[ CAS No. 405-04-9 ] {[proInfo.proName]}

Name: 405-04-9|3-Fluoro-4-hydroxybenzonitrile|98%
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SKU: A411028
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Quality Control of [ 405-04-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 405-04-9 ]

Product Details of [ 405-04-9 ]

CAS No. :	405-04-9	MDL No. :	MFCD00215834
Formula :	C₇H₄FNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	DPSSSDFTLVUJDH-UHFFFAOYSA-N
M.W :	137.11	Pubchem ID :	2782944
Synonyms :

Calculated chemistry of [ 405-04-9 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	1.0
Molar Refractivity :	33.14
TPSA :	44.02 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) :	-6.15 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.43
Log Po/w (XLOGP3) :	1.39
Log Po/w (WLOGP) :	1.82
Log Po/w (MLOGP) :	1.22
Log Po/w (SILICOS-IT) :	1.74
Consensus Log Po/w :	1.52

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.01
Solubility :	1.34 mg/ml ; 0.00978 mol/l
Class :	Soluble
Log S (Ali) :	-1.92
Solubility :	1.66 mg/ml ; 0.0121 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.16
Solubility :	0.955 mg/ml ; 0.00697 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.39

Safety of [ 405-04-9 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P301+P312-P302+P352-P304+P340-P305+P351+P338	UN#:
Hazard Statements:	H302-H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 405-04-9 ]

* 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 [ 405-04-9 ]
Downstream synthetic route of [ 405-04-9 ]

[ 405-04-9 ] Synthesis Path-Upstream 1~10

1
[ 405-04-9 ]
[ 350-29-8 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24

2
[ 405-04-9 ]
[ 405-05-0 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 20, p. 8969 - 8973

3
[ 331-62-4 ]
[ 405-04-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With boron tribromide In dichloromethane at 0℃; for 72 h; Inert atmosphere; Reflux	BBr₃ (20 mL, 0.211 mol) was added to 3-fluoro-4-methoxybenzonitrile (15.6 g, 0.103 mol) in dichloromethane (100 mL) at 0 °C. The mixture was refluxed for 3 days under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 13.3 g (94percent) of the product as a gray solid. ^:H NMR (400 MHz, CDC1₃) δ 7.38-7.42 (m, 2H), 7.09 (dd, J= 8.8 Hz, 8.4 Hz, 1H), 5.68 (s, 1H).

Reference： [1] Patent: WO2013/97773, 2013, A1, . Location in patent: Paragraph 0159; 0277
[2] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579
[3] Patent: WO2005/123748, 2005, A1, . Location in patent: Page/Page column 85-86
[4] Patent: WO2006/135316, 2006, A1, . Location in patent: Page/Page column 59
[5] Patent: WO2006/137770, 2006, A1, . Location in patent: Page/Page column 34

4
[ 557-21-1 ]
[ 2105-94-4 ]
[ 405-04-9 ]

Yield	Reaction Conditions	Operation in experiment
98%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 120℃; for 2 h;	To a solution of 4-bromo-2-fluoro phenol 14-I (500 mg, 2.62 mmol) in DMF (15 mL) was addedzinc cyanide (492 mg, 4.2 mmol) and terakis(triphenylphosphine)palladium (302 mg ,0.262mmol) and the solution was stirred at 120 °C for 2 h. The reaction mixture was cooled to roomtemperature and the black precipitate was removed by filteration. After concentrating the filtrate,saturated aqueous NaHCO3 solution was added into the residue mixture was extracted with ethylacetate (3 × 20 mL). The organic layer was washed with brine, dried over anhyd. Na2SO4 andconcentrated to get crude product which was purified by column chromatography using pet.Ether:EtOAc (8:2) to give 250 mg 4-cyano-2fluoro phenol 14-II.

Reference： [1] Synlett, 2016, vol. 27, # 9, p. 1339 - 1343

5
[ 767-00-0 ]
[ 405-04-9 ]
[ 2967-54-6 ]

Reference： [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173

6
[ 456-49-5 ]
[ 405-04-9 ]

Reference： [1] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579

7
[ 458-50-4 ]
[ 405-04-9 ]

Reference： [1] Helvetica Chimica Acta, 1984, vol. 67, p. 1572 - 1579

8
[ 367-12-4 ]
[ 405-04-9 ]

Reference： [1] Molecular Crystals and Liquid Crystals (1969-1991), 1981, vol. 67, p. 1 - 24

9
[ 2357-52-0 ]
[ 405-04-9 ]

Reference： [1] Patent: WO2013/97773, 2013, A1,

10
[ 767-00-0 ]
[ 405-04-9 ]
[ 2967-54-6 ]

Reference： [1] Journal of Fluorine Chemistry, 2000, vol. 102, # 1-2, p. 169 - 173

[ 405-04-9 ] Synthesis Path-Downstream 1~88

1
[ 49763-65-7 ]
[ 405-04-9 ]
4-hydroxy-2-fluorophenyl 4-pentylbenzoate [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1984,vol. 67,p. 1572 - 1579

2
[ 331-62-4 ]
[ 405-04-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With boron tribromide; In dichloromethane; at 0℃; for 72h;Inert atmosphere; Reflux;	BBr3 (20 mL, 0.211 mol) was added to <strong>[331-62-4]3-fluoro-4-methoxybenzonitrile</strong> (15.6 g, 0.103 mol) in dichloromethane (100 mL) at 0 °C. The mixture was refluxed for 3 days under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. The organic layer was washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 13.3 g (94percent) of the product as a gray solid. :H NMR (400 MHz, CDC13) delta 7.38-7.42 (m, 2H), 7.09 (dd, J= 8.8 Hz, 8.4 Hz, 1H), 5.68 (s, 1H).
		BBr3 (23 ml, 0.242 mol) was added to 3-Fluoro-4-methoxy-benzonitrile (24.4 g, 0.16 mol) in dichloromethane (200 ml) at -78 °C and stirring continued overnight at room temperature. Another portion of BBr3 (23 ml, 0.242 mol) was added at -78 °C and stirring continued at RT for 2 days under nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. Organic layer was washed with water and brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20 g of the sub-title compound as a solid. This was taken for next step without further purification.
		(iv) 3-Fluoro-4-hvdroxybenzonitrileBBr3 (23 mL, 0.242 mol) was added to 3-fluoro-4-niethoxy-benzonitrile (24.4 g,0.16 mol; see step (iii) above) in dichloromethane (200 mL) at -78°C. Stirring was continued at room temperature overnight. Another portion of BBr3 (23 mL, 0.242 mol) was added at -780C and stirring was continued at RT for a further 2 days under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. The organic layer was washed with water and brine, and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20 g of the sub-title compound as a solid. This was employed directly in the next step without further purification.

With boron tribromide; In dichloromethane; at -78 - 20℃; for 48h;

BBr3 (23 mL, 0.242 mol) was added to <strong>[331-62-4]3-fluoro-4-methoxy-benzonitrile</strong> (24.4 g, 0.16 mol; see step (iii) above) in dichloromethane (200 mL) at -78°C. Stirring was continued at room temperature overnight. Another portion of BBr3 (23 mL, 0.242 mol) was added at -78°C and stirring was continued at RT for a further 2 days under a nitrogen atmosphere. The reaction mixture was quenched with ice water and extracted with dichloromethane. The organic layer was washed with water and brine, and then dried over sodium sulfate. Solvent evaporation under reduced pressure gave 20 g of the sub-title compound as a solid. This was employed directly in the next step without further purification.

Reference： [1]Patent: WO2013/97773,2013,A1 .Location in patent: Paragraph 0159; 0277
[2]Helvetica Chimica Acta,1984,vol. 67,p. 1572 - 1579
[3]Patent: WO2005/123748,2005,A1 .Location in patent: Page/Page column 85-86
[4]Patent: WO2006/135316,2006,A1 .Location in patent: Page/Page column 59
[5]Patent: WO2006/137770,2006,A1 .Location in patent: Page/Page column 34

3
[ 405-04-9 ]
[ 71458-14-5 ]
3-Fluoro-4-(4-pentyl-cyclohexylmethoxy)-benzonitrile [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 1444 - 1452

4
[ 405-04-9 ]
[ 71458-12-3 ]
3-Fluoro-4-(4-propyl-cyclohexylmethoxy)-benzonitrile [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 1444 - 1452

5
[ 405-04-9 ]
[ 71458-16-7 ]
3-Fluoro-4-(4-heptyl-cyclohexylmethoxy)-benzonitrile [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 1444 - 1452

6
[ 405-04-9 ]
[ 151105-68-9 ]
4-cyano-2-fluorophenyl 4-(trans-4-propylcyclohexyl)-benzyl ether [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 1444 - 1452

7
[ 405-04-9 ]
[ 82380-26-5 ]
3-fluoro-4-<4(trans-4-pentylcyclohexyl)benzyloxy>benzonitrile [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 1444 - 1452

8
[ 405-04-9 ]
[ 122161-21-1 ]
3-Fluoro-4-[4-(4-heptyl-cyclohexyl)-benzyloxy]-benzonitrile [ No CAS ]

Reference： [1]Helvetica Chimica Acta,1985,vol. 68,p. 1444 - 1452

9
[ 405-04-9 ]
[ 350-29-8 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

10
[ 767-00-0 ]
[ 405-04-9 ]
[ 2967-54-6 ]

Reference： [1]Journal of Fluorine Chemistry,2000,vol. 102,p. 169 - 173

11
[ 367-12-4 ]
[ 405-04-9 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

12
[ 405-04-9 ]
[ 403-20-3 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

13
[ 405-04-9 ]
[ 65553-44-8 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

14
[ 405-04-9 ]
[ 326-76-1 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

15
[ 405-04-9 ]
[ 7247-24-7 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

16
[ 405-04-9 ]
[ 326-77-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

17
[ 405-04-9 ]
4-Butoxy-3-fluoro-benzoyl chloride [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

18
[ 405-04-9 ]
3-Fluoro-4-hexyloxy-benzoyl chloride [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

19
[ 405-04-9 ]
[ 111331-19-2 ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

20
[ 405-04-9 ]
3-Fluoro-4-hexyloxy-benzoic acid 4-pentyl-phenyl ester [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

21
[ 405-04-9 ]
3-Fluoro-4-heptyloxy-benzoic acid 4-pentyl-phenyl ester [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

22
[ 405-04-9 ]
3-Fluoro-4-hexyloxy-benzoic acid 4-cyano-phenyl ester [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

23
[ 405-04-9 ]
4-Butoxy-3-fluoro-benzoic acid 4-hexyloxy-phenyl ester [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

24
[ 405-04-9 ]
3-Fluoro-4-hexyloxy-benzoic acid 4-heptyloxy-phenyl ester [ No CAS ]

Reference： [1]Molecular Crystals and Liquid Crystals (1969-1991),1981,vol. 67,p. 1 - 24

25
[ 456-49-5 ]
[ 405-04-9 ]

Reference： [1]Helvetica Chimica Acta,1984,vol. 67,p. 1572 - 1579

26
[ 458-50-4 ]
[ 405-04-9 ]

Reference： [1]Helvetica Chimica Acta,1984,vol. 67,p. 1572 - 1579

27
[ 405-04-9 ]
[ 106-93-4 ]
[ 872045-88-0 ]

Yield	Reaction Conditions	Operation in experiment
71%	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃;Inert atmosphere;	A suspension of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (1.2 g, 8.76 mmol), anhydrous K2C03 (2.43 g, 17.6 mmol) and 1,2-dibromoethane (4.5 mL, 52.0 mmol) in DMF (6 mL) was stirred at 60 C overnight under a nitrogen atmosphere. The reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The extract was washed with water and brine, dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel (eluent: petroleum ether/ethyl acetate = 5/1), gave 1.52 g (71%) of the subtitle compound as a colorless oil. :H NMR (400 MHz, CDCI3) delta 7.43 (d, J = 9.2 Hz, 1H), 7.40 (d, J = 12.0 Hz, 1H), 7.03 (dd, J = 8.0 Hz, 8.4 Hz, 1H), 4.42 (t, J= 6.2 Hz, 2H), 3.68 (t, J= 6.2 Hz, 2H).
	With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 60℃; for 120h;	A suspension of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (20 g, 0.1459 mol, from step (iv) above), anhydrous. K2C03 (40.33 g, 0.2918 mol) and 1,2-dibromo ethane (76.8 ml, 0.8754 mol) in dry DMF (150 ml) was stirred at 60 C for 5 days under nitrogen atmosphere. The reaction mixture was .filtered through celite and solvent evaporated under reduced pressure. The residue was purified by column chromatography over silica gel using 2 % ethyl acetate in petroleum ether, as eluent to yield the sub-title compound (21.6 g) as a solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 120h;	(V) 4-f 2-Bromoethoxy)-3 -fluorobenzonitrileA suspension of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (20 g, 0.1459 mol; see step (iv) above), anhydrous K2CO3 (40.33 g, 0.2918 mol) and 1,2-dibromoethane (76.8 mL, 0.8754 mol) in dry DMF (150 mL) was stirred at 6O0C for 5 days under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, to yield 21.6 g of the sub-title compound as a solid.

With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 120h;

A suspension of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (20 g, 0.1459 mol; see step (iv) above), anhydrous K2CO3 (40.33 g, 0.2918 mol) and 1,2-dibromoethane (76.8 mL, 0.8754 mol) in dry DMF (150 mL) was stirred at 600C for 5 days under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 2% ethyl acetate in petroleum ether as eluent, to yield 21.6 g of the title compound as a solid.

Reference： [1]Patent: WO2013/97773,2013,A1 .Location in patent: Paragraph 0160; 0278
[2]Patent: WO2005/123748,2005,A1 .Location in patent: Page/Page column 86
[3]Patent: WO2006/135316,2006,A1 .Location in patent: Page/Page column 59
[4]Patent: WO2006/137770,2006,A1 .Location in patent: Page/Page column 34

28
[ 405-04-9 ]
[ 627-18-9 ]
[ 872046-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; at 60℃;	A mixture of 4-cyano-2-fluoro phenol (5 g, 0.0365 mol; from prep N(iv) above), 3-bromopropanol (10.15 g, 0.073 mol) and potassium carbonate (7.6 g, 0.054 mol) in dry acetone (50 ml) was stirred at 60 C overnight under nitrogen atmosphere. The reaction mixture was filtered and the solvent was concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 5 % ethyl acetate in petroleum ether to yield (5.5 g) of the sub-title compound as a solid.

Reference： [1]Patent: WO2005/123748,2005,A1 .Location in patent: Page/Page column 94-95

Yield	Reaction Conditions	Operation in experiment
		a) 4-Cyano-2-fluorophenol. 4-Bromo-2-fluorophenol (10 ml, 91 mmol) and 9.85 g (0.11 mol) of CuCN were combined in 75 ml of NMP with stirring under nitrogen, and the mixture was heated at 150 C. for 5 h. The mixture was diluted with 200 ml of ether, stirred, and decanted. The residue was diluted again with 200 ml of ether, heated, and decanted. The combined decantates were washed with water, 1N HCl solution, water, and brine, and dried over magnesium sulfate. The organic solution was concentrated in vacuo to provide 12 g of a white solid which was triturated in carbon tetrachloride and filtered to afford 7.29 g (72.1%) of the title compound.

30
[ 405-04-9 ]
[ 109-64-8 ]
[ 872046-05-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 60℃; for 72h;	Preparation E 3-Fluoro-4-[3-(9-oxa-3,7-diazabicyclo[3.3.11non-3-yl')propoxy1benzonitrile(i) 4-(3-Bromopropoxy)-3-£luorobenzonitrileA mixture of 4-cyano-2-fluororhohenol (8.5 g, 0.0620 mol; see Preparation D(iv) above), anhydrous K2CO3 (17.14 g, 0.124 mol) and 1,3-dibromoprorhoane (37.7 mL, 0.372 mol) in dry DMF (80 mL) was stirred at 60C for 3 days under a nitrogen atmosphere. The reaction mixture was filtered through Celite and the solvent was then evaporated under reduced pressure. The residue was purified by column chromatography over silica gel, using 4% ethyl acetate in petroleum ether, as eluent, to yield 8.2 g of the sub-title compound as a white solid.

Reference： [1]Patent: WO2006/135316,2006,A1 .Location in patent: Page/Page column 60

31
[ 405-04-9 ]
[ 98-59-9 ]
[ 917226-73-4 ]

Yield	Reaction Conditions	Operation in experiment
69%		ALTERNATIVE 4To <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (10 g) was added ethylene carbonate (6.85 g), potassium iodide (1.2 g) and xylene (21 mL), at 2O0C. The reaction mixture was heated to 14O0C +/- 5C, over thirty minutes, and maintained at this temperature for twelve hours. For convenience, the reaction mixture was cooled to 2O0C, over approximately eight hours. To the cooled reaction mixture was added triethylamine (7.1 mL) and 4-methyl-pentan-2-one (14.25 mL). The reaction mixture was then cooled to -100C, over approximately five minutes, after which trimethylamine hydrochloride (1.4 g) was added, followed by a solution of para- toluenesulfonyl chloride (14.6 g), dissolved in 4-methylpenatan-2-one (80 mL). During the addition, the reaction temperature was maintained at -100C +/- 5C. When the addition was complete, the reaction mixture was warmed to 2O0C. Water (60 mL) was added and the reaction mixture was heated to 750C, at which temperature the layers were separated and the lower (aqueous) layer was discarded. To the retained (organic) layer was added 1 M hydrochloric acid (60 mL), and the reaction mixture was again heated to 75C. The layers were separated and the lower (aqueous) layer was discarded. For convenience, the upper (organic) layer was cooled to 200C over approximately fourteen hours. The reaction mixture was then cooled to 50C over approximately ten minutes, after which the product was isolated by filtration and washed (on the filter) with 4- methylpenatan-2-one (10 mL, at 50C). The damp solid was then dried in vacuo, at 35C, for approximately twenty-four hours. This provided the title compound as a white crystalline solid (16.9 g; 69% yield).1H-NMR (300 MHz, CDCl3): delta 7.85 - 7.77 (m, 2H), 7.43 - 7.30 (m, 4H), 6.95 (t, J = 8.3 Hz5 IH), 4.45 - 4.37 (m, 2H), 4.35 - 4.27 (m, 2H), 2.45 (s, 3H).
60%		ALTERNATIVE 3 To <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (5 g) was added xylene (10 mL), at 2O0C. To the resulting mixture was added ethylene carbonate (3.44 g) and tetra-n- butylammonium iodide (0.71 g). The reaction mixture was heated to 125C +/- 50C, over twenty minutes, and maintained at this temperature for five hours. For convenience, the reaction mixture was cooled to 200C, over approximately fifteen and an half hours, and was analysed for water content (typically < 0.1 % w/w). To the cooled reaction mixture was added triethylamine (7.1 mL) and 4-methyl- rhoentan-2-one (16 mL). The reaction mixture was then cooled to -1O0C, over approximately twenty minutes, after which trimethylamine hydrochloride (0.70 g) was added, followed by a solution of para-tomenesulfonyl chloride (7.34 g), dissolved in 4-methylpenatan-2-one (40 mL). During the addition, the reaction temperature was maintained at -100C +/- 5C. When the addition was complete, the reaction mixture was warmed to 2O0C. Water (30 mL) was added and the reaction mixture was heated to 72C, at which temperature the layers were separated and the lower (aqueous) layer was discarded. To the retained (organic) layer was added 1 M hydrochloric acid (30 mL), and the reaction mixture was again heated to 72C. The layers were separated and the lower (aqueous) layer was discarded. For convenience, the upper (organic) layer was cooled to 2O0C over eighteen hours. The reaction mixture was then cooled to 5C over approximately ten EPO <DP n="72"/>minutes, after which the crude product was isolated by filtration and washed (on the filter) with 4-methylpenatan-2-one (5 mL, at 5C). The damp solid was then dried in vacuo, at 35 0C3 for approximately twenty-four hours. This provided the title compound as a white crystalline solid (7.3 g; 60% yield). 1H NMR (400 MHz, CDCl3): delta 7.81 (d, J= 8.3 Hz, 2H), 7.41 - 7.32 (m, 3H), 6.95 (t, J- 8.2 Hz, 2H), 4.43 - 4.38 (m, 2H), 4.33 - 4.29 (m, 2H), 1.54 (s, 3H).

Reference： [1]Patent: WO2006/135316,2006,A1 .Location in patent: Page/Page column 71
[2]Patent: WO2006/135316,2006,A1 .Location in patent: Page/Page column 70-71

32
[ 884534-90-1 ]
[ 405-04-9 ]
[ 1043928-73-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 90℃;	A mixture of intermediate 9 (0.00037 mol), <strong>[405-04-9]3-fluoro-4-hydroxy-benzonitrile</strong> (0.0005 mol) and K2CO3 (0.150 g) in acetonitrile (10 ml) was stirred overnight at 90 0C. The reaction mixture was cooled and was then washed with a 10 % aqueous NaOH solution. This mixture was extracted with DCM. The separated organic layer was washed, dried, filtered and the solvent evaporated. Yield: 0.134 g of compound 29.

Reference： [1]Patent: WO2008/92861,2008,A1 .Location in patent: Page/Page column 57

33
[ 1043875-02-0 ]
[ 405-04-9 ]
[ 1043929-16-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 100℃;	A mixture of intermediate 22 (0.00023 mol, 0.100 g), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.00035 mol, 0.050 g) and K2CO3 (0.00035 mol, 0.048 g) in acetonitrile (10 ml) was stirred overnight at 100 0C. The mixture was evaporated and the residue was solved in DCM. The mixture was washed with NaOH (10 %). The separated organic layer was dried, filtered and the solvents were evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM). The desired fractions were collected and the solvent was evaporated. Yield: 0.180 g of compound 65.

Reference： [1]Patent: WO2008/92861,2008,A1 .Location in patent: Page/Page column 59

34
[ 1043931-34-5 ]
[ 405-04-9 ]
[ 1043930-65-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 50℃;	A mixture of intermediate 68 (1.5 g, 0.0036 mol), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.730 g, 0.0053 mol) and K2CO3 (0.735 g, 0.0053 mol) in CH3CN (50 ml) was stirred <n="85"/>overnight at 50 0C. The solvent was evaporated and the residue was dissolved in DCM. The organic solution was washed with H2O, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified over silicagel (eluent: DCM). The pure fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 0C, 6 hours). Yield: 0.290 g of compound 196.

Reference： [1]Patent: WO2008/92861,2008,A1 .Location in patent: Page/Page column 83-84

35
[ 1043931-37-8 ]
[ 405-04-9 ]
[ 1043930-62-6 ]

Yield	Reaction Conditions	Operation in experiment
31%	With potassium carbonate; In acetonitrile; at 190℃; for 5h;Microwave;	A mixture of intermediate 65 (0.1 g, 0.00038 mol), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.156 g, 0.00114 mol) and K2CO3 (0.1575 g, 0.00114 mol) in CH3CN (10 ml) was stirred in the microwave for 5 hours at 190 0C. The solvent was evaporated and the residue was dissolved in DCM. The solution was washed with a 2 N NaOH solution and the separated organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by short column chromatography (Supelco) over silica gel (eluent: DCM/n-hexane 50/50). The desired fractions were collected and the solvent was evaporated. Yield: 0.043 g of compound 193 (31 %).

Reference： [1]Patent: WO2008/92861,2008,A1 .Location in patent: Page/Page column 84

36
[ 1043930-94-4 ]
[ 405-04-9 ]
[ 1043929-57-2 ]

Yield	Reaction Conditions	Operation in experiment
57%	With potassium carbonate; In acetonitrile; at 90℃;	A mixture of intermediate 29 (0.1 g, 0.0003 mol), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.057 g, 0.0004 mol) and K2CO3 (0.058 g, 0.0004 mol) in acetonitrile (10 ml) was stirred overnight at 90 0C. The solvent was evaporated and the residue was dissolved in DCM. The organic layer was washed with 1% NaOH, dried, filtered and the solvent was evaporated . The residue was purified by short column chromatography (SUPELCO) (eluent : DCM/n-Hexane 80/20). The desired fractions were collected and the solvent was evaporated. The residue was dried (vacuum, 60 0C, 12 hours). Yield: 0.073 g of compound 101 ( 57 % ).

Reference： [1]Patent: WO2008/92861,2008,A1 .Location in patent: Page/Page column 57

37
[ 1043930-97-7 ]
[ 405-04-9 ]
[ 1043928-60-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	With potassium carbonate; In acetonitrile; at 90℃;	3-Fluoro-4-hydroxy-benzonitrile (0.0005 mol) was added to a stirring mixture of intermediate 7 (0.00037 mol) and K2CO3 (0.005 mol) in acetonitrile (10 ml), and the reaction mixture was stirred overnight at 90 0C. Then the mixture was cooled and washed with an aqueous NaOH solution (2 N). This mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated under CH3OH and the precipitate was filtered off. Yield : 0.112 g of compound 16 (83 %).

Reference： [1]Patent: WO2008/92861,2008,A1 .Location in patent: Page/Page column 58

38
[ 1043883-30-2 ]
[ 405-04-9 ]
[ 1043883-18-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 90℃;	Example B5; a-1) Preparation of compound 34; A mixture of intermediate 5 (0.00035 mol), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.00035 mol) and K2CO3 (0.0005 mol) in acetonitrile (10 ml) was stirred overnight at 90 0C. The reaction mixture was cooled and then washed with a 2 N aqueous NaOH solution. The mixture was extracted with DCM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was triturated under CH3OH and the precipitate was filtered off. Yield : 0.072 g of compound 34.

Reference： [1]Patent: WO2008/92862,2008,A1 .Location in patent: Page/Page column 37; 43

39
[ 1043883-34-6 ]
[ 405-04-9 ]
[ 1043882-84-3 ]

Yield	Reaction Conditions	Operation in experiment
20%	With potassium carbonate; In acetonitrile; for 1h;Heating / reflux;	Example B6; a-1) Preparation of compound 5; Intermediate 7 (0.0006 mol) was dissolved in acetonitrile (5 ml). K2CO3 (0.2 g) and 3- fluoro-4-hydroxybenzonitrile (0.1 g; +/- 0.001 mol) were added and the reaction mixture was stirred and refluxed for one hour. Then the mixture was diluted with DCM and washed with 1 N NaOH. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from 2-propanol, filtered off and dried. Yield: 0.040 g of compound 5 (20 %).

Reference： [1]Patent: WO2008/92862,2008,A1 .Location in patent: Page/Page column 38; 40

40
[ 1043883-40-4 ]
[ 405-04-9 ]
[ 1043883-21-1 ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate; In acetonitrile; for 3h;Heating / reflux;	Example B8; a) Preparation of compound 37; A mixture of intermediate 12 (0.0004 mol), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.001 mol) and K2CO3 (0.200 g) in acetonitrile (10 ml) was stirred and refluxed for 3 hours. The reaction mixture was cooled and was then diluted with DCM. The mixture was extracted with 1 N NaOH and with brine. The separated organic layer was dried, filtered and the solvent evaporated. The residue was crystallized from 2-propanol. The <n="41"/>precipitate was filtered off and dried. If necessary, this fraction was again recrystallized from 2-propanol, filtered off and dried. Yield: 0.050 g of compound 37 (30 %).

Reference： [1]Patent: WO2008/92862,2008,A1 .Location in patent: Page/Page column 39-40; 43

41
[ 405-04-9 ]
[ 214417-24-0 ]
[ 1043883-04-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile; at 90℃;	Example Bl; a-1) Preparation of compound 22; A mixture of intermediate 2 (0.0004 mol), <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.0005 mol) and K2CO3 (0.150 g) in acetonitrile (10 ml) was stirred overnight at 90 0C. The reaction mixture was cooled and was then washed with a 10 % aqueous NaOH solution. This mixture was extracted with DCM. The separated organic layer was washed, dried, filtered and the solvent was evaporated. Yield: 0.116 g of compound 22.

Reference： [1]Patent: WO2008/92862,2008,A1 .Location in patent: Page/Page column 34; 42

42
isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate [ No CAS ]
[ 405-04-9 ]
[ 1079053-83-0 ]

Yield	Reaction Conditions	Operation in experiment
7.72%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 72h;	EXAMPLE 148Isopropyl 4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][l,4]oxazin-8(7H)- yl)piperidine-l-carboxylate[00307] To a solution of isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][l,4]oxazin-8(7H)-yl)piperidine- 1 -carboxylate from Example 2OA (10.0 mg, 0.029 mmol) and 3- fluoro-4-hydroxybenzonitrile (12.07 mg, 0.088 mmol) in DMF (0.4 mL) was added K2CO3 (12.17 mg, 0.088 mmol). The reaction mixture was stirred in a sealed vial for 3 days at 12O0C. The reaction mixture was cooled to RT. The reaction mixture was diluted with MeOH, filtered and purified by reverse phase HPLC (H2O/CH3CN) to give isopropyl 4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][l,4]oxazin- 8(7H)-yl)piperidine-l -carboxylate (1.0 mg, 2.265 mumol, 7.72 % yield) as Example 148 as an off-white solid. IH NMR (400 MHz, CDCl3) delta ppm 1.27 (d, J=6.05 Hz,6 H) 1.55 - 1.79 (m, 4 H) 2.85-2.95 (m, 2 H) 3.44 - 3.54 (m, 2 H) 4.05 - 4.15 (m, 2 H) <n="152"/>4.24 - 4.35 (m, 2 H) 4.84 - 4.95 (m, 2 H) 7.29 - 7.40 (m, 1 H) 7.45 - 7.52 (m, 2H) 7. (s, 1 H). LRMS (ESI): 442.5 [M + H]+.

Reference： [1]Patent: WO2008/137435,2008,A1 .Location in patent: Page/Page column 150-151

43
[ 2969-81-5 ]
[ 405-04-9 ]
[ 1141474-51-2 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 2h;	<strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (ABCR F03756F.AB, 2 g; 14.59 mmol; 1 eq.) was dissolved in DMF (40 ml_). Then ethyl 4-bromobutyrate (4.27 g; 21.88 mmol; 1.50 eq.) and potassium carbonate (3.02 g; 21.88 mmol; 1 .50 eq.) were added to the reaction mixture and it was heated to 80 0C for 2 hours. The reaction mixture was cooled to RT and diluted with EtOAc. The organic layer was washed with water (3x), brine, dried over MgSO4 and concentrated affording the title compound as a yellow solid (3.56 g, 97%). 1H NMR (DMSO-d6, 300 MHz) delta 7.86-7.83 (d, J= 1 1.43 Hz, 1 H), 7.68-7.66 (d, J= 8.73 Hz, 1 H), 7.37-7.32 (m, 1 H), 4.20-4.03 (m, 4H), 2.46-2.44 (m, 2H), 2.03-1.99 (m, 2H), 1.19-1 .15 (t, J= 6.62 Hz, 3H). HPLC (Method A) Rt 4.47 min (Purity: 98.8%).

Reference： [1]Patent: WO2009/43889,2009,A2 .Location in patent: Page/Page column 169

44
[ 405-04-9 ]
[ 100-51-6 ]
[ 1044067-62-0 ]

Yield	Reaction Conditions	Operation in experiment
84%	With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	Preparation No.7: Synthesis of 4-(Benzyloxy)-3-fluorobenzonitrile; Under N2, DIAD (0.32 g, 1.54 mmol) was treated with Ph3P (0.41 g, 4.54 mmol) at about 0 C in dry THF (10 mL). The mixture was stirred until there was a precipitate. Then 3-fluoro-4- hydroxybenzonitrile (0.2 g, 1.46 mmol) and benzyl alcohol (0.17 g, 1.54 mmol) were added at the same time. The mixture was warmed to RT, and stirred overnight. The reaction mixture was concentrated and purified by silica-gel column chromatography (PE:EtOAc = 4:1) to afford 4- (benzyloxy)-3-fluorobenzonitrile as a white solid (0.28 g, yield 84%). GC/MS (Table 2, Method d) Rt: 10.83 min; m/z 227.1 (M).

Reference： [1]Patent: WO2010/93704,2010,A1 .Location in patent: Page/Page column 109
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 9154 - 9170

45
[ 405-04-9 ]
[ 1235841-38-9 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In acetic acid; at 25℃;	4-Cyano-2-fluorophenol (5.0 g, 38 mmol) was dissolved in acetic acid (50 mL) and treated dropwise with stirring with bromine (6.4 g, 40 mmol). After 2 h at 25 C, H2O (100 mL) was added. The precipitated product was collected by filtration, washed well with H2O and then taken up in EtOAc (150 mL). The solution was washed with H2O (50 mL), satd NaCl solution (50dmL), dried (Na2SO4) and evaporated. The residue was crystallized from aqueous ethanol (EtOH) to give the bromophenol (4.1 g). This material (3.4 g, 16 mmol) was dissolved in dry THF (100 mL), cooled to -78 0C and treated dropwise with H-BuLi (2.5 M in hexanes; 16 mL, 39 mmol) over 15 min. After stirring for 90 min at -78 0C, DMF (3.5 mL, 3.3 g, 45 mmol) was added and stirring was continued for 30 min at -78 0C and then warmed to 25 0C over 2 h. Satd NH4Cl solution (25 mL) and Et2O (100 mL) were added, and the pH was adjusted to 2 with 1 M HCl. The separated organic phase was washed with satd NaCl solution, dried (Na2SO4) and evaporated. The residue was purified on silica gel chromatography with 10-50% EtOAc/hexane to give the aldehyde (2.1 g): 1H NMR (400 MHz, CDCl3) delta 11.48 (s, IH), 9.96 (d, / = 1.7 Hz, IH), 7.78 (t, / = 1.5 Hz, 2H), 7.61 (dd, / = 9.8, 1.9 Hz, 2H); EIMS m/z 165.

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 7796 - 7813
[2]Patent: WO2010/83307,2010,A2 .Location in patent: Page/Page column 20

46
[ 405-04-9 ]
[ 540-51-2 ]
[ 917226-74-5 ]

Yield	Reaction Conditions	Operation in experiment
		To <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (0.2 kg) was added acetonitrile (0.85 L), at 200C. To this was added potassium carbonate (404 g); this was washed in with acetonitrile (0.18 L). The reaction was then heated to 80C +/- 5C, at approximately I0C per minute. When the reaction mixture was at 8O0C +/- 5C, 2- bromoethan-1-ol (0.31 L) was added, over approximately twenty minutes. This was washed in with acetonitrile (0.18 L). The temperature was adjusted to 800C +/- 5C, and maintained at this temperature for six hours. The reaction mixture was then cooled to 300C, at approximately 1C per minute. For convenience, the reaction was held at 300C for approximately 12 hours. Toluene (1.6 L) and water (1.34 L) were then added to the reaction mixture. The reaction mixture was reheated to 300C. The layers were separated, and the lower (aqueous) layer (approximately 1.2 L) was discarded. The upper (organic) layer was distilled at reduced pressure to remove approximately six volumes of solvent (approximately 1.2 L at less than 550C). The reaction mixture was then cooled to 200C, and was analysed for water content (typically < 0.1%w/w). To this was added triethylamine (245 mL), and the reaction mixture was cooled to -1O0C. To this was added trimethylamine hydrochloride (28 g), followed by a solution of para- toluenesulfonyl chloride (292 g) dissolved in toluene (1.2 L), whilst maintaining the temperature at -1O0C +/- 100C. When the addition was complete the reaction mixture was warmed to 200C. To this was added water (1.2 L), and the reaction EPO <DP n="40"/>mixture was heated to 750C. At 75C, the layers were separated, and the lower (aqueous) layer was discarded. To the retained organic layer was added 1 M hydrochloric acid (1.2 L), the reaction mixture was heated to 8O0C. The layers were separated and the lower (aqueous) layer was discarded. The upper (organic) layer was cooled to 2O0C over approximately two hours. For convenience, the reaction mixture was held at 2O0C for approximately twelve hours. The reaction mixture was then cooled to 5C over approximately thirty minutes. The reaction mixture was held at 50C for approximately one hour. The mixture was filtered, and the crude solid was then washed with toluene (200 mL, 50C). The damp solid was dried in vacuo, at 35C, for approximately twenty-four hours, to give the title compound as a white, crystalline solid (373 g, 76% yield). 1H-NMR (CDCl3, 300 MHz) delta 7.80 (d, J= 8.4 Hz, 2H, CHar), 7.41 - 7.32 (m, 4H, CHars), 6.94 (d, J = 8.2 Hz, IH, CHa1), 4.44 - 4.38 (m, 2H, CH2), 4.34 - 4.28 (m, 2H, CH2), 2.45 (s, 3H, ArCH3).

Reference： [1]Patent: WO2006/137770,2006,A1 .Location in patent: Page/Page column 37-38

47
[ 96-49-1 ]
[ 405-04-9 ]
[ 98-59-9 ]
[ 917226-73-4 ]

Yield	Reaction Conditions	Operation in experiment
69%		Comparative Example DRecrystaUised, high surface area, crystalline fert-Butyl f2-{7-[2-(4-cyano-2- fiuororhohenoxy)ethyl]-9-oxa-3 ,7-diazabicy clo\|"3.3.1 ]non-3 -yl) ethyPcarbamate(i) 2-(4-Cvano-2-fluorophenoxy)ethyl toluene-4-sulfonate To <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (10 g) was added ethylene carbonate (6.85 g), potassium iodide (1.2 g) and xylene (21 mL), at 200C. The reaction mixture was heated to 140C +/- 50C, over thirty minutes, and maintained at this temperature for twelve hours. For convenience, the reaction mixture was cooled to 2O0C, over approximately eight hours. To the cooled reaction mixture was added triethylamine (7.1 mL) and 4-methyl-pentan-2-one (14.25 mL). The reaction mixture was then cooled to -1O0C5 over approximately five minutes, after which trimethylamine hydrochloride (1.4 g) was added, followed by a solution of para- toluenesulfonyl chloride (14.6 g), dissolved in 4-methylpenatan-2-one (80 mL). During the addition, the reaction temperature was maintained at -100C +/- .50C. When the addition was complete, the reaction mixture was warmed to 2O0C. Water (60 mL) was added and the reaction mixture was heated to 75C, at which temperature the layers were separated and the lower (aqueous) layer was discarded. To the retained (organic) layer was added 1 M hydrochloric acid (60 mL), and the reaction mixture was again heated to 750C. The layers were separated and the lower (aqueous) layer was discarded. For convenience, the upper (organic) layer was cooled to 2O0C over approximately fourteen hours. The reaction mixture was then cooled to 50C over approximately ten minutes, after which the product was isolated by filtration and washed (on the filter) with 4- methylrhoenatan-2-one (10 mL, at 5C). The damp solid was then dried in vacuo, at 350C, for approximately twenty-four hours. This provided the sub-title compound as a white crystalline solid (16.9 g; 69% yield). EPO <DP n="36"/>1H-NMR (300 MHz, CDCl3): delta 7.85 - 7.77 (m, 2H), 7.43 - 7.30 (m, 4H), 6.95 (t, J = 8.3 Hz, IH), 4.45 - 4.37 (m, 2H), 4.35 - 4.27 (m, 2H)5 2.45 (s, 3H).

Reference： [1]Patent: WO2006/137772,2006,A1 .Location in patent: Page/Page column 34-35

48
[ 405-04-9 ]
[ 100-39-0 ]
[ 1044067-62-0 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation 17: 2-Fluoro-4-(1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-tetrazol-5-yl)phenol and 2-Fluoro-4-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-tetrazol-5-yl)phenolA) 4-(Benzyloxy)-3-fluorobenzonitrileTo a stirred solution of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (1.00 g, 7.30 mmol) in 20 mL of acetonitrile was added portion-wise potassium carbonate (2.02 g, 14.6 mmol). The resulting mixture was stirred for 10 minutes before benzyl bromide (1.33 mL, 10.9 mmol) was added. The mixture was stirred at room temperature for 70 hours before it was diluted with ethyl acetate and water. The organic phase was separated and washed with water, brine, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography, eluting with a gradient of 5 to 20% of ethyl acetate in heptane to give 4-(benzyloxy)-3- fluorobenzonitrile as a white solid (1.33 g).
		To a stirred solution of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (1 .00 g, 7.30 mmol) in 20 ml. of acetonitrile was added portion-wise potassium carbonate (2.02 g, 14.6 mmol). The resulting mixture was stirred for 10 minutes before benzyl bromide (1 .33 ml_, 10.9 mmol) was added. The mixture was stirred at room temperature for 70 hours before it was diluted with ethyl acetate and water. The organic phase was separated and washed with water, brine, dried over magnesium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatography, eluting with a gradient of 5 to 20% of ethyl acetate in heptane to give 4-(benzyloxy)-3- fluorobenzonitrile as a white solid (1 .33 g).

Reference： [1]Patent: WO2010/140092,2010,A1 .Location in patent: Page/Page column 57; 58
[2]Patent: WO2012/69948,2012,A1 .Location in patent: Page/Page column 57-58

49
[ 405-04-9 ]
[ 1155354-10-1 ]

Yield	Reaction Conditions	Operation in experiment
		Plternatively, 3-fluoro-4-hydroxybenzamide can be prepared as follows: To a stirred solution of urea hydrogen peroxide (4.2 g, 43.8 mmol) in 12 ml. of water was added solid sodium hydroxide (1.04 g, 25.5 mmol). The resulting solution was cooled in an ice bath before a solution of <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (1.00 g, 7.29 mmol) in 5 ml. of ethanol was added. The mixture was vigorously stirred for 2 hours at room temperature before it was diluted with water (100 ml.) and ethyl acetate (100 ml_). The mixture was stirred for 5 minutes before 1 M hydrochloric acid was added until pH 4. The aqueous layer was separated and extracted with ethyl acetate (3X100 ml_). The combined organic layers were dried over magnesium sulfate, filtered, and the filtrate was concentrated to give a white solid. This solid was triturated with diethyl ether and heptane (2:1 , 90 ml.) for 1 hour, before filtering to give 3-fluoro-4-hydroxybenzamide as a white solid (1.05 g). 1H NMR (400 MHz, deutero dimethyl sulfoxide ) delta 6.93 (t, J=8.69 Hz, 1 H) 7.19 (br. s., 1 H) 7.53 (dd, J=8.39, 1.95 Hz, 1 H) 7.62 (dd, J=12.40, 2.05 Hz, 1 H) 7.77 (br. s., 1 H) 10.39 (s, 1 H). LCMS (ES) 156.0 (M+1 ).
	With potassium hydroxide; In ethanol; for 16h;Reflux;Product distribution / selectivity;	A mixture of commercially available <strong>[405-04-9]3-fluoro-4-hydroxybenzonitrile</strong> (500 mg, 3.65 mmol) and potassium hydroxide (1 .02 g, 18.2 mmol) in 10 mL of 80% ethanol was heated at reflux for 16 hours. After cooling to room temperature the mixture was concentrated in vacuo and the residue was taken up into water, acidified with acetic acid and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography, eluting with a gradient of 20 to 60% ethyl acetate in heptane to give 3- fluoro-4-hydroxybenzamide as a white solid (210 mg).

Reference： [1]Patent: WO2010/140092,2010,A1 .Location in patent: Page/Page column 62; 63
[2]Patent: WO2012/69948,2012,A1 .Location in patent: Page/Page column 63

50
[ 405-04-9 ]
[ 1281981-35-8 ]

Reference： [1]Patent: US2011/77273,2011,A1
[2]Patent: WO2011/39130,2011,A1

51
[ 405-04-9 ]
[ 1281981-37-0 ]

Reference： [1]Patent: US2011/77273,2011,A1

52
[ 405-04-9 ]
[ 1281981-36-9 ]

Reference： [1]Patent: US2011/77273,2011,A1

53
[ 2417-73-4 ]
[ 405-04-9 ]
[ 1281981-39-2 ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate; In acetone; for 12h;Reflux;	To a solution of 3-fiuoro-4-hydroxy-benzonitrile (1.2 g, 8.7 mmol; CAS Reg. No. 405-04- 9) in acetone (20 ml) was added cesium carbonate (4.2 g, 13.05 mmol) and 2- bromomethyl-benzoic acid methyl ester (2 g, 8.7 mmol; CAS Reg. No. 2417-73-4) and the resulting solution was heated to reflux for 12 h. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel (8-10% ethyl acetate / n-hexane) to give the desired product as a yellow sticky solid (90%). MS (Turbo Spray): m/z = 286.1 (M+H).
	With caesium carbonate; In acetone; for 12h;Reflux;	To a solution of <strong>[405-04-9]3-fluoro-4-hydroxy-benzonitrile</strong> (1.2 g, 8.7 mmol; CAS Reg. No. 405-04-9) in acetone (20 ml) was added cesium carbonate (4.2 g, 13.05 mmol) and 2-bromomethyl-benzoic acid methyl ester (2 g, 8.7 mmol; CAS Reg. No. 2417-73-4) and the resulting solution was heated to reflux for 12 h. The reaction mixture was filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel (8-10% ethyl acetate/n-hexane) to give the desired product as a yellow sticky solid (90%). MS (Turbo Spray): m/z=286.1 (M+H).

Reference： [1]Patent: WO2011/39130,2011,A1 .Location in patent: Page/Page column 105
[2]Patent: US2011/77273,2011,A1 .Location in patent: Page/Page column 43

54
[ 75-30-9 ]
[ 405-04-9 ]
[ 1153103-84-4 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; In acetone; for 24h;Reflux;	Synthesis of 3-fluoro-4-isopropoxy-benzonitrile (For Example 103)4.425.0 g 3-Fluoro-4-hydroxy-benzonitrile, 7.3 mL isopropyl iodide and 6.05 g potassium carbonate were placed in 54 mL acetone and heated to reflux where the reaction was maintained for 24 h. After this time, the mixture was cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between ethyl acetate and water and the aqueous phase was removed and extracted with additional ethyl acetate. The combined organics were dried, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound that was used without further purification.Yield: 4.75 g (73% of theory)Analysis: HPLC-MS (Method B): Rt: 2.01 min (M+H)+ = 180.
73%	With potassium carbonate; In acetone; for 24h;Reflux;	5.0 g 3-Fluoro-4-hydroxy-benzonitrile, 7.3 mL isopropyl iodide and 6.05 g potassium carbonate were placed in 54 mL acetone and heated to reflux where the reaction was maintained for 24 h. After this time, the mixture was cooled to ambient temperature and concentrated under reduced pressure. The material that remained was partitioned between ethyl acetate and water and the aqueous phase was removed and extracted with additional ethyl acetate. The combined organics were dried, filtered and the solvent was removed from the filtrate under reduced pressure to give the title compound that was used without further purification. Yield: 4.75 g (73% of theory) Analysis: HPLC-MS (Method B): Rt: 2.01 min (M+H)+=180.

Reference： [1]Patent: WO2011/92128,2011,A1 .Location in patent: Page/Page column 43
[2]Patent: US2012/28939,2012,A1 .Location in patent: Page/Page column 22

55
[ 405-04-9 ]
[ 1258001-70-5 ]