[ CAS No. 399-96-2 ] {[proInfo.proName]}

Name: 399-96-2|4-Amino-2-fluorophenol|98%
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Quality Control of [ 399-96-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 399-96-2 ]

Product Details of [ 399-96-2 ]

CAS No. :	399-96-2	MDL No. :	MFCD00671760
Formula :	C₆H₆FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MXJQJURZHQZLNN-UHFFFAOYSA-N
M.W :	127.12	Pubchem ID :	2735918
Synonyms :

Calculated chemistry of [ 399-96-2 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	32.83
TPSA :	46.25 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 :	Yes
Log Kp (skin permeation) :	-6.37 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.17
Log Po/w (XLOGP3) :	0.99
Log Po/w (WLOGP) :	1.54
Log Po/w (MLOGP) :	1.24
Log Po/w (SILICOS-IT) :	1.09
Consensus Log Po/w :	1.21

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.75
Solubility :	2.29 mg/ml ; 0.018 mol/l
Class :	Very soluble
Log S (Ali) :	-1.55
Solubility :	3.58 mg/ml ; 0.0282 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.7
Solubility :	2.52 mg/ml ; 0.0199 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.0

Safety of [ 399-96-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 399-96-2 ]

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

Upstream synthesis route of [ 399-96-2 ]
Downstream synthetic route of [ 399-96-2 ]

[ 399-96-2 ] Synthesis Path-Upstream 1~11

1
[ 399-96-2 ]
[ 2105-94-4 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178

2
[ 399-96-2 ]
[ 394-50-3 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178

3
[ 403-19-0 ]
[ 399-96-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen In methanol at 20℃;	A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) were stirred under a H₂atmosphere at 50 psi at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100percent), as a solid which was used without further purification. ¹H NMR (DMSO-d₆) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS (ESI⁺) m/z 128 (M+H)⁺.
100%	With hydrogen In methanol at 20℃;	A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H₂ atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite.(R). and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100percent), as a solid which was used without further purification. ¹H NMR (DMSO-d₆) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI⁺) m/z 128 (M+H)⁺.
100%	With hydrogen In methanol at 20℃;	B) 2-Fluoro-4-aminophenol; A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H₂atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite.(R). and the filtrate concentrated in vacuo to afford the desired compound (1.00 g, 100percent), as a solid which was used without further purification. ¹H NMR (DMSO-d₆) δ 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI⁺) m/z 128 (M+H)⁺.

99%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	[0223] To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10percent). The reaction was stirred at rt overnight in a H₂ atmosphere. The mixture was filtered through a pad of CELITE^®, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99percent). MS (ESI, pos. ion) m/z: 128.1 [M+H]⁺.
99%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	Step 1) 4-amino-2-fluorophenol To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10percent). The reaction was stirred at rt overnight in a H₂ atmosphere. The mixture was filtered through a pad of CELITE®, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99percent). MS (ESI, pos. ion) m/z: 128.1 [M+H]⁺.
96%	With hydrogen In ethanol; water for 0.5 h;	A mixture of 2-fluoro-4-nitrophenol (5.78 g, 36.8 mmol) and palladium on carbon (10percent, 50percent water, Degussa type, 0.525 g, 0.247 mmol) in 100 mL EtOH was shaken in a Parr shaker at 40 psi for 30 min. The reaction mixture was filtered though Celite.(R)., washing with additional EtOH. The filtrate and washings were combined, concentrated, and dried under high vacuum to give the title compound (4.47 g, 96percent) as a brown solid. Exact mass calculated for C₆H₆FNO: 127.04, found: LCMS mlz = 128.0 [M+H]⁺; ^lU NMR (400 MHz, DMSO- ) δ ppm 4.69 (s, 2H), 6.19-6.22 (m, 1H), 6.33-6.37 (m, 1H), 6.60-6.65 (m, 1H), 8.54 (s, 1H).
90%	With hydrogen In methanol at 20℃;	35 (1 .19g, 7.57mmol) was dissolved in methanol (40mL) and hydrogenated over 10percent Pd/C (125 mg), at rt and atmospheric pressure. The suspension was filtered over celite and washed with excess eOH. Removal of excess solvent under reduced pressure afforded 867 mg of light brown solid.
87%	With hydrogen In methanol at 20℃; for 3 h;	4-Amino-2-fluorophenol (4); To a degassed solution of 4-nitro-2-fluorophenol (3) (16 g, 102 mmol) in MeOH (150 mL) was added palladium on charcoal (10percent) Degussa type (3.0 g, 2.82 mmol). The mixture was stirred at r.t. under hydrogen atmosphere for 3h, filtered through a celite pad and evaporated under reduced pressure. The residue was triturated with Et₂O (50 mL) to afford compound 4 (11.264 g, 87percent yield) as a dark-brown solid. MS (m/z): 128.1 (M+H). ¹H NMR (400 MHz, DMSO-de) δ (ppm): 8.57 (s, IH), 6.62 (dd, J = 10.0, 8.4 Hz, IH), 6.34 (dd, J = 13.4, 2.6 Hz, IH), 6.20 (ddd, J = 8.6, 2.6, 1.2 Hz, IH), 4.67 (s, 2H).
85%	With hydrogen In ethanol at 20℃; for 3 h;	Preparation 26 4-amino-2-fluoro -phenol; A solution of 2-fluoro-4-nitro-phenol (400 mg, 2.55 mMol) and ethanol (6 ml_) was treated with 10percent Pd/C (42.6 mg). The reaction mixture was hydrogenated for 3 hours at 40 psi at room temperature. The reaction mixture was filtered through a pad of Arbocel .(R). with ethanol and then evaporated to dryness to give a dark solid (248mg, 85percent).¹H NMR (400MHz, CD₃OD) δ =6.29-6.31(d, 1 H), 6.39-6.43 (dd, 1 H), 6.58-6.62 (m, 1 H). GC/MS: 1.66 mins m/z (Cl) = 128 [MH+]
81%	With ammonium chloride; zinc In tetrahydrofuran; methanol at 0 - 20℃;	To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 0° C. was added zinc dust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a thin pad of Celite.(R). with methanol and the filtrate was concentrated in vacuo to give 4-amino-2-fluorophenol as a brown solid which was used without further purification (656 mg, 81percent). 3-(4-Fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 197 mg, 1.00 mmol) was dissolved in dimethylformamide (4 mL). Triethylamine (140 μL, 1.00 mmol) was added and the solution was cooled to 0° C. 4-Amino-2-fluorophenol (Step A of Example 19, 127 mg, 1.00 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69percent) as a white solid. ¹H NMR (CD₃OD) δ 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08-6.99 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS (ESI⁺) m/z 307.44 (M+H)⁺.
55.1%	With iron; ammonium chloride In ethanol; water at 20℃; for 0.5 h;	To a solution of 2-fluoro-4-nitrophenol (1.57 g, 10 mmol) in EtOH (50 mL) and H₂0 (18 mL) was added Fe (2.24 g, 40 mmol) and NH₄C1 (4.24 g, 80 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was added Η₂0 (50 mL) and extracted by EtOAc (60 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na₂S04 and concentrated in vacuo. The residue was beaten by PE/EtOAc (v/v, 10 mL/15 mL), filtered to give the title compound as a brown solid (700 mg, 55.1percent).LC-MS (ESI, pos, ion): 128.3 [M+H]⁺;H NMR (400 MHz, DMSO-Λ) δ (ppm): 8.56 (s, 1H), 6.62 (dd, J = 10.0, 8.6 Hz, 1H), 6.34 (dd, J= 13.4, 2.6 Hz, 1H), 6.24-6.15 (m, 1H), 4.66 (s, 2H).
55.1%	With water; iron; ammonium chloride In ethanol at 20℃;	Iron powder (2.24 g, 40 mmol) and NH4Cl (4.24 g, 80 mmol)Add to 2-fluoro-4-nitrophenol (1.57g, 10mmol)EtOH (50mL)And H2O (18mL) solution,The reaction was stirred at room temperature overnight.The reaction solution was filtered through silica gel.The filtrate was concentrated under reduced pressure.The residue obtained was added to water (50 mL).Extract and separate the organic phase with EtOAc (60 mL x 2).Combine the resulting organic phases,Wash with saturated brine,After drying with anhydrous sodium sulfate,Concentrated under reduced pressure,The residue obtained was beaten in a mixed solvent of PE/EtOAc (v/v, 10 mL / 15 mL).filter,The title compound (700 mg, 55.1percent) was obtained.
38%	With hydrogen In ethanol at 20℃; for 16 h;	2-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10percent on activated carbon, 31 mg), and EtOH (20 mL) were combined and stirred under atmospheric H2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated, and purified by preparative thin layer chromatography (30percent EtOAc in hexanes) to afford 4-amino-2-fluorophenol as a tan solid of sufficient purity for subsequent transformations (152 mg, 1.20 mmol; 38percent yield).

Reference： [1] Patent: US2005/245530, 2005, A1, . Location in patent: Page/Page column 35-36
[2] Patent: US2006/241104, 2006, A1, . Location in patent: Page/Page column 14
[3] Patent: US2007/78140, 2007, A1, . Location in patent: Page/Page column 25-26
[4] Patent: WO2014/22116, 2014, A2, . Location in patent: Paragraph 0223
[5] Patent: US2015/37280, 2015, A1, . Location in patent: Paragraph 0445; 0446
[6] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178
[7] Patent: WO2012/145361, 2012, A1, . Location in patent: Page/Page column 168
[8] RSC Advances, 2013, vol. 3, # 11, p. 3697 - 3706
[9] Patent: WO2012/4549, 2012, A1, . Location in patent: Page/Page column 35
[10] Patent: WO2009/26720, 2009, A1, . Location in patent: Page/Page column 93; 94
[11] Patent: WO2009/144632, 2009, A1, . Location in patent: Page/Page column 66
[12] Patent: US2005/245530, 2005, A1, . Location in patent: Page/Page column 35
[13] Patent: WO2015/164161, 2015, A1, . Location in patent: Paragraph 0295
[14] Patent: CN104974162, 2018, B, . Location in patent: Paragraph 0609; 0610
[15] Patent: WO2005/121125, 2005, A1, . Location in patent: Page/Page column 45-46
[16] Journal of the Chemical Society, 1949, p. 642,645
[17] Bioorganic and Medicinal Chemistry, 2006, vol. 14, # 19, p. 6525 - 6538
[18] Synthetic Communications, 2013, vol. 43, # 21, p. 2949 - 2954

4
[ 366-99-4 ]
[ 144-55-8 ]
[ 399-96-2 ]

Reference： [1] Patent: US4861799, 1989, A,

5
[ 367-12-4 ]
[ 399-96-2 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178

6
[ 402-67-5 ]
[ 399-96-2 ]

Reference： [1] Comptes Rendus Hebdomadaires des Seances de l'Academie des Sciences, 1964, vol. 259, p. 3030 - 3032
[2] Bulletin de la Societe Chimique de France, 1966, p. 1848 - 1858

7
[ 1490139-07-5 ]
[ 399-96-2 ]

Reference： [1] Asian Journal of Chemistry, 2013, vol. 25, # 15, p. 8685 - 8689

8
[ 455-93-6 ]
[ 399-96-2 ]

Reference： [1] Journal of the Chemical Society, 1949, p. 642,645

9
[ 399-96-2 ]
[ 437-83-2 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178

10
[ 399-96-2 ]
[ 320-76-3 ]

Reference： [1] Bulletin de la Societe Chimique de France, 1980, vol. 2, # 3-4, p. 175 - 178

11
[ 399-96-2 ]
[ 100-39-0 ]
[ 168268-00-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃;	p-hydroxy-3-fluoroaniline (1.0 g, 7.87 mmol) was dissolved in 10 mL of anhydrous DMF, cooled to 0° C., then potassium tert-butoxide (0.88 g, 7.87 mmol) was added thereto, after stirring for 10 min, benzyl bromide (1.35 g, 7.87 mmol) was added therein, and the reaction was monitored by TLC. After the reaction is completed, the resultant was extracted with EA, then washed with saturated NaHCO₃ and saturated brine, dried over anhydrous Na₂SO₄ and concentrated to give the crude compound 37, which was purified by column chromatography to give a colorless liquid, yield 52percent. ¹H NMR (CDCl₃, 300 MHz): δ 7.41-7.28 (m, 5H), 6.91 (dd, 1H), 6.46 (dd, 1H), 6.32 (m, 1H), 4.97 (s, 2H), 4.98 (s, 2H).

Reference： [1] Patent: US2018/244667, 2018, A1, . Location in patent: Paragraph 0083

[ 399-96-2 ] Synthesis Path-Downstream 1~62

1
[ 403-19-0 ]
[ 399-96-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With hydrogen;platinum(IV) oxide; In methanol; at 20℃; under 2585.81 Torr;	A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 ml) were stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) delta 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS (ESI+) m/z 128 (M+H)+.
100%	With hydrogen;platinum(IV) oxide; In methanol; at 20℃; under 2585.81 Torr;	A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to afford the title compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) delta 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.
100%	With hydrogen;platinum(IV) oxide; In methanol; at 20℃; under 2585.81 Torr;	B) 2-Fluoro-4-aminophenol; A mixture of platinum oxide (0.010 g) and 2-fluoro-4-nitrophenol (Aldrich, 1.24 g, 7.78 mmol, 1.0 eq) in MeOH (100 mL) was stirred under a H2 atmosphere at 50 psi at room temperature. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to afford the desired compound (1.00 g, 100%), as a solid which was used without further purification. 1H NMR (DMSO-d6) delta 8.57 (s, 1H), 6.46-6.47 (m, 1H), 6.33-6.46 (m, 1H), 6.19-6.21 (m, 1H), 4.79 (s, 2H); MS(ESI+) m/z 128 (M+H)+.

> 99%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	[0223] To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10%). The reaction was stirred at rt overnight in a H2 atmosphere. The mixture was filtered through a pad of CELITE, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99%). MS (ESI, pos. ion) m/z: 128.1 [M+H]+.
> 99%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃;	Step 1) 4-amino-2-fluorophenol To a solution of 2-fluoro-4-nitrophenol (5.0 g, 31.8 mmol) in methanol (200 mL) was added Pd/C (1.0 g, 10%). The reaction was stirred at rt overnight in a H2 atmosphere. The mixture was filtered through a pad of CELITE, then washed with MeOH (5 mL). The filtrate was concentrated in vacuo to give the title compound as a brown solid (4.02 g, >99%). MS (ESI, pos. ion) m/z: 128.1 [M+H]+.
96%	With hydrogen;palladium 10% on activated carbon; In ethanol; water; under 2068.65 Torr; for 0.5h;	A mixture of 2-fluoro-4-nitrophenol (5.78 g, 36.8 mmol) and palladium on carbon (10%, 50% water, Degussa type, 0.525 g, 0.247 mmol) in 100 mL EtOH was shaken in a Parr shaker at 40 psi for 30 min. The reaction mixture was filtered though Celite, washing with additional EtOH. The filtrate and washings were combined, concentrated, and dried under high vacuum to give the title compound (4.47 g, 96%) as a brown solid. Exact mass calculated for C6H6FNO: 127.04, found: LCMS mlz = 128.0 [M+H]+; lU NMR (400 MHz, DMSO- ) delta ppm 4.69 (s, 2H), 6.19-6.22 (m, 1H), 6.33-6.37 (m, 1H), 6.60-6.65 (m, 1H), 8.54 (s, 1H).
90%	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; under 760.051 Torr;	35 (1 .19g, 7.57mmol) was dissolved in methanol (40mL) and hydrogenated over 10% Pd/C (125 mg), at rt and atmospheric pressure. The suspension was filtered over celite and washed with excess eOH. Removal of excess solvent under reduced pressure afforded 867 mg of light brown solid.
87%	With hydrogen;palladium 10% on activated carbon; In methanol; at 20℃; for 3h;	4-Amino-2-fluorophenol (4); To a degassed solution of 4-nitro-2-fluorophenol (3) (16 g, 102 mmol) in MeOH (150 mL) was added palladium on charcoal (10%) Degussa type (3.0 g, 2.82 mmol). The mixture was stirred at r.t. under hydrogen atmosphere for 3h, filtered through a celite pad and evaporated under reduced pressure. The residue was triturated with Et2O (50 mL) to afford compound 4 (11.264 g, 87% yield) as a dark-brown solid. MS (m/z): 128.1 (M+H). 1H NMR (400 MHz, DMSO-de) delta (ppm): 8.57 (s, IH), 6.62 (dd, J = 10.0, 8.4 Hz, IH), 6.34 (dd, J = 13.4, 2.6 Hz, IH), 6.20 (ddd, J = 8.6, 2.6, 1.2 Hz, IH), 4.67 (s, 2H).
85%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; under 2068.65 Torr; for 3h;	Preparation 26 4-amino-2-fluoro -phenol; A solution of 2-fluoro-4-nitro-phenol (400 mg, 2.55 mMol) and ethanol (6 ml_) was treated with 10% Pd/C (42.6 mg). The reaction mixture was hydrogenated for 3 hours at 40 psi at room temperature. The reaction mixture was filtered through a pad of Arbocel with ethanol and then evaporated to dryness to give a dark solid (248mg, 85%).1H NMR (400MHz, CD3OD) delta =6.29-6.31(d, 1 H), 6.39-6.43 (dd, 1 H), 6.58-6.62 (m, 1 H). GC/MS: 1.66 mins m/z (Cl) = 128 [MH+]
81%	With ammonium chloride; zinc; In tetrahydrofuran; methanol; at 0 - 20℃;	To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 0 C. was added zinc dust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a thin pad of Celite with methanol and the filtrate was concentrated in vacuo to give 4-amino-2-fluorophenol as a brown solid which was used without further purification (656 mg, 81%). 3-(4-Fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 197 mg, 1.00 mmol) was dissolved in dimethylformamide (4 mL). Triethylamine (140 muL, 1.00 mmol) was added and the solution was cooled to 0 C. 4-Amino-2-fluorophenol (Step A of Example 19, 127 mg, 1.00 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69%) as a white solid. 1H NMR (CD3OD) delta 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08-6.99 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS (ESI+) m/z 307.44 (M+H)+.
55.1%	With iron; ammonium chloride; In ethanol; water; at 20℃; for 0.5h;	To a solution of 2-fluoro-4-nitrophenol (1.57 g, 10 mmol) in EtOH (50 mL) and H20 (18 mL) was added Fe (2.24 g, 40 mmol) and NH4C1 (4.24 g, 80 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was added Eta20 (50 mL) and extracted by EtOAc (60 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was beaten by PE/EtOAc (v/v, 10 mL/15 mL), filtered to give the title compound as a brown solid (700 mg, 55.1%).LC-MS (ESI, pos, ion): 128.3 [M+H]+;H NMR (400 MHz, DMSO-Lambda) delta (ppm): 8.56 (s, 1H), 6.62 (dd, J = 10.0, 8.6 Hz, 1H), 6.34 (dd, J= 13.4, 2.6 Hz, 1H), 6.24-6.15 (m, 1H), 4.66 (s, 2H).
55.1%	With water; iron; ammonium chloride; In ethanol; at 20℃;	Iron powder (2.24 g, 40 mmol) and NH4Cl (4.24 g, 80 mmol)Add to 2-fluoro-4-nitrophenol (1.57g, 10mmol)EtOH (50mL)And H2O (18mL) solution,The reaction was stirred at room temperature overnight.The reaction solution was filtered through silica gel.The filtrate was concentrated under reduced pressure.The residue obtained was added to water (50 mL).Extract and separate the organic phase with EtOAc (60 mL x 2).Combine the resulting organic phases,Wash with saturated brine,After drying with anhydrous sodium sulfate,Concentrated under reduced pressure,The residue obtained was beaten in a mixed solvent of PE/EtOAc (v/v, 10 mL / 15 mL).filter,The title compound (700 mg, 55.1%) was obtained.
38%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 16h;	2-fluoro-4-nitrophenol (500 mg, 3.18 mmol), Pd (10% on activated carbon, 31 mg), and EtOH (20 mL) were combined and stirred under atmospheric H2 at room temperature. After 16 h, the solution was diluted with EtOAc (20 mL), filtered through Celite, concentrated, and purified by preparative thin layer chromatography (30% EtOAc in hexanes) to afford 4-amino-2-fluorophenol as a tan solid of sufficient purity for subsequent transformations (152 mg, 1.20 mmol; 38% yield).
	With palladium on activated charcoal; hydrogen; In ethanol; at 20℃; for 4h;	2-fluoro-4-nitrophenol (1.15 g, 7.3 mmol) was dissolved inethanol (10 mL) and added to Pd/C (66 mg). Subsequently the flaskwas charged with hydrogen (H2) gas and the black suspension wasstirred at room temperature for 4 h. After 4 h the starting materialdisappeared as analyzed by TLC. The resulting mixture was filteredand the solvent was evaporated under reduced pressure to providethe crude product that was used directly for the next reaction step.The crude product was dissolve inwater (10 mL) with concentratedHCl (2 mL). Subsequently, NaNO2 (1.0 g, 15 mmol) and NaN3 (0.95 g,15 mmol) were added sequentially to yield 4-azido-2-fluorophenol.1H NMR (500 MHz, DMSO-d6) d 9.94 (s, 1H), 7.06e6.90 (m, 2H), 6.79(d, J 6.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) d 151.67 (d,J 242.8 Hz), 142.89 (d, J 12.1 Hz), 130.75 (d, J 8.6 Hz), 119.09,115.70, 108.26 (d, J 22.0 Hz).

Reference： [1]Patent: US2005/245530,2005,A1 .Location in patent: Page/Page column 35-36
[2]Patent: US2006/241104,2006,A1 .Location in patent: Page/Page column 14
[3]Patent: US2007/78140,2007,A1 .Location in patent: Page/Page column 25-26
[4]Patent: WO2014/22116,2014,A2 .Location in patent: Paragraph 0223
[5]Patent: US2015/37280,2015,A1 .Location in patent: Paragraph 0445; 0446
[6]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 175 - 178
[7]Patent: WO2012/145361,2012,A1 .Location in patent: Page/Page column 168
[8]RSC Advances,2013,vol. 3,p. 3697 - 3706
[9]Patent: WO2012/4549,2012,A1 .Location in patent: Page/Page column 35
[10]Patent: WO2009/26720,2009,A1 .Location in patent: Page/Page column 93; 94
[11]Patent: WO2009/144632,2009,A1 .Location in patent: Page/Page column 66
[12]Patent: US2005/245530,2005,A1 .Location in patent: Page/Page column 35
[13]Patent: WO2015/164161,2015,A1 .Location in patent: Paragraph 0295
[14]Patent: CN104974162,2018,B .Location in patent: Paragraph 0609; 0610
[15]Patent: WO2005/121125,2005,A1 .Location in patent: Page/Page column 45-46
[16]Journal of the Chemical Society,1949,p. 642,645
[17]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 6525 - 6538
[18]Synthetic Communications,2013,vol. 43,p. 2949 - 2954
[19]European Journal of Medicinal Chemistry,2020,vol. 186
[20]International Journal of Molecular Sciences,2020,vol. 21

2
[ 22536-67-0 ]
[ 399-96-2 ]
[ 110965-58-7 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1991,vol. 39,p. 2308 - 2315

3
[ 399-96-2 ]
[ 5912-18-5 ]
[ 688781-89-7 ]

Reference： [1]Tetrahedron Letters,2006,vol. 47,p. 2069 - 2072

4
[ 399-96-2 ]
[ 437-83-2 ]

Reference： [1]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 175 - 178

5
[ 399-96-2 ]
[ 320-76-3 ]

Reference： [1]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 175 - 178

6
[ 399-96-2 ]
[ 74266-66-3 ]

Reference： [1]Bulletin de la Societe Chimique de France,1980,vol. 2,p. 175 - 178

7
[ 455-93-6 ]
[ 399-96-2 ]

Reference： [1]Journal of the Chemical Society,1949,p. 642,645

8
[ 399-96-2 ]
N<SUP>1</SUP>-(3-fluoro-4-hydroxyphenyl)-N<SUP>3</SUP>-(4-fluorophenyl)malonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%		To a solution of 2-fluoro-4-nitrophenol (Avacado, 1.00 g, 6.37 mmol) in 4 mL of tetrahydrofuran and 6 mL of methanol at 0 C. was added zinc dust (2.08 g, 31.8 mmol, <10 micron) followed by ammonium chloride (1.70 g, 31.8 mmol). The mixture was stirred at room temperature overnight. The heterogeneous mixture was filtered through a thin pad of Celite with methanol and the filtrate was concentrated in vacuo to give <strong>[399-96-2]4-amino-2-fluorophenol</strong> as a brown solid which was used without further purification (656 mg, 81%). 3-(4-Fluorophenylamino)-3-oxopropanoic acid (Compound B of Example 1, 197 mg, 1.00 mmol) was dissolved in dimethylformamide (4 mL). Triethylamine (140 muL, 1.00 mmol) was added and the solution was cooled to 0 C. 4-Amino-2-fluorophenol (Step A of Example 19, 127 mg, 1.00 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 442 mg, 1.00 mmol). The reaction was allowed to warm to room temperature and was then stirred at room temperature for 3 h. The reaction mixture was concentrated to remove methylene chloride and water was added to precipitate the product. Filtration and trituration with water gave the title compound (211 mg, 69%) as a white solid. 1H NMR (CD3OD) delta 7.61-7.57 (m, 2H), 7.51 (dd, 1H, J=13, 2.5 Hz), 7.08-6.99 (m, 3H), 6.88 (t, 1H, J=9.4 Hz), 3.51 (s, 2H); MS (ESI+) m/z 307.44 (M+H)+.

Reference： [1]Patent: US2005/245530,2005,A1 .Location in patent: Page/Page column 35

9
[ 399-96-2 ]
[ 18063-02-0 ]
N-(4-(2-chloropyridin-4-yloxy)-3-fluorophenyl)-2,6-difluorobenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine; In tetrahydrofuran; at 20℃; for 0.5h;	A solution 4-(2-chloropyridin-4-yloxy)-3-fluorobenzenamine (Compound B of Example 20, 64 mg, 0.27 mmol), THF (1 ml), Et3N (100 muL) was treated dropwise with 2,6-difluorobenzoyl chloride (Aldrich, 33 muL, 0.27 mmol) and the mixture was stirred at rt for 30 min. The mixture was partitioned between EtOAc and saturated aq. NaHCO3 and the EtOAc phase was separated, dried (MgSO4) and concentrated in vacuo to give the title compound (102 mg, 100%) as white solid. MS (ESI+): m/z 418.18 (M+H)+.

Reference： [1]Patent: US2005/245530,2005,A1 .Location in patent: Page/Page column 99

10
[ 399-96-2 ]
[ 602303-26-4 ]
[ 918643-41-1 ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium <i>tert</i>-butylate In hexane; dimethyl sulfoxide	155.1 Step 1: Step 1: 3-Fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline (268) To a solution of 4-amino-2-fluorophenol (1.83 g, 14.38 mmol) in DMSO (30 mL) was added potassium tert-butoxide (1.61 g, 14.38 mmol). After 15 min, 7-chloro-2-iodothieno[3,2-b]pyridine (2.5 g, 8.46 mmol, Ragan J. A. et al, Organic Process Research and Development, 2003, 7. 676-683) was added and the reaction mixture was heated at 100° C. for 60 min. The mixture was cooled down to RT then poured into water (250 mL) at 40-45° C. and stirred for 30 min. The precipitate was collected by filtration, washed with water, dried and purified by flash column chromatography on silica gel (eluent 60% EtOAc in Hexane) to afford title compound 268 (1.06 g, 32% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ (ppm): 8.41 (d, J=5.4 Hz, 1H), 7.75 (s, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.57-6.45 (m, 3H), 3.83 (s, 2H).
	With caesium carbonate In N,N-dimethyl-formamide at 135℃; for 3h;	6.A Example 6; Preparation of N-(4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorophenylcarbamothioyl)-2-phenylacetamide; Step A: Preparation of 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)aniline; A vigorously stirred mixture of 7-chloro-2-iodothieno[3,2-b]pyridine (5.00 g, 14.4 mmol; obtained from 7-chlorothieno[3,2-b]pyridine, Example 1, Step A, according to the procedure described by Ragan, J. A. Org. Proc. Res. 2003, 7, 676), 4-amino-2-fluorophenol (2.01 g, 15.8 mmol), Cs2CO3 (4.69 g, 14.4 mmol), and DMF (60 mL) was heated to 135° C. for 3 hours under N2. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), and washed with brine (3×200 mL). The organic phase was concentrated, and the crude was purified by a Biotage 40M silica gel chromatography system eluting with 2:1 EtOAc/hexanes. The product was further purified by recrystallization from a hot mixture of 1:1 CH3CN/water (70 mL). The filtrate yielded two additional crops of product which matched the purity of the first crop. The combined crops yielded 2.35 g (40%). 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=6 Hz, 1H), 7.75 (s, 1H), 7.02 (t, J=9 Hz, 1H), 6.54 (m, 1H), 6.47 (m, 2H), 3.84 (br s, 2H). LRMS (ESI pos) m/e 387 (M+1).

Reference： [1]Current Patent Assignee: MIRATI THERAPEUTICS, INC. - US2011/257100, 2011, A1
[2]Current Patent Assignee: PFIZER INC - US2007/197537, 2007, A1 Location in patent: Page/Page column 52

11
[ 26452-80-2 ]
[ 399-96-2 ]
[ 868733-61-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With sodium hydride; In N,N-dimethyl-formamide; at 20 - 90℃; for 4.5h;	Step 1 : 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (66)[00391] To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (500 mg, 3.93 mmol) in DMF (10 ml) was added NaH (173 mg, 60% on mineral oil, 4.33 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was heated to 900C and stirred for 4 hours. The mixture was cooled-down to rt, diluted with water and EtOAc. The organic phase was washed well with water, dried over anhydrousNa2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (40% EtOAc in hexanes) to afford the title compound66 (650 mg, 70%) as a beige solid. MS (m/z): 239.1 (M+H)

Reference： [1]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 673 - 678
[2]Patent: WO2008/46216,2008,A1 .Location in patent: Page/Page column 178

12
[ 1025720-99-3 ]
[ 399-96-2 ]
[ 1025721-01-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 1h;Microwave irradiation;	The compound 1f (110 mg 0.6 mmol) obtained by the above reaction,<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (127 mg, 1 mmol) was dissolved in 1 ml of DMF,Potassium tert-butoxide (112 mg, 1 mmol) was added with vigorous stirring,Then microwave reaction at 80 C for 1 h,After the reaction is complete,Rotate dry DMF,Soluble in ethyl acetate and washed with water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil, 1 g (131 mg, 81%) of the brown powder was obtained by column chromatography (ethyl acetate: petroleum ether = 1: 1).
79%		To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (9.3 g, 73 mmol, 3B Medical Systems, 3B3290) in DMF (100 mL) was added potassium tert-butoxide (8.8 g, 79 mmol). After stirring at rt for 30 min, 3,4-dichloropicolinamide (10 g, 52 mmol) was added. The reaction mixture was stirred at 50 C. for 2.5 h. After cooling the reaction to rt, the mixture was diluted with 400 mL of ethyl acetate and washed with saturated aqueous sodium bicarbonate solution (400 mL). The aqueous layer was back-extracted with 300 mL ethyl acetate. The combined organic phases were washed with 10% aqueous lithium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting brown solid was suspended in ethyl acetate, filtered and washed with ether to give the product as a tan solid (7.4 g). The filtrate was concentrated in vacuo and then purified by flash chromatography on silica gel (2% methanol/ethyl acetate). The resulting brown solid was triturated with ether to give an additional 4.3 g of 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (79% combined yield) as a pale tan solid. 1H NMR (CD3OD) delta 8.29 (d, 1H, J=5.6 Hz), 7.00 (t, 1H, J=8.8 Hz), 6.79 (d, 1H, J=5.6 Hz), 6.63-6.55 (m, 2H); MS (ESI+) m/z 282.21 (M+H)+.
79%		To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (465 mg,3.65 mmol) in DMF (10 mL) was added potassium tert-butoxide (440 mg, 3.95 mmol). Thirty min later, 3,4-dichloropicolinamide (8) was added and the solution was heated to 50 C. When TLC showed all the starting materials consumed, the reaction mixture was diluted with EtOAc (50 mL),washed with saturated NaHCO3, brine, and dried over Na2SO4. After concentration, the residue was purified by column chromatography giving the title compound as a pale yellow solid (580 mg, 79%). 1H-NMR (DMSO-d6, 600 MHz) delta 8.29 (d, 1 H, J = 5.6 Hz, ArH), 7.00 (t, 1H, J = 8.8 Hz, ArH), 6.79(d, 1H, J = 5.6 Hz, ArH), 6.63-6.55 (m, 2H, ArH); 13C-NMR (DMSO-d6, 150 MHz) delta 166.6, 160.8,154.1, 153.9, 149.0, 148.7, 128.5, 123.7, 115.9, 110.1, 110.0, 101.3.

68%		<strong>[399-96-2]4-amino-2-fluorophenol</strong> (2.39g, 18.84mmol) and t-BuOK (2.82g, 25.12mmol) were added into DMF (50.00mL). After stirring at rt for 30min, compound 10 (2.40g, 12.56mmol) was added. The reaction mixture was stirred at 50C for 3h. The mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phases was concentrated under reduced pressure to remove solvent and the residue was purified by chromatography to afford compound 11 (2.83g, 8.54mmol) as a white solid. Yield: 68%. 1H NMR (400MHz, DMSO-d6): delta=8.31 (d, 1H, J=5.6Hz, Ar-H), 8.03 (s, 1H, Ar-H), 7.73 (s, 1H, Ar-H), 7.04 (t, 1H, J=9.2Hz, Ar-H), 6.73 (d, 1H, J=5.6Hz, Ar-H), 6.54 (dd, 1H, J=13.2, 2.4Hz, NH2), 6.45 (dd, 1H, J=8.8, 2.0Hz, NH2), 5.55 (s, 2H, NH2). ESI-MS: m/z=281.9 [M+H]+
60.2%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃;	To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (381 mg, 3 mmol) and 3,4- dichloropicolinamide (570 mg, 3 mmol) in DMF (4 mL) was added t-BuOK (404 mg, 3.6 mmol). The reaction mixture was allowed to warm up to 80 C and stirred overnight. The mixture was added H20 (15 mL) and filtered. The filter cake was washed with 2 mL of H20 and dried in vacuo to give the title compound as a black solid (508 mg, 60.2%).LC-MS (ESI, pos, ion): 282.0 [M+H]+;H NMR (400 MHz, DMSO^) delta (ppm): 8.31 (d, J = 5.6 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.04 (t, J = 9.0 Hz, 1H), 6.73 (d, J = 5.5 Hz, 1H), 6.54 (dd, J = 13.2, 2.4 Hz, 1H), 6.45 (dd, J = 8.7, 2.0 Hz, 1H), 5.55 (s, 2H).
60.2%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃;	t-BuOK (404 mg, 3.6 mmol) was added to <strong>[399-96-2]4-amino-2-fluorophenol</strong> (381 mg, 3 mmol)And 3,4-dichloro-2-carbamoylpyridine (570 mg, 3 mmol)In DMF (4mL) solution,The reaction solution was warmed to 80 C and stirred overnight. Then go to room temperature,Water (15 mL) was added to the reaction mixture, and the mixture was filtered and washed with water (2mL) The title compound (508 mg, 60.2%).
54.4%		Step 1) 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide [0174] To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (254 mg, 2.0 mmol) in DMF (5 mL) was added i-BuOK (359 mg, 3.2 mmol). The mixture was stirred at rt for 30 minutes. 3,4-dichloropicolinamide (420 mg, 2.2 mmol) was then added, and the mixture was microwaved at 120 C for 2 hours. The mixture was cooled to rt, quenched with 25 mL of water. The resulted solution was extracted with EtOAc (30 mL x 3) and the combined organic phases were washed with brine (30 mL x 3), dried over Na2S04 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v) = 2/1) to give the title compound as a pale yellow solid (306 mg, 54.4 %). MS (ESI, pos. ion) m/z: 282.1 [M+H]+; NMR (400 MHz, DMSO-i): delta (ppm) 8.30 (d, J= 5.6 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.03 (t, J= 9.0 Hz, 1H), 6.72 (dd, J= 0.8 Hz, 5.6 Hz, 1H), 6.53 (dd, J = 2.4 Hz, 13.2 Hz, 1H), 6.44 (dd, J = 1.8 Hz, 8.7 Hz, 1H), 5.55 (s, 2H).
54.4%		Step 1) 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (254 mg, 2.0 mmol) in DMF (5 mL) was added t-BuOK (359 mg, 3.2 mmol). The mixture was stirred at rt for 30 minutes. 3,4-dichloropicolinamide (420 mg, 2.2 mmol) was then added, and the mixture was microwaved at 120 C. for 2 hours. The mixture was cooled to rt, quenched with 25 mL of water. The resulted solution was extracted with EtOAc (30 mL3) and the combined organic phases were washed with brine (30 mL3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=2/1) to give the title compound as a pale yellow solid (306 mg, 54.4%). MS (ESI, pos. ion) m/z: 282.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta (ppm) 8.30 (d, J=5.6 Hz, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.03 (t, J=9.0 Hz, 1H), 6.72 (dd, J=0.8 Hz, 5.6 Hz, 1H), 6.53 (dd, J=2.4 Hz, 13.2 Hz, 1H), 6.44 (dd, J=1.8 Hz, 8.7 Hz, 1H), 5.55 (s, 2H).
30%		Under Ar protection, <strong>[399-96-2]4-amino-2-fluorophenol</strong> (0.93 g, 7.3 mmol, 1.4 eq) was dissolved in 10 mL of DMF, t-BuOK (0.88 g, 7.8 mmol, 1.6 eq) was added and reacted for 30 min at room temperature, and 3,4-dichloro-2-pyridinecarboxamide (1 g, 5.2 mmol, 1.0 eq) was added with stirring, heated to 50C and reacted for 3 h. The mixture was cooled to room temperature, saturated NaHCO3 solution was added, and exacted with ethyl acetate, subjecting same to column chromotography to obtain 440 mg (30%) of products. 1H NMR (400 MHz, d6-DMSO) delta 8.30 (d, J=5.6Hz, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.03 (t, J=8.8Hz, 1H), 6.72 (d, J=5.2Hz, 1H), 6.54 (dd, J=13.6, 2.4Hz, 1H), 6.45(m, 1H), 5.53 (s, 2H).
300 mg		Take a 100ml reaction bottle, add 0.93g of <strong>[399-96-2]4-amino-2-fluorophenol</strong>, 0.88g of potassium tert-butoxide and 10ml DMF, stirred at room temperature for 0.5 h, added 1.0g of compound I-39-2, and heated to 50 C for 6.0 h. After the reaction was completed, 100 ml of water and 100 ml of ethyl acetate were added to separate the liquids, and the organic phase was retained. The aqueous phase was back-extracted once with 100 ml of ethyl acetate, the organic phases were combined, dried, concentrated to dryness under reduced pressure, and purified by column chromatography to obtain 300 mg of compound I-39-3.

Reference： [1]Patent: CN107151240,2017,A .Location in patent: Paragraph 0137; 0138; 0139
[2]Patent: US2008/114033,2008,A1 .Location in patent: Page/Page column 6-7
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 1251 - 1254
[4]Molecules,2014,vol. 19,p. 2655 - 2673
[5]Bioorganic and Medicinal Chemistry,2017,vol. 25,p. 3195 - 3205
[6]Patent: WO2015/164161,2015,A1 .Location in patent: Paragraph 0296
[7]Patent: CN104974162,2018,B .Location in patent: Paragraph 0613; 0614
[8]Patent: WO2014/22116,2014,A2 .Location in patent: Paragraph 0174
[9]Patent: US2015/37280,2015,A1 .Location in patent: Paragraph 0294-0296
[10]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[11]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0218; 0220
[12]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 3351 - 3355
[13]Patent: CN110330479,2019,A .Location in patent: Paragraph 0237; 0238; 0241

13
[ 849217-33-0 ]
[ 399-96-2 ]
[ 849217-32-9 ]

Yield	Reaction Conditions	Operation in experiment
100%		4-Amino-2-fluoro-phenol (1.53g, 12. 0MMOL) was dissolved in dry DMF (30ml) to which was added 60% NaH (774mg, 19. 3mmol). After the mixture was stirred at room temperature for several minutes, a suspension of 5- (4-CHLORO-6-METHOXY-QUINAZOLIN-7-YLOXYMETHYL)-HEXAHYDRO- cyclopenta [C] PYRROLE-2-CARBOXYLIC acid benzyl ester (4.70g, 6. 7mmol) in dry DMF (40ml) was added. The reaction mixture was stirred at room temperature for 1-2 hrs, then diluted with EtOAc and washed with sat'd NaHCO3 (3x), H20 (LX), sat'd NaCl (LX), dried (NA2S04), and concentrated in vacuo to give crude 5- [4- (4-AMINO-2-FLUORO-PHENOXY)-6- METHOXY-QUINAZOLIN-7-YLOXYMETHYL]-HEXAHYDRO-CYCLOPENTA [c] pyrrole-2-carboxylic acid benzyl ester (5. 6G,-100%) which was used in the next reaction without further PURIFICATION

Reference： [1]Patent: WO2005/30140,2005,A2 .Location in patent: Page/Page column 184

14
[ 23056-36-2 ]
[ 399-96-2 ]
[ 868733-61-3 ]

Yield	Reaction Conditions	Operation in experiment
75%		<strong>[399-96-2]4-amino-2-fluorophenol</strong> (4.3 g, 32 mmol, 1.1 eq) was dissolved in 100 mL of DMF, added NaH (60%, 32 mmol, 1.1 eq) at room temperature and reacted for 10 min, and 2-chloro-4-nitropyridine (5 g, 31 mmol, 1.0 eq) was added with stirring, and heated to 90C and reacted overnight. The solution was cooled to room temperature, quenched with saturated NaCl, extracted with DCM/H2O several times, and the organic phases were combined, subjecting same to column chromatography to obtain 5.5g (75%) of the product.
69%	In N,N-dimethyl-formamide;	<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (635 mg, 5 mmol)And 2-chloro-4-nitropyridine (471 mg, 3 mmol)Was dissolved in DMF and then reacted with potassium tert-butoxide (560 mg, 5 mmol) under nitrogen for 12 h,After completion of the reaction, the solvent was removed,Extraction with ethyl acetate,41a (505 mg, 69%) was obtained by column chromatography.

Reference： [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 1251 - 1254
[2]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[3]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0191; 0192
[4]Patent: CN107151240,2017,A .Location in patent: Paragraph 0571; 0572; 0573

15
[ 1123838-05-0 ]
[ 399-96-2 ]
[ 1123838-11-8 ]

Yield	Reaction Conditions	Operation in experiment
88%		To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (7.42 g, 58.4 mmol) in DMSO (65 mL) was added potassium tert-butoxide (7.75 g, 69.0 mmol)). After 30 min, intermediate 317 (17.67 g, 53.1 mmol) was added and the reaction mixture was heated at 100 0C for 1.5h, cooled down to room temperature, poured in water (300 mL) at 40-45 0C and stirred for 30 min. The solid was collected by filtration, washed with water (2 x 30 mL) and dried for 2h. This material was triturated with ether (60 mL), to afford title compound 319 (19.80 g, 88% yield) as a brown solid. MS (m/z): 424.1 (M+H)

Reference： [1]Patent: WO2009/109035,2009,A1 .Location in patent: Page/Page column 50; 52

16
[ 1186375-15-4 ]
[ 399-96-2 ]
[ 1186376-05-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate; In DMF (N,N-dimethylformamide); at 120℃; for 0.5h;Microwave irradiation;	Example 182 1-(4-Amino-2-fluoro-phenoxy)-5H-benzo[c1[1 ,81naphthyridin-6-one (182); Compound 83 (250 mg, 1.08 mmol), <strong>[399-96-2]4-amino-2-fluoro-phenol</strong> (276 mg, 2.17 mmol), and cesium carbonate (1.41 g, 4.34 mmol) were suspended in DMF (5 ml_), and and stirred for 30 minutes at 120 0C in microwave. The reaction mixture was diluted with H2O. The resulting precipitate was filtered. The precipitate was tritturated with MeOH, filtered, washed with MeOH, and dried under vacuum to provide 182 (312 mg, 90 % yield) as a solid. LC-MS (M+H = 322, obsd. = 322).

Reference： [1]Patent: WO2009/108670,2009,A1 .Location in patent: Page/Page column 142

17
[ 39906-04-2 ]
[ 399-96-2 ]
[ 1198109-70-4 ]

Yield	Reaction Conditions	Operation in experiment
66%	With hydrogenchloride; In ethanol; water; at 85℃; for 6h;Inert atmosphere;	Preparation 27; 4-(5-amino-6-chloro-2-methyl-pyrimidin-4-ylamino)-2-fluoro -phenol; A 10ml flask was charged with EtOH (3ml_). 2-methyl-4,6-dichloro-5-aminopyrimidine was added (140mg, 1.89 mMol) followed by <strong>[399-96-2]4-amino-2-fluoro-phenol</strong> (100mg, 1.89 mMol) and HCI (2M aq 0.787ml_, 3.78 mMol). The reaction mixture was heated at 850C under N2 for 6 hours. The reaction mixture was evaporated, partitioned between 10 ml sodium bicarbonate solution and 10 ml ethyl acetate, the aqueous was extracted again twice with 10 ml ethyl acetate, the organics were combined, dried over magnesium sulphate, filtered and evaporated to give a purple gum (308 mg, 66%).LCMS (System 4, acidic run): 2.26 mins m/z (APCI) = 269 [MH+]

Reference： [1]Patent: WO2009/144632,2009,A1 .Location in patent: Page/Page column 66

18
[ 399-96-2 ]
[ 6980-08-1 ]
[ 884339-74-6 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 1h;Inert atmosphere;	4-Chloro-3-nitropyridin-2-amine (500 mg, 2.89 mmol) and 4-amino-2-fluorophenol (403.8 mg, 3.18 mmol) were mixed in dry DMF (10 mL), and t-BuOK (356.1 mg, 3.18 mmol) was added. This mixture was heated to 80 C under N2 for 1 h, then cooled to room temperature. Water (50 mL) was added to quench the reaction, and the mixture was extracted with EA (3 × 50 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuum, and purified by column chromatography to yield the corresponding ether 20b (618.0 mg, 81%). 1H NMR (300 MHz, DMSO) delta 7.95 (dd, J = 5.8, 0.7 Hz, 1H), 6.96 (t, J = 8.7 Hz, 1H), 6.54 - 6.40 (m, 2H), 6.15 (s, 2H), 6.03 (dd, J = 5.7, 1.3 Hz, 1H), 3.80 (s, 2H). EI-MS m/z: 264 (M)+.
45%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0℃; for 2h;	<strong>[6980-08-1]2-amino-3-nitro-4-chloropyridine</strong> (346 mg, 2 mmol)2-fluoro-4-chlorophenol (508 mg, 4 mmol)After dissolving in 1 ml of DMF,The mixture was thoroughly stirred under ice bath and potassium tert-butoxide (448 mg, 4 mmol)At 0 CReaction 2h,After completion of the reaction, dry DMF, dissolved in ethyl acetate and water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil, the brown powder 2-9a (310 mg, 45%) was obtained by column chromatography (methanol: dichloromethane = 1: 50).

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 708 - 716
[2]Patent: CN107151240,2017,A .Location in patent: Paragraph 0238; 02369; 0240
[3]Journal of Medicinal Chemistry,2009,vol. 52,p. 3881 - 3891

19
[ 849217-48-7 ]
[ 399-96-2 ]
[ 849217-58-9 ]

Yield	Reaction Conditions	Operation in experiment
93.6%		3L reaction flask (4.6 mol) of compound 4,800 mL of water and 1600 mL of tetrahydrofuran were slowly added to the system in a batchwise manner. 76.8 g (4.8 mol) of lithium hydroxide was added and the reaction was complete for 1 to 2 hours at room temperature. The reaction was stopped, the system was evaporated under reduced pressure THF, the system was cooled to 5 C, adjusted to pH 4 with 2NHC1, and a large amount of white solid precipitated. Filter, filter cake with 300mL water washing, drying cake cake, get 356. lg white solid. The solid directly into the 3L reaction bottle, add 1500mL anhydrous tetrahydrofuran, the system cooled to 0 C to the system after dropping 190. 4g (1. 6mol) thionyl chloride and 1. 5gDMF, drops complete, the system of natural After warming up to room temperature for 3-5h, the reaction was complete by TLC. The temperature of the system was reduced again to 0 C. After the temperature had stabilized, 161. 9 g (l.6 m?) of triethylamine was added dropwise. After 10min, 4-amino-2-fluorobenzoic acid (L. 6 mol) and 400 mL of anhydrous tetrahydrofuran was added over 1 h. After the reaction mixture was heated to room temperature for 5 h, HPLC and TLC were carried out. After the raw materials were reacted, the solvent was distilled off and the crude product was filtered with 1 L of water, dried, and dried to give compound 6 (49.78 g) HPLC: 98.4% , Yield: 93.6%.
91%		B. Preparation of N1-(3-Fluoro-4-hydroxyphenyl)-N1-(4-fluorophenyl)-1,1-cyclopropanedicarboxamide; To a solution of 1-[(4-fluorophenyl)amino]carbonyl}cyclopropanecarboxylic acid (21 g, 94.17 mmol) and DMF (0.11 mL) in THF (147 mL) was added oxalyl chloride (8.37 mL, 98.88 mmol) slowly to maintain a temperature in the range of 4 C. to 15 C. The solution was stirred at room temperature for about 2 h, then slowly added to a chilled (-10 C.) solution of 4-amino-2-fluoro phenol (14.05 g, 110.65 mmol) and 2,6-lutidine (21.90 mL) in THF (147 mL) over 45 min. The temperature was maintained at or below 0 C. throughout the addition. The suspension was stirred for 0.5-1 h at 0 C. EtOAc (210 mL) and H2O (147 mL) were added and the layers were separated. 1N HCl (105 mL) was added to the organic portion and the layers separated. 5% NaHCO3 (105 mL) was added to the organic portion and the layers separated. The solution was dried over Na2SO4 and concentrated to dryness. EtOAc (42 mL) was added to the residue and the resulting suspension was stirred at 55 C. for 1 h and cooled to 20 C. The suspension was stirred at room temperature overnight then cooled to 0-5 C. with stirring for 2-3 h. The solid was isolated by filtration and the cake was washed with 1:2 EtOAc/heptane (21 mL). The solid was dried under reduced pressure at 55 C. to give 28.43 g of the desired product (yield: 91%).
86.5%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;	General procedure: To a solution of the intermediate 9 (1.0g, 4.48mmol) and substituted aminophenol (5.38mmol) in DMF (15mL) was added EDCI (1.03g, 5.38mmol). The solution was stirred at room temperature for 3h. Then water (50mL) was added to precipitate white solid, adjusting pH to 4.0-5.0 by 1M HCl. The white solid was filtered off, washed and dried in vacuum to afford 10a-b [45].

81.4%	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 3h;	Take 3-fluoro-4-aminophenol (0.68g, 5.38mmol) and intermediate 1-1 (1g, 4.48mmol) in 15mL of DMF, and add EDC.HCl (1.03g, 5.38mmol) to it at room temperature. The reaction was stirred for 3h. After the reaction, water was added to the reaction solution to precipitate a white solid, and 1N HCl was added to adjust the pH to 4.0 to 5.0. After stirring for 15 minutes, the mixture was filtered, the filter cake was washed with water to neutrality, and dried under vacuum to obtain a white body 1-2: white solid. , 81.4%,
63%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	Compound 25 (2.00 g, 8.97mmol) and 4-amino-2-fluorophenol (1.14 g, 8.97 mmol) were dissolved in 10 ml of DCM, and the resulted solution was added with HOBt (1.21 g, 13.46 mmol) and EDC (1.77 g, 13.46 mmol) at room temperature. The mixture was stirred at room temperature and the reaction was monitored by TLC. After the reaction was completed, the resultant was evaporated to remove most DCM, extracted with EA, then washed with saturated NaHCO3, water (pH=3) and saturated brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was crystallized in methanol to give a tan solid, yield 63%. 1H NMR (DMSO, 400 MHz): delta 10.51 (s, 1H), 10.32 (s, 1H), 10.00 (s, 1H), 7.77 (d, J=12.9 Hz, 1H), 7.66-7.61 (D, J=8.7 Hz, 1H), 7.30 (t, J=8.8 Hz, 1H), 7.15 (d, J=9.0 Hz, 2H), 1.61 (m, 2H), 1.44).
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl acetamide; at 20℃; for 4h;	General procedure: To a solution of 3a-k (6.40 mmol) in MeOH/H2O (30 mL,1:1=V:V), lithium hydroxide (230 mg, 9.6 mmol) was added, whichwas stirredat room temperature for 2 h. The pH value was then adjustedto 3 with dilute hydrochloric acid, and a large amount of solid wasprecipitated, which was filtered and dried to give an off-white solid (4a-k). The next step was carried out without purification of these products.A mixture of 4a-k (1 mmol), aminophenol (1 mmol), and 3-(ethyliminomethyleneamino)-N,N- dimethyl-propan-1-amine (1 mmol) in 10 mLDMA, was stirred at room temperature for 4 h. The reaction mixturewas monitored by TLC. After the starting material disappeared, thewater was added and the product was extracted with ethyl acetate andthe solvent was then evaporated. Finally, the product was separated bycolumn chromatography to give a pure product (5a-k).

Reference： [1]Patent: CN105218445,2016,A .Location in patent: Paragraph 0048-0049
[2]Patent: US2010/81805,2010,A1 .Location in patent: Page/Page column 9
[3]European Journal of Medicinal Chemistry,2017,vol. 140,p. 212 - 228
[4]Patent: CN110386901,2019,A .Location in patent: Paragraph 0072; 0077; 0078
[5]Patent: US2018/244667,2018,A1 .Location in patent: Paragraph 0068
[6]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 673 - 678
[7]Cell Chemical Biology,2019,vol. 26,p. 1240 - 11,1252
[8]Bioorganic Chemistry,2019,vol. 88

20
[ 205448-32-4 ]
[ 399-96-2 ]
[ 479690-10-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium t-butanolate; In N,N-dimethyl acetamide; at 50 - 100℃; for 36h;	Solid sodium ferf-butoxide (1.20 g; 12.5 mmol) was added to a suspension of the chloroquinoline (3.37 g; 10 mmol) in dimethylacetamide (35 mL), followed by solid 2- fluoro-4-hydroxyaniline. The dark green reaction mixture was heated at 95-100 0C for 18 h. HPLC analysis showed approximately. 18% starting material remaining and ca. 79% product. The reaction mixture was cooled to below 50 0C and additional sodium fe/t-butoxide (300 mg; 3.125 mmol) and aniline (300 mg; 2.36 mmol) were added and heating at 95-100 0C was resumed. HPLC analysis after 18 h revealed less than 3% starting material remaining. The reaction was cooled to below 30 0C, and ice water (50 mL) was added while maintaining the temperature below 30 0C. After stirring for 1 hour at room temperature, the product was collected by filtration, washed with water (2 x 10 mL) and dried under vacuum on the filter funnel, to yield 4.11 g of the coupled product as a tan solid (96% yield; 89%, corrected for water content).
66%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 105℃; for 1h;Microwave irradiation;	Compound 4a (110 mg, 0.33 mmol) was added,<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (127 mg, 1 mmol) was dissolved in 1 ml of DMF,Potassium tert-butoxide (112 mg, 1 mmol) was added with vigorous stirring,Then microwave reaction at 105 C for 1 h,After completion of the reaction, dry DMF, dissolved in ethyl acetate and water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil, brown powder 4b (100 mg, 66%) was obtained by column chromatography (methanol: dichloromethane = 1: 50).

Reference： [1]Patent: WO2010/56960,2010,A1 .Location in patent: Page/Page column 36-37
[2]Patent: CN107151240,2017,A .Location in patent: Paragraph 0165; 0166; 0167

21
[ 875765-03-0 ]
[ 399-96-2 ]
[ 875765-04-1 ]

Yield	Reaction Conditions	Operation in experiment
85%		To a round bottom flask equipped with a magnetic stir bar was added 4-aminophenol (0.146g, 1.16 mmol, 2.0 eq) and DMF (3 ml). The mixture was cooled to 0 C followed by the addition of NaH (0.051g, 2.6 mmol, 2.2 eq). After stirring for 10 minutes 4-chloro-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6- carboxylic acid ethyl ester (0.17 g, 0.47 mmol, 1.0 eq.) was added and the reaction was allowed to warm to room temperature, and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 ml), washed (2x) water, (Ix) NaHCO3, (2x) 5% LiCl, (Ix) brine, and dried over sodium sulfate. Upon removal of solvent in vacuo, 4- chloro-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid ethyl ester was obtained as a cream solid (0.18 g, 85%). MS (ESI) for C2)H27FN4O4Si: 447 (MH+).

Reference： [1]Patent: WO2006/14325,2006,A2 .Location in patent: Page/Page column 59-62

22
[ 300816-22-2 ]
[ 399-96-2 ]
[ 1335636-32-2 ]

Yield	Reaction Conditions	Operation in experiment
93.2%		To the solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (41 mg, 0.32 mmol) in dried DMF (3 mL), was added NaH (13 mg, 0.54 mmol). The mixture was stirred at 0 C for 10 min, and then a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine 4i (50 mg, 0.19 mmol) in dried DMF (1 mL) was added. The mixture was stirred at 0 C for 1.5 h. Ice water (5 mL) was added to quench the reaction and the mixture was extracted by Et2O (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatograph.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

23
[ 384351-45-5 ]
[ 399-96-2 ]
[ 1321618-77-2 ]

Yield	Reaction Conditions	Operation in experiment
88.9%		To the solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (41 mg, 0.32 mmol) in dried DMF (3 mL), was added NaH (13 mg, 0.54 mmol). The mixture was stirred at 0 C for 10 min, and then a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine 4i (50 mg, 0.19 mmol) in dried DMF (1 mL) was added. The mixture was stirred at 0 C for 1.5 h. Ice water (5 mL) was added to quench the reaction and the mixture was extracted by Et2O (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatograph to give compound 5i (60 mg, 88.9%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3) delta: 3.76 (s, 2H), 6.43 (d, J = 9.0 Hz, 1H), 6.49 (m, 1H), 6.89 (t, J = 8.4 Hz, 1H), 7.09 (t, J = 8.4 Hz, 2H), 7.34 (s, 1H), 7.57 (t, J = 8.4 Hz, 2H), 8.63 (s, 1H); 13C NMR (100 MHz, CDCl3) delta: 103.2 (d, J = 21.4 Hz), 110.4, 114.8 (d, J = 21.9 Hz), 116.7, 123.0, 124.0, 130.4 (d, J = 13.2 Hz), 131.0 (d, J = 8.2 Hz), 131.6, 134.7, 145.8 (d, J = 9.5 Hz), 153.1, 154.5 (d, J = 245.1 Hz), 162.5 (d, J = 245.5 Hz), 163.6, 170.1; MS (EI) m/z: 355 (M+).

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

24
[ 873306-25-3 ]
[ 399-96-2 ]
[ 1336879-45-8 ]

Yield	Reaction Conditions	Operation in experiment
75%		Under Ar protection, 563 mg of <strong>[399-96-2]4-amino-2-fluorophenol</strong> was dissolved in 20 mL of DMF at 0C, 300 mg ofNaH was added in portions, stirred for 30 min, 600 mg (compound 38) was dissolved in 10 mL of DMF, and then added dropwise into the reaction system and reacted at 0C for 4 h. The solution was quenched by addition of saturated NH4Cl solution, extracted with EA three times, subjecting same to rotary drying and column chromatography to obtain 628 g (75%) of products. 1H NMR (400 MHz, d6-DMSO) delta 8.55 (s, 1H), 8.46 (s, 1H), 7.80 (m, 2H), 7.48 (m, 2H), 7.40 (t, J = 7.2 Hz, 1H), 7.06 (t, J = 4.8 Hz, 1H), 6.49 (dd, J = 13.2, 2.4 Hz, 1H), 6.40 (dd, J = 8.8, 2.4 Hz, 1H), 5.39 (s, 2H).

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[2]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0197; 0201
[3]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

25
[ 1321618-96-5 ]
[ 399-96-2 ]
[ 1336879-40-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

26
[ 1321618-96-5 ]
[ 399-96-2 ]
[ 1321619-00-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

27
[ 399-96-2 ]
[ 81765-97-1 ]
[ 1335636-33-3 ]

Yield	Reaction Conditions	Operation in experiment
		To the solution of 4-amino-2-fluorophenol (41 mg, 0.32 mmol) in dried DMF (3 mL), was added NaH (13 mg, 0.54 mmol). The mixture was stirred at 0 °C for 10 min, and then a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine 4i (50 mg, 0.19 mmol) in dried DMF (1 mL) was added. The mixture was stirred at 0 °C for 1.5 h. Ice water (5 mL) was added to quench the reaction and the mixture was extracted by Et2O (3 .x. 10 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatograph.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

28
[ 399-96-2 ]
[ 81765-97-1 ]
[ 1321618-91-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

29
[ 399-96-2 ]
[ 35970-79-7 ]
[ 1335636-31-1 ]

Yield	Reaction Conditions	Operation in experiment
87.6%		To the solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (41 mg, 0.32 mmol) in dried DMF (3 mL), was added NaH (13 mg, 0.54 mmol). The mixture was stirred at 0 C for 10 min, and then a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine 4i (50 mg, 0.19 mmol) in dried DMF (1 mL) was added. The mixture was stirred at 0 C for 1.5 h. Ice water (5 mL) was added to quench the reaction and the mixture was extracted by Et2O (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatograph.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

30
[ 399-96-2 ]
[ 182198-35-2 ]
[ 1321618-70-5 ]

Yield	Reaction Conditions	Operation in experiment
95%	With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 2h;	The compound 6d (246 mg, 1 mmol)<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (254 mg, 2 mmol)After dissolving in 1 ml of DMF,The mixture was thoroughly stirred under ice bath and sodium hydride (48 mg, 2 mmol)Reaction at 0C for 2 h,After the reaction is complete,Rotate dry DMF, soluble in ethyl acetate and water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil,Brown powder 6e (310 mg, 95%) was obtained by column chromatography (petroleum ether: ethyl acetate = 4: 1).

Reference： [1]Patent: CN107151240,2017,A .Location in patent: Paragraph 0196; 0197; 0198
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

31
[ 399-96-2 ]
[ 40106-58-9 ]
[ 1335636-34-4 ]

Yield	Reaction Conditions	Operation in experiment
		To the solution of 4-amino-2-fluorophenol (41 mg, 0.32 mmol) in dried DMF (3 mL), was added NaH (13 mg, 0.54 mmol). The mixture was stirred at 0 C for 10 min, and then a solution of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine 4i (50 mg, 0.19 mmol) in dried DMF (1 mL) was added. The mixture was stirred at 0 C for 1.5 h. Ice water (5 mL) was added to quench the reaction and the mixture was extracted by Et2O (3 × 10 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatograph.

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

32
[ 399-96-2 ]
[ 40106-58-9 ]
[ 1321618-92-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 3906 - 3918

33
[ 1341216-35-0 ]
[ 1342836-83-2 ]
[ 399-96-2 ]
[ 1342836-88-7 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In potassium tert-butylate; water;	Step 3. tert-butyl 4-(2-(4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)-1H-imidazol-1-yl)ethyl)piperazine-1-carboxylate (306) To a stirred solution of 4-amino-2-fluorophenol x HCl (1.64 g, 10.05 mmol) in NMP (30 mL) was added t-BuOK (2.25 g, 20.1 mmol). After 30 min, compound 305 (3.75 g, 8.37 mmol) was added and the reaction mixture was heated at 100 C. for 1 h. A solution of 4-amino-2-fluorophenol HCl (1.64 g, 10.05 mmol) in NMP (30 mL) in a separate flask was treated with t-BuOK (2.25 g, 20.1 mmol) and the resultant phenolate solution was added to the reaction mixture at 100 C. After 30 min, the reaction was quenched by addition of water and the precipitate was collected by filtration, dried and triturated with MTBE to afford the title compound 306 (2.10 g, 3.90 mmol, 47% yield) as a beige solid. MS (m/z): 539.39 (M+H).

Reference： [1]Patent: US2011/257100,2011,A1

34
[ 1265634-73-8 ]
[ 399-96-2 ]
[ 1265635-29-7 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate; In N,N-dimethyl-formamide; at 150℃; for 4h;	1 .4 400 mg (1 .31 mmol) of 4, 250 mg (1 .97 mmol, 1 .5 eq.) of 4-amino-2-fluoro- phenol and 854 mg (2.62 mmol, 2.0 eq.) of caesium carbonate are suspended in 1 0 ml of DMF and stirred at 150C for 4 hours. The solvent is then removed by distillation in vacuo, and the residue is chromatographed on about 50 g of silica gel with the eluent DCM/methanol (99/1 v/v), giving 222 mg (43%) of 5 as a crystalline solid.

Reference： [1]Patent: WO2013/22519,2013,A1 .Location in patent: Page/Page column 37
[2]Patent: US2012/190654,2012,A1 .Location in patent: Page/Page column 23-24

35
[ 399-96-2 ]
[ 122-51-0 ]
[ 1037798-26-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium azide; acetic acid; at 140℃; for 5h;	A mixture of the aniline (5 g, 39.4 mmol), HC(OEt)3 (17.4 g, 118.1 mmol) and NaN3 (3.8g, 59.1 mmol) in HOAc (80 mL) was stirred at 140 C for 5 hours. Then the mixture wasadjusted to pH= 12, and extracted with EtOAc (100 mL x 3). The organic layers were dried overanhydrous Na2S04 ,concentrated and purified by column chromatography (PE: EtOAc = 10:1 ~3:1) to give the compound as a yellow solid (4.0 g, yield: 56%). 1H NMR (400 MHz, MeOH) 820 9.66 (s, 1H), 7.69-7.65 (m, 1H), 7.54-7.50 (m, 1H), 7.16-7.12 (m, 1H).
26.7%	With sodium azide; In acetic acid; at 100℃; for 0.333333h;	A mixture of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (1.01 g, 7.95 mmol), sodium azide (0.73 g, 11.23 mmol), and triethoxymethane (1.7 mL, 10.29 mmol) in AcOH (10 mL) was stirred at 100 C (oil bath). After 20 min, the mixture was partitioned between water and EtOAc. The organic phases were combined, dried over MgS04, filtered, and concentrated. The residue was purified by column chromatography (Si02, hexane/EtOAc gradient). Fractions containing the desired product were combined and concentrated. The residue was triturated with MTBE to give the title compound (0.403 g, 26.7%) as a tan solid. Exact mass calculated for C7H5FN4O: 180.04, found: LCMS mlz = 181.2 [M+H]+; lU NMR (400 MHz, DMSO) delta ppm 7.15-7.19 (m, 1H), 7.54-7.56(m, 1H), 7.79-7.82 (m, 1H), 9.94 (s, 1H), 10.6 (s, 1H).
	With sodium azide; In acetic acid; for 1.2h;Inert atmosphere; Reflux;	General procedure: Intermediate 33[198]Synthesis of 2-fluoro-4-(1H-tetrazol-1-yl)phenol[199] [200]4.8 g of <strong>[399-96-2]4-amino-2-fluorophenol</strong>was dissolved in 100 mL of acetic acid with stirring in a 250 mL flaskunder a nitrogen atmosphere. 3.3 g of sodium azide and 7.58 g of triethyl orthofomate were added dropwise to the solutionwhich was then heated under reflux for 1.2 hours or more. After completion ofthe reaction, the reaction solution was distilled under reduced pressure toremove acetic acid, after which it was dissolved in 100 mL of EA and washedwith 100 mL of distilled water and 100 mL of saturated NaHCO3 aqueous solution. The EA layer wasdried with anhydrous magnesium sulfate, concentrated and then crystallizedusing EA and hexane, thereby obtaining the title compound.[201]1H NMR (400, DMSO) : 10.68 (1H, s), 9.91 (1H, s), 7.81(1H, d), 7.56 (1H, d), 7.17 (1H, t).

Reference： [1]Patent: WO2014/52379,2014,A1 .Location in patent: Page/Page column 54
[2]Patent: WO2012/145361,2012,A1 .Location in patent: Page/Page column 168; 169
[3]Patent: WO2013/105753,2013,A1 .Location in patent: Paragraph 197; 198; 199; 200; 201

36
[ 628-36-4 ]
[ 399-96-2 ]
[ 1339328-46-9 ]

Yield	Reaction Conditions	Operation in experiment
36.5%	With toluene-4-sulfonic acid; In N,N-dimethyl-formamide; toluene; at 120℃; for 3h;microwave irradiation;	A mixture of 4-amino-2-fluorophenol (509 mg, 4.00 mmol), N-formylformohydrazide(426 mg, 4.84 mmol), and /?-toluenesulfonic acid (826 mg, 4.34 mmol) in toluene (15 mL) and DMF (1.5 mL) was heated under microwave irradiation at 120 °C for 3 h. The mixture was concentrated and the residue was partitioned between DCM and water. The organic phases were combined, dried over MgS04, filtered, and concentrated. The residue was purified by column chromatography (Si02, hexane/EtOAc gradient and then EtOAc/MeOH 10: 1) to give the title compound as a tan solid (262 mg, 36.5percent). Exact mass calculated for C8H6FN30: 179.05, found: LCMS mlz = 180.2 [M+H]+; lU NMR (400 MHz, DMSO- ) delta ppm 7.06-7.10 (m, 1H), 7.32- 7.35(m, 1H), 7.62-7.66 (m, 1H), 8.98 (s, 2H). 10.2 (s, 1H).

Reference： [1]Patent: WO2012/145361,2012,A1 .Location in patent: Page/Page column 169

37
[ 286371-49-1 ]
[ 399-96-2 ]
[ 479690-04-5 ]

Yield	Reaction Conditions	Operation in experiment
73%		Sodium hydride (60% disp. in mineral oil, 0.534 g, 13.3 mmol) was added to 4-amino-2- fluorophenol in dry N,N-dimethylformamide (10.3 mL) at rt and stirred for 30 min under an atmosphere of nitrogen. Then solid 7-benzyloxy-4-chloro-6-methoxyquinoline (2.00 g, 6.67 mmol) was added and the reaction stirred at 100 C for 30 h. The mixture was concentrated, dissolved in EtOAc ( about 75 mL), and washed with IN Na2C03, water and brine, then dried over MgSC^. The product was chromatographed on silica gel (5%MeOH/DCM) to give a brown solid 1.9 g (73%). LCMS m/z = 391 (M + 1); 1H NMR (DMSO) ?: 8.43 (s, 1H), 7.36-7.52 (m, 7H), 7.07 (m, 1H), 6.38-6.56 (m, 3H), 5.50 (m, 2H), 5.3 (s, 2H), 3.95 (s, 3H).

Reference： [1]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 67

38
[ 35654-56-9 ]
[ 399-96-2 ]
[ 347161-74-4 ]

Yield	Reaction Conditions	Operation in experiment
70%		Sodium hydride (60% disp. in mineral oil; 1.3 g, 33.5 mmol) was added to 4-amino-2- fluoro-phenol in dry N,N-dimethylformamide (50 mL) and stirred at rt for 30 min under an atmosphere of nitrogen. Then solid 4-chloro-6,7-dimethoxyquinoline (5.0 g, 22.4 mmol) was added and the reaction stirred at 100C for 30 h. The mixture was concentrated, dissolved in EtOAc (100 mL) and washed with IN Na2C03, water and brine, then dried over MgSC^. The product was chromatographed on silica gel (5%methanol/dichloromethane (MeOH/DCM)) to give a tan solid 4.9 g, 70%. mp = 172-5 C; LCMS m/z = 315 (M + 1); 1H NMR (DMSO) ?: 8.48 (d, 1H, J = 5.4 Hz), 7.50 (s, 1H), 7.38 (s, 1H), 7.07 (t, 1H, J = 8.6 Hz), 6.53,6.56 (dd, 1H, J = 2.6, 13.4 Hz), 6.45, 6.47 (dd, 1H, J = 2, 8 Hz), 6.38, 6.39 (dd, 1H, J = 1, 5.4 Hz), 5.48 (s, 2H), 3.94 (s, 6H).
66%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 1.5h;Microwave irradiation;	The compound 4-chloro-6,7-dimethoxyquinoline (110 mg, 0.5 mmol)<strong>[399-96-2]2-fluoro-4-aminophenol</strong> (127 mg, 1 mmol) was dissolved in 1 ml of DMF,Potassium tert-butoxide (112 mg, 1 mmol) was added with vigorous stirring,Then microwave reaction at 80 C for 1.5 h,After completion of the reaction, dry DMF, dissolved in ethyl acetate and water,Saturated aqueous ammonium chloride solution.After drying the solvent to give a black oil,Brown powder 3a (100 mg, 66%) was obtained by column chromatography (ethyl acetate: petroleum ether = 1: 1).
1.50 g	With sodium t-butanolate; In N,N-dimethyl acetamide; at 105℃; for 12h;	Take a 100ml three-necked flask, add 2.23g 4-chloro-6,7-dimethoxyquinoline, 1.91g <strong>[399-96-2]4-amino-2-fluorophenol</strong>, 1.44g sodium tert-butoxide, 10ml DMAC, and react at 105 C for 12h. The basic reaction of the raw materials was complete, poured into 100 ml of water, and filtered with suction to obtain a brown-black solid. Column chromatography gave 1.50 g of compound I-2-1.

Reference： [1]Patent: WO2013/74633,2013,A1 .Location in patent: Page/Page column 50
[2]Patent: CN107151240,2017,A .Location in patent: Paragraph 0154; 0155; 0156
[3]Patent: CN110330479,2019,A .Location in patent: Paragraph 0087-0089

39
[ 399-96-2 ]
[ 1341216-35-0 ]

Reference： [1]Synthetic Communications,2013,vol. 43,p. 2949 - 2954

40
[ 1005787-88-1 ]
[ 399-96-2 ]
N-[6-(4-Amino-2-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate; In dimethyl sulfoxide; at 100℃; for 5h;	To a solution of 4 (4.80g, 14.6mmol) and <strong>[399-96-2]4-amino-2-fluorophenol</strong> (2.48g, 19.5mmol) in DMSO (25mL) was added cesium carbonate (9.77g, 30.0mmol), and the mixture was stirred at 100C for 5h. H2O (100mL) and THF (100mL) was added to the mixture. The precipitate was filtered through Celite pad, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give 5b (3.50g, 71%) as white solid. 1H NMR (DMSO-d6) delta 0.49-0.96 (4H, m), 1.77-2.02 (1H, m), 5.41 (2H, s), 6.37-6.43 (1H, m), 6.49 (1H, dd, J=13.2, 2.5Hz), 6.99-7.09 (2H, m), 7.88 (1H, s), 7.99 (1H, d, J=9.6Hz), 11.04 (1H, s).

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 7686 - 7698

41
[ 346599-62-0 ]
[ 399-96-2 ]
[ 1528549-21-4 ]

Yield	Reaction Conditions	Operation in experiment
660 mg	With caesium carbonate; In dimethyl sulfoxide; at 135℃;Inert atmosphere;	Compound 52 (1.12g, 66mmol), fluoro-4-aminophenol ( 930mg, 73mmol) and cesiumcarbonate ( 4.30mg, 132mmoD was mixed in DMS0(15ml) and heated to 135 DC overnight underN2. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and dried. Evaporation of the organic layer gave compound 53 (660mg).

Reference： [1]Patent: WO2014/713,2014,A1 .Location in patent: Page/Page column 42

42
[ 83-10-3 ]
[ 399-96-2 ]
[ 1552281-00-1 ]

Yield	Reaction Conditions	Operation in experiment
93.4%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 45℃; for 12h;	Step 1 ) N-(3-fluoro-4-hvdroxyphenyl)- 1 ,5-dimethyl-3 -oxo-2-phenyl-2,3 -dihydro- 1H- pyrazole-4- carboxamide [0193] To a suspension of 4-amino-2-fluorophenol (2.54 g, 20 mmol) and 1,5- dimethyl-3 -oxo-2- phenyl-2,3 -dihydro- lH-pyrazole-4-carboxylic acid (4.74 g, 20.4 mmol) in DCM (60 mL) were added EDCI (4.6 g, 24 mmol) and HOAT (0.54 g, 4 mmol). The reaction was stirred at 45 C for 12 hours, then cool to rt, quenched with H20 (10 mL), and stirred for another 4 hours. The solid was obtained by filtration and washed with DCM (20 mL x 3), then dried at 60 C in vacuo for 12 hours to give the title compound as a pale yellow solid (6.37 g, 93.4%). MS (ESI, pos. ion) m/z: 342.1 [M+H]+; NMR (400 MHz, DMSO-i): delta (ppm) 10.59 (s, 1H), 9.58 (s, 1H), 7.64 (dd, J= 2.4 Hz, 13.5 Hz, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.42 (m, 2H), 6.97 (m, 1H), 6.88 (dd, J= 9.6 Hz, 8.8 Hz, 1H), 3.34 (s, 3H), 2.70 (s, 3H).
93.4%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 45℃; for 12h;	Step 1) N-(3-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide To a suspension of 4-amino-2-fluorophenol (2.54 g, 20 mmol) and <strong>[83-10-3]1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid</strong> (4.74 g, 20.4 mmol) in DCM (60 mL) were added EDCI (4.6 g, 24 mmol) and HOAT (0.54 g, 4 mmol). The reaction was stirred at 45 C. for 12 hours, then cool to rt, quenched with H2O (10 mL), and stirred for another 4 hours. The solid was obtained by filtration and washed with DCM (20 mL*3), then dried at 60 C. in vacuo for 12 hours to give the title compound as a pale yellow solid (6.37 g, 93.4%). MS (ESI, pos. ion) m/z: 342.1 [M+H]+; 1H NMR (400 MHz, DMSO-d6): delta (ppm) 10.59 (s, 1H), 9.58 (s, 1H), 7.64 (dd, J=2.4 Hz, 13.5 Hz, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.42 (m, 2H), 6.97 (m, 1H), 6.88 (dd, J=9.6 Hz, 8.8 Hz, 1H), 3.34 (s, 3H), 2.70 (s, 3H).

Reference： [1]Patent: WO2014/22116,2014,A2 .Location in patent: Paragraph 0193
[2]Patent: US2015/37280,2015,A1 .Location in patent: Paragraph 0357-0359

43
[ 7677-24-9 ]
[ 399-96-2 ]
[ 67-64-1 ]
2-((3-fluoro-4-hydroxyphenyl)amino)-2-methylpropanenitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.6%	With trimethylsilyl trifluoromethanesulfonate; In dichloromethane; for 2.5h;Inert atmosphere;	4-Amino-2-fluorophenol 1a (6 g, 0.05 mol) was dissolved in 90 mL of a mixture of acetone and dichloromethane (V/V=1:2), followed by addition of trimethylsilyl cyanide (9.4 mL, 0.07 mol) and trifluoromethanesulfonic acid trimethylsilyl ester (0.4 mL, 2.30 mmol). The reaction solution was stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 2-((3-fluoro-4-hydroxyphenyl)amino)-2-methylpropanenitrile 1b (7.02 g, yield 76.6%) as a brown solid MS m/z (ESI): 194.4 [M+1]
76.6%	With trimethylsilyl trifluoromethanesulfonate; In dichloromethane; at 20 - 30℃; for 2.5h;	4-Amino-2-fluorophenol 1a (6 g, 0.05 mol) was dissolved in 90 mL of a mixture of acetone and dichloromethane (v/v=1:2), followed by addition of trimethylsilyl cyanide (9.4 mL, 0.07 mol) and trifluoromethanesulfonic acid trimethylsilyl ester (0.4 mL, 2.30 mmol). The reaction solution was stirred for 2.5 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with elution system B to obtain the title compound 2-((3-fluoro-4-hydroxyphenyl)amino)-2-methylpropanenitrile 1b (7.02 g, yield 76.6%) as a brown solid. MS m/z (ESI): 194.4 [M+1]

Reference： [1]Patent: EP2894151,2015,A1 .Location in patent: Paragraph 0112; 0113
[2]Patent: US2015/225381,2015,A1 .Location in patent: Paragraph 0133-0135

44
[ 3697-66-3 ]
[ 399-96-2 ]
ethyl 1-[(3-fluoro-4-hydroxyphenyl)carbamoyl]cyclopropane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%		To a 500 ml three-necked flask was added 20 g of 1- (ethoxycarbonyl) cyclopropanecarboxylic acid prepared in Example 1 and tetrahydrofuran 200ml, cooled to 0 ~ 10 , dropping 18.0ml of thionyl chloride, 0 ~ 10 for 2h, after the end of the reaction, the solvent was evaporated under reduced pressure to give colorless translucent oil. To the oil was added 100 ml of tetrahydrofuran. 300 ml of tetrahydrofuran, 28.8 g of 4-amino-2-fluorophenol and 26.5 ml of triethylamine were added to a 1 L three-necked flask, and the reaction solution was added dropwise at 0 to 10 C, and the reaction was carried out at room temperature for 2 hours. The filtrate was evaporated under reduced pressure to remove the solvent. Ethyl acetate (300 ml) and 2 mol / L hydrochloric acid (200 ml) were added to the residue, and the layers were stirred and the organic phase was washed with 2 mol / L hydrochloric acid (200 ml) and washed with saturated sodium bicarbonate solution (200 ml) Sodium sulfate. (Mobile phase V / V: dichloromethane / methanol = 20/1) to give 18.9 g (60.0%) of a yellow solid
	With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; at -15℃; for 5h;	General procedure: Diethyl cyclopropane-1,1-dicarboxylatederivatives (1.0 eq.) were dissolved in EtOH. KOH (1.0 eq.)in ethanol solution was added and stirred for 5 h. After the completion of the reaction, the intermediatewas dissolved in THF solution at 15 C. 4-Methylmorpholine (1.2 eq.), isobutyl chloroformate(1.0 eq.) and 4-amino-2-fluorophenol (1.0 eq.) were added. The crude product was purified by columnchromatography, and the above process was repeated. The final product compounds 12 were obtained.

Reference： [1]Patent: CN103965104,2017,B .Location in patent: Paragraph 0127-0130
[2]Molecules,2016,vol. 21

45
[ 54450-84-9 ]
[ 399-96-2 ]
C₁₄H₁₆FNO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 4-methyl-morpholine; isobutyl chloroformate In tetrahydrofuran at -15℃; for 5h;	3.1.5. General Procedure for the Preparation ofN1-(3-Fluoro-4-hydroxyphenyl)-N3-(4-fluorophenyl)malonamide Derivatives Compounds 12 General procedure: Diethyl cyclopropane-1,1-dicarboxylatederivatives (1.0 eq.) were dissolved in EtOH. KOH (1.0 eq.)in ethanol solution was added and stirred for 5 h. After the completion of the reaction, the intermediatewas dissolved in THF solution at 15 °C. 4-Methylmorpholine (1.2 eq.), isobutyl chloroformate(1.0 eq.) and 4-amino-2-fluorophenol (1.0 eq.) were added. The crude product was purified by columnchromatography, and the above process was repeated. The final product compounds 12 were obtained.

Reference： [1]Jiang, Yingnan; Zhang, Ke; Gao, Suyu; Wang, Guihua; Huang, Jian; Wang, Jinhui; Chen, Lixia [Molecules, 2016, vol. 21, # 5]

46
[ 1527475-76-8 ]
[ 399-96-2 ]
3-fluoro-4-((5-(1-methyl-1H-pyrazole-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64%		Under Ar protection, <strong>[399-96-2]4-amino-2-fluorophenol</strong> (430 mg, 3.4 mmol, 1.7 eq) was dissolved in 20 mL of DMF, NaH (230 mg, 5.8 mmol, 2.9 eq) was added and reacted at 0C for 15 min, and 4-chloro-5-(1-methyl-1H-pyrazole-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (720 mg, 2.0 mmol, 1.0 eq) was added with stirring, and stirred overnight. The reaction was quenched with saturated NH4Cl solution, and extracted with EtOAc three times, subjecting same to column chromotography to obtain 580 mg (64%) of products. 1H NMR (400 MHz, d6-DMSO): delta 8.34 (s, 1H), 7.99 (s, 1H), 7.82 (m, 2H), 7.07 (t, J = 7.2 Hz, 1H), 6.49 (dd, J = 10.4, 2.0 Hz, 1H), 6.42 (dd, J = 6.8, 2.0 Hz, 1H), 5.61 (s, 2H), 5.36 (s, 2H), 3.85 (s, 3H), 3.55 (t, J = 6.4 Hz, 2H); 0.85 (t, J = 6.4 Hz, 2H); -0.08 (s, 9H).

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[2]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0208; 0212

47
[ 99586-65-9 ]
[ 399-96-2 ]
[ 868733-71-5 ]

Yield	Reaction Conditions	Operation in experiment
85%		Under Ar protection, 4-amino-2-fluorophenol (2.43 g, 19 mmol, 1.5 eq) was dissolved in 25 mL of DMSO, t-BuOK (2.3 g, 21 mmol, 1.6 eq) was added and reacted for 15 min at room temperature, and <strong>[99586-65-9]4-chloropyridine-2-carboxamide</strong> (2 g, 13 mmol, 1.0 eq) was added with stirring, heated to 80C and reacted for 1 h. The solution was cooled to room temperature, 25 mL of 1 M NaOH solution and 25 mL of water were added, stirred for 5 h, filtered, washed with water and dried to obtain 2.7 g (85%) of products. 1H NMR (400 MHz, d6-DMSO) delta 8.49 (d, J = 5.6 Hz, 1H), 8.09 (s, 1H), 7.68 (s, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.14 (q, J = 2.8 Hz, 1H), 7.02 (t, J = 8.8 Hz, 1H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H), 6.53 (dd, J = 13.2, 2.4 Hz, 1H), 6.44 (dd, J = 8.4, 1.6 Hz, 1H), 5.50 (s, 2H).

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 6807 - 6825
[2]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0203; 0204

48
[ 399-96-2 ]
[ 2941-58-4 ]
2-fluoro-4-((6-methoxybenzo[d]thiazol-2-yl)amino)phenol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With toluene-4-sulfonic acid; In ethanol; at 80℃; for 4h;	Compound 5 (50mg, 0.2 mmol) and 4-amino-2-fluorophenol (30.5mg, 0.24mmol) was dissolved in EtOH (2 ml) and pTsOH-H2O(30.4 mg, 0.16 mmol) and the mixture was stirred for 4 hours at 80 C. After checking the completion of the reaction, then cooled at room temperature, then evaporated under reduced pressure to remove thesolvent. The concentrated residue was extracted with ethyl acetate (5 ml) and water (3 x 3ml). The extracted organic layer wasfiltered, and then dried over anhydrous magnesium sulfate, filtered and distilled under a reduced pressure fluid and purified bycolumn chromatography. As a result, 6 compound (43 mg, yield: 75%) was obtained.

Reference： [1]Patent: KR101659952,2016,B1 .Location in patent: Paragraph 0218; 0219; 0222

49
[ 615-20-3 ]
[ 399-96-2 ]
4-(benzo[d]thiazol-2-ylamino)-2-fluorophenol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With toluene-4-sulfonic acid; In ethanol; at 80℃; for 4h;	2-Chlorobenzothiazole(169 mg, 1 mmol) and EtOH (5 ml), and <strong>[399-96-2]3-fluoro-4-hydroxyaniline</strong> (127 mg, 1 mmol) was dissolved in and p-TsOH*H2O (30.4 mg, 0.1 mmol) was added and the mixture was stirred for 4 hours at 80 C. After checking the completion of the reaction, then cooled at room temperature, then evaporated under reducedpressure to remove the solvent. The concentrated residue was extracted with ethyl acetate (5 ml) and water (3 x 3ml). The extractedorganic layer was filtered and then dried over anhydrous magnesium sulfate, the reduced pressure of the filtrate was evaporated,and purified by column chromatography, and diluted with an equal volume of HCl solution and dried. As a result, 4-(benzo[d]thiazol-2-ylamino)-2-fluorophenol was obtained (222 mg, 75% yield).

Reference： [1]Patent: KR101659952,2016,B1 .Location in patent: Paragraph 0227-0230

50
[ 6626-40-0 ]
[ 399-96-2 ]
C₁₉H₁₃ClFN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91.1%	With sulfuric acid; In N,N-dimethyl-formamide; at 120℃;	First, 50 ml of DMF (N, N-dimethylformamide) was addedAnd 13 ml of concentrated sulfuric acid,Further 12.9 g of p-fluoro-o-fluorophenol and 27.8 g of finely ground compound 4 were heated to 120 C,To stir,The plate was traced to compound 4 completely,While hot filter,The precipitate was washed with dilute aqueous ammonia,And then washed with cold water,And finally with a small amount of 95% ethanol washing,Dried to give a red-orange crystalline solid (Compound 5c),32 g, yield: 91.1%

Reference： [1]Patent: CN106032379,2016,A .Location in patent: Paragraph 0107; 0108

51
[ 399-96-2 ]
[ 74420-05-6 ]
3-fluoro-4-((1-methyl-1H-pyrrolo [2,3-b]pyridin-4-yl)oxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With sodium carbonate; sodium hydroxide; In tetrahydrofuran; 1,4-dioxane; water; at 80℃;	General procedure: P-aminophenol or 2-fluoro-4-aminphenol 18a-b (0.1 mol)whichwas dissolved in tetrahydrofuran (50 ml),was added to a 1,4-dioxane/H2O(50 ml, 5:1) solution of compounds 17a-b or 20a-b,sodium carbonate and hydrogen sodium at 80 C for 2 h. Then thesolution was concentrated in vacuum and washed with water,filtered to give a solid.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 538 - 551

52
[ 399-96-2 ]
[ 7781-10-4 ]
3-fluoro-4-((7-methyl-7H-pyrrolo[2,3-d]pyrimidine-4-yl)oxy)aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59%	With sodium carbonate; sodium hydroxide; In tetrahydrofuran; 1,4-dioxane; water; at 80℃;	General procedure: P-aminophenol or 2-fluoro-4-aminphenol 18a-b (0.1 mol)whichwas dissolved in tetrahydrofuran (50 ml),was added to a 1,4-dioxane/H2O(50 ml, 5:1) solution of compounds 17a-b or 20a-b,sodium carbonate and hydrogen sodium at 80 C for 2 h. Then thesolution was concentrated in vacuum and washed with water,filtered to give a solid.

Reference： [1]European Journal of Medicinal Chemistry,2017,vol. 141,p. 538 - 551
[2]Chemical Biology and Drug Design,2018,vol. 92,p. 1301 - 1314

53
[ 201230-82-2 ]
[ 399-96-2 ]
[ 536-74-3 ]
C₁₅H₁₂FNO₂ [ No CAS ]

Reference： [1]ACS Catalysis,2017,vol. 7,p. 2220 - 2229

54
[ 201230-82-2 ]
[ 399-96-2 ]
[ 536-74-3 ]
C₁₅H₁₂FNO₂ [ No CAS ]

Reference： [1]ACS Catalysis,2017,vol. 7,p. 2220 - 2229

55
[ 399-96-2 ]
[ 16269-66-2 ]
3‐fluoro‐4‐{thieno[3,2‐d]pyrimidin‐4‐yloxy}aniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate; sodium hydroxide In tetrahydrofuran; 1,4-dioxane; water at 80℃;	5.9. General procedure for the key intermediate 21a, 22a-b and 23a-b General procedure: 4-Aminophenol or 2-fluoro-4-aminphenol 20a-b (0.1 mol)which was dissolved in tetrahydrofuran (50 ml), was added to a1,4-dioxane/H2O (50 ml, 5:1) solution of compounds 19a-c,sodium carbonate and hydrogen sodium at 80 C for 2 h. Thenthe solution was concentrated in vacuum and washed with water,filtered to give a solid.
	With sodium hydride In dimethyl sulfoxide at 0 - 60℃;

Reference： [1]Wang, Linxiao; Xu, Shan; Chen, Xiuying; Liu, Xiaobo; Duan, Yongli; Kong, Dejia; Zhao, Dandan; Zheng, Pengwu; Tang, Qidong; Zhu, Wufu [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 245 - 256]
[2]Fang, Sen-Biao; Li, Hui-Jing; Nan, Xiang; Wu, Rui; Wu, Yan-Chao; Zhang, Jing; Zhang, Zhi-Zhou [European Journal of Medicinal Chemistry, 2020, vol. 200]

56
[ 399-96-2 ]
[ 162364-72-9 ]
4-((7-benzyloxy)-(6-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 2h;	To the reaction flask were added <strong>[162364-72-9]7-benzyloxy-4-chloro-6-methoxyquinazoline</strong> (4.5 g, 15 mmol), 4-amino-2-fluorophenol (2.3 g, 18 mmol), potassium tert-butoxide (2.4 g, 21 mmol), and DMF (250 mL), heated to 80C and reacted for 2 hours, the reaction was then stopped, and the solvent was removed under reduced pressure, subjecting same to drying and column chromotography to obtain 3.6 g (62%) of 4-((7-benzyloxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline. 1H NMR (400 MHz, d6-DMSO) δ 8.53 (s, 1H), 7.55 (s, 1H), 7.52 (m, 2H), 7.49 (s, 1H), 7.44 (t, J= 7.2 Hz, 2H), 7.37 (t, J= 7.2 Hz, 1H), 7.04 (t, J= 8.8 Hz, 1H), 6.50 (dd, J= 2.4, 13.2 Hz, 1H), 6.42 (dd, J= 2.4, 8.8 Hz, 1H), 5.39 (s, 2H), 5.35 (s, 2H), 3.97 (s, 3H). MS (ESI), m/z: 391 [M+H]+.
62%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 2h;	To a reaction flask were added 7- benzyloxy-4-chloro-6-methoxyquinazoline (4.5 g, 15 mmol), 4-amino-2-fluorophenol (2.3 g, 18 mmol), potassium tert-butoxide (2.4 g, 21 mmol) and DMF (250 mL), and the mixture was heated to 80 C for reaction for 2 hours. After the reaction was stopped and the solvent was removed under reduced pressure, the mixture was subjected to dry column chromatography to give 3.6 g (62%) of 4-((7-(benzyloxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline. 1H NMR (400 MHz, d6-DMSO) δ 8.53 (s, 1 H), 7.55 (s, 1 H), 7.52 (m, 2 H), 7.49 (s, 1 H), 7.44 (t, J = 7.2 Hz, 2 H), 7.37 (t, J = 7.2 Hz, 1 H), 7.04 (t, J = 8.8 Hz, 1 H), 6.50 (dd, J = 2.4, 13.2 Hz, 1 H), 6.42 (dd, J = 2.4, 8.8 Hz, 1 H), 5.39 (s, 2 H), 5.35 (s, 2 H), 3.97 (s, 3 H). MS (ESI), m/z: 391 [M+H]+.
62%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 80℃; for 2h;	Add <strong>[162364-72-9]7-benzyloxy-4-chloro-6-methoxyquinazoline</strong> (6) (4.5g, 15mmol), 4-amino-2-fluorophenol (2.3g, 18mmol), tert-butyl potassium alkoxide (2.4g, 21mmol), DMF (250mL), heated to 80C and reacted for 2 hours, the reaction was stopped, the solvent was removed under reduced pressure, and the column was dry-processed to obtain 4-((7-(benzyloxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline 3.6 g (62%).

Reference： [1]Patent: EP3339294,2018,A1 .Location in patent: Paragraph 0230; 0231
[2]Patent: EP3778585,2021,A1 .Location in patent: Paragraph 0045; 0050
[3]Patent: CN113278010,2021,A .Location in patent: Paragraph 0150-0151; 0165-0167

57
[ 399-96-2 ]
[ 100-39-0 ]
[ 168268-00-6 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium tert-butylate; In N,N-dimethyl-formamide; at 0℃;	p-hydroxy-3-fluoroaniline (1.0 g, 7.87 mmol) was dissolved in 10 mL of anhydrous DMF, cooled to 0 C., then potassium tert-butoxide (0.88 g, 7.87 mmol) was added thereto, after stirring for 10 min, benzyl bromide (1.35 g, 7.87 mmol) was added therein, and the reaction was monitored by TLC. After the reaction is completed, the resultant was extracted with EA, then washed with saturated NaHCO3 and saturated brine, dried over anhydrous Na2SO4 and concentrated to give the crude compound 37, which was purified by column chromatography to give a colorless liquid, yield 52%. 1H NMR (CDCl3, 300 MHz): delta 7.41-7.28 (m, 5H), 6.91 (dd, 1H), 6.46 (dd, 1H), 6.32 (m, 1H), 4.97 (s, 2H), 4.98 (s, 2H).

Reference： [1]Patent: US2018/244667,2018,A1 .Location in patent: Paragraph 0083

58
[ 399-96-2 ]
[ 13790-39-1 ]
[ 1201939-89-0 ]

Yield	Reaction Conditions	Operation in experiment
65%	With sodium hydride; In dimethyl sulfoxide; at 80℃; for 1h;Inert atmosphere;	Sodium hydride (60 mg, 2.5 mmol) was added to a mixture of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (200mg, 1.6 mmol) and 4-chloro-6,7-dimethoxyquinazoline (424 mg, 1.9 mmol) in DMSO (8 mL)under nitrogen. The resulting mixture was stirred at 80C for 1 hour, then concentrated. The5 crude product was purified by flash silica chromatography, elution gradient 1 to 10% methanolin DCM. Pure fractions were evaporated to dryness to afford the title compound as a black oil(320 mg, 65%). 1H NMR (DMSO-d6, 300 MHz) 8 3.99 (6H, d), 5.42 (2H, s), 6.33- 6.57 (2H,m), 7.06 (lH, t), 7.40 (lH, s), 7.54 (lH, s), 8.56 (lH, s); m/z: ES+ [M+H]+ 316.
64%		To a solution of <strong>[399-96-2]4-amino-2-fluorophenol</strong> (17.8 g, 140 mmol, 1.4 eq) in DMF (200 mL) was added NaH (10 g, 250 mmol, 2.5 eq) at 0 C. The reaction was stirred at rt for 30 min and 4-chloro-6,7-dimethoxyquinazoline (22.4 g, 100 mmol, 1.0 eq) was added to the mixture under stirring. The reaction solution was warmed to 90 C and stirred overnight. After cooling to room temperature, the reaction was quenched with saturated aqueous NH4Cl. The mixture was extracted with ethyl acetate (3×250 mL) twice. The combined organic layer was washed with brine (2×150 mL), dried over Na2SO4, concentrated in vacuo and further purified by flash chromatography on silica gel to get the product as a solid. (20.2 g, 64%). 1H NMR (400 MHz, d6-DMSO) delta 8.54 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.04 (t, J = 8.8 Hz, 1H), 6.50 (dd, J1 = 2.4 Hz, J2 = 12.8 Hz, 1H), 6.42 (dd, J1 = 2.0 Hz, J2 = 8.4 Hz, 1H), 5.38 (s, 2H), 3.98 (s, 3H) , 3.97 (s, 3H). HRMS (ESI) for C16H14FN3O3 [M+H]+, calcd: 316.1044, found: 316.1045.
9.1 g	With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 20 - 60℃; for 2h;	(1)Add <strong>[399-96-2]4-amino-2-fluorophenol</strong> (6.5g, 51mmol) to 100mLEthyl acetate,After stirring at room temperature, diisopropylethylamine (19.4 g, 150 mmol) was added.At the same time, the temperature is raised to 60 C, and 4-chloro-6,7-dimethoxyquinazoline is added.(13.5 g, 60 mmol) of an ethyl acetate solution was slowly added to the above reaction solution.Stop the reaction after 2 hours.Extract twice with water, dry the ethyl acetate layer with anhydrous magnesium sulfate and spin dry4-(6,7-dimethoxyquinazolin-4-yloxy)-3-fluoroaniline(9.1g, 29mmol);

Reference： [1]Patent: WO2018/197643,2018,A1 .Location in patent: Page/Page column 37; 38
[2]European Journal of Medicinal Chemistry,2019,vol. 166,p. 318 - 327
[3]Patent: CN109553612,2019,A .Location in patent: Paragraph 0023; 0024; 0027; 0028; 0031; 0032

59
[ 357927-50-5 ]
[ 399-96-2 ]
C₁₁H₈BrFN₂O [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019

60
[ 399-96-2 ]
[ 1885-14-9 ]
phenyl N-(3-fluoro-4-hydroxyphenyl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 24h;Cooling with ice;	General procedure: To an ice-cooled stirred solution of the appropriate 4-hydroxyarylamine (5 mmol) and DIPEA (0.69 mL, 4 mmol) inanhydrous THF (10 ml) phenylchloroformiate (0.5 mL, 4 mmol) wasadded dropwise. The reaction mixture was stirred at room temperaturefor 24 h, thenwater (100 mL) was added; the mixture wasstirred for additional 2 h, the formed solid filtered off, and vacuumdried to give carbamates. 4.2.2.1. Phenyl N-(3-fluoro-4-hydroxyphenyl)carbamate (3b).Following the general procedure, the title compound was preparedstarting from 2-fluoro-4-hydroxyphenyl amine. Yield 88%. M.p.129e130 C. 1H NMR (DMSO-d6) d 6.91 (m, 1H, Ar), 7.07 (m, 1H, Ar),7.21 (m, 3H, Ar), 7.35 (m, 1H, Ar), 7.43 (m, 2H, Ar), 9.54 (s, 1H, NH),10.09 (s, 1H, OH). IR (Nujol) 3321, 1718, 1615 cm1 m/z 248(M H). Anal. Calcd. for C13H10FNO3 (247.22) C, 63.16; H, 4.08; N,5.67. Found C, 63.23; H, 4.06; N, 5.70.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 182

61
[ 399-96-2 ]
2-chloro-8-isopentyl-7,8-dihydropteridin-6(5H)-one [ No CAS ]
2-((3-fluoro-4-hydroxyphenyl)amino)-8-isopentyl-7,8-dihydropteridin-6(5H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With trifluoroacetic acid; In 2,2,2-trifluoroethanol; at 140℃; for 0.5h;Microwave irradiation;	General procedure: The relevant halogenated heterocycle (1.0equiv.), substituted aniline (2.0 equiv.) and TFA (5.0 equiv.) were takenup in TFE (0.1 M) and heated under microwave irradiation conditionsat 140 C for 30 min before being concentrated in vacuo. The residuewas resuspended in EtOAc:THF (1:1, 20 mL/mmol), washed with saturatedNaHCO3 solution (20 mL/mmol), and the aqueous phase wasfurther extracted with EtOAc:THF (1:1, 3 × 15 mL/mmol). The combinedorganic extracts were washed with brine, dried (MgSO4) andconcentrated in vacuo. The resultant residue was purified via columnchromatography and/or triturated as specified to afford the desired compound.

Reference： [1]Bioorganic and medicinal chemistry,2020,vol. 28

62
[ 399-96-2 ]
[ 1053657-15-0 ]
[ 2685737-78-2 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: 4-amino-2-fluorophenol With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide at 0℃; for 0.166667h; Inert atmosphere; Stage #2: tert-butyl 4-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere;	1.5. tert-butyl 4-(4-amino-2-fluorophenoxy)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (9) To a solution of 4-amino-2-fluorophenol (3) (197 mg, 1.55 mmol) in DMF (6 mL) was added tBuOK (217 mg, 1.94 mmol) at 0°C. The reaction mixture was stirred at 0°C under N2 atmosphere for 10 minutes. Tert-butyl 4-chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (8) (330 mg, 1.29 mmol) was added to the reaction mixture at 0°C. The mixture was stirred at 0°C under N2 atmosphere for 30 minutes. The mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried over MgSO4, filtered and then concentrated. The residue was purified with column chromatography on NH silica gel (n-heptane/EtOAc=7/3~2/8) to afford the title compound 9 as a white solid (340 mg, 982 μmol, 76%). 1H NMR (500 MHz, CDCl3): d = 1.52 (s, 9H), 3.76 (br s, 2H), 4.64-4.73 (m, 2H), 4.75 (t, J=2.1 Hz, 2H), 6.46 (d, J=8.6 Hz, 1H), 6.50 (dt, J=11.6, 3.1 Hz, 1H), 6.97 (td, J=8.6, 4.3 Hz, 1H), 8.64 (s, 1H); 13C NMR (126 MHz, CDCl3): d = 28.5, 48.1 (d, Jrotamer=39.1 Hz), 52.9 (d, Jrotamer=32.8 Hz), 80.5, 103.3 (d, JCF=22.7 Hz), 110.6, 115.2 (d, Jrotamer=30.2 Hz), 124.0, 130.6 (t, JCF=12.6 Hz), 146.2 (d, JCF=10.1 Hz), 154.73 (d, JCF=248.2 Hz), 154.3 (d, JCF=8.8 Hz), 158.5, 164.1 (d, Jrotamer=12.6 Hz), 169.0 (d, Jrotamer=30.0 Hz). *Coupling was observed due to the rotamer; HRMS-ESI m/z [M+H]+ calcd. for C17H20FN4O3+: 347.1514, found: 347.1505.

Reference： [1]Azuma, Hiroshi; Fukushima, Sayo; Goto, Aya; Hata Sugi, Naoko; Ichikawa, Kenji; Inoue, Satoshi; Ito, Daisuke; Kakiuchi, Dai; Kato, Yu; Matsui, Junji; Matsushima, Tomohiro; Murai, Norio; Nagao, Satoshi; Nakagawa, Takayuki; Nishibata, Kyoko; Tsukamoto, Shuntaro; Ueno, Takashi; Yamane, Yoshinobu [Bioorganic and Medicinal Chemistry Letters, 2021, vol. 48]

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H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 399-96-2 ] {[proInfo.proName]}

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[ 399-96-2 ] Synthesis Path-Upstream 1~11

[ 399-96-2 ] Synthesis Path-Downstream 1~62

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Fluorinated Building Blocks

Aryls

Amines

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[ 399-96-2 ]