]
[ 105184-38-1 ]
2-[2-[2-(3,5-difluorophenyl)acetylamino]-(2S)-pentanoylamino]-5-(1-methylethyl)thiazole-4-N,N-dimethylcarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 16h;	A solution of 0.23 g of 2-((2S)-pentanoyl-amino)-5-(1-methylethyl)thiazole-4-N,N-dimethyl-carboxamide, obtained in step 9.4, in 15 ml of dimethylformamide at 0 C. is admixed with 0.088 g of N-methylmorpholine and then 0.416 g of PyBOP and 0.138 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong>. The reaction medium is allowed to return to ambient temperature for 16 h and then is concentrated. The residue is taken up in ethyl acetate and washed twice with a 0.5N aqueous solution of hydrochloric acid, once with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and concentrated. Chromatography on a silica column, eluted with a 1:1 (v/v) mixture of ethyl acetate and petroleum ether, gives 0.26 g of a white solid. LC/MS: MH+=467. NMR 500 MHz (DMSO) delta ppm: 0.87 (t, 3H); 1.24 (d, 6H); 1.29-1.67 (m, 4H); 2.86 (s, 3H); 2.95 (s, 3H); 3.22 (m, 1H); 3.54 (m, 2H); 4.41 (m, 1H); 6.98 (d, 2H); 7.08 (m, 1H); 8.49 (d, 1H); 12.21 (s, 1H). alpha20D=-740 (c=1.0, MeOH)

Reference： [1]Patent: US2005/182104,2005,A1 .Location in patent: Page/Page column 10

31
[ 105184-38-1 ]
[ 75-36-5 ]
[ 210530-70-4 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; at 0 - 20℃;	Preparation of the Intermediates of Formulae (III) and (IV); Preparation 2.1; Methyl 2-(3,5-difluorophenyl)-3-dimethyl-amino-2-propenoate (IV); A) Methyl (3,5-difluorophenyl)acetate; A solution comprising 25 ml of acetyl chloride in 250 ml of methanol is prepared at 0 C., then, at ambient temperature, 25.5 g of 3,5-difluorophenylacetic acid are dissolved in this solution and the solution is left stirring at AT. The reaction is monitored by thin layer chromatography. After the starting material has disappeared, the medium is evaporated under reduced pressure and then the residue is dissolved in 250 ml of MTBE. The organic phase is washed three times with 100 ml of water, dried over MgSO4 and then evaporated to dryness under reduced pressure. 26.9 g of the expected compound are obtained.

Reference： [1]Patent: US2005/288318,2005,A1 .Location in patent: Page/Page column 9

32
L-norvalinyl-L-phenylglycine methyl ester hydrochloride [ No CAS ]
[ 105184-38-1 ]
[ 53308-95-5 ]
[ 78733-46-7 ]
N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 253 Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-norvalinyl-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-L-norvaline (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=204-205° C.). The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent.

Reference： [1]Patent: US6191166,2001,B1

33
L-norvalinyl-L-phenylglycine methyl ester hydrochloride [ No CAS ]
[ 105184-38-1 ]
[ 53308-95-5 ]
[ 78733-46-7 ]
N-[N-(3,5-Difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine Methyl Ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 253 Synthesis of N-[N-(3,5-Difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and L-norvalinyl-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-L-norvaline (Lancaster) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=204-205° C.). The product was purified by flash chromatography using ethyl acetate/hexanes as the eluent.

Reference： [1]Patent: US6207710,2001,B1

34
(S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycine methyl ester hydrochloride [ No CAS ]
(4S)-4-benzyl-2-oxaxolidinone [ No CAS ]
[ 5239-82-7 ]
[ 105184-38-1 ]
[ 155976-13-9 ]
N-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycine Methyl Ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 257 Synthesis of N-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-(S)-2-amino-2-cyclopropylacetic acid (prepared from cyclopropylacetic acid (Lancaster) and (4S)-4-benzyl-2-oxaxolidinone (Aldrich) using the procedures described in Evans et al., J. Am. Chem. Soc., 1990, 112, 4011-4030 and references cited therein) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=225-226.5 C.). The product was purified by flash chromatography using MeOH/CHCl3 as the eluent. C22H22N2O4F2 (MW=416.42); mass spectroscopy (MH+) 417.3.
		EXAMPLE 257 Synthesis of N-[N-(3,5-Difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycine Methyl Ester Following General Procedure E and using 3,5-difluorophenylacetic acid (Aldrich) and (S)-2-amino-2-(cyclopropyl)acetyl-L-phenylglycine methyl ester hydrochloride (prepared from N-BOC-(S)-2-amino-2-cyclopropylacetic acid (prepared from cyclopropylacetic acid (Lancaster) and (4S)-4-benzyl-2-oxaxolidinone (Aldrich) using the procedures described in Evans et al., J. Am. Chem. Soc., 1990, 112, 4011-4030 and references cited therein) and L-phenylglycine methyl ester hydrochloride (Aldrich) using General Procedure E, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=225-226.5 C.). The product was purified by flash chromatography using MeOH/CHCl3 as the eluent. C22H22N2O4F2 (MW=416.42); mass spectroscopy (MH+) 417.3.

Reference： [1]Patent: US6191166,2001,B1
[2]Patent: US6207710,2001,B1

35
[ 859149-03-4 ]
[ 105184-38-1 ]
[ 859148-94-0 ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	EXAMPLE 1.6 Methyl 2-{2-(S)-[2-(3,5-difluorophenyl)acetylamino]-pentanoyl}amino-5-[2-(4-fluorophenoxy)phenyl]thiazole-4-carboxylate 0.20 g of N-methylmorpholine, 0.99 g of PyBOP and then 0.33 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> are added to 0.7 g of methyl 2-amino-2-[2-(S)-pentanoylamino]-5-[2-(4-fluorophenoxy)phenyl]thiazole-4-carboxylate, obtained in Example 1.5, dissolved in 30 ml of N,N-dimethylformamide at 0 C. The mixture is allowed to warm to room temperature and is stirred for 18 hours. The reaction medium is evaporated. The residue is taken up in ethyl acetate and washed twice with saturated aqueous sodium bicarbonate solution, twice with water, once with aqueous 1M potassium hydrogensulfate solution, and then with saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and then concentrated. The residue is chromatographed on a column of silica, eluding with a 1/1 (v/v) petroleum ether/ethyl acetate mixture to give 0.56 g of a white solid. LC/MS: MH+=558

Reference： [1]Patent: US2006/293365,2006,A1 .Location in patent: Page/Page column 7

36
[ 105184-38-1 ]
[ 71-43-2 ]
[ 1071784-13-8 ]

Yield	Reaction Conditions	Operation in experiment
60%		To a solution of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (10.0 g, 0.058 mol) in dichloromethane (100 mL) was added thionyl chloride (8 mL, 0.11 mol) followed by a drop of DMF. The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and then the residue was dissolved in benzene (150 mL). The solution was cooled and aluminium chloride (16.7 g, 0.13 mol) was added portionwise. The reaction mixture was stirred at RT for 10 h and then quenched with ice water. The mixture was extracted with diethyl ether. The organic layer was washed with aqueous 15% NaHCO3 and then with brine. The solution was dried over Na2SO4 and the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether. There was obtained 8.0 g (60%) of 2-(3,5-difluorophenyl)-l-phenylethanone as a yellow oil.

Reference： [1]Patent: WO2008/123821,2008,A1 .Location in patent: Page/Page column 27

37
[ 1086685-29-1 ]
[ 105184-38-1 ]
[ 1086682-87-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	With 2,6-dimethylpyridine; HATU; In N,N-dimethyl-formamide; at 20℃; for 48h;	Method D2-(3,5-Difluoro-phenyl)-lambda/-(4-oxo-2-thiazolidin-3-yl-4/-/-quinazolin-3-yl)-acetamide (Compound DD3,5-Difluorophenylacetic acid (0.152 g, 0.88 mmol), 3-Amino-2-thiazolidin-3-yl-3H-quinazolin-4-one (0.146 g, 0.59 mmol) and HATU (0.268 g, 0.71 mmol) were dissolved in dry DMF (2.5 ml_), followed by addition of 2,6-lutidine (205 mul_, 1.76 mmol).The reaction mixture was stirred at RT for 48h and then poured into 1 M HCI (20 ml_). The formed precipitate was collected by filtration and washed with water and heptane, which after drying gave the title compound (0.180 g, 76%). LC-ESI-HRMS of [M+H]+ shows 403,1047 Da. CaIc. 403,104028 Da.

Reference： [1]Patent: WO2008/142140,2008,A2 .Location in patent: Page/Page column 38

38
[ 1160931-75-8 ]
[ 105184-38-1 ]
[ 1160931-61-2 ]

Yield	Reaction Conditions	Operation in experiment
50%		lambda/-r2-Diethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl1-2-(3,5-difluoro-phenyl)- acetamide (Compound 1 )To a stirred suspension of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> 1 .12g; 6.48 mmol) in dichloromethane (50 ml_) under N2 atm, triethylamine (2.47 ml 17.67 mmol), EDC-HCI (1 .7Og; 8.84 mmol) and 1 -hydroxybenzotriazole hydrate 81 .3 mg; 0.59 mmol) were added at 00C. The reaction mixture was stirred at 00C for 15 min, after which 2-diethylamino-6-(4-fluoro-benzylamino)-3-aminopyhdine (1 .69g; 5.90 mmol) was added at 00C and stirred at room temperature overnight. The reaction mixture was diluted with water (100 ml_) and extracted with ethylacetate (2 x 500 ml). The combined organic layer was washed with water (1 x 50 ml_), brine (1 x 50 ml_), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a dark brownish solid. The crude product was purified by column chromatography over silica gel (60-120 mesh, 20 cm silica gel height in column of 2.0 cm diameter) using 10% ethylacetate in pet ether as a eluent to afford the title compound (1 .3 g) as a greenish gum which was further purified by recrystallisation (pet ether) to give 1 .2 g (50%) pure compound. LC-ESI-HRMS of [M+H]+ shows 443.2061 Da. CaIc. 443.20587 Da.

Reference： [1]Patent: WO2009/74592,2009,A1 .Location in patent: Page/Page column 18; 19

39
[ 1160930-36-8 ]
[ 105184-38-1 ]
N-[2-ethylmethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl]-2-(3,5-difluoro-phenyl)-acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	lambda/-r2-Dimethylamino-6-(4-fluoro-benzylamino)-pyridin-3-yl1-2-(3,5-difluoro-phenyl)- acetamide (Compound 1 )2-Ethylmethylamino-6-(4-fluoro-benzylamino)-3-aminopyridine (0.1 ; 0.36 mmol) was dissolved in DCM (4 ml_) and <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (0.70 mg; 0.4 mmol), HOAt (74 mg; 0.54 mmol) and EDC-HCI (104 mg; 0.54 mmol). The reaction mixture was stirred overnight at room temperature. Water (3 ml_) was added to the reaction mixture and the mixture was stirred vigorously for 30 min. The reaction mixture was filterd over a phase separator and the solvents were evaporated to dryness to give a solid which was purified using preparative LC-MS to give 54mg (34%) of the title compound. LC-ESI-HRMS of [M+H]+ shows 429.191 Da. CaIc. 429.19022 Da.

Reference： [1]Patent: WO2009/74594,2009,A1 .Location in patent: Page/Page column 18; 19

40
[ 105184-38-1 ]
[ 100-51-6 ]
[ 1182351-19-4 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1: (3-Benzyloxy-5-fluoro-phenyl)-acetic acid[00508] To benzyl alcohol (1 4g, 12 8mmol) in NMP (3OmL) was added sodium hydride (60% m mineral oil, 0 5g, 12 8mmol), and the mixture was stored for 20 minutes 3,5-Difluorophenylacetic acid (1 Og, 5 8mmol) was added, and the reaction was stirred at 100C for 2 hours, and then 6O0C overnight The mixture was worked-up to give the desired product, plus ~30% of benzyl alcohol impu?ty (2 Og)

Reference： [1]Patent: WO2009/102893,2009,A2 .Location in patent: Page/Page column 131

41
(2S)-2-amino-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)propionamide hydrochloride [ No CAS ]
[ 105184-38-1 ]
[ 498574-11-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1.8 (2S)-N-(5-{(2-[(cyclohexyloxy)-methyl]phenyl}-1,3-thiazol-2-yl)-2-[2-(3,5-difluorophenyl)acetyl]amino}propanamide 0.884 g of benzotriazol-1-yloxy-tris(dimethylamine)phosphonium hexafluorophosphate and 0.5 ml of N-ethylmorpholine are added at 0 C. to 0.344 g of <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> in solution in 10 ml of dimethylformamide, and the mixture is stirred for 15 minutes at this temperature. 0.65 g of (2S)-2-amino-N-(5-{2-[(cyclohexyloxy)methyl]phenyl}-1,3-thiazol-2-yl)propionamide hydrochloride, obtained in step 1.7, is introduced in portions, and the mixture is stirred for 18 hours at 20 C. The medium is taken up in ethyl acetate and washed twice with water.The organic phase is dried over anhydrous sodium sulfate and concentrated.The residue is chromatographed on a silica gel column, eluding with a dichloromethane/methanol 98/2 (v/v) mixture to give, after precipitation from water, 0.73 g of a white solid. m.p. =140 C. 1H NMR: delta in ppm (DMSO d6): 1.15-1.36 (unresolved complex, 8H); 1.46 (m, 1H); 1.64-1.86 (unresolved complex, 4H); 3.35 (m, 1H); 3.56 (s, 2H); 4.47 (s, 2H); 4.52 (m, 1H); 6.98-7.11 (unresolved complex, 3H); 7.36-7.53 (unresolved complex, 4H); 7.56 (s, 1H); 8.58 (d, 1H); 12.27 (s, 1H). [alpha]D20=-138.6 (c=1/CH3OH).

Reference： [1]Patent: US2004/171643,2004,A1 .Location in patent: Page/Page column 7

42
[ 794566-91-9 ]
[ 105184-38-1 ]
2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1-pyrrolidin-1-yl-ethyl)-isoxazol-3-yl]-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Carboxylic acid (0.3 MMOL) was dissolved in 2.0 mL of anhydrous DMF at rt under N2. Diisopropylethylamine (0.6 MMOL) was added, followed by EDCI (0.4 MMOL) and HOBt (0.4 MMOL). The reaction was then stirred for 10 minutes before adding an appropriate template R2 (0.3 MMOL). The reaction was then stirred for an additional 16 hours. The crude material was diluted with 20 mL EtOAc and washed with two 20 mL portions of water, followed by one 20 mL portion of saturated aqueous sodium chloride solution. The organics were then dried over NA2SO4, filtered and concentrated under reduced pressure. The crude products were then purified through flash chromatography on silica gel to yield the desired analogs (Table 8).

Reference： [1]Patent: WO2004/99200,2004,A1 .Location in patent: Page 45; 52

43
[ 444287-40-5 ]
[ 105184-38-1 ]
[ 927672-04-6 ]

Yield	Reaction Conditions	Operation in experiment
56%		5.148 2-(3,5-DIFLUORO-PHENYL)-N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISINDOL-4-YLMETHYL]-ACETAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (0.4 g, 2.4 mmol) were added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was filtered, and the solid was reslurried in hot acetone (15 mL) to afford 2-(3,5-difluoro-phenyl)-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-acetamide (0.5 g, 56%) as a white solid: mp, 238-240 C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=3.63 min. (97%); 1H NMR (DMSO-d6) delta 2.02-2.07 (m, 1H), 2.51-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.60 (s, 2H), 4.73 (d, J=5.8 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 6.89-7.14 (m, 3H), 7.65-7.84 (m, 3H), 8.70 (t, J=5.8 Hz, 1H), 11.14 (s, 1H); 13C NMR (DMSO-d6) delta 21.94, 30.90, 37.91, 41.41, 48.83, 101.62 (101.95, 102.30), 112.18 (112.28, 112.41, 112.51), 121.95, 127.16, 131.52, 133.29, 134.68, 138.91, 140.24 (140.37, 140.50), 160.39 (160.57, 163.64, 163.82), 166.88, 167.41, 169.53, 169.77, 172.72; Anal. Calcd. for C22H17N3O5F2: C, 59.87; H, 3.88; N, 9.52; F, 8.61. Found: C, 59.66; H, 3.83; N, 9.77; F, 8.47.

Reference： [1]Patent: US2007/49618,2007,A1 .Location in patent: Page/Page column 127

44
[ 105184-38-1 ]
[ 1300581-99-0 ]

Yield	Reaction Conditions	Operation in experiment
77%	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane;	Intermediate 69 1-(5-bromo-2-hydroxyphenyl)-2-(3,5-difluorophenyl)ethanone 3,5-Difluorophenylacetic acid (5.0 g, 29.0 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (3.8 ml, 43.57 mmoles) and DMF (3 drops) were added at 0 C. and stirred for 30 min. The solvent was evaporated and dissolved in 50 ml dichloromethane. To this mixture, 4-bromooanisole (5.42 g, 29.0 mmoles) was added and cooled to 0 C. At 0 C. AlCl3 (5.80 g, 47.57 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl, extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (7.21 g, 77% yield. 1H-NMR (delta ppm, DMSO-D6, 400 MHz): delta 11.44 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.65 (dd, J=8.9, 2.6 Hz, 1H), 7.13 (tt, J=9.1, 2.4 Hz, 1H), 7.02 (m, 3H), 4.50 (s, 2H).

Reference： [1]Patent: US2011/118257,2011,A1 .Location in patent: Page/Page column 94

45
[ 3196-73-4 ]
[ 105184-38-1 ]
[ 1370417-14-3 ]

Yield	Reaction Conditions	Operation in experiment
75%	With dmap; diisopropyl-carbodiimide; In tetrahydrofuran; at 20℃; for 14h;Inert atmosphere;	General procedure: Procedure A: A solution of a phenylacetic acid (3.7 mmol), DMAP (5.55 mmol) and DCC (5.55 mmol) in THF (40-70 ml) was stirred at room temperature (rt) for 30 min. The hydrochloride salt of the carboxy protected aminoacid (3.7 mmol) was added and the solution was stirred for 48 h at rt. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. The methyl ester (1eq) was dissolved in methanol. A solution of NaOH (1N, 17 ml) was added and the reaction mixture was stirred for 1 h at rt. H2O was added and methanol only was evaporated under reduced pressure. The pH was reduced to 2 using HCl solution 1N. The crude material was extracted with ethyl acetate and the organic phase was dried with Na2SO4 anhydrous. The solvent was removed in vacuo to afford 4 without any further purification. Procedure B: A solution of phenylacetic acid (6 mmol), the hydrochloride salt of the carboxy protected aminoacid (6 mmol), DMAP (3 mmol) and DCI (10 mmol) in (50-80 ml) was stirred at r.t. for 14 h. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. Treatment with NaOH as reported in procedure A.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 47,p. 239 - 254

46
[ 7524-50-7 ]
[ 105184-38-1 ]
[ 1370416-64-0 ]

Yield	Reaction Conditions	Operation in experiment
75%		General procedure: Procedure A: A solution of a phenylacetic acid (3.7 mmol), DMAP (5.55 mmol) and DCC (5.55 mmol) in THF (40-70 ml) was stirred at room temperature (rt) for 30 min. The hydrochloride salt of the carboxy protected aminoacid (3.7 mmol) was added and the solution was stirred for 48 h at rt. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. The methyl ester (1eq) was dissolved in methanol. A solution of NaOH (1N, 17 ml) was added and the reaction mixture was stirred for 1 h at rt. H2O was added and methanol only was evaporated under reduced pressure. The pH was reduced to 2 using HCl solution 1N. The crude material was extracted with ethyl acetate and the organic phase was dried with Na2SO4 anhydrous. The solvent was removed in vacuo to afford 4 without any further purification. Procedure B: A solution of phenylacetic acid (6 mmol), the hydrochloride salt of the carboxy protected aminoacid (6 mmol), DMAP (3 mmol) and DCI (10 mmol) in (50-80 ml) was stirred at r.t. for 14 h. The crude mixture was filtered over celite and the solvent was removed in vacuo. The product was purified by flash chromatography. Treatment with NaOH as reported in procedure A.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 47,p. 239 - 254

47
[ 1446332-78-0 ]
[ 105184-38-1 ]
[ 1446332-82-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 1h;	Step A: tert-Butyl 4-(3-fluoro-4-formyl-5-hydroxyphenyl)piperazine-l -carboxylate (65 mg, 0.2 mmol, prepared in Example 6, Step B) was combined with 2-(3,5- difluorophenyl)acetic acid (55 mg, 0.2 mmol), N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (57 mg, 0.3 mmol) and N,N-diisopropylethylamine (70 mu, 0.4 mmol) in DMF (1 mL). The mixture was heated to 60 C for 1 h. After cooling to room temperature, the mixture was filtered. The solid was washed with MeOH:H20 (1 : 1) and dried under vacuum to afford tert-butyl 4-(3-(3,5-difluorophenyl)-5-fluoro-2-oxo-2H-chromen-7- yl)piperazine- 1 -carboxylate.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 1h;	Step A: tert-Butyl 4-(3-fluoro-4-formyl-5-hydroxyphenyl)piperazine-1-carboxylate (65 mg, 0.2 mmol, prepared in Example 6, Step B) was combined with <strong>[105184-38-1]2-<strong>[105184-38-1](3,5-difluorophenyl)acetic acid</strong></strong> (55 mg, 0.2 mmol), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (57 mg, 0.3 mmol) and N,N-diisopropylethylamine (70 muL, 0.4 mmol) in DMF (1 mL). The mixture was heated to 60 C. for 1 h. After cooling to room temperature, the mixture was filtered. The solid was washed with MeOH:H2O (1:1) and dried under vacuum to afford tert-butyl 4-(3-(3,5-difluorophenyl)-5-fluoro-2-oxo-2H-chromen-7-yl)piperazine-1-carboxylate.

Reference： [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00629; 00630
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 330

48
[ 105184-38-1 ]
[ 76456-06-9 ]
[ 1548754-54-6 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 968 - 971

49
[ 105184-38-1 ]
[ 76456-06-9 ]
[ 1548753-29-2 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 968 - 971

50
[ 105184-38-1 ]
[ 957121-38-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pivaloyl chloride; triethylamine / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 0 °C / Inert atmosphere 2.1: potassium hexamethylsilazane / tetrahydrofuran / 0.5 h / -78 °C / Inert atmosphere 2.2: 0.17 h / -78 °C / Inert atmosphere 3.1: lithium borohydride; water / tetrahydrofuran / 24.5 h / 0 - 20 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / Inert atmosphere
	Multi-step reaction with 5 steps 1.1: pivaloyl chloride; triethylamine / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 0 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; di-n-butylboryl trifluoromethanesulfonate / dichloromethane / 1.25 h / -78 - 0 °C / Inert atmosphere 2.2: 2 h / -78 °C / Inert atmosphere 3.1: sodium azide / acetonitrile / 7 h / 0 - 20 °C 4.1: lithium borohydride; water / tetrahydrofuran / 24.5 h / 0 - 20 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / Inert atmosphere

Reference： [1]Chen, Chia-Yu; Liao, Yung-Feng; Chang, Ming-Yun; Hu, Ming-Kuan [Archiv der Pharmazie, 2014, vol. 347, # 3, p. 161 - 173]
[2]Chen, Chia-Yu; Liao, Yung-Feng; Chang, Ming-Yun; Hu, Ming-Kuan [Archiv der Pharmazie, 2014, vol. 347, # 3, p. 161 - 173]

51
[ 105184-38-1 ]
[ 1212932-15-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: pivaloyl chloride; triethylamine / tetrahydrofuran / -78 °C / Inert atmosphere 1.2: 0.5 h / -78 - 0 °C / Inert atmosphere 2.1: N-ethyl-N,N-diisopropylamine; di-n-butylboryl trifluoromethanesulfonate / dichloromethane / 1.25 h / -78 - 0 °C / Inert atmosphere 2.2: 2 h / -78 °C / Inert atmosphere 3.1: sodium azide / acetonitrile / 7 h / 0 - 20 °C 4.1: lithium borohydride / tetrahydrofuran; water / 24.5 h / 0 - 20 °C 5.1: palladium 10% on activated carbon; hydrogen / methanol / 4 h / Inert atmosphere

Reference： [1]Chen, Chia-Yu; Liao, Yung-Feng; Chang, Ming-Yun; Hu, Ming-Kuan [Archiv der Pharmazie, 2014, vol. 347, # 3, p. 161 - 173]

52
1‐(4‐chloro‐3‐(trifluoromethyl)phenyl)‐3‐(4‐((2‐(hydrazinecarbonyl)pyridin‐4‐yl)oxy)phenyl)urea [ No CAS ]
[ 105184-38-1 ]
[ 1610930-12-5 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 12h;	General procedure: Added compound 4 (1equiv.), appropriate acids (1.2equiv.), 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (1.2equiv.), Et3N (1.5equiv.) to anhydrous DMF (5mL) and stirred the solution at room temperature for 12h. The reaction mixture was poured into H2O (100mL). The precipitates were collected by filtration and washed with water to give the target compound 5a-r in a reasonable yield.

Reference： [1]Chinese Chemical Letters,2014,vol. 25,p. 702 - 704

53
[ 6832-87-7 ]
[ 105184-38-1 ]
N-(2-bromophenyl)-2-(3,5-difluorophenyl)-N-methylacetamide [ No CAS ]

Reference： [1]Organic Letters,2015,vol. 17,p. 334 - 337

54
[ 105184-38-1 ]
[ 95-01-2 ]
7-oxy-3-(3,5-difluorophenyl)coumarin [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54.36%	With sodium acetate; In acetic anhydride; at 160℃; for 8h;Inert atmosphere;	A mixture of 2,4-dihydroxybenzaldehyde (2 g, 14.5 mmol), <strong>[105184-38-1]3,5-<strong>[105184-38-1]difluorophenylacetic acid</strong></strong> (2.49 g, 14.5 mmol), anhydrous NaOAc (1.78 g, 21.75 mmol) and 15 mL acetic anhydride was heated with stirring at 160 C under nitrogen for 8 h. After removal of acetic acid by distillation, the resulting mixture was treated with 10% HCl/methanol, and the precipitates were collected by filtration. The dried product was purified by recrystallization from methanol. Yield: 2.158 g (54.36%), mp: 275 C. IR (KBr tablet); numax/cm-1: 3153 (-OH), 3040-3080 (Ar C-H), 1699 (lactone, C=O), 1600 (C=C), 1591-1465 (Ar C=C) and 1120 (Ar C-F). 1H NMR (DMSO-d6), (delta:ppm): 7.18 (dd, 1H, J = 8 and 2 Hz, Ar-H), 7.28 (t, 1H, J = 6 Hz, Ar-H), 7.32 (d, 1H, J = 2 Hz, Ar-H), 7.48 (dd, 2H, J = 8 and 2 Hz, Ar-H), 7.83 (d, 1H, J = 8 Hz, Ar-H), 8.35 (s, 1H, coumarin 4-H), 9.32 (bs, 1H, -OH). MS (MALDI-TOF), (m/z): 274.04 [M]+, 275.08 [M + H]+, 276.11 [M + 2H]+. C15H8F2O3: calcd. C, 65.64; H, 2.92; F, 13.86%; found: C, 65.67; H, 2.89; F, 13.83.

Reference： [1]Journal of Photochemistry and Photobiology A: Chemistry,2015,vol. 300,p. 6 - 14

55
[ 105184-38-1 ]
[ 100-66-3 ]
2-(3,5-difluorophenyl)-1-(4-methoxyphenyl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%		General procedure: PPA (H6P4O13, polyphosphoric acid, 1.7 g, 5.0 mmol) was added to a solution of substituted arenes (3.3 mmol) and phenylacetic acids (3.0 mmol) in MeCN (10 mL) at rt. The reaction mixture was stirred at rt for 10 min. TFAA (trifluoroacetic anhydride, 850 mg, 4.0 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 8 h. The solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (320 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc=8/1-4/1) afforded 3.

Reference： [1]Tetrahedron,2015,vol. 71,p. 9187 - 9195

56
[ 91-16-7 ]
[ 105184-38-1 ]
2-(3,5-difluorophenyl)-1-(3,4-dimethoxyphenyl)ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%		General procedure: PPA (H6P4O13, polyphosphoric acid, 1.7 g, 5.0 mmol) was added to a solution of substituted arenes (3.3 mmol) and phenylacetic acids (3.0 mmol) in MeCN (10 mL) at rt. The reaction mixture was stirred at rt for 10 min. TFAA (trifluoroacetic anhydride, 850 mg, 4.0 mmol) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 8 h. The solvent was concentrated. The residue was diluted with water (10 mL) and the mixture was extracted with CH2Cl2 (320 mL). The combined organic layers were washed with brine, dried, filtered and evaporated to afford crude product under reduced pressure. Purification on silica gel (hexanes/EtOAc=8/1-4/1) afforded 3.

Reference： [1]Tetrahedron,2015,vol. 71,p. 9187 - 9195

57
[ 105184-38-1 ]
[ 74-88-4 ]
[ 210530-70-4 ]

Yield	Reaction Conditions	Operation in experiment
90%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 6h;	(3,5-Difluorophenyl)acetic acid (Sigma-Aldrich, 690 mg, 4.0 mmol) and potassium carbonate (1.1 g, 8.0 mmol) were added to DMF (12 mL). After subsequent addition of methyl iodide (750 mu, 12 mmol), the resultant reaction mixture was stirred at room temperature for 6 h. After this time, water was added to the reaction mixture and the product was extracted with EtOAc. Combined organic fractions were washed with brine, dried over Na2S04 and solvents were evaporated under reduced pressure. The crude product was purified by Biotage Isolera to give the desired compound (670 mg, 90%).

Reference： [1]Advanced Synthesis and Catalysis,2020,vol. 362,p. 1106 - 1111
[2]Patent: WO2016/196244,2016,A1 .Location in patent: Page/Page column 96-97

58
1-(1H-benzimidazol-2-yl)-1H-pyrazol-4-amine hydrochloride [ No CAS ]
[ 105184-38-1 ]
N-[1-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-(3,5-difluorophenyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	(3,5-Difluorophenyl)acetic acid (60.9 mg, 354 muiotatauiotaomicronIota) was provided in DMF (1.5 mL). N,N- diisopropylethylamine (250 mu, 1.4 mmol), the compound of intermediate 4 (100 mg, 424 muiotatauiotaomicronIota) and propane phosphonic acid anhydride (T3P, 250 mu, 50% in DMF, 420 muiotatauiotaomicronIota) were added, and the mixture was stirred at room temperature over night. After filtration, purification by HPLC (method 1) yielded 75.0 mg (59% of theory) of the title compound. (0496) LC-MS (method 2): Rt = 1.06 min; MS (ESIpos): m/z = 354 [M+H]+ (0497) XH-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.908 (0.52), 2.075 (0.48), 2.083 (0.91), 2.323 (0.48), 2.327 (0.70), 2.332 (0.50), 2.523 (3.56), 2.540 (0.87), 2.665 (0.56), 2.669 (0.78), 2.674 (0.56), 3.741 (16.00), 7.050 (0.60), 7.056 (1.32), 7.066 (5.37), 7.072 (7.93), 7.088 (7.28), 7.094 (6.54), 7.104 (1.57), 7.109 (0.98), 7.117 (1.96), 7.122 (2.97), 7.128 (1.63), 7.140 (3.67), 7.146 (5.92), 7.152 (3.13), 7.164 (2.77), 7.170 (9.82), 7.179 (7.04), 7.186 (7.23), 7.193 (8.80), 7.195 (7.78), 7.206 (1.57), 7.416 (2.66), 7.428 (2.82), 7.435 (2.55), 7.439 (2.38), 7.561 (2.83), 7.572 (2.98), 7.584 (2.62), 7.951 (9.31), 8.651 (14.94), 10.604 (5.49), 13.063 (1.88).

Reference： [1]Patent: WO2016/202758,2016,A1 .Location in patent: Page/Page column 53

59
[ 210530-70-4 ]
[ 105184-38-1 ]

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 130,p. 73 - 85

60
[ 105184-38-1 ]
[ 172366-38-0 ]

Reference： [1]Patent: EP2182804,2017,B1
[2]Patent: CN111018663,2020,A

61
1-(2,2,2-trichloroethyl)-3,4,5-trifluorobenzene [ No CAS ]
[ 105184-38-1 ]

Yield	Reaction Conditions	Operation in experiment
168 g	With sulfuric acid; In toluene; at 80 - 95℃; for 8h;	2L three bottles, Add 600 g of 17% sulfuric acid solution. Heated to 80 ~ 95 C. A solution of 300 g of intermediate 1- (2,2,2-trichloroethyl) -3,5-difluorobenzene and 100 g of toluene was added dropwise. After dripping, the incubation reaction was carried out for 8 hours. The reaction is complete. The system will drop into the ice water quenching. Filter, wash, dry. Toluene recrystallization to obtain pure product 3,5-difluorobenzoic acid 168.0 g, HPLC purity greater than 99 wt%

Reference： [1]Patent: CN106928044,2017,A .Location in patent: Paragraph 0098; 0099; 0101

62
[ 35196-48-6 ]
[ 105184-38-1 ]
ethyl N'-((3,5-difluorobenzyl)carbonyl)hydrazino-2-oxoacetate [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2018,vol. 57,p. 14602 - 14607
Angew. Chem.,2018,vol. 130,p. 14811 - 14816,6

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CAS No. :	105184-38-1	MDL No. :	MFCD00010316
Formula :	C₈H₆F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	IGGNSAVLXJKCNH-UHFFFAOYSA-N
M.W :	172.13	Pubchem ID :	145424
Synonyms :

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	2
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.9
TPSA :	37.3 Å²

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) :	-6.22 cm/s

Log Po/w (iLOGP) :	1.52
Log Po/w (XLOGP3) :	1.59
Log Po/w (WLOGP) :	2.43
Log Po/w (MLOGP) :	2.52
Log Po/w (SILICOS-IT) :	2.39
Consensus Log Po/w :	2.09

[ CAS No. 105184-38-1 ] {[proInfo.proName]}

Quality Control of [ 105184-38-1 ]

Related Doc. of [ 105184-38-1 ]

Product Details of [ 105184-38-1 ]

Calculated chemistry of [ 105184-38-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 105184-38-1 ]

Application In Synthesis of [ 105184-38-1 ]

[ 105184-38-1 ] Synthesis Path-Upstream 1~4

[ 105184-38-1 ] Synthesis Path-Downstream 1~62

Related Functional Groups of
[ 105184-38-1 ]

Fluorinated Building Blocks

Aryls

Carboxylic Acids

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-2.15
Solubility :	1.23 mg/ml ; 0.00713 mol/l
Class :	Soluble
Log S (Ali) :	-1.98
Solubility :	1.78 mg/ml ; 0.0104 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.73
Solubility :	0.321 mg/ml ; 0.00187 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.46

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

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