[ CAS No. 455-87-8 ] {[proInfo.proName]}

Name: 455-87-8|4-Amino-3-fluorobenzoic acid|98%
Brand: Ambeed
SKU: A140966
Price: 8.0 USD
Availability: InStock
Rating: 97 (29 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

DV 2D 3D

3d Animation Molecule Structure of 455-87-8

Structure of 455-87-8 * Storage: {[proInfo.prStorage]}

Cart0 Add to My Favorites Add to My Favorites Bulk Inquiry Inquiry Add To Cart

Search after Editing

* Storage: {[proInfo.prStorage]}

For Research Only 110K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 455-87-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 455-87-8 ]

SDS Specification

Alternatived Products of [ 455-87-8 ]

Product Details of [ 455-87-8 ]

CAS No. :	455-87-8	MDL No. :	MFCD01660374
Formula :	C₇H₆FNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JSKXHTHMCCDEGD-UHFFFAOYSA-N
M.W :	155.13	Pubchem ID :	9971
Synonyms :

Calculated chemistry of [ 455-87-8 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	3.0
Num. H-bond donors :	2.0
Molar Refractivity :	37.76
TPSA :	63.32 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.25 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.91
Log Po/w (XLOGP3) :	1.41
Log Po/w (WLOGP) :	1.53
Log Po/w (MLOGP) :	0.32
Log Po/w (SILICOS-IT) :	0.92
Consensus Log Po/w :	1.02

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.03
Solubility :	1.46 mg/ml ; 0.00938 mol/l
Class :	Soluble
Log S (Ali) :	-2.34
Solubility :	0.702 mg/ml ; 0.00453 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.68
Solubility :	3.27 mg/ml ; 0.0211 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.09

Safety of [ 455-87-8 ]

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

Application In Synthesis of [ 455-87-8 ]

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

Upstream synthesis route of [ 455-87-8 ]
Downstream synthetic route of [ 455-87-8 ]

[ 455-87-8 ] Synthesis Path-Upstream 1~7

1
[ 455-87-8 ]
[ 825-98-9 ]

Reference： [1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356

2
[ 403-21-4 ]
[ 455-87-8 ]

Yield	Reaction Conditions	Operation in experiment
98.6%	With palladium on activated charcoal; hydrogen In tetrahydrofuran; methanol at 20℃; for 15 h;	In a 1000 mL round bottom single-necked flask, palladium on carbon (2 g)And the mixture was dissolved in 300 ml of a mixed solvent of methanol and tetrahydrofuran,Further 3-fluoro-4-nitrobenzoic acid (30 g, 190 mmol, leq) was added,The reaction system was filled with hydrogen gas and stirred at room temperature for 15 hours.After completion of the reaction, the reaction solution was filtered through Celite to obtain a filtrate, and the filtrate was dried to obtain a white solid,Dry the solids in an oven to give a dry white solid (24. 86 g, 98.6percent).
98%	With 5%-palladium/activated carbon; hydrogen In ethanolFlow reactor	General procedure: Before each run, the system (see Fig.4) was allowed to equilibrate by pumping solvent through for 30min with the Tube-in-Tube device at 16bar of hydrogen. An omnifit cartridge (20.0mm OD, 15.0mm ID) containing 1g of Pd-C catalyst was used. To avoid an overpressure of the system in the event of blockage, the upper pressure cut-off limit on the Knauer pump was set to 25bar. With the injection loop disconnected from the flow line, the loop was opened and filled manually (using a syringe) with 3.6mL of a 0.076M solution of starting material in ethanol (excess starting material solution exiting the loop was recovered for reuse). The injection loop was then closed off and switched into the flow stream. The outlet from the system (downstream of the back-pressure regulator) was collected for 120min. The solvent was removed under reduced pressure (using a rotary evaporator followed by a 2-stage rotary vane pump) to afford the product.

Reference： [1] Patent: CN105294567, 2016, A, . Location in patent: Paragraph 0033-0036
[2] Tetrahedron, 2018, vol. 74, # 47, p. 6795 - 6803
[3] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[4] Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 12, p. 2697 - 2706

3
[ 403-21-4 ]
[ 7439-89-6 ]
[ 455-87-8 ]

Reference： [1] Patent: US6201007, 2001, B1,

4
[ 446-34-4 ]
[ 455-87-8 ]

Reference： [1] Journal of the American Chemical Society, 1944, vol. 66, p. 1631
[2] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356

5
[ 713-11-1 ]
[ 455-87-8 ]

Reference： [1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356

6
[ 352-70-5 ]
[ 455-87-8 ]

Reference： [1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356

7
[ 326-67-0 ]
[ 455-87-8 ]

Reference： [1] Journal of Organic Chemistry, 1961, vol. 26, p. 3351 - 3356

[ 455-87-8 ] Synthesis Path-Downstream 1~88

1
[ 455-87-8 ]
[ 825-98-9 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

2
[ 713-11-1 ]
[ 455-87-8 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

3
[ 455-87-8 ]
[ 1003-03-8 ]
[ 959785-34-3 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; for 6h;	EXAMPLE 203A; To a solution of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (0.50 g) in THF (40 mL) was added cyclopentanamine (0.478 ml), HOBt-hydrate (0.653), EDCI (0.926 g) and TEA(0.673 mL). The mixture was stirred at ambient temperature for 6 hours and concentrated.The concentrate was treated with water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate and brine and dried (MgSC*4), filtered and concentrated. The concentrate was triturated with ethyl acetate/hexane.

Reference： [1]Patent: WO2007/140233,2007,A1 .Location in patent: Page/Page column 93

4
[ 41838-46-4 ]
[ 455-87-8 ]
[ 1001345-97-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 18 - 25℃; for 18h;	4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-1-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0-10% 2M ammonia in MeOH/DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 50 g SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%)1H NMR (399.902 MHz, CDCl3) ?1.55 (m, 2H), 2.03 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.95 (m, 1H), 4.01 (s, 2H), 5.77 (d, 1H), 6.75 (m, 1H), 7.34 (m, 1H), 7.45 (m, 1H); MS m/z 252 [M+H]+.
100%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl acetamide; at 18 - 25℃; for 18h;	4-Amino-3-Fluorobenzoic acid (Fluorochem; 1 g, 6.44 mmol), 4-Amino-l-methylpiperidine (Fluorochem; 811 mg, 7.09 mmol), HATU (2.70 g, 7.09 mmol), DIPEA (3.4 mL, 19.32 mmol) and DMF (15 mL) were combined and stirred for 18 hrs at room temperature. The solvent was evaporated and the resultant material dissolved in DCM (with a little MeOH to aid solubility) and chromatographed on silica eluting with a gradient of 0 - 10% 2M ammonia in MeOH / DCM. Fractions containing product were combined and evaporated to give an orange solid which was dissolved in MeOH and added to a 5Og SCX-2 column pre-wet with MeOH (2 column volumes). The column was flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated to yield the title compound as a beige solid. (1.72 g, 100%) 1H NMR (399.902 MHz, CDC13) delta 1.55 (m, 2H), 2.03 (m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 2.81 (m, 2H), 3.95 (m, IH), 4.01 (s, 2H), 5.77 (d, IH), 6.75 (m, IH), 7.34 (m, IH), 7.45 (m, IH); MS m/z 252 [M+H]+.

Reference： [1]Patent: US2008/9482,2008,A1 .Location in patent: Page/Page column 114
[2]Patent: WO2008/40951,2008,A1 .Location in patent: Page/Page column 142-143

5
[ 455-87-8 ]
C₇H₃⁽²⁾HFNO₄ [ No CAS ]

Reference： [1]Tetrahedron,2001,vol. 57,p. 4753 - 4757

6
[ 446-34-4 ]
[ 455-87-8 ]

Reference： [1]Journal of the American Chemical Society,1944,vol. 66,p. 1631
[2]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

7
[ 352-70-5 ]
[ 455-87-8 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

8
[ 326-67-0 ]
[ 455-87-8 ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

9
[ 455-87-8 ]
N-<3-Fluor-4-jod-benzoyl>-L-glutaminsaeure [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

10
[ 455-87-8 ]
N-<3-Fluor-4-methylamino-benzoyl>-4-glutaminsaeure [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1961,vol. 26,p. 3351 - 3356

11
[ 123-75-1 ]
[ 455-87-8 ]
[ 209960-85-0 ]

Yield	Reaction Conditions	Operation in experiment
78%		To a solution of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (1.00 g) in methylene chloride (20 mL) were added pyrrolidine (700 muL), N-hydroxybenzotriazole monohydrate (1.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.6 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated sodium hydrogencarbonate solution, and then the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on NH silica-gel (Chromatorex; Fuji Silysia Chemical Ltd., solvent; hexane/ethyl acetate = 80/20 to 25/75) to give the titled compound (1.04 g) as a powder (yield: 78%). MS(APCI)m/z; 209[M+H]+.

Reference： [1]Patent: EP2390254,2011,A1 .Location in patent: Page/Page column 76
[2]Patent: WO2005/111014,2005,A1 .Location in patent: Page/Page column 156

12
[ 455-87-8 ]
[ 74-88-4 ]
3-fluoro-4-methylaminobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.83 g(98%)	With sodium carbonate; potassium carbonate; trifluoroacetic anhydride; In methanol; dichloromethane; N,N-dimethyl-formamide;	Preparation 39 Methlyl 3-fluoro-4-methylaminobenzoate To a solution of methlyl <strong>[455-87-8]4-amino-3-fluorobenzoate</strong>(1.77 g, 10.5 mmol) in CH2Cl2(50 ml) was added Na2CO3(3.33 g, 31.4 mmol) and trifluoroacetic anhydride(2.96 ml, 20.9 mmol) at room temperature. After stirring for 2.5 h, the solid was filtered off. The filtrate was washed with water, brine, dried(Na2SO4), and concentrated to give 2.70 g(97%) of white solid. To a solution of this solid(2.70 g, 10.2 mmol) in DMF(48 ml) was added Na2CO3(16.9 g, 160 mmol) and iodomethane(20.8 ml, 334 mmol) at 0 C. After stirring for 2 h at 0 C., for 1 h at room temperature, the mixture was poured into 2NHCl with ice and extracted with AcOEt: toluene=2:1(200 ml*2). The extract was washed with water, brine, dried(Na2SO4), and concentrated to give 3.06 g(quant) of brown oil. This oil was dissolved in MeOH(25 ml) and 7%K2CO3 solution(12.5 ml) was added at 0 C. After stirring for 2 h at 0 C., for 4 h at room temperature, 7%K2CO3 solution(12.5 ml) was added. After stirring for 1.5 h at room temperature, the mixture was acidified with 5NHCl and MeOH was evapolated. The residue was extracted with AcOEt. The extract was washed with water, brine, dried(Na2SO4), and concentrated to give 1.83 g(98%) of pale brown solid. 1H NMR (270 MHz, CDCl3) delta 7.80-7.72(1H, m), 7.62(1H, dd, J=1.8, 12.5 Hz), 6.63(1H, t, J=8.6 Hz), 4.40(1H, br. s), 3.86(3H, S), 2.94(3H, d, J=5.1 Hz).

Reference： [1]Patent: US6201007,2001,B1

13
[ 403-21-4 ]
[ 7439-89-6 ]
[ 455-87-8 ]

Yield	Reaction Conditions	Operation in experiment
1.77 g(97%)	In dichloromethane; water; acetic acid;	Preparation 38 Methlyl 4-amino-3-fluorobenzoate A mixture of methlyl 3-fluoro-4-nitrobenzoate(2.14 g, 10.8 mmol) and iron powder(2.63 g) in acetic acid(22 ml) was stirred at 50 C. for 2.5 h. After cooling down to room temperature, CH2Cl2(100 ml) and water(300 ml) was added to the mixture and filtered to remove iron powder. The organic layer was separated and the aqueous layer was extracted with CH2Cl2(70 ml*2). The CH2Cl2 solution was combined, washed with water, brine, dried(Na2SO4), and concentrated to give 1.77 g(97%) of pale brown solid. 1H NMR (270 MHz, CDCl3) delta 7.70-7.62(2H, m), 6.79-6.70(1H, m), 4.13(2H, br. s), 3.86(3H, S).

Reference： [1]Patent: US6201007,2001,B1

14
[ 455-87-8 ]
[ 76272-41-8 ]
[ 1001346-74-2 ]

Yield	Reaction Conditions	Operation in experiment
61%		4-amino-3-fluorobenzoic acid (Fluorochem; 5.0 g, 32.2 mmol), HATU (13.5 g, 35.4 mmol) and DIPEA (18.5 mL, 106 mmol) were stirred together in anhydrous DMA (100 mL) for 25 minutes. Endo-9-methyl-9-azabicyclo[3,3,l]nonane-3-one (Chempacific; 5.5 g, 35.4 mmol) was added and the solution stirred at ambient temperature overnight. The solvent was evaporated and the residue dissolved in MeOH and loaded onto an SCX-2 column (50g x 4) pre-wet with MeOH. The column was washed with MeOH (2 column <n="155"/>volumes) and the product eluted with 2MNH3/MeOH (2 column volumes). The ammoniacal solution was evaporated and the resultant material purified on a silica column eluted with 0- 10percent 2NH3/MeOH/DCM. Product containing fractions were evaporated to yield the title compound as a white solid after trituration with ethyl acetate (5.7 g, 61percent) 1H NMR (400.132 MHz, DMSO-d6) delta 0.91 (m, 2H)5 1.42 (m, 3H), 1.90 (m, 4H), 2.03 (m, IH), 2.14 (m, 3H), 2.40 (s, 3H), 2.96 (m, 2H), 4.27 (m, IH), 5.60 (bs, 2H), 6.74 (m, IH), 7.46 (m, IH), 7.53 (m, IH), 7.70 (d, IH); MS m/z 292 [M+H]+.

Reference： [1]Patent: WO2008/40951,2008,A1 .Location in patent: Page/Page column 153-154

15
[ 455-87-8 ]
[ 674792-07-5 ]
[ 1124215-20-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;	To tert-butyl 2,2-dimethylpiperazine-1-carboxylate (0.902 mmol, 0.193 g) in dichloro-methane (5 mL) was added <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (0.902 mmol, 0.14 g), and triethylamine (1.805 mmol, 0.252 mL, 0.183 g). To this mixture was added 1-propanephosphonic acid cyclic anhydride (1.805 mmol, 1.074 mL, 1.149 g, 50% solution in ethyl acetate). After 2 hours stirring, ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic layer was dried with sodium sulfate, filtered and concentrated under vacuum to give the intermediate tert-butyl 4-(4-amino-3-fluorobenzoyl)-2,2-dimethylpiperazine-1-carboxylate (264 mg).
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;	To tert-butyl 2,2-dimethylpiperazine-1-carboxylate (0.902mmol, 0.193g) in dichloromethane (5mL) was added <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (0.902mmol, 0.14g), and triethylamine (1.805mmol, 0.252mL, 0.183g). To this mixture was added 1- propanephosphonic acid cyclic anhydride (1.805mmol, 1.074mL, 1.149g, 50% solution in <n="68"/>ethyl acetate). After 2 hours stirring, ethyl acetate was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic layer was dried with sodium sulfate, filtered and concentrated under vacuum to give the intermediate tert-butyl 4-(4-amino-3-fluorobenzoyl)-2,2- dimethylpiperazine-1-carboxylate (264mg).

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 36
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 66-67

16
[ 674792-05-3 ]
[ 455-87-8 ]
[ 1124214-97-6 ]

Yield	Reaction Conditions	Operation in experiment
		1-Propanephosphonic acid cyclic anhydride (1.752mmol, 1.043ml_, 1115mg) was added to a solution of <strong>[674792-05-3](S)-tert-butyl 2-isopropylpiperazine-1-carboxylate</strong> (0.876mmol, 200mg), 4-amino-3-fluorobenzoic acid (0.876mmol, 136mg) and triethylamine (1.752mmol, 0.244 mL, 177mg) in dichloromethane and stirred at room temperature for 2 hours. After this time, ethyl acetate (10OmL) was then added to the reaction. The organic mixture was washed with saturated sodium hydrogen carbonate, water, dried over sodium sulphate and concentrated under vacuum. The residue was then dissolved in dichloromethane <n="65"/>(5ml_) and trifluoroacetic acid (17.52mmol, 1997mg) added. The resultant solution was allowed to stand at room temperature overnight. The reaction was concentrated under vacuum and purified by strong cation exchange chromatography to give the title compound (200mg) as a clear oil. MS (ESI) m/z 266.3 [M+H]+

Reference： [1]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 63-64

17
[ 1124214-88-5 ]
[ 455-87-8 ]
[ 1124214-90-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃;	1-Propanephosphonic acid cyclic anhydride (1.967 g, 3 mmol, 1.840 mL, 50% solution in ethyl acetate) was added dropwise to a solution of (R)N-tert-butyl-3-((2-methylpiperazin-1-yl)methyl)benzamide (500 mg, 1.7 mmol), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (239.7 mg, 1.5 mmol) and triethylamine (469 mg, 4.5 mmol, 1.84 mL) in dichloromethane. The reaction was stirred at room temperature for 2 hours. The dichloromethane was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic layer was concentrated under vacuum to afford the title compound (476.3 mg). MS (ESI) m/z 427.4 [M+H]+
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 2h;	1-Propanephosphonic acid cyclic anhydride (1.967g, 3mmol, 1.84OmL, 50% solution in ethyl acetate) was added dropwise to a solution of (R)-N-tert-butyl-3-((2- methylpiperazin-1-yl)methyl)benzamide (500mg, 1.7mmol), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (239.7mg, 1.5mmol) and triethylamine (469mg, 4.5mmol, 1.84mL) in dichloromethane. The reaction was stirred at room temperature for 2 hours. The dichloromethane was removed under reduced pressure and the residue was taken up in <n="64"/>ethyl acetate, washed with water, sodium hydrogen carbonate and brine. The organic layer was concentrated under vacuum to afford the title compound (476.3mg).MS (ESI) m/z 427.4 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 34
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 62-63

18
[ 1124215-36-6 ]
[ 455-87-8 ]
[ 1124215-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 2h;	A mixture of N-tert-butyl-3-(2-methyl-1 -(piperazin-1 -yl)propyl)benzamide (13.6mg, 0.043mmol), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (10mg, 0.065mmol), N-ethyl-N-isopropyl- propan-2-amine (11 mg, 0.086mmol) and 1-propanephosphonic acid cyclic anhydride (55mg, 0.086mmol, 50% solution in ethyl acetate) in dichloromethane (2.OmL) was stirred at room temperature for 2 hours. The mixture was treated with strong cation exchange column chromatography and purified with silica column chromatography (eluting with 33% ethyl acetate in heptane then 66% ethyl acetate in heptane) to afford the title compound (11.8mg). MS (ESI) m/z 455.5 [M+H]+

Reference： [1]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 70

19
[ 1124216-41-6 ]
[ 455-87-8 ]
[ 1124216-51-8 ]

Yield	Reaction Conditions	Operation in experiment
		3-(Piperazin-1-ylmethyl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)benzamide (1.518 mmol, 0.5 g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (1.518 mmol, 0.235 g) and triethylamine (3.80 mmol, 0.529 mL, 0.384 g) were dissolved in dichloromethane (15.18 mL) and stirred for 5 minutes. 1-Propanephosphonic acid cyclic anhydride (3.04 mmol, 1,799 mL, 1.932 g, 50% solution in ethyl acetate) was added dropwise and the reaction mixture was allowed to stir for 1 hour. Dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (500 mg). MS (ESI) m/z 467.4 [M+H]+
		3-(Piperazin-1-ylmethyl)-N-(1 ,1 ,1-trifluoro-2-methylpropan-2-yl)benzamide (1.518mmol, 0.5g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (1.518mmol, 0.235g) and triethylamine (3.80mmol, 0.529mL, 0.384g) were dissolved in dichloromethane (15.18ml_) and stirred for 5 minutes. 1-Propanephosphonic acid cyclic anhydride (3.04mmol, 1.799ml_, 1.932g, 50% solution in ethyl acetate) was added dropwise and the reaction mixture was allowed to stir for 1 hour. Dichloromethane was added and the organic mixture was washed with saturated sodium hydrogen carbonate, water, and saturated sodium chloride. The organic phase was dried with sodium sulfate, filtered and concentrated to yield the title compound (500mg). MS (ESI) m/z 467.4 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 48-49
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 85-86

20
[ 1124216-61-0 ]
[ 455-87-8 ]
[ 1124216-63-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 1h;	To a solution of N-cyclobutyl-3-(piperazin-1-ylmethyl)benzamide (8.78 mmol, 2.4 g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (8.78 mmol, 1.362 g) and triethylamine (26.3 mmol, 3.67 mL, 2.67 g) in dichloromethane (50 mL) was added 1-propanephosphonic acid cyclic anhydride (13.17 mmol, 7.84 mL, 8.38 g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour then was diluted with ethyl acetate/sodium hydrogen carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.4 g). MS (ESI) m/z 411.5 [M+H]+
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 1h;	To a solution of N-cyclobutyl-3-(piperazin-1-ylmethyl)benzamide (8.78mmol, 2.4g), 4- amino-3-fluorobenzoic acid (8.78mmol, 1.362g) and triethylamine (26.3mmol, 3.67mL, 2.67g) in dichloromethane (5OmL) was added 1-propanephosphonic acid cyclic anhydride (13.17mmol, 7.84mL, 8.38g, 50% solution in ethyl acetate). The reaction was stirred for 1 hour then was diluted with ethyl acetate / sodium hydrogen carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.4g). MS (ESI) m/z 411.5 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 50
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 88

21
[ 1124216-71-2 ]
[ 455-87-8 ]
[ 1124216-73-4 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 1h;	To a solution of (R)-N-sec-butyl-3-(piperazin-1-ylmethyl)benzamide (5.08 mmol, 1.4 g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (5.08 mmol, 0.789 g) and triethylamine (15.25 mmol, 2.126 mL, 1.543 g) in dichloromethane (80 mL) was added 1-propanephosphonic acid cyclic anhydride (7.63 mmol, 2.270 mL, 2.426 g, 50% solution in ethyl acetate). The reaction mixture was stirred for 1 hour then was diluted with ethyl acetate and potassium carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. Chromatography on silica (eluding with ethyl acetate to ethyl acetate/methanol (5%)) gave the intermediate (R)-3-((4-(4-amino-3-fluorobenzoyl)piperazin-1-yl)methyl)-N-sec-butylbenzamide (1.2 g).
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 1h;	To a solution of (R)-N-sec-butyl-3-(piperazin-1-ylmethyl)benzamide (5.08mmol,1.4g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (5.08mmol, 0.789g) and triethylamine (15.25mmol, 2.126mL, 1.543g) in dichloromethane (8OmL) was added 1-propanephosphonic acid cyclic anhydride (7.63mmol, 2.27OmL, 2.426g, 50% solution in ethyl acetate). The reaction mixture was stirred for 1 hour then was diluted with ethyl acetate and potassium carbonate (aqueous). The organic layer was separated, dried (magnesium sulfate) and concentrated under reduced pressure. Chromatography on silica (eluting with ethyl acetate to ethyl acetate/methanol (5%)) gave the intermediate (R)-3-((4-(4-amino-3- fluorobenzoyl)piperazin-1-yl)methyl)-N-sec-butylbenzamide (1.2g).

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 51
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 89

22
[ 1124216-82-5 ]
[ 455-87-8 ]
[ 1124216-84-7 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃;	N-(3,3-Difluorocyclobutyl)-3-(piperazin-1-ylmethyl)benzamide (5.14 mmol, 1.59 g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (5.14 mmol, 0.797 g) and triethylamine (15.42 mmol, 2.143 mL, 1.560 g) were stirred in dichloromethane (30 mL) at room temperature. 1-Propanephosphonic acid cyclic anhydride (7.71 mmol, 4.59 mL, 4.91 g, 50% solution in ethyl acetate) was added dropwise and the reaction stirred for 1 hour. The reaction mixture was concentrated under vacuum and the residue taken up in ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated under vacuum to afford the title compound (1.255 g). MS (ESI) m/z 447.5 [M+H]+
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 1h;	N-(3,3-Difluorocyclobutyl)-3-(piperazin-1-ylmethyl)benzamide (5.14mmol, 1.59g), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (5.14mmol, 0.797g) and triethylamine (15.42mmol, 2.143mL, 1.56Og) were stirred in dichloromethane (3OmL) at room temperature. 1 - Propanephosphonic acid cyclic anhydride (7.71 mmol, 4.59mL, 4.91g, 50% solution in ethyl acetate) was added dropwise and the reaction stirred for 1 hour. The reaction mixture was concentrated under vacuum and the residue taken up in ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution, dried over sodium sulfate and concentrated under vacuum to afford the title compound (1.255g). MS (ESI) m/z 447.5 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 52
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 91

23
[ 1124212-41-4 ]
[ 455-87-8 ]
[ 1124212-35-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃;Inert atmosphere;	4-Amino-3-fluorobenzoic acid (500 mg, 3.22 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (888 mg, 3.22 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (926 mg, 4.83 mmol, EDCl) and triethylamine (984 mg, 898 mul, 6.44 mmol) were combined and stirred in acetonitrile (10 mL) at room temperature overnight (under nitrogen). The reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane (30 mL) and washed with water. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (eluding with a solvent gradient from dichloromethane to 4% methanol/dichloromethane) to give the title compound (355 mg). MS (ESI) m/z 413.5 [M+H]+
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile; at 20℃;	4-Amino-3-fluorobenzoic acid (500mg, 3.22mmol), N-tert-butyl-3-(piperazin-1- ylmethyl)benzamide (888mg, 3.22mmol), N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride (926mg, 4.83mmol, EDCI) and triethylamine (984mg, 898mul, 6.44mmol) were combined and stirred in acetonitrile (1OmL) at room temperature overnight (under nitrogen). The reaction was concentrated under reduced pressure. The residue was taken up in dichloromethane (3OmL) and washed with water. The organic phase was dried over sodium sulfate and concentrated under vacuum. The residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol / dichloromethane) to give the title compound (355mg). MS (ESI) m/z 413.5 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 10
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 22

24
[ 455-87-8 ]
[ 552-70-5 ]
4-amino-3-fluoro-N-[(3-endo)-9-methyl-9-azabicyclo[3.3.1]non-3-yl]-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		4-Amino-3-fluorobenzoic acid (5.0 g), HATU (13.5 g) and DIPEA (18.5 mL) were stirred together in anhydrous DMA (100 mL) for 25 mins. enJo-9-methyl-9-azabicyclo[3.3.1]- nonane-3-one (5.5 g) was added and the mixture was stirred at r.t. for 16h. The solvent was removed in vacuo and the residue was dissolved in MeOH and semi-purified by SCX-2 washing with MeOH and eluting with 2M NH3ZMeOH. Further purification by FCC using 0-10% (2M NH3/Me0H) in DCM afforded the title compound (5.7 g, 61%) as a white solid after trituration with EtOAc; 1H NMR: 0.91 (m, 2H), 1.42 (m, 3H), 1.90 (m, 4H), 2.03 (m, IH), 2.14 (m, 3H), 2.40 (s, 3H), 2.96 (m, 2H), 4.27 (m, IH), 5.60 (bs, 2H), 6.74 (m, IH), 7.46 (m, IH), 7.53 (m, IH), 7.70 (d, IH); m/z: MH+ 292.

Reference： [1]Patent: WO2009/24824,2009,A1 .Location in patent: Page/Page column 86

25
[ 946826-28-4 ]
[ 455-87-8 ]
[ 1137211-17-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; for 132h;Heating / reflux;	Intermediate 9: 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5', 6',8',9'- tetrahydrospiro[cyclopropane-l, 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 '-ylamino)-3- betauorobenzoic acid; 2'-Chloro-9'-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclopropane- 1 ,7'-pyrimido[4,5- b][l,4]diazepin]-6'(5eta)-one (Intermediate 2) (0.42 g, 1.36 mmol, 1 eq), 4-amino-3- fluorobenzoic acid (0.63 g, 4.1 mmol, 3 eq) and TFA (0.51 mL, 6.8mmol, 5 eq) were heated to reflux in TFE (10 mL) for 36 hours. Further <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (0.63 g, 4.1 mmol, 3 eq) and TFA (0.51 mL, 6.8 mmol, 5 eq) were added and the reaction was heated to reflux again for 4 days. Solvent was evaporated in vacuo and the <n="85"/>resulting residue was triturated with EtOAc to give 4-(9'-cyclopentyl-5'-methyl-6'-oxo- 56',8',9 '-tetrahydrospirofcyclopropane-l, 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 - ylamino)-3-fluorobenzoic acid (0.41 g, 71%).Rt = 1.93 min (Analytical_l); MS(+ve): 426.3

Reference： [1]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 83-84

26
[ 946826-25-1 ]
[ 455-87-8 ]
[ 1137213-46-7 ]

Yield	Reaction Conditions	Operation in experiment
55%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; for 138h;Heating / reflux;	Intermediate 10: 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5', 6',8',9'- tep-ahydrospiro[cyclobutane-l, 7'-pyrimido[4, 5-b][l, 4]diazepine]-2 '-ylamino)-3- fluorobenzoic acid; 2'-Chloro-9l-cyclopentyl-5'-methyl-8',9'-dihydrospiro[cyclobutane-l,7'-pyrimido[4,5- b][l,4]diazepin]-6'(5'H)-one (Intermediate 4) (0.20 g, 0.63 mmol, 1 eq), 4-amino-3- fluorobenzoic acid (0.30 g, 1.9 mmol, 3 eq) and TFA (0.24 mL, 3.2 mmol, 5 eq) were heated to reflux in TFE for 18 hours. Further <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (0.20 g) and TFA (0.1 mL) were added and the reaction was heated to reflux again for 2 days. Further TFA (0.24 mL) was added and the reaction was heated to reflux again for 3 days. Solvent was evaporated in vacuo and the resulting residue was triturated with EtOAc to give 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5'.6',8',9'-tetrahydrospiro [cyclobutane-1, 7'-pyrimido[4,5-b][l,4]diazepine]-2'-ylamino)-3-fluorobenzoic acid (0.15 g, 55%).Rt = 2.02 min (Analytical); MS(+ve): 440.3; MS(-ve): 438.4

Reference： [1]Patent: WO2009/40556,2009,A1 .Location in patent: Page/Page column 84

27
[ 1124215-36-6 ]
[ 455-87-8 ]
[ 7087-68-5 ]
[ 1124215-38-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; ethyl acetate; at 20℃; for 2h;	A mixture of N-tert-butyl-3-(2-methyl-1-(piperazin-1-yl)propyl)benzamide (13.6 mg, 0.043 mmol), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (10 mg, 0.065 mmol), N-ethyl-N-isopropylpropan-2-amine (11 mg, 0.086 mmol) and 1-propanephosphonic acid cyclic anhydride (55 mg, 0.086 mmol, 50% solution in ethyl acetate) in dichloromethane (2.0 mL) was stirred at room temperature for 2 hours. The mixture was treated with strong cation exchange column chromatography and purified with silica column chromatography (eluding with 33% ethyl acetate in heptane then 66% ethyl acetate in heptane) to afford the title compound (11.8 mg). MS (ESI) m/z 455.5 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 37

28
[ 23474-98-8 ]
[ 455-87-8 ]
2-(4-amino-3-fluorophenyl)-6-chlorobenzothiazole [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 6728 - 6737

29
[ 674792-05-3 ]
[ 455-87-8 ]
C₁₉H₂₉FN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 2h;	1-Propanephosphonic acid cyclic anhydride (1.752 mmol. 1.043 ml, 1115 mg) was added to a solution of <strong>[674792-05-3](S)-tert-butyl 2-isopropylpiperazine-1-carboxylate</strong> (0.876 mmol, 200 mg), 4-amino-3-fluorobenzoic acid (0.876 mmol, 136 mg) and triethylamine (1.752 mmol, 0.244 ml, 177 mg) in dichloromethane and stirred at room temperature for 2 hours. After this time, ethyl acetate (100 mL) was then added to the reaction. The organic mixture was washed with saturated sodium hydrogen carbonate, water, dried over sodium sulphate and concentrated under vacuum. The residue was then dissolved in dichloromethane (5 ml) and trifluoroacetic acid (17.52 mmol, 1997 mg) added. The resultant solution was allowed to stand at room temperature overnight. The reaction was concentrated under vacuum and purified by strong cation exchange chromatography to give the title compound (200 mg) as a clear oil. MS (ESI) m/z 266.3 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 34

30
[ 455-87-8 ]
[ 57260-71-6 ]
[ 1196691-56-1 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 12h;	To a mixture of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (182 mg, 1.1 mmol) and tert- butyl piperazine-1- carboxylate (228 mg, 1.2 mmol) in DCM (5 mL) were added DIEA (0.26 mL, 1.5 mmol) and EDCI (236 mg, 1 .2 mmol). The resulting solution was stirred at rt for 12 h before being quenched with water. After concentration under reduced pressure, the resulting residue was purified by reverse-phase chromatography to yield the title compound (306 mg, 81% yield) as white solid. NMR (600 MHz, CDCb) d 7.13 (d, J= 11.3 Hz, 1H), 7.06 (d, J= 8.0 Hz, 1H), 6.78 (t, J= 8.4 Hz, Hi), 3.99 (s, 21 1 ), 3.60 (br, 41 I f 3 47 (br, 4H), 1.49 (s, 9H)
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;	1-Propanephosphonic acid cyclic anhydride (9.67mmol, 5.76mL, 50% solution in ethyl acetate) was added to a solution of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (6.45mmol, 1g), tert-butyl piperazine-1 -carboxylate (6.45mmol, 1.2g) and triethylamine (12.89mmol, 1.74mL) in dichloromethane (2OmL) and stirred for 2 hours. The reaction mixture was washed with sodium bicarbonate solution and concentrated under vacuum to give the title compound (2.09g). MS (ESI) m/z 324.5 [M+H]+
	With triethylamine;2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In dichloromethane; ethyl acetate;	To a stirred solution of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (4.97g, 32.04mmo), tert- butyl piperazine-1-carboxyiate (5.97g, 32.04mmoi) and triethylamine (1OmL) in dichloromethane (10OmL) was added 1-propanephosphonic acid cyclic anhydride (2OmL, 50% solution in ethyl acetate, dropwise). The reaction mixture was stirred for 1 hour then was diluted with ethyl acetate, washed with potassium carbonate (aqueous), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (9.5g). MS (ESl) m/z: 324.5 [M+H]+.

Reference： [1]Patent: WO2020/10204,2020,A1 .Location in patent: Page/Page column 103
[2]Patent: WO2009/138438,2009,A1 .Location in patent: Page/Page column 30
[3]Patent: WO2010/25179,2010,A1 .Location in patent: Page/Page column 27

31
[ 2759-28-6 ]
[ 455-87-8 ]
[ 1196693-38-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 1h;	4-Amino-3-fluorobenzoic acid (28.4mmol, 4.4Og), 1-benzylpiperazine (28.4mmol, 4.93ml_, 5g) and triethylamine (85mmol, 11.86mL, 8.61 g) were stirred in dichloromethane at room temperature. 1-Propanephosphonic acid cyclic anhydride (42.6mmol, 25.2ml_, 27.1 g, 50% solution in ethyl acetate) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and concentrated under reduced pressure to afford the title compound (7.51g). MS (ESI) m/z 314.1 [M+H]+

Reference： [1]Patent: WO2009/138438,2009,A1 .Location in patent: Page/Page column 62

32
[ 1196694-06-0 ]
[ 455-87-8 ]
[ 1196694-10-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; at 20℃; for 2h;	To a stirring solution of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (1.965mmol, 305mg), 1-(4- (1 ,1 ,1 ,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-2-one (1.965mmol, 700mg) and triethylamine (5.89mmol, 596mg) in dichloromethane (1 OmL) was added 1- propanephosphonic acid cyclic anhydride (2.95mmol, 1876mg; 50% solution in ethyl acetate). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (2OmL) and washed with saturated aqueous sodium hydrogen carbonate solution (3OmL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with 50% ethyl acetate / 50% dichloromethane - 100% ethyl acetate gradient) to afford the title compound (550mg). MS (ESI) m/z 492.3 [M-H]"

Reference： [1]Patent: WO2009/138438,2009,A1 .Location in patent: Page/Page column 76-77

33
[ 1062246-03-0 ]
[ 455-87-8 ]
[ 1137870-06-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In ethanol; water; for 18h;Reflux;	Example 182 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182) A mixture of 0.1 g (0.32 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.059 g (0.57 mmole) of <strong>[455-87-8]4-amino-3-fluoro-benzoic acid</strong> and 0.7 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then cooled and partially concentrated under reduced pressure. The resulting solid was collected by filtration, washed with water and dried to give 0.11 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-fluoro-benzoic acid (I-182).

Reference： [1]Patent: US2009/318408,2009,A1 .Location in patent: Page/Page column 72

34
[ 420-04-2 ]
[ 455-87-8 ]
[ 1204526-55-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a stirred solution of <strong>[455-87-8]4-amino-3-fluoro-benzoic acid</strong> (6.0 g, 38.6 mmol) in a mixture of concentrated HCl/water (5.4 mL/33 mL) was added cyanamide (3.7 g, 88.9 mmol) at room temperature. The reaction mixture was stirred at reflux temperature for 6 hours and then allowed to stand at room temperature (without stirring) for 16 hours. The precipitated solid was filtered off and dried under vacuum to provide Int-1 (5.0 g) as HCl salt. Mass (m/z): 199 [M++1]. To a stirred suspension of Int-1 (5.0 g, 195.5 mmol) in methanol (40 mL) was added acetyl chloride (10 mL) drop wise at 0 C. over a period of 10 minutes. The reaction mixture was warmed to room temperature and then stirred for 16 hours. The reaction mixture was neutralized (about pH 7) using NaHCO3 at 0 C. The solids were filtered off and the filtrate was evaporated under vacuum to get crude compound. This crude compound was washed with EtOAc (10 mL) to afford Int-2 (5.0 g, 94%) as white solid. Mass (m/z): 212 [M++1]. To a stirred suspension of Int-3 (1.08 g, 4.7 mmol) in DMF (10 mL) was added Int-2 (2.5 g, 11.8 mmol), followed by K2CO3 (1.94 g, 14.0 mmol) at room temperature. The resulting mixture was heated to 100 C. and then stirred for 16 hours. The reaction mixture was cooled to room temperature, diluted with ice cold water (100 mL) and stirred for 15 minutes. The precipitated solid was filtered off, washed with water (3×10 mL) and dried under vacuum to afford Int-4 (0.7 g, 16%) as solid. Mass (m/z): 378 [M++1]. To a stirred solution of Int-4 (0.6 g, 1.6 mmol) in methanol (8 mL) and THF (8 mL) was added lithium hydroxide (0.33 g, 7.9 mmol) at room temperature, followed by water (4 mL). The resulting mixture was stirred at room temperature for 16 hours. The volatiles were concentrated under reduced pressure, diluted with water (10 mL) and acidified to about pH 5 using 3 N HCl at 0 C. The precipitated solid was filtered off, washed with water (2×5 mL) and dried under vacuum to provide Int-5 (0.46 g, 80%) as solid. Mass (m/z): 364 [M++1]. To a stirred solution Int-5 (0.6 g, 1.65 mmol) in DMF (10 mL) was added HOBt (0.22 g, 1.65 mmol), EDCI (0.78 g, 4.12 mmol), NH2OTHP (0.38 g, 3.3 mmol) and N-ethyldiisopropylamine (0.7 mL, 4.12 mmol) at 0 C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and evaporated under vacuum. The crude material was purified over silica gel column chromatography eluting with 3% MeOH/DCM to afford Int-6 (0.35 g, 45.7%) as solid. Mass (m/z): 463 [M++1].

Reference： [1]Patent: US2010/29638,2010,A1 .Location in patent: Page/Page column 87

35
[ 1209996-45-1 ]
[ 455-87-8 ]
[ 1209996-46-2 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate;	To a solution of 4-amino-3-fluorobenzalphaic acid (0.703g, 4.53mmol), N-tert- butyl-2-{piperaztn-1-y[methy.)thiazo.e-4-carboxamide (1.28g, 4.53mmol) and triethyiamine (0.459g, 4.53mmoi. 0.63OmL) in dichloromethane was added 1- propanephosphonic acid cyclic anhydride (2.88g5 4.5SnImOi, 2,7OmL, 50% solution in ethyl acetate), The reaction was concentrated under reduced pressure and the residue was taken up in ethyl acetate, washed with sodium bicarbonate (x3) and brine. The organic phase was concentrated under reduced pressure to afford the title compound (0.87g). MS (ESI) m/z 420.3 [M+H]+

Reference： [1]Patent: WO2010/25179,2010,A1 .Location in patent: Page/Page column 16-17

36
[ 1209996-51-9 ]
[ 455-87-8 ]
[ 1209996-53-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;	To a solution of 4~amino-3~fiuorobenzoic acid (0.883g, 5.69mmol), N-tert- butyl-5-(piperazin-1-ylmethyl)furan-2~carboxamide (1.5Ig5 5.69mmol) and triethyl- amine (0.576g, 5.69mmol, 0.791 mL) in dichlorometha?e was added 1-propanephos- phonic acid cyclic anhydride (3.62g, 5,69mmol, 3.39mL, 50% solution in ethyl acetate). The reaction was stirred for 2 hours then concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed with sodium bicarbonate, water and brine. The organic phase was concentrated under reduced pressure to give the title compound (0.93g). MS (ESi) m/z 403.6 [M+Hf

Reference： [1]Patent: WO2010/25179,2010,A1 .Location in patent: Page/Page column 18-19

37
[ 124-13-0 ]
[ 455-87-8 ]
[ 1344028-83-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With alpha-picoline-borane; In methanol; at 20℃;	General procedure: 4-amino-3-methoxybenzoic acid (4b) (~3 mmol) was dissolved in 15 mL methanol with alpha-picoline-borane (1.1 mol eq) and butanal (1.1 mol eq). The reaction was stoppered with a vent needle and stirred overnight at room temperature. After 16-24 h, solvent was removed in vacuo, 10 mL 1 M HCl was added to the flask, and stirred at room temperature for an additional 30 min. The pH was adjusted to neutral using NaHCO3 and the intermediate product was extracted with ethyl acetate (2 60 mL). The organic layer was washed with brine (1x 45 mL), dried with magnesium sulfate, filtered, removed in vacuo, and subsequently purified via column chromatography with 30% ethyl acetate in hexane to yield 3 (84%).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6417 - 6419

38
[ 455-87-8 ]
[ 1344029-01-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6417 - 6419

39
[ 455-87-8 ]
C₁₈H₂₄FN₃O [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 6417 - 6419

40
[ 455-87-8 ]
[ 506-59-2 ]
[ 536748-06-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With N-ethyl-N,N-diisopropylamine; 1,1'-carbonyldiimidazole; In acetonitrile; at 0 - 20℃; for 0.5h;Product distribution / selectivity;	Method B4-Amino-3-fluorobenzoic acid (CASNo.455-87-8, 221.85 g, 1.402 mol) was suspended in acetonitrile (1.80 L). To this suspension was added di(lH-imidazol-l -yl)methanone (250 g, 1.542 mol) at room temperature and the reaction bubbled and became a clear solution. The reaction mixture was cooled down to 0 C then N-ethyl-N-isopropylpropan-2-amine (0.416 L, 2.383 mol) was added followed by dimethylamine hydrochloride (137 g, 1.682 mol). The reaction mixture was allowed to stir at room temp for 30 min. LCMS showed the reaction was complete. The solvent was removed under reduced pressure. The residue was taken up in DCM (2 L) and washed with 1 M HC1 (2 x 2 L). The separation of the layers was difficult to observe due to the presence of some solids. The resulting mixture was filtered and the layers separated. The aqueous layer was back extracted with DCM (2 x 2 L). The organic layers were combined and dried (Na2S04), filtered by vacuum filtration through a sintered glass funnel and solvent was removed under reduced pressure to give 270 g of a dark brown solid. To this solid was added a mixture of 2:1 toluene :hexane (2000 mL) and the mixture was heated to 45 C to form a slurry. The resulting precipitate was collected by vacuum filtration and washed with 1 : 1 toluene:hexane (2 L) and with hexane (2 L). The resulting solid was dried (vacuum oven). The filtrate contained some of the product and the solvent was removed under reduced pressure and the slurry was repeated. The first batch was 196 g and the 2nd batch contained 32.528 g. Both batches were the same by NMR and LC/MS and were combined to give 4-amino-3-fluoro-N,N- dimethylbenzamide (CASNo.536748-06-8, 228.93 g, 1.257 mol, 90% yield) as a light brown solid.1.. NMR (400 MHz, DMSO-i ) delta ppm 2.9 (s, 6H), 5.5 (s, 2H), 6.8 (t, 1H), 7.0 (dd, 7=8.21, 1.9 Hz, 1H), 7.1 (dd, 7=12.13, 1.8 Hz, 1H). Exact mass calculated for CsHnFNzO 182.2, found: LCMS m/z = 183.2 [M+H]+).

Reference： [1]Patent: WO2012/40279,2012,A1 .Location in patent: Page/Page column 89-90

41
[ 455-87-8 ]
[ 1369872-08-1 ]

Reference： [1]Patent: WO2012/40279,2012,A1

42
[ 455-87-8 ]
[ 1369872-11-6 ]

Reference： [1]Patent: WO2012/40279,2012,A1

43
[ 455-87-8 ]
[ 1369872-12-7 ]

Reference： [1]Patent: WO2012/40279,2012,A1
[2]Patent: WO2012/40279,2012,A1

44
[ 455-87-8 ]
[ 1370016-94-6 ]

Reference： [1]Patent: WO2012/40279,2012,A1

45
[ 1561811-19-5 ]
[ 455-87-8 ]
[ 1561811-54-8 ]

Yield	Reaction Conditions	Operation in experiment
55%	With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In 1,4-dioxane; for 17h;Inert atmosphere; Reflux;	General procedure: In a 25mL reaction vial, Pd(PPh3)2Cl2 (19mg, 0.027mmol) and 2N Na2CO3 solution (0.27mL, 0.54mmol) were added to a solution of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (55mg, 0.27mmol) and 12 (50mg, 0.27mmol) in dioxane (5mL). The mixture was stirred at 70C for 16h under N2 atmosphere. The reaction mixture was cooled to room temperature and filtrated. The filtrate was diluted with H2O (100mL) and then extracted with EtOAc, and the organic layer was dried over anhydrous Na2SO4, After filtration, the filtrate was evaporated and purified by chromatography (petroleum ether/EtOAc, 5:1) to give the product 20 as a yellow solid (55mg, 88%).

Reference： [1]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 1429 - 1440

46
[ 455-87-8 ]
[ 1414882-26-0 ]

Reference： [1]Patent: WO2014/66506,2014,A2

47
[ 455-87-8 ]
[ 1414880-75-3 ]

Reference： [1]Patent: WO2014/66506,2014,A2

48
[ 455-87-8 ]
[ 56-81-5 ]
[ 1061650-25-6 ]

Yield	Reaction Conditions	Operation in experiment
28%	With sulfuric acid; sodium 3-nitrobenzenesulfonate; In water; at 120 - 140℃; for 1.5h;	4-Amino-3-fluorobenzoic acid (C-1, 25.0g, 161.3 mmol) and sodium 3-nitrobenzenesulfonate (43.2 g, 192.0 mmol) wereadded to the mixture of H2SO4 (60 ml) and water (24 ml).When the mixture was heated to 120C, glycerin (44.2 g, 480.4 mmol) was addedslowly, then the reaction was stirred at 140C for 1.5h. After cooled to rt,the mixture was poured to a large amount of ice water, concentrated ammoniawater was added to adjust to pH=5-6, thenfiltrated, washed with water and dried, then the crude product was purified byflash column chromatography to afford 8-fluoroquinoline-6-carboxylic acid aspale white solid (C-2, 8.7 g, 28%yield). LC-MS (ESI): [M+H]+=192. 1H NMR (400 MHz, DMSO-d6) delta 13.49 (brs, 1H), 9.08(s, 1H), 8.66 (d, J=8.4 Hz, 1H),8.54-8.53 (m, 1H), 7.93 (d, J=11.2Hz, 1H), 7.76-7.72 (m, 1H).
28.2%	With sulfuric acid; sodium 3-nitrobenzenesulfonate; In water; at 120 - 140℃; for 1.5h;	The starting <strong>[455-87-8]3-fluoro-4-aminobenzoic acid</strong> D-1 (25 g, 0.16 mol) And the catalyst sodium 3-nitrobenzenesulfonate (43.2 g, 0.192 mol) were added to a mixed solution of concentrated sulfuric acid (60 mL) and water (24 mL) After heating to an internal temperature of 120 C, glycerol (44.2 g, 0.48 mol, 3 eq) After the addition is complete, the temperature is raised to 130-140 DEG C and reacted for 1.5 hours, and then cooled. The reaction was poured into crushed ice, concentrated ammonia water to adjust the pH to 5 ~ 6, the precipitated solid was filtered off, washed with water, After drying, column chromatography gave 8.7 g of compound D-2 as an off-white solid in a yield of 28.2%
	With sulfuric acid; nitrobenzene; at 150℃; for 3h;	To a 0 C mixture of glycerol (36.8 g, 0.4 mol), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> 1 (15.5 g, 0.1 mol) and nitrobenzene (7.4 g, 0.06 mol) was concentrated sulfuric acid (17.4 mL). The mixture was then stirred at 150 C for 3 hours. The resulting solution was cooled down to the room temperature and diluted with water (100 mL).It was then neutralized with saturated aqueous Na2CO3 solution to adjust pH = 4. The precipitated solid was collected by filtration and washed with water (20 mL) and methanol (20 mL), the residue was dried to obtain the crude product 2 (7 g, 3 7%), which was used in the next step without further purification. LRMS (M-Hj m/z: cacld. 190.04, found 190.01; ?H-NMR (DMSO-d6): 13.45 (br, 1H), 9.07 (dd,1H), 8.66 (d, 1H), 8.53 (s, 1H), 7.93 (dd, 1H), 7.74 (dd, 1H).

With sulfuric acid; sodium 3-nitrobenzenesulfonate; at 140℃; for 20h;

To a mixture of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (380 g, 2.45 mol, 1.0 eq), glycerol (451 g, 4.90 mol, 2.0 eq) and sodium 3-nitrobenzenesulfonate (829 g, 3.68 mol, 1.5 eq) was added 70% H2S04 (1420 mL) slowly. The reaction mixture was then heated at 140 C for 20 h. The mixture was cooled to rt, poured into ice-water (5 L) and adjusted to pH 3~4 with 25% aqueous NaOH. The resulting precipitate was collected by filtration and dried at 90 C overnight to give 8-fluoroquinoline-6-carboxylic acid.

Reference： [1]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 4281 - 4290
[2]Patent: CN105968115,2016,A .Location in patent: Paragraph 0457-0459
[3]Patent: WO2014/66506,2014,A2 .Location in patent: Page/Page column 105/1; 106
[4]Patent: WO2019/142053,2019,A2 .Location in patent: Paragraph 00133

49
[ 455-87-8 ]
[ 1608997-32-5 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; sodium nitrite; In water; at 0 - 2℃; for 0.5h;	General procedure: Aniline derivative (1 eq) was mixed with iced water and/or absolute EtOH (2 mL by mmol of reagent) and stirred at 0 C then hydrochloric acid 37% (4 eq) was added dropwise rapidly. Sodium nitrite (1.1 eq or 1.3 eq aniline substituent depending) was added solid or in solution (H2O/EtOH 1 M) and the reaction mixture was stirred at 0-2 C for 30 min. The solvent was removed carefully under reduced pressure without heating and can be used without further purification.

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 78,p. 236 - 247

50
[ 455-87-8 ]
C₂₄H₁₅F₂N₅O₁₁S₂ [ No CAS ]

Reference： [1]European Journal of Medicinal Chemistry,2014,vol. 78,p. 236 - 247

51
[ 455-87-8 ]
[ 152120-54-2 ]
[ 1427753-38-5 ]

Yield	Reaction Conditions	Operation in experiment
669 mg	In tetrahydrofuran; at 20℃; for 72h;	Preparation Example 65 To a solution of <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (500 mg) in tetrahydrofuran (10. 0 mL) was added N,N'-bis-tert-butoxycarbonyl-1-guanylpyrazole (1.20 g), followed by stirring at room temperature for 3 days. The reaction suspension was concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 4-[N',N'-bis(tert-butoxycarbonyl)carbamimidamido]-3-fluorobenzoic acid (669 mg).

Reference： [1]Patent: EP2757093,2014,A1 .Location in patent: Paragraph 0198

52
[ 455-87-8 ]
[ 108-24-7 ]
[ 713-11-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With pyridine; at 60℃;	Amixture of<strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (233 mg, 1.5 mmol) and acetic anhydride(459 mg, 425 ml, 4.5 mmol) in anhydrous pyridine (7 ml) was heated at60C overnight. Then, themixture was concentrated in vacuo. Over theresidue, water (6 ml) was added and then the aqueous solution wasacidified with HCl 2N until pH 5 1. The product precipitated and wascollected by filtration and dried providing 281 mg (95%) of compound4-acetamido-3-fluorobenzoic acid as a slightly brownish solid. 1HNMR(CD3OD, 400 MHz) d 2.20 (s, 3H), 7.74 (dd, 1H, J 5 11.5, J 5 1.8), 7.80(doublet of doublets of doublets, 1H, J 5 8.5, J 5 1.8, J 5 0.9), 8.20(dd, 1H, J 5 8.1, J 5 8.1); 13C NMR (CD3OD, 100 MHz) d 24.2, 117.3(d, 21.1), 123.6, 127.1 (d, 3.1), 128.2, 132.2 (d, 11.3), 153.8 (d, 243.9),167.8 (d, 2.6), 171.5; 19F NMR (CD3OD, 376 MHz) d -128.6.

Reference： [1]Molecular Pharmacology,2015,vol. 87,p. 338 - 348

53
[ 455-87-8 ]
5-chloro-4-(1-(phenylsulfonyl)-1-indol-3-yl)-N-(piperidin-4-yl)pyrimidin-2-amine [ No CAS ]
(4-amino-3-fluorophenyl)(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 23℃;	(4-amino-3-fluorophenyl)(4-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)piperidin-1-yl)methanoneA solution of 5-chloro-4-(l-(phenylsulfonyl)-lH-indol-3-yl)-N-(piperidin-4-yl)pyrimidin-2- amine (lOOmg, 0.21mmol), <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (33mg, 0.21mmol), HBTU (162mg, 0.43mmol) and DIPEA (0.1 lmL, 0.64mmol) in DCM (1.42mL) was stirred overnight at 23C before being concentrated under reduced pressure. The residue was purified by flash chromatography (Hex/EtOAc 0 to 100% gradient) and afforded the title compound (127mg, 0.21mmol, 100%) as a white solid.

Reference： [1]Patent: WO2015/58163,2015,A2 .Location in patent: Paragraph 208

54
[ 455-87-8 ]
(1R,3S)-N₁-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine hydrochloride [ No CAS ]
4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	4-amino-N-((1S,3R)-3-(5-chloro-4-(1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-ylamino)cyclohexyl)-3-fluorobenzamide[00401] A solution of (1R,3S )-N1-(5-chloro-4-( 1-(phenylsulfonyl)-1H-indol-3-yl)pyrimidin-2-yl)cyclohexane-1,3-diamine.HCl prepared as in Example 1 (150 mg, 0.29 mmol)and <strong>[455-87-8]4-amino-3-fluorobenzoic acid</strong> (45 mg, 0.29 mmol) in DMF (1.9 mL) was treated with HBTU (219 mg, 0.58 mmol) and DIPEA (0.870 mmol). The resulting mixture was stirred overnight at rt and diluted with MeTHF (30 mL) and saturated NaHCO3 (15 mL). The layers were separated and the aqueous layer was extracted with MeTHF (2 x 30 mL). The combined organic layerswere dried over MgSO4 , filtered and evaporated to dryness. The residue was purified by SiO2 chromatography (DCM/EtOAc 0 to 100% gradient) and afforded the title compound (178 mg, 0.287 mmol, 99%) as a pale yellow solid.
99%	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	[272j A solution of (IR.3 S)-N1 -(5-chloro-4-(i -(phenylsulfonvl)-iFi-indol-3-vi)pyrimidin-2- yi)cyclohexane-1,3-diamineHCI prepared as in example 3 (150 mg, 0.29 mrnol) and 4amino-3- fluorobenzoic acid (45 mg, 0.29 rnrnol) in DMF (1.9 rnL) was treated with F[BTU (219 rng, 0.58 rnmol) and DIPEA (150 iL, 0.870 mrnoi). The resulting mixture was stirred overnight at rt and diluted with MeTF[F (30 mL) and saturated NaHCO3 (15 mL). The layers were separated and theaqueous layer was extracted with MeTF[F (2 x 30 rnL). The combined organic layers were dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by Si02 chromatography (DCMIEtOAc 0 to 100% gradient) to affordthe title compound (178 mg, 0.287 rnrnol, 99%) as a pale yellow solid.

Reference： [1]Patent: WO2015/58140,2015,A1 .Location in patent: Paragraph 00401
[2]Patent: WO2016/58544,2016,A1 .Location in patent: Paragraph 271; 272

55
[ 455-87-8 ]
N-[4-(2-ethyl-butyramido)-3-fluorobenzoyl]homocycloleucyl-glycinonitrile [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6928 - 6937

56
[ 455-87-8 ]
C₁₃H₁₅ClFNO₂ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6928 - 6937

57
[ 455-87-8 ]
N-(4-amino-3-fluorobenzoyl)piperidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6928 - 6937

58
[ 2736-40-5 ]
[ 455-87-8 ]
4-(2-ethyl-butyramido)-3-fluorobenzoic acid [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6928 - 6937

59
[ 13939-69-0 ]
[ 455-87-8 ]
N-(4-amino-3-fluorobenzoyloxycarbonyl)piperidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6928 - 6937

60
[ 13939-69-0 ]
[ 455-87-8 ]
N-(4-amino-3-fluorobenzoyl)piperidine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 6928 - 6937

61
[ 455-87-8 ]
[ 146019-45-6 ]

Yield	Reaction Conditions	Operation in experiment
48.4%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;	To a suspension of lithium aluminum hydride (I .835 g, 48.3 rnmol) in THF (20 mL) was added dropwise at 0C a solution of 4-arnino-3-fiuorobenzoic acid (5 g, 32.2 mrnol) in THF (20 mL). The reaction mixture was stirred at room temperature overnight. The mixturewas then cooled down to 00 C, quenched with ethyl acetate (30 rnL) and water (10 mL). The slurry obtained was filtered through Celite and washed with ethyl acetate (50 mL). The aqueous layer was separated and organic layer was dried, filtered and concentrated in vacuum to dryness to give crude product. The crude was purified by flash column chromatography (silica gel 80 g, eluting with 0-100% ethyl acetate in hexane) to furnish (4-Arnino-3-fluorophenyl)methanol (15b) (2.2 g, 48.4 % yield) as a tan solid; ?H NMR (300MHz, DMSO-d6) 6.91 (dd,J 12.5, 1.8 Hz, III), 6.81 (dd,J 8.1, 1.8 Hz, 1H), 6.70(dd,J 9.3, 8.0 Hz, I H), 5.03 - 4.93 (m, 3H), 4.31 (d, J = 5.5 Hz, 2H); MS (ES+) 142.0 (M+ 1);(ES-) 140.0 (M-1).
44%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 45℃; for 3.25h;	In a 500 mL round bottom single-necked flask,Add fourLithium aluminum hydride(4.8 g, 129 mmol, 2 Oeq.)And 250 mL of tetrahydrofuran, and stirred at 0 C15 minutes.A solution of <strong>[455-87-8]3-fluoro-4-aminobenzoic acid</strong> (10 g, 64.5 mmol, 1. Oeq) in tetrahydrofuran solution was slowly added at 0 C and the reaction was carried out at 45 C for 3 hours.After completion of the reaction, 4 mL of water was slowly added to the reaction solution for quenching,The filtrate was extracted with ethyl acetate (50 mL of X 3)The organic phase was washed with saturated sodium chloride solution (30 mL)Dried over anhydrous sodium sulphate and dried under reduced pressure to give a red liquid (4 g, 44%).

Reference： [1]Patent: WO2015/134998,2015,A1 .Location in patent: Page/Page column 151; 152
[2]Patent: CN105294567,2016,A .Location in patent: Paragraph 0037-0038
[3]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334

62
[ 455-87-8 ]
1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/134998,2015,A1

63
[ 455-87-8 ]
1-(3-cyanophenyl)-N-(2-fluoro-4-formylphenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/134998,2015,A1

64
[ 455-87-8 ]
1-(3-cyanophenyl)-N-(2-fluoro-4-(hydroxy(phenyl)methyl)phenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/134998,2015,A1

65
[ 455-87-8 ]
1-(3-cyanophenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl )-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/134998,2015,A1

66
[ 455-87-8 ]
1-(3-(aminomethyl)phenyl)-N-(4-((cyclopropylmethoxy)(phenyl)methyl)-2-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/134998,2015,A1

67
[ 455-87-8 ]
tert-butyl 3-(5-(2-fluoro-4-(hydroxy(phenyl)methyl)phenylcarbamoyl)-3-(trifluoromethyl )-1H-pyrazol-1-yl)benzylcarbamate [ No CAS ]

Reference： [1]Patent: WO2015/134998,2015,A1

68
[ 455-87-8 ]
[ 1028745-45-0 ]