[ CAS No. 114435-86-8 ]

Name: 114435-86-8|Fluoromethyl 4-methylbenzenesulfonate|97%
Brand: Ambeed
SKU: A276228
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Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 114435-86-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 114435-86-8 ]

Product Details of [ 114435-86-8 ]

CAS No. :	114435-86-8	MDL No. :	MFCD20482732
Formula :	C₈H₉FO₃S	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	RFCGZPLGJZELOK-UHFFFAOYSA-N
M.W :	204.22	Pubchem ID :	13862289
Synonyms :

Calculated chemistry of [ 114435-86-8 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.25
Num. rotatable bonds :	3
Num. H-bond acceptors :	4.0
Num. H-bond donors :	0.0
Molar Refractivity :	45.64
TPSA :	51.75 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-6.2 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.04
Log Po/w (XLOGP3) :	1.89
Log Po/w (WLOGP) :	3.13
Log Po/w (MLOGP) :	1.94
Log Po/w (SILICOS-IT) :	1.42
Consensus Log Po/w :	2.08

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.44
Solubility :	0.741 mg/ml ; 0.00363 mol/l
Class :	Soluble
Log S (Ali) :	-2.6
Solubility :	0.514 mg/ml ; 0.00252 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.14
Solubility :	0.148 mg/ml ; 0.000724 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.17

Safety of [ 114435-86-8 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P210-P280-P305+P351+P338-P310	UN#:	3265
Hazard Statements:	H227-H302-H314-H317	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 114435-86-8 ]

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

Upstream synthesis route of [ 114435-86-8 ]
Downstream synthetic route of [ 114435-86-8 ]

[ 114435-86-8 ] Synthesis Path-Upstream 1~7

1
[ 24124-59-2 ]
[ 114435-86-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With cesium fluoride In tert-Amyl alcohol at 90℃; for 0.25 h; Microwave irradiation; Sealed tube	Methylene ditosylate (100 mg, 0.28 mmol) and caesium fluoride (213 mg, 1.4 mmol) were dissolved in tert-amyl alcohol (5 mL) and irradiated in a microwave for 15 minutes at 90 °C. The reaction was allowed to cool and the tert-amyl alcohol was removed under reduced pressure, ice-cold diethyl ether was added and the suspension filtered, then washed with plenty of ice-cold diethyl ether. The filtrate was concentrated under reduced pressure to yield Fluoromethyl 4-methylbenzenesulfonate as a colourless oil (49 mg, 88percent yield). ¹H NMR (500 MHz, CDCl₃) δ: 2.43 (s, 3H, ArCH₃), 5.72 (d, 2H, CH₂, J = 51.0 Hz), 7.35 (d, 2H, ArH, J = 8.0 Hz), 7.81 (d, 2H, ArH, J = 8.0 Hz); ¹³C (125 MHz, CDCl₃) δ: 21.67, 98.16 (d, J = 221 Hz), 127.87, 129.96, 133.77, 145.63; ¹⁹F (471 MHz, CDCl3) δ: -153.24 (t, J = 50.7 Hz).
41.3%	With pentaethylene glycol; cesium fluoride In acetonitrile for 2.5 h; Reflux	A stirred solution of methylene bis(tosylate) (2.0 g, 5.61 mmol), hexaethylene glycol(2.11 mL, 8.42 mmol) and cesium fluoride (1.279 g, 8.42 mmol) in acetonitrile(17 mL) was refluxed for 2.5 h. The reaction mixture was diluted with ether, and extracted three times with water to remove hexaethylene glycol. The ether layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash chromatography (4 g silica-gel column, flow rate of 24 ml/min) eluting with100percent hexane for 3 min and increased ethyl acetate from 0percent to 10percent in 20 min togive the product as colorless oil (473 mg, 2.32 mmol, 41.3percent yield).¹H NMR (500MHz, CDCl₃) δ ppm 7.84 (d, J= 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz,2H), 5.74 (d, J = 51.0 Hz, 2H), 2.46(s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ ppm 145.92, 134.14, 130.27, 128.22, 98.45 (d, J = -229.5 Hz), 22.01; ¹⁹FNMR (470 MHz, CDCl₃) δppm 153.2 (t, J = 50.5 Hz).
11%	With potassium fluoride; [2.2.2]cryptande In acetonitrile at 110℃; for 1 h; Inert atmosphere	Example 3. Preparation of Fluoromethyltosylate (8)C H₂OTos₂ ^ FCH₂OTos7⁸ Methylene ditosylate (7) was prepared according to an established literature procedure and analytical data was consistent with reported values (Emmons, W.D., et al. , Journal of the American Chemical Society, 1953; 75:2257; and Neal, T.R., et al. , Journal of Labelled Compounds and Radiopharmaceuticals 2005; 48:557-68).To a solution of methylene ditosylate (7) (0.67 g, 1.89 mmol) in dry acetonitrile (10 mL) was added Kryptofix K₂₂₂ [4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane] (1.00 g, 2.65 mmol) followed by potassium fluoride (0.16 g, 2.83 mmol). The suspension was then heated to 110°C under nitrogen. After 1 h TLC (7:3 hexane/ethyl acetate/silica/UV₂5₄) indicated complete conversion of (7). The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (2 x 15 mL) and dried over MgS0₄. Chromatography (5--> 10percent ethyl acetate/hexane) gave the desired product (8) as a colorless oil (40 mg, 11percent). ^]H NMR (CDC1₃, 400 MHz) δ 7.86 (d, 2H, / = 8 Hz, aryl CH), 7.39 (d, 2 H, / = 8 Hz, aryl CH), 5.77 (d, 1 H, / = 52 Hz, CH₂F), 2.49 (s, 3H, tolyl CH₃). ¹³C NMR (CDC1₃) δ 145.6 (aryl), 133.8 (aryl), 129.9 (aryl), 127.9 (aryl), 98.1 (d, / = 229 Hz, CH₂F), 21.7 (tolyl CH₃). HRMS (CI) = 222.0604 (M + NH₄)⁺. Calcd. for C₈H₁₃FN0₃S 222.0600.

11%	With potassium fluoride; [2.2.2]cryptande In acetonitrile at 110℃; for 1 h; Inert atmosphere	Example 3. Preparation of Fluoromethyltosylate (8)C H₂OTos₂ ^ FCH₂OTos7⁸ Methylene ditosylate (7) was prepared according to an established literature procedure and analytical data was consistent with reported values (Emmons, W.D., et al. , Journal of the American Chemical Society, 1953; 75:2257; and Neal, T.R., et al. , Journal of Labelled Compounds and Radiopharmaceuticals 2005; 48:557-68).To a solution of methylene ditosylate (7) (0.67 g, 1.89 mmol) in dry acetonitrile (10 mL) was added Kryptofix K₂₂₂ [4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane] (1.00 g, 2.65 mmol) followed by potassium fluoride (0.16 g, 2.83 mmol). The suspension was then heated to 110°C under nitrogen. After 1 h TLC (7:3 hexane/ethyl acetate/silica/UV₂54) indicated complete conversion of (7). The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (2 x 15 mL) and dried over MgS0₄. Chromatography (5--> 10percent ethyl acetate/hexane) gave the desired product (8) as a colorless oil (40 mg, 11percent). ^]H NMR (CDC1₃, 400 MHz) δ 7.86 (d, 2H, / = 8 Hz, aryl CH), 7.39 (d, 2 H, / = 8 Hz, aryl CH), 5.77 (d, 1 H, / = 52 Hz, CH₂F), 2.49 (s, 3H, tolyl CH₃). ¹³C NMR (CDC1₃) δ 145.6 (aryl), 133.8 (aryl), 129.9 (aryl), 127.9 (aryl), 98.1 (d, J = 229 Hz, CH₂F), 21.7 (tolyl CH₃). HRMS (CI) = 222.0604 (M + NH₄)⁺. Calcd. for C₈H₁₃FN0₃S 222.0600.
11%	With potassium fluoride; [2.2.2]cryptande In acetonitrile at 110℃; for 1 h; Inert atmosphere	Example 3. Preparation of Fluoromethyltosylate (8)C H₂OTos₂ FCH₂OTos7 8Methylene ditosylate (7) was prepared according to an established literature procedure and analytical data was consistent with reported values (Emmons, W.D., et al. , Journal of the American Chemical Society, 1953; 75:2257; and Neal, T.R., et al. , Journal of Labelled Compounds and Radiopharmaceuticals 2005; 48:557-68).To a solution of methylene ditosylate (7) (0.67 g, 1.89 mmol) in dry acetonitrile (10 mL) was added Kryptofix K₂₂₂ [4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane] (1.00 g, 2.65 mmol) followed by potassium fluoride (0.16 g, 2.83 mmol). The suspension was then heated to 110°C under nitrogen. After 1 h TLC (7:3 hexane/ethyl acetate/silica/UV₂5₄) indicated complete conversion of (7). The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (2 x 15 mL) and dried over MgS0₄. Chromatography (5--> 10percent ethyl acetate/hexane) gave the desired product (8) as a colorless oil (40 mg, 11percent). ^]H NMR (CDC1₃, 400 MHz) δ 7.86 (d, 2H, / = 8 Hz, aryl CH), 7.39 (d, 2 H, / = 8 Hz, aryl CH), 5.77 (d, 1 H, / = 52 Hz, CH₂F), 2.49 (s, 3H, tolyl CH₃). ¹³C NMR (CDC1₃) δ 145.6 (aryl), 133.8 (aryl), 129.9 (aryl), 127.9 (aryl), 98.1 (d, / = 229 Hz, CH₂F), 21.7 (tolyl CH₃). HRMS (CI) = 222.0604 (M + NH₄)⁺. Calcd. for C₈H₁₃FN0₃S 222.0600.

Reference： [1] Tetrahedron Letters, 2018, vol. 59, # 17, p. 1635 - 1637
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 18, p. 3956 - 3960
[3] Journal of Labelled Compounds and Radiopharmaceuticals, 2003, vol. 46, # 6, p. 555 - 566
[4] ChemMedChem, 2016, vol. 11, # 1, p. 108 - 118
[5] Patent: WO2012/40133, 2012, A2, . Location in patent: Page/Page column 36-37
[6] Patent: WO2012/40138, 2012, A2, . Location in patent: Page/Page column 36
[7] Patent: WO2012/40151, 2012, A2, . Location in patent: Page/Page column 39
[8] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487
[9] Journal of Labelled Compounds and Radiopharmaceuticals, 2005, vol. 48, # 8, p. 557 - 568
[10] Journal of Labelled Compounds and Radiopharmaceuticals, 2013, vol. 56, # 7, p. 360 - 363
[11] Patent: WO2014/137883, 2014, A1, . Location in patent: Page/Page column 62
[12] Patent: WO2015/120320, 2015, A1, . Location in patent: Page/Page column 89

2
[ 1280126-09-1 ]
[ 104-15-4 ]
[ 114435-86-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2011, vol. 50, # 8, p. 1885 - 1889

3
[ 75-11-6 ]
[ 16836-95-6 ]
[ 114435-86-8 ]

Yield	Reaction Conditions	Operation in experiment
28%	for 20 h; Reflux	Example 8. Synthesis of cold Fluoromethyltosylate (15)i iiCH₂I₂ CH₂OTos₂ FCH₂OTos13 14 ₁₅ Scheme 3 i: Silver p-toluenesulfonate, MeCN, reflux, 20 h;ii: KF, MeCN, reflux, 1 h.According to Scheme 3 above:(a) Synthesis of methylene ditosylate (14)Commercially available diiodomethane (13) (2.67 g, 10 mmol) was reacted with silver tosylate (6.14 g, 22 mmol), using the method of Emmons and Ferris, to give methylene ditosylate (10) (0.99g) in 28percent yield (Emmons, W.D., et ah, "Metathetical Reactions of Silver Salts in Solution. II. The Synthesis of Alkyl Sulfonates", Journal of the American Chemical Society, 1953; 75:225).

Reference： [1] Patent: WO2012/40151, 2012, A2, . Location in patent: Page/Page column 43

4
[ 104-15-4 ]
[ 114435-86-8 ]

Reference： [1] Angewandte Chemie - International Edition, 2017, vol. 56, # 33, p. 9930 - 9934[2] Angew. Chem., 2017, vol. 129, p. 10062 - 10066,5

5
[ 16836-95-6 ]
[ 114435-86-8 ]

Reference： [1] Patent: WO2012/40133, 2012, A2,
[2] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487
[3] Patent: WO2014/137883, 2014, A1,
[4] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 18, p. 3956 - 3960
[5] Tetrahedron Letters, 2018, vol. 59, # 17, p. 1635 - 1637
[6] Patent: WO2012/40138, 2012, A2,

6
[ 24124-59-2 ]
[ 455-16-3 ]
[ 114435-86-8 ]

Reference： [1] Tetrahedron Letters, 2018, vol. 59, # 17, p. 1635 - 1637

7
[ 104-15-4 ]
[ 114435-86-8 ]

Reference： [1] ChemMedChem, 2014, vol. 9, # 7, p. 1476 - 1487

[ 114435-86-8 ] Synthesis Path-Downstream 1~50

1
[ 24124-59-2 ]
[ 114435-86-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With cesium fluoride; In tert-Amyl alcohol; at 90℃; for 0.25h;Microwave irradiation; Sealed tube;	Methylene ditosylate (100 mg, 0.28 mmol) and caesium fluoride (213 mg, 1.4 mmol) were dissolved in tert-amyl alcohol (5 mL) and irradiated in a microwave for 15 minutes at 90 C. The reaction was allowed to cool and the tert-amyl alcohol was removed under reduced pressure, ice-cold diethyl ether was added and the suspension filtered, then washed with plenty of ice-cold diethyl ether. The filtrate was concentrated under reduced pressure to yield Fluoromethyl 4-methylbenzenesulfonate as a colourless oil (49 mg, 88% yield). 1H NMR (500 MHz, CDCl3) delta: 2.43 (s, 3H, ArCH3), 5.72 (d, 2H, CH2, J = 51.0 Hz), 7.35 (d, 2H, ArH, J = 8.0 Hz), 7.81 (d, 2H, ArH, J = 8.0 Hz); 13C (125 MHz, CDCl3) delta: 21.67, 98.16 (d, J = 221 Hz), 127.87, 129.96, 133.77, 145.63; 19F (471 MHz, CDCl3) delta: -153.24 (t, J = 50.7 Hz).
41.3%	With pentaethylene glycol; cesium fluoride; In acetonitrile; for 2.5h;Reflux;	A stirred solution of methylene bis(tosylate) (2.0 g, 5.61 mmol), hexaethylene glycol(2.11 mL, 8.42 mmol) and cesium fluoride (1.279 g, 8.42 mmol) in acetonitrile(17 mL) was refluxed for 2.5 h. The reaction mixture was diluted with ether, and extracted three times with water to remove hexaethylene glycol. The ether layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to flash chromatography (4 g silica-gel column, flow rate of 24 ml/min) eluting with100% hexane for 3 min and increased ethyl acetate from 0% to 10% in 20 min togive the product as colorless oil (473 mg, 2.32 mmol, 41.3% yield).1H NMR (500MHz, CDCl3) delta ppm 7.84 (d, J= 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz,2H), 5.74 (d, J = 51.0 Hz, 2H), 2.46(s, 3H); 13C NMR (125 MHz, CDCl3) delta ppm 145.92, 134.14, 130.27, 128.22, 98.45 (d, J = -229.5 Hz), 22.01; 19FNMR (470 MHz, CDCl3) deltappm 153.2 (t, J = 50.5 Hz).
11%	With potassium fluoride; [2.2.2]cryptande; In acetonitrile; at 110℃; for 1h;Inert atmosphere;Product distribution / selectivity;	Example 3. Preparation of Fluoromethyltosylate (8)C H2OTos2 ^ FCH2OTos7 8 Methylene ditosylate (7) was prepared according to an established literature procedure and analytical data was consistent with reported values (Emmons, W.D., et al. , Journal of the American Chemical Society, 1953; 75:2257; and Neal, T.R., et al. , Journal of Labelled Compounds and Radiopharmaceuticals 2005; 48:557-68).To a solution of methylene ditosylate (7) (0.67 g, 1.89 mmol) in dry acetonitrile (10 mL) was added Kryptofix K222 [4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane] (1.00 g, 2.65 mmol) followed by potassium fluoride (0.16 g, 2.83 mmol). The suspension was then heated to 110C under nitrogen. After 1 h TLC (7:3 hexane/ethyl acetate/silica/UV254) indicated complete conversion of (7). The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (2 x 15 mL) and dried over MgS04. Chromatography (5? 10% ethyl acetate/hexane) gave the desired product (8) as a colorless oil (40 mg, 11%). ]H NMR (CDC13, 400 MHz) delta 7.86 (d, 2H, / = 8 Hz, aryl CH), 7.39 (d, 2 H, / = 8 Hz, aryl CH), 5.77 (d, 1 H, / = 52 Hz, CH2F), 2.49 (s, 3H, tolyl CH3). 13C NMR (CDC13) delta 145.6 (aryl), 133.8 (aryl), 129.9 (aryl), 127.9 (aryl), 98.1 (d, / = 229 Hz, CH2F), 21.7 (tolyl CH3). HRMS (CI) = 222.0604 (M + NH4)+. Calcd. for C8H13FN03S 222.0600.

11%	With potassium fluoride; [2.2.2]cryptande; In acetonitrile; at 110℃; for 1h;Inert atmosphere;Product distribution / selectivity;	Example 3. Preparation of Fluoromethyltosylate (8)C H2OTos2 ^ FCH2OTos7 8 Methylene ditosylate (7) was prepared according to an established literature procedure and analytical data was consistent with reported values (Emmons, W.D., et al. , Journal of the American Chemical Society, 1953; 75:2257; and Neal, T.R., et al. , Journal of Labelled Compounds and Radiopharmaceuticals 2005; 48:557-68).To a solution of methylene ditosylate (7) (0.67 g, 1.89 mmol) in dry acetonitrile (10 mL) was added Kryptofix K222 [4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane] (1.00 g, 2.65 mmol) followed by potassium fluoride (0.16 g, 2.83 mmol). The suspension was then heated to 110C under nitrogen. After 1 h TLC (7:3 hexane/ethyl acetate/silica/UV254) indicated complete conversion of (7). The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (2 x 15 mL) and dried over MgS04. Chromatography (5? 10% ethyl acetate/hexane) gave the desired product (8) as a colorless oil (40 mg, 11%). ]H NMR (CDC13, 400 MHz) delta 7.86 (d, 2H, / = 8 Hz, aryl CH), 7.39 (d, 2 H, / = 8 Hz, aryl CH), 5.77 (d, 1 H, / = 52 Hz, CH2F), 2.49 (s, 3H, tolyl CH3). 13C NMR (CDC13) delta 145.6 (aryl), 133.8 (aryl), 129.9 (aryl), 127.9 (aryl), 98.1 (d, J = 229 Hz, CH2F), 21.7 (tolyl CH3). HRMS (CI) = 222.0604 (M + NH4)+. Calcd. for C8H13FN03S 222.0600.
11%	With potassium fluoride; [2.2.2]cryptande; In acetonitrile; at 110℃; for 1h;Inert atmosphere;Product distribution / selectivity;	Example 3. Preparation of Fluoromethyltosylate (8)C H2OTos2 FCH2OTos7 8Methylene ditosylate (7) was prepared according to an established literature procedure and analytical data was consistent with reported values (Emmons, W.D., et al. , Journal of the American Chemical Society, 1953; 75:2257; and Neal, T.R., et al. , Journal of Labelled Compounds and Radiopharmaceuticals 2005; 48:557-68).To a solution of methylene ditosylate (7) (0.67 g, 1.89 mmol) in dry acetonitrile (10 mL) was added Kryptofix K222 [4,7,13,16,21,24-hexaoxa-l,10- diazabicyclo[8.8.8]hexacosane] (1.00 g, 2.65 mmol) followed by potassium fluoride (0.16 g, 2.83 mmol). The suspension was then heated to 110C under nitrogen. After 1 h TLC (7:3 hexane/ethyl acetate/silica/UV254) indicated complete conversion of (7). The reaction mixture was diluted with ethyl acetate (25 mL), washed with water (2 x 15 mL) and dried over MgS04. Chromatography (5? 10% ethyl acetate/hexane) gave the desired product (8) as a colorless oil (40 mg, 11%). ]H NMR (CDC13, 400 MHz) delta 7.86 (d, 2H, / = 8 Hz, aryl CH), 7.39 (d, 2 H, / = 8 Hz, aryl CH), 5.77 (d, 1 H, / = 52 Hz, CH2F), 2.49 (s, 3H, tolyl CH3). 13C NMR (CDC13) delta 145.6 (aryl), 133.8 (aryl), 129.9 (aryl), 127.9 (aryl), 98.1 (d, / = 229 Hz, CH2F), 21.7 (tolyl CH3). HRMS (CI) = 222.0604 (M + NH4)+. Calcd. for C8H13FN03S 222.0600.
	With tetrabutyl ammonium fluoride; In acetonitrile; at 80℃;	A mixture of methylene bis(4-methylbenzenesulfonate) (1.6 g, 4.48 mmol) and TBAF (1.15 g, 4.48 mmol) in acetonitrile (15 mL) was heated at 80 C overnight. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (1 :5 EtOAc in petroleum ether), providing the title compound as a colorless oil.
	With tetrabutyl ammonium fluoride; In acetonitrile;Reflux;	Example 30.2. Preparation of fluoromethyl 4-toluene-sulfon ate. Methylene bis(toluene-4-sulfonate) (2.12 g; 5.96 mmol; Matrix Scientific) and tetrabutylammonium fluoride (6 mL; 1 M solution in THF; Aldrich) were refluxed in 6 mL acetonitrile overnight. Upon cooling, the reaction mixture wasevaporated and purified by silica chromatography (ethyl acetate gradient in hexanes) to afford fluoromethyl 4-toluene-sulfonate.

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 1635 - 1637
[2]Chemical Communications,2019,vol. 55,p. 11798 - 11801
[3]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3956 - 3960
[4]Journal of labelled compounds and radiopharmaceuticals,2003,vol. 46,p. 555 - 566
[5]ChemMedChem,2016,vol. 11,p. 108 - 118
[6]Journal of labelled compounds and radiopharmaceuticals,2019,vol. 62,p. 588 - 595
[7]Patent: WO2012/40133,2012,A2 .Location in patent: Page/Page column 36-37
[8]Patent: WO2012/40138,2012,A2 .Location in patent: Page/Page column 36
[9]Patent: WO2012/40151,2012,A2 .Location in patent: Page/Page column 39
[10]ChemMedChem,2014,vol. 9,p. 1476 - 1487
[11]Journal of labelled compounds and radiopharmaceuticals,2005,vol. 48,p. 557 - 568
[12]Journal of labelled compounds and radiopharmaceuticals,2013,vol. 56,p. 360 - 363
[13]Patent: WO2014/137883,2014,A1 .Location in patent: Page/Page column 62
[14]Patent: WO2015/120320,2015,A1 .Location in patent: Page/Page column 89

2
[ 4326-36-7 ]
[ 114435-86-8 ]
[ 627092-19-7 ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2003,vol. 46,p. 555 - 566

3
[ 878805-86-8 ]
[ 114435-86-8 ]
[ 878805-92-6 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	100 mg of the 4-(8-hydroxyimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [158-1] was dissolved in 3 mL of N,N-dimethylformamide, 146 mg of potassium carbonate and 216 mg of <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (synthesized according to a method disclosed in page 555 to 566 in J. Labelled Compd. Radio pharm. 2003, 46) were added, and stirred at 80C for 5 hours. After cooling the reaction mixture back to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added, and was extracted with a mixture solvent of chloroform and methanol (chloroform : methanol = 9:1). The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in a small amount of a mixture solvent of chloroform and methanol (chloroform : methanol =9:1), and solidified by adding diethyl ether, to obtain 44.1 mg of 4-[8-(fluoromethoxy)imidazo[1,2-a]pyridin-3-yl]-2-(methylthio)pyrimidine-5-carbonitrile [160-1] as a brown solid.

Reference： [1]Patent: EP1790650,2007,A1 .Location in patent: Page/Page column 100

4
trans-5'-hydroxy-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide [ No CAS ]
[ 114435-86-8 ]
trans-5'-fluoromethoxy-3'-oxo-N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; at 70℃; for 20h;	Example 32 trans-5'-Fluoromethoxy-3'-oxo-(N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide hydrochloride; [Show Image] Fluoromethyl tosylate (0.05 mL) and potassium carbonate (50 mg) were added to a solution of trans-5'-hydroxy-3'-oxo-(N-methyl-N-(2-piperidin-1-ylethyl)-spiro[cyclohexane-1,1'-(3'H)-isobenzofuran]-4-carboxamide (50 mg) produced in Example 23 in acetone (0.8 mL) and the mixture was stirred in a sealed tube at 70C for 20 hours. After water was added thereto, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over sodium sulfate, filtered, concentrated in vacuo and purified by a reverse phase HPLC (0.1% TFA acetonitrile : H2O = 5% to 50%, gradient) to give a free base of the title compound as a colorless oily compound. The resulting free base (40 mg) was dissolved in ethyl acetate (1.0 mL), a 4N solution of hydrogen chloride in ethyl acetate (0.05 mL) was added thereto and the mixture was concentrated in vacuo. Ethyl acetate was added thereto to suspend and the solid separated out therefrom was filtered to give the title compound (30 mg, 69%) as a colorless solid. 1HNMR (400MHz, DMSO-d6, delta): 1.29-2.10 (14H, m), 2.82-3.30 (5H, m), 2.86 (3Hx1/4, s), 3.09 (3Hx3/4), 3.42-3.55 (2H, m), 3.63-3.88 (2H, m), 5.97 (2H, d, J=53.8Hz), 7.49-7.73 (3H, m), 9.65 (1Hx3/4, brs), 10.55 (1Hx1/4, brs); mass spectrum (ESI): 419.2 (M+H)

Reference： [1]Patent: EP1795527,2007,A1 .Location in patent: Page/Page column 62

5
N-Boc-2-(4'-aminophenyl)-6-(2-methoxyethoxymethoxy)benzothiazole [ No CAS ]
[ 114435-86-8 ]
2-[4'-(N-Boc-N-(fluoromethyl)amino)phenyl]-6-(2-methoxyethoxymethoxy)benzothiazole [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2008,vol. 51,p. 137 - 145

6
[ 1017599-94-8 ]
[ 114435-86-8 ]
[ 1017599-92-6 ]
[ 1017599-93-7 ]

Yield	Reaction Conditions	Operation in experiment
		Example 2-2: Production of (E)-(3,4-difluorophenyl)[6-(1H,1'H-spiro[furo[3,4-c]pyridine-3,4'-piperidin]-1'-ylmethyl)pyridin-3-yl]methanone O-(fluoromethyl)oxime and (E)-(3,4-difluorophenyl)[6-(1H,1'H-spiro[furo[3,4-c]pyridine-3,4'-piperidin]-1'-ylmethyl)pyridin-3-yl]methanone O-(4-methylbenzenesulfonyl)oxime At 0C, a DMF solution (1.00 mL) of potassium carbonate (32.0 mg) and <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (14.3 mg) was added to a DMF solution (500 muL) of (E)-(3,4-difluorophenyl)[6-(1H,1'H-spiro[furo[3,4-c]pyridine-3,4'-piperidin]-1'-ylmethyl)-3-pyridinyl]methanone oxime (20.1 mg) which was obtained according to the same manner as in Example 1-1 but using the compound obtained in Reference Example 5-1-1, and stirred for 1 hour. Aqueous sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with diethyl ether. The organic layer was washed with water and saturated saline, and dried with anhydrous sodium sulfate. After the organic layer was concentrated under reduced pressure, the residue was purified through preparative thin-layer silica gel chromatography (chloroform/methanol = 95/5) to obtain the entitled compound, fluoromethyl-form (5.4 mg) as a colorless oil, and the entitled compound, tosyl-form (7.5 mg) as a red oil.Fluoromethyl form: 1HNMR (400 MHz, CDCl3, delta ppm): 1.80-1.83 (2H, m), 2.05-2.12 (2H, m), 2.53-2.59 (2H, m), 2.85-2.88 (2H, m), 3.78 (2H, s), 5.06 (2H, s), 5.70 (1H, s), 5.84 (1H, s), 7.11-7.15 (1H, m), 7.18-7.20 (1H, m), 7.24-7.32 (1H, m), 7.45 (1H, s), 7.48-7.51 (1H, m), 7.82-7.84 (1H, m), 8.45 (1H, s), 8.51 (1H, d, J=4.8 Hz), 8.635-8.640 (1H, m). ESI-MS Found: m/z 469[M+H]+ Tosyl form: 1HNMR (400 MHz, CDCl3, delta ppm): 1.80-1.83 (2H, m), 2.04-2.14 (2H, m), 2.48 (3H, s), 2.52-2.64 (2H, m), 2.82-2.90 (2H, m), 3.79 (2H, brs), 5.06 (2H, s), 7.09-7.13 (1H, m), 7.16-7.20 (2H, m), 7.27-7.33 (1H, m), 7.39 (2H, d, J=8.0 Hz), 7.48-7.52 (1H, m), 7.63-7.66 (1H, m), 7.91 (2H, d, J=8.0 Hz), 8.45 (1H, s), 8.52 (1H, d, J=4.8 Hz), 8.55-8.56 (1H, m). ESI-MS Found: m/z 591[M+H]+

Reference： [1]Patent: EP2072519,2009,A1 .Location in patent: Page/Page column 64

7
[ 13924-95-3 ]
[ 114435-86-8 ]
[ 1174321-01-7 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5.5h;	Fluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds & Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in N,N-dimethylformamide (2.0 mL). The reaction solution was stirred at 70 C. for five hours and 30 minutes and then cooled to room temperature. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg).1H-NMR (400 MHz, CDCl3) delta (ppm): 4.03 (s, 3H), 6.14 (d, J=51.2 Hz, 2H), 8.42 (d, J=1.2 Hz, 1H), 8.94 (d, J=1.2 Hz, 1H).
	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 5.5h;	1) Synthesis of methyl 5-fluoromethoxypyrazine-2-carboxylateFluoromethyl toluene-4-sulfonate (Journal of Labelled Compounds and Radiopharmaceuticals, 46 (6), 555-566; 2003) (344 mg) and cesium carbonate (824 mg) were added to a solution of methyl 5-hydroxypyrazine-2-carboxylate (130 mg) in DMF (2.0 mL). The reaction solution was stirred at 70C for 5 h and 30 min and then cooled to RT. Water was added to the reaction solution, followed by extraction with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (18.0 mg). 1H-NMR (400 MHz, CDCl3) delta (ppm): 4.03 (s, 3H), 6.14 (d, J = 51.2 Hz, 2H), 8.42 (d, J = 1.2 Hz, IH), 8.94 (d, J = 1.2 Hz, IH).

Reference： [1]Patent: US2010/93999,2010,A1 .Location in patent: Page/Page column 35
[2]Patent: WO2011/9898,2011,A1 .Location in patent: Page/Page column 84-85

8
[ 921590-81-0 ]
[ 114435-86-8 ]
[ 1146629-96-0 ]

Reference： [1]European Journal of Medicinal Chemistry,2009,vol. 44,p. 593 - 608

9
[ 1059188-84-9 ]
[ 114435-86-8 ]
[ 1059188-86-1 ]

Reference： [1]Journal of Medicinal Chemistry,2008,vol. 51,p. 5833 - 5842

10
[ 1228535-00-9 ]
[ 114435-86-8 ]
[ 1228535-13-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 2h;Sealed tube;	Example 290; 3-[2-(2,3-Dihydro-benzo[l,4ldioxin-6-yl)-2ff-pyrazol-3-yll-l-(3-fluoromethoxy-phenyl)-lff- pgammaridazin-4-one; To a solution of 3-[2-(2,3-Dihydro-benzo[l,4]dioxin-6-yl)-2H-pyrazol-3-yl]-l-(3-hydroxy- phenyl)-lH-pyridazin-4-one (example 277) (50 mg, 0.13 mmol) in DMF (0.5 ml) were added CsCO3 (80 mg, 0.25 mmol) and a solution of <strong>[114435-86-8]fluoromethyl tosylate</strong> (38 mg, 0.18 mmol; R. Iwata et al., J Label Compd Radiopharm 2003, 46, 555-566) in DMF (0.5 ml). The reaction mixture was heated under stirring in a sealed tube 2 h at 70 0C. After cooling H2O was added and the product was extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent was evaporated. Chromatography (5 g SiO2, CH2Cl2/MeOH 95:5) afforded the product as a light brown foam (52 mg, 97%).MS: M = 421.1 (M+H)+

Reference： [1]Patent: WO2010/63610,2010,A1 .Location in patent: Page/Page column 207

11
[ 228867-86-5 ]
[ 114435-86-8 ]
[ 1262860-53-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 70 - 100℃; for 2h;	To a solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol) in DMF (10 ml) was added a solution of toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (521 mg, 2.55 mmol) and Cs2CO3 (1.386 g, 4.26 mmol) in DMF (4 ml). The reaction mixture was stirred for 1 h at 100 C., then for 1 h at 70 C., diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a white solid after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-30 min 95:5 to 65:35).HPLC RtH10=0.77 min; ESIMS: 167 [(M+H)+];1H NMR (400 MHz, CDCl3): 8.36 (d, 1H), 7.34 (d, 1H), 5.79 (d, 2H), 2.59 (s, 3H).
	With caesium carbonate; In N,N-dimethyl-formamide; at 70 - 100℃; for 2h;	a) 5-Fluoromethoxy-3-methyl-pyridine-2-carbonitrile To a solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol) in DMF (10 ml) was added a solution of toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (521 mg, 2.55 mmol) and Cs2CO3 (1.386 g, 4.26 mmol) in DMF (4 ml). The reaction mixture was stirred for 1 h at 100 C., then for 1 h at 70 C., diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a white solid after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-30 min 95:5 to 65:35). HPLC RtH10=0.77 min; ESIMS: 167 [(M+H)+]; 1H NMR (400 MHz, CDCl3): 8.36 (d, 1H), 7.34 (d, 1H), 5.79 (d, 2H), 2.59 (s, 3H).
	With caesium carbonate; In N,N-dimethyl-formamide;	a) 5-Fluoromethoxy-3-methyl-pyridine-2-carbonitrile To a solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol) in DMF (10 ml) was added a solution of toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (521 mg, 2.55 mmol) and Cs2CO3 (1.386 g, 4.26 mmol) in DMF (4 ml). The reaction mixture was stirred for 1 h at 100 C., then for 1 h at 70 C., diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a white solid after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-30 min 95:5 to 65:35). HPLC RtH10=0.77 min; ESIMS: 167 [(M+H)+]; 1H NMR (400 MHz, CDCl3): 8.36 (d, 1H), 7.34 (d, 1H), 5.79 (d, 2H), 2.59 (s, 3H).

Reference： [1]Patent: US2011/21520,2011,A1 .Location in patent: Page/Page column 108
[2]Patent: US2012/172359,2012,A1 .Location in patent: Page/Page column 115
[3]Patent: US8338413,2012,B1

12
[ 30766-12-2 ]
[ 114435-86-8 ]
[ 1174321-05-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 3h;	(1) Synthesis of methyl 5-fluoromethoxypyridine-2-carboxylateA solution containing fluoromethyl toluene-4- sulfonate (233 mg) in DMF was added to a solution containing methyl 5-hydroxypyridine-2-carboxylate (100 mg) and cesium carbonate (532 mg) in DMF (5 mL). The reaction solution was stirred at 70C for 3 h. The reaction solution was cooled to RT. EtOAc and saturated aqueous NH4Cl were added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous MgSO4, and the insoluble matter was separated by filtration.The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain the title compound (51 mg). l H-NMR (CDCl3 ) delta (ppm): 4.00 (s, 3H), 5.80 (d, J = 45.1 Hz, 2H), 7.51 (ddd, J = 0.8, 2.8, 8.8 Hz, IH), 8.16 (d, J = 0.4, 8.8 Hz, IH), 8.54 (d, J = 2.8 Hz, IH).

Reference： [1]Patent: WO2011/9898,2011,A1 .Location in patent: Page/Page column 85

13
[ 1280126-09-1 ]
[ 104-15-4 ]
[ 114435-86-8 ]

Reference： [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 1885 - 1889

14
3-(7-Amino-imidazo[1,2-a]pyrimidin-2-yl)-phenol hydrobromide [ No CAS ]
[ 114435-86-8 ]
[ 1335300-02-1 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 9h;	In a sealed tube 3-(7-aminoimidazo[l,2-a]pyrimidin-2-yl)phenol hydrobromide (260 mg, 0.85 mmol) was combined in DMF (3 ml) to give a brown solution. Toluene-4-sulfonic acid fluoromethyl ester (249 mg, 1.22 mmol; CAS Nr. 114435-86-8) was dissolved in DMF and added. CS2CO3 (527 mg, 1.62 mmol) was added. The reaction mixture was heated under argon to 70 C for 9 h, then stirring was continued overnight at RT. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (3x 30 ml). The combined organic layers were dried (MgSC^) and concentrated under vacuum and the crude product was purified by flash chromatography (50 g Si02, DCM/MeOH/NH3aq. 140:10: 1). The title compound (105 mg, 48%) was obtained as a yellow solid.MS (m/z) = 259.1 [M+H+].

Reference： [1]Patent: WO2011/117264,2011,A1 .Location in patent: Page/Page column 100-101

15
3-(7-amino-imidazo[1,2-a]pyrimidin-2-yl)-phenol hydrobromide [ No CAS ]
[ 114435-86-8 ]
[ 1335300-02-1 ]

Yield	Reaction Conditions	Operation in experiment
48%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃;Sealed tube; Inert atmosphere;	2-(3-Fluoromethoxy-phenyl)-imidazo[1,2-a]pyrimidin-7-ylamine In a sealed tube 3-(7-aminoimidazo[1,2-a]pyrimidin-2-yl)phenol hydrobromide (260 mg, 0.85 mmol) was combined in DMF (3 ml) to give a brown solution. Toluene-4-sulfonic acid fluoromethyl ester (249 mg, 1.22 mmol; CAS Nr. 114435-86-8) was dissolved in DMF and added. Cs2CO3 (527 mg, 1.62 mmol) was added. The reaction mixture was heated under argon to 70 C. for 9 h, then stirring was continued overnight at RT. The reaction mixture was diluted with H2O (30 ml) and extracted with EtOAc (3*30 ml). The combined organic layers were dried (MgSO4) and concentrated under vacuum and the crude product was purified by flash chromatography (50 g SiO2, DCM/MeOH/NH3aq. 140:10:1). The title compound (105 mg, 48%) was obtained as a yellow solid. MS (m/z)=259.1 [M+H+].

Reference： [1]Patent: US2011/237564,2011,A1 .Location in patent: Page/Page column 38

16
[ 16836-95-6 ]
[ 114435-86-8 ]

Reference： [1]Patent: WO2012/40133,2012,A2
[2]ChemMedChem,2014,vol. 9,p. 1476 - 1487
[3]Patent: WO2014/137883,2014,A1
[4]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3956 - 3960
[5]Tetrahedron Letters,2018,vol. 59,p. 1635 - 1637
[6]Patent: WO2012/40138,2012,A2
[7]Chemical Communications,2019,vol. 55,p. 11798 - 11801

17
[ 75-11-6 ]
[ 16836-95-6 ]
[ 114435-86-8 ]

Yield	Reaction Conditions	Operation in experiment
28%	In acetonitrile; for 20h;Reflux;	Example 8. Synthesis of cold Fluoromethyltosylate (15)i iiCH2I2 CH2OTos2 FCH2OTos13 14 15 Scheme 3 i: Silver p-toluenesulfonate, MeCN, reflux, 20 h;ii: KF, MeCN, reflux, 1 h.According to Scheme 3 above:(a) Synthesis of methylene ditosylate (14)Commercially available diiodomethane (13) (2.67 g, 10 mmol) was reacted with silver tosylate (6.14 g, 22 mmol), using the method of Emmons and Ferris, to give methylene ditosylate (10) (0.99g) in 28% yield (Emmons, W.D., et ah, "Metathetical Reactions of Silver Salts in Solution. II. The Synthesis of Alkyl Sulfonates", Journal of the American Chemical Society, 1953; 75:225).

Reference： [1]Patent: WO2012/40151,2012,A2 .Location in patent: Page/Page column 43

18
[ 1262860-70-7 ]
[ 114435-86-8 ]
[ 1262860-71-8 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 24h;	b) 3-Chloro-5-fluoromethoxy-pyridine-2-carbonitrile To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (315 mg, 2.03 mmol) in DMF (16 ml) was added Cs2CO3 (1.652 g, 5.07 mmol) and toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (621 mg, 3.04 mmol) and the reaction mixture was heated at 80 C. for 24 h. The solvent was removed under reduced pressure and the residue taken up in TBME, washed with water and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a yellow oil after chromatography on silica gel (hexane-EtOAc 10:1 to 2:1) to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.62; HPLC RtH5=0.872 min; ESIMS: 185 and 187 [(M-H)-]; 1H NMR (360 MHz, CDCl3): 8.35 (s, 1H), 7.47 (s, 1H), 5.72 (d, 2H).
	With caesium carbonate; In N,N-dimethyl-formamide;	b) 3-Chloro-5-fluoromethoxy-pyridine-2-carbonitrile To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (315 mg, 2.03 mmol) in DMF (16 ml) was added Cs2CO3 (1.652 g, 5.07 mmol) and toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (621 mg, 3.04 mmol) and the reaction mixture was heated at 80 C. for 24 h. The solvent was removed under reduced pressure and the residue taken up in TBME, washed with water and brine, dried over MgSO4, filtered and concentrated. The title compound was obtained as a yellow oil after chromatography on silica gel (hexane-EtOAc 10:1 to 2:1) to provide the title compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.62; HPLC RtH5=0.872 min; ESIMS: 185 and 187 [(M-H)-]; 1H NMR (360 MHz, CDCl3): 8.35 (s, 1H), 7.47 (s, 1H), 5.72 (d, 2H).

Reference： [1]Patent: US2012/172359,2012,A1 .Location in patent: Page/Page column 118
[2]Patent: US8338413,2012,B1

19
[ 1443151-98-1 ]
[ 114435-86-8 ]
[ 1443151-77-6 ]

Yield	Reaction Conditions	Operation in experiment
0.2 g	With caesium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3.5h;	A mixture of 0.3 g of the compound obtained in the preceding step, 0.15 g <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> and 0.47 g of Cs2CO3 in 4 ml of DMF is heated at 80C for 3 hours 30 minutes. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water and with saturated NaCl solution, and dried over MgS04, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane/EtOAc mixture in a gradient of from (100/0 v/v) to (70/30 v/v). 0.2 g of the expected compound is obtained.

Reference： [1]Patent: WO2013/87643,2013,A1 .Location in patent: Page/Page column 27

20
[ 1443152-00-8 ]
[ 114435-86-8 ]
[ 1443152-01-9 ]

Yield	Reaction Conditions	Operation in experiment
0.12 g	With caesium carbonate; In N,N-dimethyl-formamide; at 100℃; for 4h;	A mixture of 0.17 g of the compound obtained in the preceding step, 0.1 g <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> and 0.22 g of Cs2CO4 in 4 ml of DMF is heated at 100C for 4 hours in a sealed tube. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with water and with saturated NaCl solution, and dried over MgS04, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel, eluting with a cyclohexane/EtOAc mixture in a gradient of from (100/0 v/v) to (90/10 v/v). 0.12 g of the expected compound is obtained.

Reference： [1]Patent: WO2013/87643,2013,A1 .Location in patent: Page/Page column 38
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 283 - 287

21
[ 1607429-54-8 ]
[ 114435-86-8 ]
[ 1607428-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃;	A solution of 2-[(3R,6R)-1-[6-hydroxy-2-(2H-1,2,3-triazol-2-yl)pyridin-3-yl]carbonyl}-6-methylpiperidin-3-yl]oxy}-3-methylpyridine-4-carbonitrile (30 mg, 0.072 mmol) and <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (29 mg, 0.14 mmol) in DMF (477 .iL) was treated with potassium carbonate (20 mg, 0.14 mmol) and stirred at 50 C overnight. The reaction was diluted with saturated, aqueous NaHCO3, then with water. The reaction mixture was extracted 2x with EtOAc. The organics were washed with brine, dried over MgSO4, filtered, andconcentrated. The crude material was purified by silica gel gradient chromatography (0-80% ethyl acetate in hexanes), providing the titled compound as a white foam. HRMS m/z (M+H) 452.1833 found, 452.1841 required.

Reference： [1]Patent: WO2014/66196,2014,A1 .Location in patent: Page/Page column 57; 58

22
(R)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline-7-ol [ No CAS ]
[ 114435-86-8 ]
(R)-7-(fluoromethoxy)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline [ No CAS ]
[ 1638151-15-1 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 1476 - 1487

23
(R)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline-7-ol [ No CAS ]
[ 114435-86-8 ]
(R)-7-(fluoromethoxy)-6-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline [ No CAS ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 1476 - 1487

24
(R)-6-hydroxy-7-methoxy-4-[3-(quinoxaline-2-yloxy)pyrrolidine-1-yl]quinazoline [ No CAS ]
[ 114435-86-8 ]
(R)-6-(fluoromethoxy)-7-methoxy-4-(3-(quinoxaline-2-yloxy)pyrrolidine-1-yl)quinazoline [ No CAS ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 1476 - 1487

25
[ 104-15-4 ]
[ 114435-86-8 ]

Reference： [1]ChemMedChem,2014,vol. 9,p. 1476 - 1487

26
2-[(3R,6R)-6-methyl-1-[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}piperidin-3-yl]oxy}pyridin-4-ol [ No CAS ]
[ 114435-86-8 ]
(2-(2H-1,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-(fluoromethoxy)pyridin-2-yl)oxy)-2-methylpiperidin-1-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone;Reflux;	A mixture of <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (55 mg, 0.27 mmol), (2- (2H-l,2,3-triazol-2-yl)phenyl)((2R,5R)-5-((4-hydroxypyridin-2-yl)oxy)-2 -methylpiperidin- 1- yl)methanone (85 mg, 0.22 mmol), and potassium carbonate (62 mg, 0.45 mmol) in acetone (20 mL) was heated at reflux overnight. The mixture was cooled to RT and concentrated in vacuo. The residue was extracted with dichloromethane/water and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep- HPLC to give the title compound as white solid. LRMS m/z (M+H) 412.2 found, 412.2 required.

Reference： [1]Patent: WO2014/137883,2014,A1 .Location in patent: Page/Page column 62; 63

27
3-(7-(pyrrolidin-1-yl)imidazo[1,2-a]pyrimidin-2-yl)phenol [ No CAS ]
[ 114435-86-8 ]
2-[3-(fluoromethoxy)phenyl]-7-pyrrolidin-1-ylimidazo[1,2-a]pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
46%	With caesium carbonate; In N,N-dimethyl-formamide; at 70℃; for 16h;Inert atmosphere;	To a light yellow solution of 3-(7-(pyrrolidin-l-yl)imidazo[l,2-a]pyrimidin-2-yl)phenol (100 mg, 357 muiotaetaomicron) and <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (72.9 mg, 357 muiotaetaomicron) in DMF (1.00 mL) was added under argon cesium carbonate (151 mg, 464 muiotaetaomicron). The reaction mixture was heated to 70C and stirred for 16 h. The yellow suspension was diluted with water (5 mL) and extracted with ethyl acetate (3 x 5 mL). The organic layers were combined, washed with brine, dried over MgS04, filtered and evaporated. The product was obtained after purification by flash chromatography (using silica gel and a dichloromethane/methanol/ammonia gradient) as light yellow solid (52 mg, 46 %). MS: m/z = 313.5 (M+H)+

Reference： [1]Patent: WO2014/187762,2014,A1 .Location in patent: Page/Page column 43

28
3-(7-(azetidin-1-yl)imidazo[1,2-a]pyridin-2-yl)phenol [ No CAS ]
[ 114435-86-8 ]
7-(azetidin-1-yl)-2-(3-(fluoromethoxy)phenyl)imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With caesium carbonate; In N,N-dimethyl-formamide; at 90℃;Inert atmosphere;	3-(7-(Azetidin-l-yl)imidazo[l,2-a]pyridin-2-yl)phenol (110 mg, 373 muiotaetaomicron; Example 95), <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (107 mg, 522 muiotaetaomicron) and CS2CO3 (243 mg, 746 muiotaetaomicron) were combined in sealed tube with DMF (1.85 ml) under Ar. The reaction mixture was stirred at 90 C overnight. After cooling to r.t. the mixture was diluted with CH2CI2 and H2O. The aqueous layer (pH~9) was extracted back with CH2CI2. The organic layers were washed three times with H20 and one time with brine. The combined organic layers were dried over MgS04, filtered and concentrated. The crude product was dried under high vacuum overnight to remove residual DMF. The residue was absorbed on Isolute and purified by flash chromatography (10 g NH2- silica gel cartridge with heptane/EtOAc 1 :1). A second chromatography was performed on a lOg NH2-silica gel cartridge with heptane/EtOAc 0-50 %. The product was then further purified by trituration with EtOAc and finally by prep. HPLC to yield 7-(azetidin-l-yl)-2-(3- (fluoromethoxy)phenyl)imidazo[l,2-a]pyridine as light yellow solid (39 mg, 34 ). MS m/z: 298.1 [M+H]+.

Reference： [1]Patent: WO2014/177458,2014,A1 .Location in patent: Page/Page column 91-92

29
7-bromo-2-(4-(hydroxy)phenyl)imidazo[1,2-a]pyridine [ No CAS ]
[ 114435-86-8 ]
7-bromo-2-(4-(fluoromethoxy)phenyl)imidazo[1,2-a]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.69 g	With caesium carbonate; In N,N-dimethyl-formamide; at 70 - 100℃; for 18.5h;Microwave irradiation;	Example 2b) 7-Bromo-2-(4-(fluoromethoxy)phenyl)imidazo[1,2-a]pyridineTo a solution of 4-(7-bromoimidazo[l,2-a]pyridin-2-yl)phenol (2.37 g, 6.56 mmol) and <strong>[114435-86-8]fluoromethyl 4-methylbenzenesulfonate</strong> (1.34 g, 6.56 mmol) in DMF (10.00 mL) was added cesium carbonate (2.78 g, 8.52 mmol) and heated to 70 C for 18 h and then irradiated for 30 minutes at 100 C in the microwave. It was poured into water and extracted two times with dichloromethane. The organic layers were combined, dried over sodium sulfate, filtrated and concentrated. To the resulting oil was added toluene (-200 mL) and the solvent was evaporated to remove the remaining DMF. Some NaOHaq IN was added and stirring was continued for 15 minutes. It was filtrated and dried at high vacuum affording the title compound (1.69 g, purity -60 ) as a light brown oil which was used without further purification. MS m/z: 321.3 [M+H]+

Reference： [1]Patent: WO2015/44095,2015,A1 .Location in patent: Paragraph 12

30
[ 1454840-93-7 ]
[ 114435-86-8 ]
N-(4-chloro-3-(fluoromethoxy)phenyl)-2-picolinamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40.2%	With potassium carbonate; In acetone; at 20 - 40℃; for 45h;	To a solution of N-(3-hydroxy-4-chlorophenyl)-2-picolinamide (50.0 mg, 0.201mmol) and potassium carbonate (55.6 mg, 0.402 mmol) in acetone(2.0 mL) was added <strong>[114435-86-8]fluoromethyl tosylate</strong> (108.5 mg, 0.402mmol) at room temperature and the mixture was stirred for 2 h. The mixture was heated to 40oC, and stirred 43 h. The reaction mixture was quenched with ammonium chloride solution, and extracted three times with ethyl acetate. The organic layers were separated, collected, dried over anhydrous sodium sulfate, and the solvent was evaporated. The reaction mixture was separated with from 10%to 15% of ethyl acetate in hexane to give the product as a white solid (22.7mg, 0.081 mmol, 40.2% yield). 1H NMR (500MHz, CDCl3) deltappm 10.10(s, 1H), 8.64 (d, J = 4.5 Hz, 1H),8.30 (d, J = 7.5 Hz, 1H), 7.94 (td, J = 7.5, 1.5 Hz, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.52 (dd, J = 6.0, 4.8 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H), 7.40 (d, J = 9.0 Hz, 1H), 5.82 (d, J = 54.0 Hz, 2H);13C NMR (125MHz, CDCl3) delta ppm162.46, 152.92, 149.67, 148.40, 138.19, 138.02, 130.99, 127.11, 122.83, 119.27,115.78, 109.09, 101.25 (d, J = 220.9Hz);19F NMR (470 MHz, CDCl3) delta ppm -149.60 (t, J = 8.3 Hz); LC-MS,calculated for C13H10N2O2ClF: 280.04; observed: 281.3 [M+H]+.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,p. 3956 - 3960

31
N-(1-((2-hydroxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)benzamide [ No CAS ]
[ 114435-86-8 ]
N-(1-((2-(fluoromethoxy)phenyl)amino)-1-oxo-3-phenylpropan-2-yl)benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetone; for 48h;Reflux;	Example 30.3. Preparation of IX-27.Fluoromethyl 4-toluene-sulfonate (Example 30.2; 91.4 mg, 0.448 mmol), N-(1-((2-hydroxyphenyl)amino)- 1 -oxo-3-phenylpropan-2-yl)benzamide (Example30.1; 122.8 mg; 0.355 mmol) and potassium carbonate (72.7 mg; 0.526 mmol) were mixed and refluxed in 1 mL acetone for 48 hours. Upon cooling, the reaction mixture was evaporated and purified by silica chromatography (ethyl acetate gradient in hexanes) to give IX-27.MS (MALDI): calculated: m/z 393.42 (MH); found: 393.24, 415.42 (M+Na).

Reference： [1]Patent: WO2015/120320,2015,A1 .Location in patent: Page/Page column 89

32
N-(1-((5-fluoro-2-hydroxyphenyl)amino)-1-oxo-3-phenylpropan-2-yl)-2-methylbenzamide [ No CAS ]
[ 114435-86-8 ]
N-(1-((5-fluoro-2-(fluoromethoxy)phenyl)amino)-1-oxo-3-phenyl-propan-2-yl)-2-methylbenzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 18h;	Example 91.2. Preparation of IX-ill.N-( 1 -((5-Fluoro-2-hydroxyphenyl)amino)- 1 -oxo-3-phenylpropan-2-yl)-2-methylbenzamide(Example 91.2; 80 mg; 0.2 mmol) was mixed with <strong>[114435-86-8]fluoromethyl 4-toluene-sulfonate</strong> (Example 30.2; 61 mg; 0.3 mmol) and cesium carbonate (130 mg, 0.4mmol) in 2 mE of dry DMF, stirred and heated at 60C for 18 hours. The mixture was evaporated to dryness, re-dissolved in 50 mL ethyl acetate and extracted with water. The ethyl acetate layer was dried and purified by silica gel chromatograpy (20% ethyl acetate/hexane) to give Tx-i ii.Yield: 49 mg, 58%.MS (MALDT): calculated: m/z 425.45 (MH); found: 425.06, 447.02 (M+Na).

Reference： [1]Patent: WO2015/120320,2015,A1 .Location in patent: Page/Page column 116

33
2-[2-(2-hydroxy-5-methoxyphenyl)oxazol-4-ylmethyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline [ No CAS ]
[ 114435-86-8 ]
C₂₃H₂₅FN₂O₅ [ No CAS ]

Reference： [1]ChemMedChem,2016,vol. 11,p. 108 - 118

34
[ 132683-32-0 ]
[ 114435-86-8 ]
(R)-4-(3-(fluoromethoxy)-4-methoxyphenyl)pyrrolidin-2-one [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2016,vol. 59,p. 205 - 213

35
R-desmethylrolipram [ No CAS ]
[ 114435-86-8 ]
(R)-4-(3-(cyclopentyloxy)-4-(fluoromethoxy)phenyl)pyrrolidin-2-one [ No CAS ]

Reference： [1]Journal of labelled compounds and radiopharmaceuticals,2016,vol. 59,p. 205 - 213

36
[ 501126-38-1 ]
[ 114435-86-8 ]
tert-butyl 4-(2-fluoro-4-(fluoromethoxy)phenyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1936 - 1943

37
[ 114435-86-8 ]
[ 158985-25-2 ]
tert-butyl 4-(4-(fluoromethoxy)phenyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]ChemMedChem,2016,p. 1936 - 1943

38
[ 106-53-6 ]
[ 114435-86-8 ]
[ 530080-20-7 ]

Yield	Reaction Conditions	Operation in experiment
91.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;	Compound 207 (3.00 g, 15.87 mmol) was dissolved in DMF (15 ml), to which was then added cesium carbonate (3.56 g, 17.45 mmol), and the resulting mixture was stirred at room temperature. After that, a solution of Compound 208 (2.21 g, 6.78 mmol) diluted in DMF (3 ml) was added to the reaction mixture, and the resulting mixture was further stirred at room temperature. Water was added to the reaction mixture, which was then extracted with dichloromethane. The obtained organic layer was washed with water, dried over magnesium sulfate, and filtered. The obtained filtrate was concentrated under reduced pressure to obtain Compound 209 (7.44 g, 91.4%).

Reference： [1]Patent: EP3187498,2017,A1 .Location in patent: Paragraph 0417; 0418

39
monofluoromethyl-phenyl bis(carbomethoxy) methylide [ No CAS ]
[ 104-15-4 ]
[ 114435-86-8 ]

Reference： [1]Angewandte Chemie - International Edition,2017,vol. 56,p. 9930 - 9934
Angew. Chem.,2017,vol. 129,p. 10062 - 10066,5

40
[ 24124-59-2 ]
[ 455-16-3 ]
[ 114435-86-8 ]

Reference： [1]Tetrahedron Letters,2018,vol. 59,p. 1635 - 1637

41
[ 374063-92-0 ]
[ 114435-86-8 ]
C₅H₄BrFN₂O [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 5122 - 5137

42
methyl 3-{bis[(tert-butoxy)carbonyl]amino}-5-hydroxypyrazine-2-carboxylate [ No CAS ]
[ 114435-86-8 ]
methyl 3-{bis[(tert-butoxy)carbonyl]amino}-5-(fluoromethoxy)pyrazine-2-carboxylate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 5122 - 5137

43
[ 374063-92-0 ]
[ 67-56-1 ]
[ 201230-82-2 ]
[ 114435-86-8 ]
[ 1174321-01-7 ]

Reference： [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 5525 - 5546

44
2-(2-(3-(4-hydroxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)-ethyl)-4-isopropoxyisoindoline-1,3-dione [ No CAS ]
[ 114435-86-8 ]
2-(2-(3-(4-(fluoromethoxy)phenyl)-7-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)ethyl)-4-isopropoxyisoindoline-1,3-dione [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 688 - 698

45
7-(6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one [ No CAS ]
[ 114435-86-8 ]
3-(fluoromethyl)-7-{6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carbonyl}-3H,4H,5H,6H,7H,8H-pyrido[3,4-d]pyrimidin-4-one [ No CAS ]
5-[4-(fluoromethoxy)-5H,6H,7H,8H-pyrido[3,4-d]pyrimidine-7-carbonyl]-6-methyl-N-(1-methylcyclopropyl)furo[2,3-d]pyrimidin-4-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
20%; 29%	With caesium carbonate; In N,N-dimethyl-formamide; at 60℃; for 1h;	To a solution of 7-(6-methyl-4-((1- methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carbonyl)-5,6,7,8-tetrahydropyrido[3,4- d]pyrimidin-4(3H)-one (38 mg, 0.06 mmol) in DMF (0.38 mL) was added cesium carbonate (38 mg, 0.12 mmol) and a solution of <strong>[114435-86-8]fluoromethyl 4-methylbenzene-1-sulfonate</strong> (24 mg, 0.12 mmol) in DMF (0.19 mL). After 1 h stirring at 60oC, the reaction mixture was cooled, diluted with methanol, filtered and purified by prep HPLC (elution with 15-50% ACN in water containing 0.05% TFA). Fractions containing the two products were lyophilized to afford Example 16 (6.2 mg, 20%) and Example 17 (8.9 mg, 29%), both as yellow solids. Example 16: 1H NMR (400 MHz, CD3OD) delta 8.44 (s, 1H), 8.41 - 8.37 (m, 1H), 6.08 - 5.90 (m, 2H), 4.65 (br s, 2H), 3.91 (br s, 2H), 2.72 (br s, 2H), 2.58 (s, 3H), 1.49 (s, 3H), 0.88 (d, J = 10.6 Hz, 4H). [M+H] = 413.1. Example 17: 1H NMR (400 MHz, CD3OD) delta 8.64 (s, 1H), 8.41 (s, 1H), 6.27 - 6.04 (m, 2H), 4.92 (br s, 2H), 4.22 - 3.82 (m, 2H), 2.90 (t, J = 5.3 Hz, 2H), 2.59 (s, 3H), 1.48 (s, 3H), 0.95 - 0.83 (m, 4H). [M+H] = 413.0.

Reference： [1]Patent: WO2019/104285,2019,A1 .Location in patent: Page/Page column 149-150

46
N-[(5-hydroxypyridin-2-yl)methyl]-6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide [ No CAS ]
[ 114435-86-8 ]
N-((5-(fluoromethoxy)pyridin-2-yl)methyl)-6-methyl-4-((1-methylcyclopropyl)amino)furo[2,3-d]pyrimidine-5-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
19%	With caesium carbonate; In N,N-dimethyl-formamide; at 20 - 70℃; for 1.75h;	To a solution of N-[(5-hydroxypyridin-2-yl)methyl]-6-methyl-4-[(1- methylcyclopropyl)amino]furo[2,3-d]pyrimidine-5-carboxamide (Example 10, 100 mg, 0.16 mmol) in DMF (1.1 mL) was added cesium carbonate (107 mg, 0.33 mmol) and a solution of <strong>[114435-86-8]fluoromethyl 4-methylbenzene-1-sulfonate</strong> (67 mg, 0.33 mmol) in DMF (0.55 mL). After 1 h stirring at room temperature, the reaction mixture was heated at 70oC for 45 min. The reaction was cooled, diluted with methanol, filtered and purified by prep HPLC (elution with 5-50% ACN in water containing 0.05% TFA). Fractions containing product were combined and lyophilized to afford the title compound (3.0 mg, 19%) as an orange solid. 1H NMR (400 MHz, CD3OD) delta 8.39 (d, J = 2.8 Hz, 1H), 8.37 (s, 1H), 7.68 - 7.58 (m, 1H), 7.49 (d, J = 8.7 Hz, 1H), 5.95 - 5.72 (m, 2H), 4.71 (s, 2H), 2.76 (s, 3H), 1.51 (s, 3H), 0.96 - 0.84 (m, 4H). [M+H] = 386.0.

Reference： [1]Patent: WO2019/104285,2019,A1 .Location in patent: Page/Page column 146

47
[ 92-69-3 ]
[ 114435-86-8 ]
4-phenyl-1-(fluoromethoxy)benzene [ No CAS ]

Reference： [1]Chemical Communications,2019,vol. 55,p. 11798 - 11801

48
[ 1414025-67-4 ]
[ 114435-86-8 ]
[ 1417187-95-1 ]

Reference： [1]Chemical Communications,2019,vol. 55,p. 11798 - 11801

49
[ 1082041-90-4 ]
[ 114435-86-8 ]
5-bromo-4-chloro-2-(fluoromethyl)-2H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
346 mg	With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 60℃; for 11h;	The mixture of 5-bromo-4-chloro-1H-indazole (1.00 g, 4.32 mmol), <strong>[114435-86-8]fluoromethyl p-toluenesulfonate</strong> (0.970 g, 4.75 mmol), Cs 2CO 3 (1.68 g, 5.18 mmol) and NMP (10 mL) was stirred at 60 C for 11 h, cooled to RT, poured into water, and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na 2SO 4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0 - 60% EtOAc/hexane) to give 5-bromo-4-chloro-2-(fluoromethyl)-2H-indazole (346 mg). MS: [M+H] + = 263, 265.

Reference： [1]Patent: WO2020/22323,2020,A1 .Location in patent: Paragraph 0575

50
[ 114435-86-8 ]
Benzyl 4,4-difluoro-1-[4-(fluoromethoxy)phenyl]cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;	(Step 6) Benzyl 4,4-difluoro-1-[4-(fluoromethoxy)phenyl]cyclohexanecarboxylate To a solution of the compound (1.00 g) obtained in Step 5 above and <strong>[114435-86-8]fluoromethyl p-toluenesulfonate</strong> (0.710 g) in N,N-dimethylformamide (10 mL), cesium carbonate (1.9 g) was added and stirred at 60C for 4 hours. The reaction mixture was diluted with diethyl ether and then washed with water and saturated brine. The residue obtained by drying the organic layer over sodium sulfate, filtering and concentrating was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (0.957 g) as an oil. 1H-NMR (DMSO-D6) delta: 1.78-2.07 (6H, m), 2.42-2.52 (2H, m), 5.12 (2H, s), 5.86 (2H, d, J = 54.3 Hz), 7.06-7.12 (2H, m), 7.19-7.25 (2H, m), 7.27-7.35 (3H, m), 7.37-7.43 (2H, m) .

Reference： [1]Patent: EP3643703,2020,A1

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P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
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. 114435-86-8 ]

Quality Control of [ 114435-86-8 ]

Related Doc. of [ 114435-86-8 ]

Product Details of [ 114435-86-8 ]

Calculated chemistry of [ 114435-86-8 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 114435-86-8 ]

Application In Synthesis of [ 114435-86-8 ]

[ 114435-86-8 ] Synthesis Path-Upstream 1~7

[ 114435-86-8 ] Synthesis Path-Downstream 1~50

Related Functional Groups of [ 114435-86-8 ]

Fluorinated Building Blocks

Aryls

Sulfonates

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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[ 114435-86-8 ]