[ CAS No. 227609-86-1 ] {[proInfo.proName]}

Name: 227609-86-1|(3-Amino-4-fluorophenyl)methanol|98%
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Quality Control of [ 227609-86-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 227609-86-1 ]

CAS No. :	227609-86-1	MDL No. :	MFCD09865016
Formula :	C₇H₈FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	REROQYYZGYOCBU-UHFFFAOYSA-N
M.W :	141.14	Pubchem ID :	13563644
Synonyms :

Calculated chemistry of [ 227609-86-1 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.14
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	36.93
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 :	No
Log Kp (skin permeation) :	-6.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.42
Log Po/w (XLOGP3) :	0.46
Log Po/w (WLOGP) :	1.18
Log Po/w (MLOGP) :	1.31
Log Po/w (SILICOS-IT) :	1.38
Consensus Log Po/w :	1.15

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.38
Solubility :	5.84 mg/ml ; 0.0414 mol/l
Class :	Very soluble
Log S (Ali) :	-1.0
Solubility :	14.1 mg/ml ; 0.1 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.12
Solubility :	1.07 mg/ml ; 0.00757 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.08

Safety of [ 227609-86-1 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P271-P261-P280	UN#:	N/A
Hazard Statements:	H319-H315	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 227609-86-1 ]

* 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.

Downstream synthetic route of [ 227609-86-1 ]

[ 227609-86-1 ] Synthesis Path-Downstream 1~37

1
[ 2365-85-7 ]
[ 227609-86-1 ]

Yield	Reaction Conditions	Operation in experiment
94%	With borane-THF; In tetrahydrofuran; at 0 - 20℃;	Following literature procedure [3] a solution of <strong>[2365-85-7]3-amino-4-fluorobenzoic acid</strong> (4.0 g, 26.3 mmol) in dry THF (20 ml) was treated with 1 M solution of BH3 in THF (53 mmol, 53 mL) at 0 °C. The reaction mixture was stirred at rt for 24 h, MeOH (10 mL) was slowly added, and stirred for 15 min, the solvents were evaporated, and the residue was purified on a silica gel plug (CH2Cl2/ EtOAc, 1:1) to give 3.47 g (94percent yield) of alcohol 9e as a white solid.
	In tetrahydrofuran;	Example 2A 3-Amino-4-fluorobenzyl alcohol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in tetrahydrofuran at 0° C. was treated with 1.0M borane-tetrahydrofuran complex (50 mL), stirred overnight at ambient temperature, treated with an additional 130 mL of 1.0M borane-tetrahydrofuran complex, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at ambient temperature, concentrated and partitioned between aqueous sodium bicarbonate/methylene chloride. The methylene chloride layer was separated, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate:hexanes 1:1) to provide 7.0 g of the title compound. 1H NMR (CDCl3) delta4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).
	In tetrahydrofuran;	EXAMPLE 12A (3-amino-4-fluorophenyl)methanol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in tetrahydrofuran at 0° C. wastreated with 1.0 M borane-tetrahydrofuran complex (50 mL). After stirring overnight at ambient temperature, the mixture was treated with an additional 130 mL of 1.0 M borane-tetrahydrofuran complex. After stirring for 10 hours, the mixture was quenched by the addition of methanol, stirred 3 hours at ambient temperature, concentraed and partitioned between aqueous sodium bicarbonate/methylene chloride. The methylene chloride layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound. 1H NMR (300 MHz, CDCT) delta 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

	In tetrahydrofuran;	EXAMPLE 30A 3-Amino-4-fluorobenzyl Alcohol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in tetrahydrofuran at 0° C. was treated with 1.0M borane-tetrahydrofuran complex (50 mL), stirred overnight at room temperature, treated with an additional 130 mL of 1.0M borane-tetrahydrofuran complex, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, concentrated and partitioned between aqueous sodium bicarbonate/methylene chloride. The methylene chloride layer was separated, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound. 1H NMR (CDCl3) delta 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).
	In tetrahydrofuran;	EXAMPLE 30A 3-Amino-4-fluorobenzyl alcohol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in tetrahydrofuran at 0° C. was treated with 1.0 M borane-tetrahydrofuran complex (50 mL), stirred overnight at room temperature, treated with an additional 130 mL of 1.0 M borane-tetrahydrofuran complex, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, concentrated and partitioned between aqueous sodium bicarbonate/methylene chloride. The methylene chloride layer was separated, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound. 1H NMR (CDCl3) delta 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

Reference： [1]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1873 - 1880
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 3163 - 3179
[3]Patent: US2003/65182,2003,A1
[4]Patent: US2002/7059,2002,A1
[5]Patent: US6642222,2003,B2
[6]Patent: US6191140,2001,B1

2
[ 227609-86-1 ]
[ 227609-87-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; sulfuric acid; sodium nitrite; In water;	Example 2B 4-Fluoro-3-iodobenzylalcohol The product from Example 2A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C. and then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated to 60° C. for 2 hours, cooled and extracted with methylene chloride. The methylene chloride layer was washed with 10percent sodium hydroxide, washed with 1M sodium thiosulfate, washed with 10percent hydrochloric acid, washed with aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H NMR (CDCl3) delta1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).
	With potassium iodide; sulfuric acid; sodium nitrite; In water;	EXAMPLE 8B 4-Fluoro-3-iodobenzylalcohol The product from Example 8A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C., then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated to 60° C. for 2 hours, cooled, and extracted with methylene chloride. The organic phase was washed with 10percent sodium hydroxide, 1 M sodium thiosulfate, 10percent hydrochloric acid, aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and the solvent evaporated. The crude product was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H NMR (CDCl3) delta1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).
	With potassium iodide; sulfuric acid; sodium nitrite; In water;	EXAMPLE 30B 4-Fluoro-3-iodobenzylalcohol The product from Example 30A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C. and then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated to 60° C. for 2 hours, cooled and extracted with methylene chloride. The methylene chloride layer was washed with 10percent sodium hydroxide, washed with 1M sodium thiosulfate, washed with 10percent hydrochloric acid, washed with aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H NMR (CDCl3) delta 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).

	With potassium iodide; sulfuric acid; sodium nitrite; In water;	EXAMPLE 89B 4-fluoro-3-iodobenzylalcohol The product from Example 89A (7.0 g, 50 mmol) in water (100 mL) at 0 ° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10 ° C., then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated to 60 ° C. for 2 hours, cooled, extracted with methylene chloride, the organics washed with 10percent sodium hydroxide, 1M sodium thiosulfate, 10percent hydrochloric acid, aqueous sodium bicarbonate, dried (sodium sulfate), filtered and solvent evaporated. The material was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H-NMR (CDCl3) delta 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).
	With potassium iodide; sulfuric acid; sodium nitrite; In water;	EXAMPLE 30B 4-Fluoro-3-iodobenzylalcohol The product from example 30A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C. and then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated to 60° C. for 2 hours, cooled and extracted with methylene chloride. The methylene chloride layer was washed with 10percent sodium hydroxide, washed with 1 M sodium thiosulfate, washed with 10percent hydrochloric acid, washed with aqueous sodium bicarbonate, dried (sodium sulfate), filtered, and concentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H NMR (CDCl3) delta 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).
	With potassium iodide; sulfuric acid; sodium nitrite; In water;	EXAMPLE 89B 4-Fluoro-3-iodobenzylalcohol The product from Example 89A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C., then treated dropwise with an aqueous solution of sodium nitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated to 60° C. for 2 hours, cooled, extracted with methylene chloride, the organics washed with 10percent sodium hydroxide, 1 M sodium thiosulfate, 10percent hydrochloric acid, aqueous sodium bicarbonate, dried (sodium sulfate), filtered and solvent evaporated. The material was purified by flash chromatography over silica gel (ethyl acetate/hexane 7:3) to provide 6.4 g of the title compound. 1H NMR (CDCl3) 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 3163 - 3179
[2]Patent: US2003/65182,2003,A1
[3]Patent: US2002/7065,2002,A1
[4]Patent: US6642222,2003,B2
[5]Patent: US6593335,2003,B1
[6]Patent: US6191140,2001,B1
[7]Patent: US6265417,2001,B1

3
[ 227609-86-1 ]
[ 227609-88-3 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 3163 - 3179

4
[ 227609-86-1 ]
9-(4-fluoro-3-iodo-phenyl)-1,1-dioxo-1,2,3,4,5,6,7,9-octahydro-1λ⁶-thieno[3,2-<i>b</i>]quinolin-8-one [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 3163 - 3179

5
[ 227609-86-1 ]
[ 227609-71-4 ]

Reference： [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 3163 - 3179

6
BH_3.THF [ No CAS ]
[ 2365-85-7 ]
[ 227609-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	EXAMPLE 8A 3-Amino-4-fluorobenzyl alcohol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in THF at 0° C. was treated with 1.0 M BH3.THF (50 mL) with stirring overnight at room temperature. An additional 130 mL 1.0 M BH3.THF was added with stirring for 10 hours. The reaction mixture was quenched by the addition of methanol, stirred 3 hours at room temperature, solvent evaporated, and the product partitioned between aqueous sodium bicarbonate/methylene chloride. The organic layer was dried (sodium sulfate), filtered, and the solvent evaporated. The crude product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound. 1H NMR (CDCl3) delta4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).
	In tetrahydrofuran;	EXAMPLE 89A 3-Amino-4-fluorobenzyl alcohol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in THF at 0° C. was treated with 1.0 M BH3.THF (50 mL), stirred overnight at room temperature, treated with an additional 130 mL 1.0 M BH3.THF, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, solvent evaporated, the product partitioned between aqueous sodium bicarbonate/methylene chloride, the organic layer dried (sodium sulfate), filtered and solvent evaporated. The product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound. 1H NMR (CDCl3) 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

Reference： [1]Patent: US2002/7065,2002,A1
[2]Patent: US6265417,2001,B1

7
[ 7632-00-0 ]
[ 227609-86-1 ]
[ 227609-87-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium iodide; sulfuric acid; In water;	EXAMPLE 12B (4-fluoro-3-iodophenyl)methanol The product from Example 12A (7.0 g, 50 mmol) in water (100 mL) at 0° C. was treated slowly with concentrated sulfuric acid (30 mL) at a rate to maintain the temperature below 10° C. and then treated dropwise with an aqueous solution of sodiumnitrite (3.45 g, 50 mmol). This solution was then added to a solution of potassium iodide (8.13 g, 50 mmol) in water (15 mL), heated at 60° C. for 2 hours, cooled and extracted with methylene chloride. The methylene chloride layer was washed with 10percent sodiumhydroxide, washed with 1 M sodium thiosulfate, washed with 10percent hydrochloric acid, washed with aqueous sodium bicarbonate, dried (sodium sulfate), filtered andconcentrated. The residue was purified by flash chromatography over silica gel (ethyl acetate/lexane 7:3) to provide 6.4 g of the title compound. 1H NMR (300 MHz, CDCl) delta 1.69 (t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).

Reference： [1]Patent: US2002/7059,2002,A1

8
BH₃THF [ No CAS ]
[ 2365-85-7 ]
[ 227609-86-1 ]

Yield	Reaction Conditions	Operation in experiment
	In tetrahydrofuran;	EXAMPLE 89A 3-Amino-4-fluorobenzyl alcohol <strong>[2365-85-7]3-Amino-4-fluorobenzoic acid</strong> (15 g, 97 mmol) in THF at 0 ° C. was treated with ].OM BH3THF (50 mL), stirred overnight at room temperature, treated with an additional 130 mL 1.0 M BH3THF, stirred 10 hours, quenched by the addition of methanol, stirred 3 hours at room temperature, solvent evaporated, the product partitioned between aqueous sodium bicarbonate/methylene chloride, the organic layer dried (sodium sulfate), filtered and solvent evaporated. The product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:1) to provide 7.0 g of the title compound. 1H NMR (CDCI3) delta 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t, 1H).

Reference： [1]Patent: US6593335,2003,B1

9
[ 20274-69-5 ]
[ 227609-86-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃;	a. (3-Amino-4-fluoro-phenyl)-methanol (Intermediate Ha) 4-Fluoro-3-nitrobenzyl alcohol (3.17 g, 18.5 mmol) was suspended in EtOH, and a slurry of palladium on carbon (10 wt percent, 317 mg) in EtOH was added. The flask was sealed with a septum, evacuated, and a H2 filled balloon was introduced via syringe and the reaction was stirred at RT overnight. The reaction mixture was then filtered through a pad of Celite, washed with EtOH and the filtrates concentrated in vacuo to afford a oil which upon scratching crystallised to give the title compound (2.56 g, 98percent). 1H NMR (300 MHz, CDCl3): 4.57 (2H, s), 6.63-6.71 (1H, m), 6.77-6.84 (1H, m), 6.90-7.00 (1H, dd, J=8.2, 11.0 Hz). No OH or NH signals observed.
98%	With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃;Sealed tube;	4-Fluoro-3-nitrobenzyl alcohol (3.17 g, 18.5 mmol) was suspended in EtOH, and a slurry of palladium on carbon (10wtpercent, 317 mg) in EtOH was added. The flask was sealed with a septum, evacuated, and a H2 filled balloon was introduced via syringe and the reaction was stirred at RT overnight. The reaction mixture was then filtered through a pad of Celite, washed with EtOH and the filtrates concentrated in vacuo to afford a oil which upon scratching crystallised to give the title compound (2.56 g, 98percent). NMR (300 MHz, CDCls): 4.57 (2H, s), 6.63-6.71 (1H, m), 6.77-6.84 (1H, m), 6.90-7.00 (1H, dd, J = 8.2, 11.0 Hz). No OH or NH signals observed.
97%	With palladium 10% on activated carbon; hydrogen; In methanol; under 3102.97 Torr; for 1h;	To a solution of(4-fluoro-3-nitrophenyl)methanol (30a) (3.81 g, 22.24 mmol) in methanol (30 rnL) was added palladium on carbon (10percent) (0.39 g, 3.67 mmol) andhydrogenated at 60 PSI for I h. The catalyst was removed by filtration through Celite andthe filtrate was concentrated in vacuum. The residue obtained was purified by flash columnchromatography [silica gel 40g. eluting with 0-100percent ethyl acetate/methanol (9:1) inhexanes] to furnish (3-amino-4-fluorophenyl)methanol (30b) (3.05 g, 21.61 mmol, 97percentyield) as a white solid; ?H NMR (300 MHz, DMSO-d6) oe 6.89 (dd, J = 11.6, 8.2 Hz, I H),6.73 (dd, J 9.1, 2.1 Hz, IH), 6.52 ?6.33 (m, I H), 5.20?4.91 (m, 31-1), 4.32 (dd, J = 5.8,0.9 Hz, 2H); ?9F NMR (282 MHz, DMSO-d6) oe -138. 13.

92%	With hydrogen;palladium 10% on activated carbon; In ethanol; at 21℃; under 760.051 Torr; for 1h;	A suspension of (4-fluoro-3-nitrophenyl)methanol (2.5 g, 14.61 mmol) and palladium 10percent on carbon (0.25 g, 2.35 mmol) in ethanol (70 ml), was hydrogenated under 1 atm of hydrogen at 21 0C for 1 hour. The resulting suspension was filtered and the filtrate was concentrated to dryness to afford the crude (3-amino-4-fluorophenyl)methanol (1.900 g, 92 percent) as a pale beige solid. Mass Spectrum: M+H+ 142. NMR Spectrum (DMSOd6): 4.32(d, 2H), 5.00-5.07 (m, 3H), 6.43 (ddd, IH), 6.73 (dd, IH), 6.88 (dd, IH)
	With hydrogen;platinum on carbon; In ethyl acetate; at 17 - 25℃; under 1368.09 Torr; for 1h;	The 6-fluoro-3-hydroxymethylaniline used as a starting material was prepared as 15 follows :-A mixture of 4-fluoro-3-nitrobenzyl alcohol (0.5 g), 10percent platinum-on-carbon catalyst (0.1 g) and ethyl acetate (25 ml) was stirred under 1.8 atmospheres pressure of hydrogen for 1 hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 2:1 mixture of methylene chloride and EPO <DP n="95"/>ethyl acetate as eluent. There was thus obtained 6-fluoro-3-hydroxymethylaniline 1H NMR: (DMSOd6) 4.41 (d, 2H), 5.19 (m, 3H) 6.42 (m, IH), 6.77 (s, IH), 6.95 (m, IH).
	With hydrogen;platinum on carbon; In ethyl acetate; under 760.051 Torr; for 1h;	The 6-fluoro-3-hydroxymethylaniline used as a starting material was prepared as follows :-A mixture of 4-fluoro-3-nitrobenzyl alcohol (0.5 g), 10percent platinum-on-carbon catalyst (0.1 g) and ethyl acetate (25 ml) was stirred under 1.8 atmospheres pressure of hydrogen for 1 hour. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 2:1 mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained 6-fluoro-3-hydroxymethylaniline 1H NMR: (DMSOd6) 4.41 (d, 2H), 5.19 (m, 3H) 6.42 (m, IH), 6.77 (s, IH), 6.95 (m, IH).

Reference： [1]Patent: US2014/364412,2014,A1 .Location in patent: Paragraph 0477; 0478
[2]Patent: WO2014/195402,2014,A1 .Location in patent: Page/Page column 101; 102
[3]Patent: WO2015/134998,2015,A1 .Location in patent: Page/Page column 185; 186
[4]Patent: WO2008/104754,2008,A1 .Location in patent: Page/Page column 170
[5]Patent: WO2006/40520,2006,A1 .Location in patent: Page/Page column 93-94
[6]Patent: WO2006/40526,2006,A1 .Location in patent: Page/Page column 87
[7]Bioscience, Biotechnology and Biochemistry,2015,vol. 79,p. 707 - 709

10
[ 3934-20-1 ]
[ 227609-86-1 ]
[ 1051899-70-7 ]

Yield	Reaction Conditions	Operation in experiment
45.8%	With N-ethyl-N,N-diisopropylamine; In butan-1-ol; for 15h;Heating / reflux;	A solution of 2,4-dichloropyrimidine (1.5 g, 10.07 mmol), (3-amino-4- fluorophenyl)methanol (1.421 g, 10.07 mmol) and n,n-diisopropylethylamine (1.929 ml, 11.08 mmol) in n-butanol (13 ml), was stirred 15 hrs at reflux as described in Method 1. Work-up and purification gave (3-(2-chloropyrimidin-4-ylamino)-4-fluorophenyl) methanol (1.170 g, 45.8 percent) as a beige solid. Mass Spectrum: M+H+ 254. NMR Spectrum (DMSOd6): 4.48 (d, 2H), 5.29 (t, IH), 6.72 (d, IH), 7.18 (ddd, IH), 7.27 (dd, IH), 7.60 (d, IH), 8.17 (d, IH), 9.81 (bs, IH)

Reference： [1]Patent: WO2008/104754,2008,A1 .Location in patent: Page/Page column 170

11
[ 79917-38-7 ]
[ 227609-86-1 ]
2-(2-fluoro-5-(hydroxymethyl)phenylazo)-4-picoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With acetic acid; In dichloromethane; at 20℃; for 24h;Darkness;	General procedure: Method A. To the solution of amine (1.0 mmol) in dry CH2Cl2 (2 mL), 2-nitroso-4-picoline (7, 1.0 mmol) was added followed by a catalytic amount (1 drop) of acetic acid. The reaction mixture was stirred at rt for 24 h, protected from a light. The solvent was evaporated and the residue was purified on a silica gel plug (CH2Cl2/EtOAc, 5:1) to give the corresponding azo compound as orange-red crystals. Analytically pure samples were obtained by recrystallization (hexane/CH2Cl2).

Reference： [1]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1873 - 1880

12
[ 453-71-4 ]
[ 227609-86-1 ]

Reference： [1]Beilstein Journal of Organic Chemistry,2013,vol. 9,p. 1873 - 1880

13
[ 227609-86-1 ]
[5-tert-butyl-2-(2-fluoro-5-hydroxymethyl-phenyl)-2H-pyrazol-3-yl]-carbamic acid 2,2,2-trichloroethyl ester [ No CAS ]

Reference： [1]Patent: US2014/364412,2014,A1
[2]Patent: WO2014/195402,2014,A1

14
[ 227609-86-1 ]
(4-fluoro-3-hydrazino-phenyl)-methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		b. (4-Fluoro-3-hydrazino-phenyl)-methanol (Intermediate Hb) A solution of Intermediate Ha (1.00 g, 7.10 mmol) in concentrated HCl (10 mL) was cooled to -5° C. in an acetone/dry ice bath, and while stirring, a solution of NaNO2 (513 mg, 7.40 mmol) in H2O (2 mL) was added dropwise over 5 min. The reaction was stirred for 5 min, then a solution of SnCl2 (2.96 g, 15.6 mmol) in concentrated HCl (4 mL) was added dropwise, ensuring the internal temperature did not exceed 0° C. After stirring for 40 min, 4N NaOH solution was added to adjust the pH to 14 (?75 mL). The reaction mixture was then extracted three times with EtOAc, and the organic extracts combined, dried over MgSO4, and concentrated in vacuo to afford the title compound (866 mg, 78percent). 1H NMR (300 MHz, d6-DMSO): 4.77 (2H, bs), 5.18 (2H, d, J=5.4 Hz), 5.85 (1H, t, J=5.6 Hz), 7.27-7.34 (2H, m), 7.68 (1H, dd, J=8.3, 12.1 Hz), 7.90 (1H, dd, J=2.0, 8.6 Hz).
78%		A solution of Intermediate Ha (1.00 g, 7.10 mmol) in concentrated HC1 (10 mL) was cooled to -5 °C in an acetone/dry ice bath, and while stirring, a solution of NaN02 (513 mg, 7.40 mmol) in H20 (2 mL) was added dropwise over 5 min. The reaction was stirred for 5 min, then a solution of SnCl2 (2.96 g, 15.6 mmol) in concentrated HC1 (4 mL) was added dropwise, ensuring the internal temperature did not exceed 0 °C. After stirring for 40 min, 4N NaOH solution was added to adjust the pH to 14 (~75 mL). The reaction mixture was then extracted three times with EtOAc, and the organic extracts combined, dried over MgS04, and concentrated in vacuo to afford the title compound (866 mg, 78percent). NMR (300 MHz, de-DMSO): 4.77 (2H, bs), 5.18 (2H, d, J = 5.4 Hz), 5.85 (1H, t, J = 5.6 Hz), 7.27-7.34 (2H, m), 7.68 (1H, dd, J = 8.3, 12.1 Hz), 7.90 (1H, dd, J = 2.0, 8.6 Hz).

Reference： [1]Patent: US2014/364412,2014,A1 .Location in patent: Paragraph 0479; 0480
[2]Patent: WO2014/195402,2014,A1 .Location in patent: Page/Page column 102

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[ 227609-86-1 ]
[3-(5-amino-3-tert-butyl-pyrazol-1-yl)-4-fluoro-phenyl]-methanol [ No CAS ]

Reference： [1]Patent: US2014/364412,2014,A1
[2]Patent: WO2014/195402,2014,A1

16
[ 227609-86-1 ]
1-{5-tert-butyl-2-[2-fluoro-5-hydroxymethyl-phenyl]-2H-pyrazol-3-yl}-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea [ No CAS ]

Reference： [1]Patent: US2014/364412,2014,A1
[2]Patent: WO2014/195402,2014,A1

17
[ 227609-86-1 ]
methanesulfonic acid 3-[3-tert-butyl-5-(3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-ureido)-pyrazol-1-yl]-4-fluoro-benzyl ester [ No CAS ]

Reference： [1]Patent: US2014/364412,2014,A1
[2]Patent: WO2014/195402,2014,A1

18
[ 227609-86-1 ]
1-[5-tert-butyl-2-(2-fluoro-5-(4-methyl-piperazin-1-ylmethyl)-phenyl)-2H-pyrazol-3-yl]-3-{(1S,4R)-4-[3-((2S,6R)-2,6-dimethyl-piperidin-1-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy]-1,2,3,4-tetrahydro-naphthalen-1-yl}-urea [ No CAS ]

Reference： [1]Patent: WO2014/195402,2014,A1

19
[ 459-57-4 ]
[ 227609-86-1 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2015,vol. 79,p. 707 - 709

20
[ 42564-51-2 ]
[ 227609-86-1 ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2015,vol. 79,p. 707 - 709

21
[ 227609-86-1 ]
3-azide-4-fluorobenzyl alcohol [ No CAS ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2015,vol. 79,p. 707 - 709

22
[ 227609-86-1 ]
3-azide-4-fluorobenzylbromide [ No CAS ]

Reference： [1]Bioscience, Biotechnology and Biochemistry,2015,vol. 79,p. 707 - 709

23
[ 227609-86-1 ]
N-(5-(chloromethyl)-2-fluorophenyl )-1-(3-cyanophenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

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

24
[ 227609-86-1 ]
N-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-cyanophenyl )-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

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

25
[ 227609-86-1 ]
tert-butyl 3-(5-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenylcarbamoyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzylcarbamate [ No CAS ]

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

26
[ 227609-86-1 ]
N-(5-((1H-imidazol-1-yl)methyl)-2-fluorophenyl)-1-(3-(aminomethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]

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

27
[ 209917-93-1 ]
[ 227609-86-1 ]
1-(3-cyanophenyl)-N-(2-fluoro-5-(hydroxymethyl)phenyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide [ No CAS ]