[ CAS No. 128577-47-9 ] {[proInfo.proName]}

Name: 128577-47-9|Methyl 4-(bromomethyl)-3-fluorobenzoate|95%
Brand: Ambeed
SKU: A211185
Price: 7.0 USD
Availability: InStock
Rating: 97 (30 reviews)

,{[proInfo.pro_purity]}

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

HazMat Fee +

There will be a HazMat fee per item when shipping a dangerous goods. The HazMat fee will be charged to your UPS/DHL/FedEx collect account or added to the invoice unless the package is shipped via Ground service. Ship by air in Excepted Quantity (each bottle), which is up to 1g/1mL for class 6.1 packing group I or II, and up to 25g/25ml for all other HazMat items.

Type	HazMat fee for 500 gram (Estimated)
Excepted Quantity	USD 0.00
Limited Quantity	USD 15-60
Inaccessible (Haz class 6.1), Domestic	USD 80+
Inaccessible (Haz class 6.1), International	USD 150+
Accessible (Haz class 3, 4, 5 or 8), Domestic	USD 100+
Accessible (Haz class 3, 4, 5 or 8), International	USD 200+

DV 2D 3D

3d Animation Molecule Structure of 128577-47-9

Structure of 128577-47-9 * Storage: {[proInfo.prStorage]}

Please Login or Create an Account to: See VIP prices and availability

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

Search after Editing

* Storage: {[proInfo.prStorage]}

* Shipping: {[proInfo.prShipping]}

For Research Only 120K+ Compounds Competitive Price 1-2 Day Shipping

Quality Control of [ 128577-47-9 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 128577-47-9 ]

SDS Specification

Alternatived Products of [ 128577-47-9 ]

Product Details of [ 128577-47-9 ]

CAS No. :	128577-47-9	MDL No. :	MFCD00273345
Formula :	C₉H₈BrFO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	OJBQAHZJVDWSFD-UHFFFAOYSA-N
M.W :	247.06	Pubchem ID :	18766370
Synonyms :

Calculated chemistry of [ 128577-47-9 ] Expand+

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.22
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	50.52
TPSA :	26.3 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) :	-6.08 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.47
Log Po/w (XLOGP3) :	2.43
Log Po/w (WLOGP) :	2.78
Log Po/w (MLOGP) :	3.11
Log Po/w (SILICOS-IT) :	3.14
Consensus Log Po/w :	2.79

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.05
Solubility :	0.222 mg/ml ; 0.000899 mol/l
Class :	Soluble
Log S (Ali) :	-2.63
Solubility :	0.586 mg/ml ; 0.00237 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.02
Solubility :	0.0238 mg/ml ; 0.0000964 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.92

Safety of [ 128577-47-9 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P260-P264-P270-P280-P301+P330+P331-P303+P361+P353-P304+P340-P305+P351+P338-P310-P363-P405-P501	UN#:	3261
Hazard Statements:	H302-H314	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 128577-47-9 ]

* 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 [ 128577-47-9 ]
Downstream synthetic route of [ 128577-47-9 ]

[ 128577-47-9 ] Synthesis Path-Upstream 1~15

1
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane; water for 6 h; Reflux	Procedure for bromination: 4-methyl-3-fluoro-benzoic acid methyl ester (18.3 mmol) in CC (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25percent of water (0.55 g, 1.7 mmole) are stirred and heated to reflux for 6 h. Solvent is evaporated, a water solution of K₂C0₃ is added and product is extracted with EtOAc to obtain a pale yellow solid. 4-(bromomethyl)-3-fluoro benzoic acid methyl ester Yield = quant (5.9g), ESI-MS: [M+H]⁺= 247 Da.
100%	With N-Bromosuccinimide; Perbenzoic acid In tetrachloromethane; water for 6 h; Reflux	General procedure for bromination: 4-Methyl-3-fluoro benzoic acid methyl ester (18.3 mmol) in CCL, (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25percent of water (0.55 g, 1.7 mmole) are stirred and heated to reflux for 6 h. Solvent is evaporated, a water solution of K₂CO₃ is added and product is extracted with EtOAc to obtain a pale yellow solid. 4-(Bromomethyl)-3-fluoro benzoic acid methyl ester Yield = quant (5.9g), ESI-MS: [M+H]⁺= 247 Da.
93%	With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide In water at 120℃; Microwave irradiation	General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0–200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 °C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc–hexane gradient

75%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 5 h; Heating / reflux	EXAMPLE 185 4-[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester; 4-Bromomethyl-3-fluoro-benzoic acid methyl ester 3-Fluoromethyl benzoic acid methyl ester (4.2 g, 25 mmol), N-bromosuccinimide (4.90 g, 27.50 mmol) and dibenzoyl peroxide (0.18 g, 0.75 mmol) were dissolved in CCl₄ (100 ml) and the mixture was irradiated with a 150 W lamp and refluxed under an argon atmosphere for 5 h. The reaction mixture was allowed to cool to r.t. and then filtered. The concentrated filtrate was purified over silica gel (isopropyl ether/n-heptane 1:10 v/v): colourless oil 4.6 g (75percent); MS: m/e=248.0 (M), 167.1 (M-Br, 100percent).
68%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 18 h; Heating / reflux	4-Bromomethyl-3-fluorobenzoic acid methyl ester N-Bromosuccinimide (2.4g, 13.5mmol) and 2,2'-azobisisobutyronitrile (213mg, 1.3mmol) were added to a solution of 3-fluoro-4-methylbenzoic acid methyl ester (2.1g, 12.5mmol) in carbon tetrachloride (60ml) and heated at reflux for 18h. The mixture was cooled, filtered and reduced in vacuo. The residue was purified by flash column chromatography on silica gel (eluant EtOAc:hexanes, 10:90) to afford a colourless oil identified as 4-bromomethyl-3-fluorobenzoic acid methyl ester, yield 2.1g, 68percent.
60.9%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In dichloromethane for 18 h; Reflux	Methyl 3-fluoro-4-methylbenzoate (8.500 g, 50.544 mmol), 1-bromopyrolidin-2,5-one (NBS, 9.446 g, 53.071 mmol) and azobisisobutyronitrile (AIBN, 0.415 g, 2.527 mmol) were mixed in dichloromethane (150 mL) at room temperature, and the mixture was heated under reflux for 18 hours, and then cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO₂, 40 g cartridge; ethyl acetate/hexane = from 0percent to 50percent) and concentrated to give the title compound (7.600 g, 60.9percent) as a white solid.
48%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Reflux	INTERMEDIATE 33 - PREPARATION of Methyl 4-(bromomethyl)-3-fluorobenzoate. To a mixture of methyl 3-fluoro-4-methylbenzoate (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12percent ethyl acetate in heptane) to give 0.444 g (48percent) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step.
48%	With N-Bromosuccinimide; dibenzoyl peroxide In tetrachloromethane for 18 h; Reflux	To a mixture of methyl 3-fluoro-4-methylbenzoate (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094 g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12percent ethyl acetate in heptane) to give 0.444 g (48percent) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step.
41%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 74 h; Heating / reflux	3-Fluoro-4-methylbenzoic acid methyl ester from Example E3.1 (4.5g, 26.6mmol) was dissolved in carbon tetra;chloride (150ml). AIBN (457mg, 2.7mmol) and N-bromosuccinimide (5.2g, 29.3mmol) were added and the mixture was heated at reflux for 18h. The mixture was allowed to cool and further portions of AIBN (457mg, 2.7mmol) and W-bromosuccinimide (5.2g, 29.3mmol) were added. The mixture was heated at reflux for 56h. The mixture was allowed to cool and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10percent EtOAc:90percent pet ether) to yield the title compound (2.7g, 41percent).
200 mg	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane at 80℃;	To a stirred solution of 3-fluoro-4-methylbenzoic acid (308 mg, 2 mmol) in DMF (3 mL) were added K₂CO₃ (552 mg, 4.0 mmol) and CH₃I (0.2 mL, 3.0 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 5 h. Then the reaction was quenched with water (15 mL) extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was used directly into next step (220 mg, 1.3 mmol, 65percent). The methyl ester intermediate was dissolved in CC1₄ (5 mL). To the solution were added NBS (278 mg, 1.56 mmol) and AIBN (21 mg, 0.13 mmol). The resulting mixture was heated at 80 °C overnight. Then the reaction was quenched with water (15 mL) extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 50percent EtOAc/hexanes) to afford as colorless solid (200 mg, 62percent). ¹H NMR (400 MHz, CDC1₃) δ 7.81 (dd, / = 8.0, 1.3 Hz, 1H), 7.72 (dd, / = 10.2, 1.3 Hz, 1H), 7.47 (t, = 7.7 Hz, 1H), 4.52 (s, 2H), 3.99 - 3.78 (m, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 165.5 (d, = 2.7 Hz), 161.5, 159.0, 132.4 (d, = 7.7 Hz), 131.2 (d, = 3.0 Hz), 130.1 (d, = 14.7 Hz), 125.6 (d, = 3.6 Hz), 117.0, 116.8, 52.5, 24.6 (d, = 4.2 Hz).

Reference： [1] Patent: WO2014/102376, 2014, A1, . Location in patent: Page/Page column 45
[2] Patent: WO2014/102377, 2014, A1, . Location in patent: Page/Page column 49-50
[3] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6058 - 6080
[4] Synlett, 2014, vol. 25, # 17, p. 2485 - 2487
[5] Patent: US2006/14945, 2006, A1, . Location in patent: Page/Page column 60
[6] Patent: EP1512687, 2005, A1, . Location in patent: Page/Page column 11-12
[7] Patent: EP3330259, 2018, A1, . Location in patent: Paragraph 0310; 0311
[8] Patent: WO2016/11930, 2016, A1, . Location in patent: Page/Page column 173
[9] Patent: WO2012/80221, 2012, A1, . Location in patent: Page/Page column 82-83
[10] Patent: US2013/274260, 2013, A1, . Location in patent: Paragraph 0616
[11] Patent: WO2006/21213, 2006, A2, . Location in patent: Page/Page column 29-30
[12] Journal of Medicinal Chemistry, 1992, vol. 35, # 5, p. 877 - 885
[13] Patent: US5811459, 1998, A,
[14] Patent: EP1748048, 2007, A1, . Location in patent: Page/Page column 40
[15] Patent: WO2004/29041, 2004, A1, . Location in patent: Page 26
[16] Journal of Chemical Research, 2016, vol. 40, # 4, p. 224 - 227
[17] Patent: WO2017/142883, 2017, A1, . Location in patent: Paragraph 0176-0177
[18] Patent: WO2017/156165, 2017, A1, . Location in patent: Paragraph 00570; 00573; 00574

2
[ 87808-48-8 ]
[ 128577-47-9 ]

Reference： [1] Patent: WO2009/36996, 2009, A2, . Location in patent: Page/Page column 83-84

3
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-Bromosuccinimide; azobisisobutyronitrile In tetrachloromethane	Methyl 4-(bromomethyl)-3-fluorobenzoate. To a stirred mixture of N-bromosuccinimide (6.75 g, 37.5 mmol) in carbon tetrachloride (100 mL) was added a solution of methyl 3-fluoro-4-methylbenzoate (6.31 g, 37.5 mmol) in carbon tetrachloride (50 mL) and 2,2'-azobisisobutyronitrile [AIBN] (32 mg, 0.2 mmol). The reaction mixture was heated at 75 °C for 3 hours. To the flask was added additional AIBN (31 mg, 0.2 mmol) and the mixture was heated at reflux (~80 °C) for 2.5 hours. The solids were filtered and rinsed with carbon tetrachloride. The filtrate was washed with 10percent sodium thiosulfate (2x15 mL), saturated sodium bicarbonate (15 mL), and dried over sodium sulfate. Evaporation of the solvent on a rotary evaporator, followed by evacuation under high vacuum, gave a pale yellow oil (8.67 g). This liquid was purified by flash chromatography on a silica gel column eluted with 95:5 hexanes:ethyl acetate to afford a very pale yellow liquid (4.70 g, 51percent). (Where the term 'hexanes' is used, the term means that the solvent is a mixture of hexane isomers).

Reference： [1] Patent: EP1026156, 2000, A2,

4
[ 87808-48-8 ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Reference： [1] Patent: US2012/258982, 2012, A1, . Location in patent: Page/Page column 53

5
[ 56-23-5 ]
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
64.7%	for 5 h; Reflux	Step 2: Synthesis of methyl 4-(bromomethyl)-3-fluorobenzoate: To a solution of the above product (21 g, 125 mmol) in CC1₄ (200 ml) was added a mixture of NBS (20 g, 113 mmol) and benzoyl peroxide (1.5 g, 6 mmol). The resulting solution was refluxed for 5 hours. Then the solvent was evaporated and the residue was dissolved in DCM (300 ml) and washed with H₂0 (200 ml x 3). The organic layer was dried with anhydrous Na₂S0₄, filtered and evaporated to give the crude product as colorless oil (18 g, 64.7percent).

Reference： [1] Patent: WO2011/100433, 2011, A1, . Location in patent: Page/Page column 56

6
[ 123-56-8 ]
[ 87808-48-8 ]
[ 128577-47-9 ]

Reference： [1] Patent: US5639906, 1997, A,

7
[ 350-28-7 ]
[ 128577-47-9 ]

Reference： [1] Patent: WO2012/80221, 2012, A1,
[2] Patent: WO2011/100433, 2011, A1,
[3] Patent: US2013/274260, 2013, A1,
[4] Patent: WO2014/102376, 2014, A1,
[5] Patent: WO2014/102377, 2014, A1,
[6] Journal of Medicinal Chemistry, 2015, vol. 58, # 15, p. 6058 - 6080
[7] Patent: WO2017/142883, 2017, A1,
[8] Patent: WO2017/156165, 2017, A1,

8
[ 112704-79-7 ]
[ 128577-47-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524

9
[ 188582-62-9 ]
[ 128577-47-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524

10
[ 930785-23-2 ]
[ 128577-47-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524

11
[ 1008517-99-4 ]
[ 128577-47-9 ]

Reference： [1] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524

12
[ 350-28-7 ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Reference： [1] Patent: US2012/258982, 2012, A1,

13
[ 128577-47-9 ]
[ 74733-25-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dimethyl sulfoxide In hexane; dichloromethane; water; ethyl acetate	(1) Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0° C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48percent) as a white solid. NMR spectrum (400 MHz, CDCl₃) δ ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M⁺, 100percent).

Reference： [1] Patent: US2003/176480, 2003, A1,

14
[ 87808-48-8 ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Reference： [1] Patent: US2012/258982, 2012, A1, . Location in patent: Page/Page column 53

15
[ 350-28-7 ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Reference： [1] Patent: US2012/258982, 2012, A1,

[ 128577-47-9 ] Synthesis Path-Downstream 1~109

1
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-Bromosuccinimide; Perbenzoic acid; In tetrachloromethane; water; for 6h;Reflux;	Procedure for bromination: <strong>[87808-48-8]4-methyl-3-fluoro-benzoic acid methyl ester</strong> (18.3 mmol) in CC (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25% of water (0.55 g, 1.7 mmole) are stirred and heated to reflux for 6 h. Solvent is evaporated, a water solution of K2C03 is added and product is extracted with EtOAc to obtain a pale yellow solid. 4-(bromomethyl)-3-fluoro benzoic acid methyl ester Yield = quant (5.9g), ESI-MS: [M+H]+= 247 Da.
100%	With N-Bromosuccinimide; Perbenzoic acid; In tetrachloromethane; water; for 6h;Reflux;	General procedure for bromination: 4-Methyl-3-fluoro benzoic acid methyl ester (18.3 mmol) in CCL, (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25% of water (0.55 g, 1.7 mmole) are stirred and heated to reflux for 6 h. Solvent is evaporated, a water solution of K2CO3 is added and product is extracted with EtOAc to obtain a pale yellow solid. 4-(Bromomethyl)-3-fluoro benzoic acid methyl ester Yield = quant (5.9g), ESI-MS: [M+H]+= 247 Da.
93%	With tert.-butylhydroperoxide; cetyltrimethylammonim bromide; potassium bromide; In water; at 120℃; under 750.075 Torr;Microwave irradiation;	General procedure: The reaction mixture was treated in a controlled microwavesynthesizer (Biotage Initiator+SP Wave model, 0-200 W at2.45 GHz, capped at 60 W during steady state) for severalminutes (the reaction attained 120 C at 1 bar pressure). Thefinal products were isolated by column chromatographyusing an EtOAc-hexane gradient

75%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 5h;Heating / reflux;	EXAMPLE 185 4-[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid methyl ester; 4-Bromomethyl-3-fluoro-benzoic acid methyl ester 3-Fluoromethyl benzoic acid methyl ester (4.2 g, 25 mmol), N-bromosuccinimide (4.90 g, 27.50 mmol) and dibenzoyl peroxide (0.18 g, 0.75 mmol) were dissolved in CCl4 (100 ml) and the mixture was irradiated with a 150 W lamp and refluxed under an argon atmosphere for 5 h. The reaction mixture was allowed to cool to r.t. and then filtered. The concentrated filtrate was purified over silica gel (isopropyl ether/n-heptane 1:10 v/v): colourless oil 4.6 g (75%); MS: m/e=248.0 (M), 167.1 (M-Br, 100%).
68%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 18h;Heating / reflux;	4-Bromomethyl-3-fluorobenzoic acid methyl ester N-Bromosuccinimide (2.4g, 13.5mmol) and 2,2'-azobisisobutyronitrile (213mg, 1.3mmol) were added to a solution of 3-fluoro-4-methylbenzoic acid methyl ester (2.1g, 12.5mmol) in carbon tetrachloride (60ml) and heated at reflux for 18h. The mixture was cooled, filtered and reduced in vacuo. The residue was purified by flash column chromatography on silica gel (eluant EtOAc:hexanes, 10:90) to afford a colourless oil identified as 4-bromomethyl-3-fluorobenzoic acid methyl ester, yield 2.1g, 68%.
60.9%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In dichloromethane; for 18h;Reflux;	<strong>[87808-48-8]Methyl 3-fluoro-4-methylbenzoate</strong> (8.500 g, 50.544 mmol), 1-bromopyrolidin-2,5-one (NBS, 9.446 g, 53.071 mmol) and azobisisobutyronitrile (AIBN, 0.415 g, 2.527 mmol) were mixed in dichloromethane (150 mL) at room temperature, and the mixture was heated under reflux for 18 hours, and then cooled to room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to give the title compound (7.600 g, 60.9%) as a white solid.
48%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux;	INTERMEDIATE 33 - PREPARATION of Methyl 4-(bromomethyl)-3-fluorobenzoate. To a mixture of <strong>[87808-48-8]methyl 3-fluoro-4-methylbenzoate</strong> (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12% ethyl acetate in heptane) to give 0.444 g (48%) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step.
48%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 18h;Reflux;	To a mixture of <strong>[87808-48-8]methyl 3-fluoro-4-methylbenzoate</strong> (0.630 g; 3.75 mmol) in carbon tetrachloride (30 mL) was added N-bromosuccinimide (0.840 g, 4.67 mmol) and benzoyl peroxide (0.094 g; 0.375 mmol). The mixture was refluxed for 18 hours and the resulting suspension was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent 1 to 12% ethyl acetate in heptane) to give 0.444 g (48%) of methyl 4-(bromomethyl)-3-fluorobenzoate as an oily residue which was directly used in the next step.
41%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 74h;Heating / reflux;	3-Fluoro-4-methylbenzoic acid methyl ester from Example E3.1 (4.5g, 26.6mmol) was dissolved in carbon tetrachloride (150ml). AIBN (457mg, 2.7mmol) and N-bromosuccinimide (5.2g, 29.3mmol) were added and the mixture was heated at reflux for 18h. The mixture was allowed to cool and further portions of AIBN (457mg, 2.7mmol) and W-bromosuccinimide (5.2g, 29.3mmol) were added. The mixture was heated at reflux for 56h. The mixture was allowed to cool and evaporated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% EtOAc:90% pet ether) to yield the title compound (2.7g, 41%).
	With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane;	(C) A mixture of <strong>[87808-48-8]methyl 3-fluoro-4-methylbenzoate</strong> (4.3 g), N-bromosuccinimide (4.5 g) and AIBN (20 mg) in carbon tetrachloride was irradiated with a 100 W Tungsten lamp at reflux for 1 hour. The mixture was filtered through diatomaceous earth, and evaporated to give methyl 3-fluoro-4-(bromomethyl)benzoate (5.0 g).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 4h;Heating / reflux;	Production Example 15-1: Methyl 4-bromomethyl-3-fluorobenzenecarboxylate: 3-Fluoro-4-methylbenzenecarboxylic acid (1.0 g) was dissolved in methanol (33 mL), and thionyl chloride (0.72 mL) was added thereto and heated under reflux for 1 hour. After the reaction, the reaction solution was entirely concentrated, the resulting residue (500 mg) was dissolved in carbon tetrachloride (3 mL), and N-bromosuccinimide (hereafter abbreviated as "NBS") (510 mg) and 2,2'-azobis(isobutyronitrile) (hereafter abbreviated as "AIBN") (50 mg) were added in that order to it, and heated under reflux for 4 hours. After the reaction, the reaction solution was entirely concentrated, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate = 95/5) to obtain the entitled compound (405 mg).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6h;Heating / reflux; UV-irradiation;	Methyl [3-FLUORO-4-METHYL] benzoate (0.97 g), N-bromosuccinimide (1.13 g) and azobisisobutyronitrile (0.02 g) were added to carbon tetrachloride (2 mL) and the mixture was heated under reflux, whilst being irradiated with a [100W] lamp, for 6h. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and 1 M hydrochloric acid. The organic phase was washed with brine, dried [(MGS04)] and filtered to give a crude yellow oil which was purified by flash chromatography, eluting with 5% ethyl acetate in isohexane to give the title compound as a colourless oil (0.63 g). ['H] NMR [8 (CDCI3)] 3.93 (3H, s), 4.52 (2H, d), 7.47 [(1H,] t), 7.73 [(1H,] dd), 7.81 [(1H,] dd)
200 mg	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;	To a stirred solution of 3-fluoro-4-methylbenzoic acid (308 mg, 2 mmol) in DMF (3 mL) were added K2CO3 (552 mg, 4.0 mmol) and CH3I (0.2 mL, 3.0 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 5 h. Then the reaction was quenched with water (15 mL) extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was used directly into next step (220 mg, 1.3 mmol, 65%). The methyl ester intermediate was dissolved in CC14 (5 mL). To the solution were added NBS (278 mg, 1.56 mmol) and AIBN (21 mg, 0.13 mmol). The resulting mixture was heated at 80 C overnight. Then the reaction was quenched with water (15 mL) extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 50% EtOAc/hexanes) to afford as colorless solid (200 mg, 62%). 1H NMR (400 MHz, CDC13) delta 7.81 (dd, / = 8.0, 1.3 Hz, 1H), 7.72 (dd, / = 10.2, 1.3 Hz, 1H), 7.47 (t, = 7.7 Hz, 1H), 4.52 (s, 2H), 3.99 - 3.78 (m, 3H). 13C NMR (100 MHz, CDCI3) delta 165.5 (d, = 2.7 Hz), 161.5, 159.0, 132.4 (d, = 7.7 Hz), 131.2 (d, = 3.0 Hz), 130.1 (d, = 14.7 Hz), 125.6 (d, = 3.6 Hz), 117.0, 116.8, 52.5, 24.6 (d, = 4.2 Hz).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 78℃; for 16h;	To a solution of methyl 3-fluoro-4-methyl-benzoate (9.90 g, 58.9 mmol) in carbon tetrachloride (120 mL) was added 2,2-azobisisobutyronitrile (966 mg, 5.89 mmol) and n- bromosuccinimide (11.0 g, 61.8 mmol) at rt, then the mixture was heated to reflux at 78 C for 16 hours. On completion, the solvent was removed in vacuo, and the residue was dissolved with ethyl acetate (200 mL), washed with water (2 X 50mL), brine (1 X 50 mL), dried and concentrated to give the title compound (crude). NMR (400 MHz, CDCh) delta = 7.83 (dd, J = 1.1, 7.9 Hz, 1H), 7.74 (dd, J= 1.1, 9.9 Hz, 1H), 7.49 (t, J= 7.7 Hz, 1H), 4.53 (s, 2H), 3.94 (s, 3H).

Reference： [1]Patent: WO2014/102376,2014,A1 .Location in patent: Page/Page column 45
[2]Patent: WO2014/102377,2014,A1 .Location in patent: Page/Page column 49-50
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 6058 - 6080
[4]Synlett,2014,vol. 25,p. 2485 - 2487
[5]Patent: US2006/14945,2006,A1 .Location in patent: Page/Page column 60
[6]Patent: EP1512687,2005,A1 .Location in patent: Page/Page column 11-12
[7]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0310; 0311
[8]Patent: WO2016/11930,2016,A1 .Location in patent: Page/Page column 173
[9]Patent: WO2012/80221,2012,A1 .Location in patent: Page/Page column 82-83
[10]Patent: US2013/274260,2013,A1 .Location in patent: Paragraph 0616
[11]Patent: WO2006/21213,2006,A2 .Location in patent: Page/Page column 29-30
[12]Journal of Medicinal Chemistry,1992,vol. 35,p. 877 - 885
[13]Patent: US5811459,1998,A
[14]Patent: EP1748048,2007,A1 .Location in patent: Page/Page column 40
[15]Patent: WO2004/29041,2004,A1 .Location in patent: Page 26
[16]Journal of Chemical Research,2016,vol. 40,p. 224 - 227
[17]Patent: WO2017/142883,2017,A1 .Location in patent: Paragraph 0176-0177
[18]Patent: WO2017/156165,2017,A1 .Location in patent: Paragraph 00570; 00573; 00574

2
[ 128577-47-9 ]
[ 744200-35-9 ]

Yield	Reaction Conditions	Operation in experiment
100%	With Caswell No. 744A; In N,N-dimethyl-formamide; for 18h;	Sodium azide (609mg) was added to a solution of 4-bromomethyl-3-fluorobenzoic acid methyl ester from Example E3.2 (2.1g, 8.5mmol) in DMF (30ml). The mixture was stirred for 18h, diluted with EtOAc, washed with water and brine and concentrated in vacuo to give a colourless oil identified as the title compound (1.8 g, 100%) .
100%	With Caswell No. 744A; In DMF (N,N-dimethyl-formamide); for 18h;	4-Azidomethyl-3-fluorobenzoic acid methyl ester Sodium azide (609mg, 9.36mmol) was added to a solution of 4-bromomethyl-3-fluorobenzoic acid methyl ester (2.1g, 8.5mmol) in DMF (30ml) and stirred for 18h. The mixture was diluted with EtOAc, washed with water and brine, dried and reduced in vacuo to afford a colourless oil identified as 4-azidomethyl-3-fluorobenzoic acid methyl ester, yield 1.78g, 100%.
88.6%	With Caswell No. 744A; In N,N-dimethyl-formamide; at 50℃; for 5h;	Methyl 4-(bromomethyl)-3-fluorobenzoate (2.000 g, 8.095 mmol) and sodium azide (0.632 g, 9.714 mmol) were dissolved in N,N-dimethylformamide (50 mL) at 50C, after which the resulting solution was stirred at the same temperature for 5 hours, and then a reaction was finished by lowering a temperature to room temperature. Water was poured into the reaction mixture and an extraction was performed with ethyl acetate. An organic layer was washed with saturated ammonium chloride aqueous solution, dehydrated with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting concentrate was purified via column chromatography (S1O2, 24 g cartridge; ethyl acetate/hexane = 0 to 20%), and concentrated to obtain methyl 4-(azidomethyl)-3-fluorobenzoate (1.500 g, 88.6%) in a yellow oil form.

Reference： [1]Patent: WO2006/21213,2006,A2 .Location in patent: Page/Page column 30
[2]Patent: EP1512687,2005,A1 .Location in patent: Page/Page column 11-12
[3]Patent: WO2022/13728,2022,A1 .Location in patent: Page/Page column 202; 203

3
triethylamine-N-oxide dihydrate [ No CAS ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dimethyl sulfoxide; In hexane; dichloromethane; water; ethyl acetate;	(1) Methyl 3-fluoro-4-bromomethylbenzoate (80 mg, 0.32 mmol), described in J. Med. Chem., 35(5) 877 (1992), was dissolved in a mixture of anhydrous dimethyl sulfoxide (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution cooled to 0 C. was added dropwise with stirring triethylamine N-oxide dihydrate (180 mg, 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture and this mixture was partitioned between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column using ethyl acetate-hexane (1:10) as the eluant to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48%) as a white solid. NMR spectrum (400 MHz, CDCl3) delta ppm: 3.97 (3H, s), 7.85 (1H, d, J=11 Hz), 7.9-8.0 (2H, m), 10.43 (1H, s). Mass spectrum m/z (EI): 182 (M+, 100%).

Reference： [1]Patent: US2003/176480,2003,A1

4
[ 123-56-8 ]
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In carbontetrachloride (CCl4);	Methyl-3-fluoro-4-bromomethyl benzoate (6) A mixture of 7.32 g (43.6 mmol) methyl-3-fluoro-4-methylbenzoate, 4.92 g N-bromosuccinimide (NBS) and a few mg of 2,2-azobisisobutyronitrile (AIBN) in 80 ml of carbontetrachloride (CCl4) were brought to reflux and illuminated with a high intensity lamp. The reaction was rapid and within 2 hours, all of the NBS has been converted to succinimide. TLC and NMR analysis indicated a 1:1 mixture of product and starting material as judged by the appearance of a new signal at 4.49 corresponding to bromination of the methyl group. The mixture was worked up by filtering the succinimide and washing the CCl4 solution, first with aqueous sodium sulfate (Na2 S2 O3) and then with aqueous sodium bicarbonate (NaHCO3). The product obtained after drying and removal of the solvent was recycled with additional NBS and treated as above to yield 7.46 g of yellow oil which was an 8:1 mixture of product and starting material and was used as such in the next step.

Reference： [1]Patent: US5639906,1997,A

5
2,2'-azobisisobutyronitrile [AIBN] [ No CAS ]
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	With N-Bromosuccinimide; azobisisobutyronitrile; In tetrachloromethane;	Methyl 4-(bromomethyl)-3-fluorobenzoate. To a stirred mixture of N-bromosuccinimide (6.75 g, 37.5 mmol) in carbon tetrachloride (100 mL) was added a solution of <strong>[87808-48-8]methyl 3-fluoro-4-methylbenzoate</strong> (6.31 g, 37.5 mmol) in carbon tetrachloride (50 mL) and 2,2'-azobisisobutyronitrile [AIBN] (32 mg, 0.2 mmol). The reaction mixture was heated at 75 C for 3 hours. To the flask was added additional AIBN (31 mg, 0.2 mmol) and the mixture was heated at reflux (~80 C) for 2.5 hours. The solids were filtered and rinsed with carbon tetrachloride. The filtrate was washed with 10% sodium thiosulfate (2x15 mL), saturated sodium bicarbonate (15 mL), and dried over sodium sulfate. Evaporation of the solvent on a rotary evaporator, followed by evacuation under high vacuum, gave a pale yellow oil (8.67 g). This liquid was purified by flash chromatography on a silica gel column eluted with 95:5 hexanes:ethyl acetate to afford a very pale yellow liquid (4.70 g, 51%). (Where the term 'hexanes' is used, the term means that the solvent is a mixture of hexane isomers).

Reference： [1]Patent: EP1026156,2000,A2

6
[ 87808-48-8 ]
[ 128577-47-9 ]
4-dibromomethyl-3-fluorobenzoic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide;dibenzoyl peroxide; In tetrachloromethane; at 80℃;	After stirring a suspension of <strong>[87808-48-8]3-fluoro-4-methyl-benzoic acid methyl ester</strong> (500 mg, 2.97 mmol), l-bromo-pyrrolidine-2,5-dione (1.73 g, 8.33 mmol) and benzoyl peroxide (53.1 mg, 0.47 mmol) in tetrachloromethane (36 mL) at 800C overnight the mixture was concentrated in vacuo and the residue was partitioned between EA (150 mL) and water (100 mL). The organic layer was washed with sat. NaHCC^ solution (1 x 100 mL), water (1 x 100 mL) and sat. NaCl solution (1 x 100 mL). The organic layer was dried over Na2SC>4, filtered and concentrated in vacuo. The residue, a mixture of 4-bromomethyl-3-fluoro-benzoic acid methyl ester and 4-dibromornethyl-3-fluoro-benzoic acid methyl ester, was used in the following step without further purification. The residue (50 mg, 0.30 mmol) was dissolved in acetone (2 mL) and water (0.4 mL) and AgNtheta3 (171 mg, 0.87 mmol) were added. The flask was covered with aluminum foil to avoid decomposition of the AgNU3. The mixture was <n="85"/>stirred at RT overnight. After filtration of th ixture and evaporation of the solvent, the residue was partitioned between EA (30 mL) and sat. NaHCO3 solution (15 mL). The organic layer was washed with water (1 x 15 mL) and sat. NaCl solution (1 x 15 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. GC/MS (m/z): 182.2

Reference： [1]Patent: WO2009/36996,2009,A2 .Location in patent: Page/Page column 83-84

7
[ 768-35-4 ]
[ 128577-47-9 ]
[ 1382991-44-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 130℃; for 0.333333h;Microwave irradiation;	INTERMEDIATE 34 - PREPARATION of Methyl 3-fluoro-4-(3-fluorobenzyl)benzoate. Methyl 4-(bromomethyl)-3-fluorobenzoate (0.285 g; 1.15 mmol) was suspended in a mixture of water (1 mL) and 1 ,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.183 g; 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (0.067 g; 0.0058 mmol) and sodium carbonate (0.246 g; 2.31 mmol) were successively added. The resulting suspension was heated at 130 C in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.199 g (66%) of methyl 3-fluoro-4-(3- fluorobenzyl)benzoate as an oily residue which was directly used in the next step.
66%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; water; at 130℃; for 0.333333h;Microwave irradiation;	Methyl 4-(bromomethyl)-3-fluorobenzoate (0.285 g; 1.15 mmol) was suspended in a mixture of water (1 mL) and 1,2-dimethoxyethane (3 mL) and 3-fluorophenylboronic acid (0.183 g; 1.27 mmol), tetrakis(triphenylphosphine)palladium(0) (0.067 g; 0.0058 mmol) and sodium carbonate (0.246 g; 2.31 mmol) were successively added. The resulting suspension was heated at 130 C. in a microwave oven for 20 minutes. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic layer was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel (eluent 1 to 12% of ethyl acetate in heptane) to give 0.199 g (66%) of methyl 3-fluoro-4-(3-fluorobenzyl)benzoate as an oily residue which was directly used in the next step.

Reference： [1]Patent: WO2012/80221,2012,A1 .Location in patent: Page/Page column 83
[2]Patent: US2013/274260,2013,A1 .Location in patent: Paragraph 0617

8
[ 56-23-5 ]
[ 87808-48-8 ]
[ 128577-47-9 ]

Yield	Reaction Conditions	Operation in experiment
64.7%	With N-Bromosuccinimide; dibenzoyl peroxide; for 5h;Reflux;	Step 2: Synthesis of methyl 4-(bromomethyl)-3-fluorobenzoate: To a solution of the above product (21 g, 125 mmol) in CC14 (200 ml) was added a mixture of NBS (20 g, 113 mmol) and benzoyl peroxide (1.5 g, 6 mmol). The resulting solution was refluxed for 5 hours. Then the solvent was evaporated and the residue was dissolved in DCM (300 ml) and washed with H20 (200 ml x 3). The organic layer was dried with anhydrous Na2S04, filtered and evaporated to give the crude product as colorless oil (18 g, 64.7%).

Reference： [1]Patent: WO2011/100433,2011,A1 .Location in patent: Page/Page column 56

9
[ 350-28-7 ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Reference： [1]Patent: US2012/258982,2012,A1

10
[ 87808-48-8 ]
[ 128577-47-9 ]
[ 74733-25-8 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of <strong>[87808-48-8]3-fluoro-4-methyl-benzoic acid methyl ester</strong> (2.26 g, 13.4 mmol) in carbon tetrachloride (168 mL) was treated with N-bromosuccinimide (6.7 g, 37.6 mmol) and 2,2'-azobis(2-methylpropionitrile) (110 mg, 99.4 muL, 672 mumol). The reaction was heated to reflux at 100 C. for 20 h. At this time, the reaction was cooled to 25 C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (100 mL) and was then washed with water (1150 mL), a saturated aqueous sodium bisulfite solution (1150 mL) and a saturated sodium chloride solution (1150 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in acetone (80 mL) and water (18 mL) (0.14M, 5:1) and was treated with silver nitrate (6.39 g, 37.6 mmol). The flask was covered with tin foil and the hood light was turned off. The reaction was stirred under these conditions for 24 h. At this time, the reaction was filtered through a coarse sintered glass funnel. The filtrate was concentrated in vacuo. The resulting solution was transferred to a separatory funnel, diluted with methylene chloride (100 mL) and treated with a saturated aqueous sodium bicarbonate solution (1100 mL). Upon addition of the saturated aqueous sodium bicarbonate solution, a white precipitate resulted. This precipitate was removed by filtration through a coarse sintered glass funnel and was washed with methylene chloride (20 mL). The filtrate was transferred to another separatory funnel and washed with water (1100 mL) and a saturated aqueous sodium chloride solution (1100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (40 g, 5-15% ethyl acetate/hexanes) afforded a ~1:1 mixture of 3-fluoro-4-formyl-benzoic acid methyl ester and 4-bromomethyl-3-fluoro-benzoic acid methyl ester (1.56 g) as colorless oil. The material was used without further purification. A mixture of 1-(2-phenylamino-pyridin-3-yl)-ethanone (700 mg, 3.3 mmol) in methanol (16.5 mL) at 25 C. was treated with 3-fluoro-4-formyl-benzoic acid methyl ester (601 mg, 3.3 mmol, calculated from 50% mixture) and sodium methoxide in methanol (4.37M, 1.51 mL, 6.6 mmol). The reaction was stirred at 25 C. for 48 h. At this time, the reaction was diluted with water (50 mL), neutralized with a 2N aqueous hydrochloric acid solution, and extracted with methylene chloride (3*75 mL). The combined organics were dried over sodium sulfate and filtered. Silica gel was added to the filtrate, concentrated in vacuo and dried under high vacuum. Flash Chromatography (40 g silica column, 1% methanol/methylene chloride) afforded 3-fluoro-4-[(E)-3-oxo-3-(2-phenylamino-pyridin-3-yl)-propenyl]-benzoic acid methyl ester (1 g, 80.6%) as a red solid.

Reference： [1]Patent: US2012/258982,2012,A1 .Location in patent: Page/Page column 53

11
[ 1125867-36-8 ]
[ 128577-47-9 ]
C₁₇H₁₄FN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
40%		NaH (60%, 48.5mg, 1.2lmmol) was added to a solution of (3) (200mg, 1.l5mmol) in DMF (7mL) at 5C under N2(g). The reaction mixture was stirred for 20mm then<strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (371mg, 1.5mmol) was added as a solution in DMF (3mL). The stirring was continued at 70C for lh. Reaction cooled to rt and poured onto water (lOOmL). Brine (25mL) was added and the aqueous was extracted with EtOAc (2 x lOOmL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography withEtOAc/CH2CI2 (0:1-1:0) then EtOAc/MeOH (1:0-4:1) yielded (4) (1 58mg, 40%).1H NMR (500 MHz, Chloroform-d), OH ppm: 8.87 (d, J=1.4 Hz, 1H), 8.76-8.78 (m,1H), 8.36-8.40 (m, 2H), 8.31 (d, J=2.6 Hz, 1H), 7.69 (d, J=9.2 Hz, 2H), 7.30 (t, J=7.6Hz, 1H), 6.92 (dd, J=6.1, 1.2 Hz, 1H), 5.50 (5, 2H), 3.87 (5, 3H).LCMS (ES): Found 340.0 [M+H].
40%		NaH (60%, 48.5mg, 1 .21 mmol) was added to a solution of (3) (200mg, 1 .15mmol) in DMF (7mL) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (371 mg, 1 .5mmol) was added as a solution in DMF (3ml_). The stirring was continued at 70C for 1 h. Reaction cooled to rt and poured onto water (100ml_). Brine (25ml_) was added and the aqueous was extracted with EtOAc (2 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. Purification by flash column chromatography with EtOAc/CH2CI2 (0: 1 -1 :0) then EtOAc/MeOH (1 :0- 4: 1 ) yielded (4) (158mg, 40%). 1 H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.87 (d, J=1 .4 Hz, 1 H), 8.76-8.78 (m, 1 H), 8.36-8.40 (m, 2H), 8.31 (d, J=2.6 Hz, 1 H), 7.69 (d, J=9.2 Hz, 2H), 7.30 (t, J=7.6 Hz, 1 H), 6.92 (dd, J=6.1 , 1 .2 Hz, 1 H), 5.50 (s, 2H), 3.87 (s, 3H). LCMS (ES): Found 340.0 [M+H]+.
40%		Example EE (0445) N-Hydroxy-4-[(pyrazin-2-yl)(pyrimidin-4-yl)amino]methyl}benzami (0446) (0447) (0448) EE NaH (60%, 48.5mg, 1.21 mmol) was added to a solution of (3) (200mg, 1.15mmol) in DMF (7mL) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (371 mg, 1.5mmol) was added as a solution in DMF (3ml_). The stirring was continued at 70C for 1 h. Reaction cooled to rt and poured onto water (100ml_). Brine (25ml_) was added and the aqueous layer was extracted with EtOAc (2 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. Purification by flash column chromatography with EtOAc/CH2CI2 (0: 1-1 :0) then EtOAc/MeOH (1 :0-4: 1) yielded (4) (158mg, 40%). (0449) 1 H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.87 (d, J=1.4 Hz, 1 H), 8.76-8.78 (m, 1 H), 8.36-8.40 (m, 2H), 8.31 (d, J=2.6 Hz, 1 H), 7.69 (d, J=9.2 Hz, 2H), 7.30 (t, J=7.6 Hz, 1 H), 6.92 (dd, J=6.1 , 1.2 Hz, 1 H), 5.50 (s, 2H), 3.87 (s, 3H). (0450) LCMS (ES): Found 340.0 [M+H]+.

Reference： [1]Patent: WO2014/181137,2014,A1 .Location in patent: Page/Page column 61
[2]Patent: WO2017/29514,2017,A1 .Location in patent: Page/Page column 92
[3]Patent: WO2017/208032,2017,A1 .Location in patent: Page/Page column 69

12
[ 533930-18-6 ]
[ 128577-47-9 ]
C₁₇H₁₄FN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		HHNaH (60%, 49mg, 1.2lmmol) was added to a solution of (3) (200 mg, 1.lSmmol) inDMF (7mL) at 5C under N2(g). The reaction mixture was stirred for 20mm then<strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (371mg, 1.Smmol) was added as a solution in DMF (3mL). The stirring was continued at 70C for lh. Reaction cooled to rt and poured onto water (lOOmL). Brine (25mL) was added and the aqueous was extracted with EtOAc (2 x lOOmL). Combined organics were dried over Na2504, filtered and concentrated in vacuo. Purification by flash column chromatography withCH2CI2/EtOAc (1:0-0:1) then EtOAc/MeOH (1:0-4:1) yielded (4) (195mg, 50%).1H NMR (500 MHz, Chloroform-d), OH ppm: 8.65 (d, ...&-1.4 Hz, 2H), 8.25 (dd, J=2.5,1.5 Hz, 2H), 8.18 (d, J=2.6 Hz, 2H), 7.65-7.72 (m, 2H), 7.31 (t, J=7.8 Hz, 1H), 5.53(s, 2H), 3.87 (s, 3H).LCMS (ES): Found 339.9 [M+H].
50%		NaH (60%, 49mg, 1 .21 mmol) was added to a solution of (3) (200 mg, 1 .15mmol) in DMF (7mL) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (371 mg, 1 .5mmol) was added as a solution in DMF (3ml_). The stirring was continued at 70C for 1 h. Reaction cooled to rt and poured onto water (100ml_). Brine (25ml_) was added and the aqueous was extracted with EtOAc (2 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. Purification by flash column chromatography with CH2CI2/EtOAc (1 :0-0: 1 ) then EtOAc/MeOH (1 :0-4: 1 ) yielded (4) (195mg, 50%). 1 H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.65 (d, J=1 .4 Hz, 2H), 8.25 (dd, J=2.5, 1 .5 Hz, 2H), 8.18 (d, J=2.6 Hz, 2H), 7.65-7.72 (m, 2H), 7.31 (t, J=7.8 Hz, 1 H), 5.53 (s, 2H), 3.87 (s, 3H). LCMS (ES): Found 339.9 [M+H]+.
50%		Example HH (0482) -[Bis(pyrazin-2-yl)amino]methyl}-3-fluoro-N-hydroxybenzamide (0483) (0484) HH (0485) NaH (60%, 49mg, 1.21 mmol) was added to a solution of (3) (200 mg, 1.15mmol) in DMF (7ml_) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (371 mg, 1.5mmol) was added as a solution in DMF (3ml_). The stirring was continued at 70C for 1 h. Reaction cooled to rt and poured onto water (100ml_). Brine (25ml_) was added and the aqueous was extracted with EtOAc (2 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. Purification by flash column chromatography with CH2CI2/EtOAc (1 :0-0:1) then EtOAc/MeOH (1 :0-4: 1) yielded (4) (195mg, 50%). (0486) 1 H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.65 (d, J=1.4 Hz, 2H), 8.25 (dd, J=2.5, 1.5 Hz, 2H), 8.18 (d, J=2.6 Hz, 2H), 7.65-7.72 (m, 2H), 7.31 (t, J=7.8 Hz, 1 H), 5.53 (s, 2H), 3.87 (s, 3H). (0487) LCMS (ES): Found 339.9 [M+H]+.

Reference： [1]Patent: WO2014/181137,2014,A1 .Location in patent: Page/Page column 64; 65
[2]Patent: WO2017/29514,2017,A1 .Location in patent: Page/Page column 96
[3]Patent: WO2017/208032,2017,A1 .Location in patent: Page/Page column 72-73

13
C₁₀H₁₀N₄O [ No CAS ]
[ 128577-47-9 ]
C₁₉H₁₇FN₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%		KKNaH (60%, 41.5mg, 1 .O4mmol) was added to a solution of (3) (200mg, 0.99mmol) in DMF (l0mL) at 5C under N2(g). The reaction mixture was stirred for 20mm then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (318mg, 1.29mmol) was added. Thestirring was continued at 70C under N2(g) for lh. The reaction cooled to rt and poured onto water (l5OmL) and brine (5OmL), the aqueous extracted with EtOAc (3 x lOOmL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1:0-0:1) then EtOAc/MeOH (1:0-4:1) to give (4) (269mg, 74%).1H NMR (500 MHz, Chloroform-d), OH ppm: 8.09 (dd, J=4.7, 1.4 Hz, 1H), 8.06 (dd,J=2.6, 1.6 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.68 (dd, J=8.0,1.4 Hz, 1H), 7.62 (dd, J=10.5, 1.4 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.27 (dd, J=8.3,1.5 Hz, 1H), 7.18 (dd, J=8.2, 4.7 Hz, 1H), 5.43 (5, 2H), 3.86 (5, 3H), 3.77 (5, 3H).LCMS (ES): Found 368.9 [M+H].
74%		NaH (60%, 41.5mg, 1.04mmol) was added to a solution of (3) (200mg, 0.99mmol) in DMF (10mL) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (318mg, 1.29mmol) was added. The stirring was continued at 70C under N2(g) for 1h. The reaction cooled to rt and poured onto water (150ml_) and brine (50ml_), the aqueous extracted with EtOAc (3 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1:0-0:1) then EtOAc/MeOH (1:0-4:1) to give (4) (269mg, 74%). 1H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.09 (dd, J=4.7, 1.4 Hz, 1H), 8.06 (dd, J=2.6, 1.6 Hz, 1H), 7.90 (d, J=2.7 Hz, 1H), 7.80 (d, J=1.3 Hz, 1H), 7.68 (dd, J=8.0, 1.4 Hz, 1H), 7.62 (dd, J=10.5, 1.4 Hz, 1H), 7.56 (t, J=7.7 Hz, 1H), 7.27 (dd, J=8.3, 1.5 Hz, 1H), 7.18 (dd, J=8.2, 4.7 Hz, 1H), 5.43 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H). LCMS (ES): Found 368.9 [M+H]+.
74%		Example KK (0510) 3-Fluoro-N-hydroxy-4-[(3-methoxypyridin-2-yl)(pyrazin-2- yl)amino]methyl}benzamide (0511) (0512) NaH (60%, 41.5mg, 1.04mmol) was added to a solution of (3) (200mg, 0.99mmol) in DMF (10ml_) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (318mg, 1.29mmol) was added. The stirring was continued at 70C under N2(g) for 1 h. The reaction cooled to rt and poured onto water (150ml_) and brine (50ml_), the aqueous layer extracted with EtOAc (3 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1 :0-0: 1) then EtOAc/MeOH (1 :0-4:1) to give (4) (269mg, 74%). 1 H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.09 (dd, J=4.7, 1.4 Hz, 1 H), 8.06 (dd, J=2.6, 1.6 Hz, 1 H), 7.90 (d, J=2.7 Hz, 1 H), 7.80 (d, J=1.3 Hz, 1 H), 7.68 (dd, J=8.0, (0513) 1.4 Hz, 1 H), 7.62 (dd, J=10.5, 1.4 Hz, 1 H), 7.56 (t, J=7.7 Hz, 1 H), 7.27 (dd, J=8.3, (0514) 1.5 Hz, 1 H), 7.18 (dd, J=8.2, 4.7 Hz, 1 H), 5.43 (s, 2H), 3.86 (s, 3H), 3.77 (s, 3H). LCMS (ES): Found 368.9 [M+H]+.

Reference： [1]Patent: WO2014/181137,2014,A1 .Location in patent: Page/Page column 68
[2]Patent: WO2017/29514,2017,A1 .Location in patent: Page/Page column 100
[3]Patent: WO2017/208032,2017,A1 .Location in patent: Page/Page column 76

14
C₁₀H₁₀N₄O [ No CAS ]
[ 128577-47-9 ]
C₁₈H₁₇N₅O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
55%		NaH (60%, 41.5mg, 1 .O4mmol) was added to a solution of (3) (200mg, 0.99mmol) inDMF (l0mL) at 5C under N2(g). The reaction mixture was stirred for 20 mm thenmethyl 6-(bromomethyl) pyridine-3-carboxylate (296mg, 1 .29mmol) was added. The stirring was continued at 70C under N2(g) for lh. The reaction was cooled to rt and poured onto water (l5OmL) and brine (5OmL) and the aqueous extracted with EtOAc (3 x lOOmL). Combined organics were dried over Na2SO4, filtered and concentratedin vacuo. The residue was purified by flash column chromatography withCH2CI2/EtOAc (1:0-0:1) then EtOAc/MeOH (1:0-4:1) to give (4) (191mg, 55%).1H NMR (500 MHz, Chloroform-d), OH ppm: 9.07 (d, J=1.9 Hz, 1H), 8.12 (dd, J=8.2,2.1 Hz, 1H), 8.06 (dd, J=4.7, 1.4 Hz, 1H), 8.01 (dd, J=2.6, 1.6 Hz, 1H), 7.88 (d,J=2.7 Hz, 1H), 7.84 (d, J=1.4 Hz, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.2, 1.4Hz, 1H), 7.17 (dd, J=8.2, 4.7 Hz, 1H), 5.46 (5, 2H), 3.86 (5, 3H), 3.76 (5, 3H).LCMS (ES): Found 352.0 [M+H].

Reference： [1]Patent: WO2014/181137,2014,A1 .Location in patent: Page/Page column 69

15
C₈H₇N₅ [ No CAS ]
[ 128577-47-9 ]
C₁₇H₁₄FN₅O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24%		NaH (60%, 73mg, 1.82mmol) was added to a solution of (3) (300mg, 1.73mmol) in DMF (llmL) at 5C under N2(g). The reaction mixture was stirred for 20mm then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (556mg, 2.25mmol) in DMF (4mL) was added. The stirring was continued at 70C under N2(g) for lh. The reaction wascooled to rt and poured onto water (l5OmL) and brine (25mL) and the aqueous extracted with EtOAc (150+lOOmL). Combined organic were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1:0-0:1) then EtOAc/MeOH (1:0-4:1) to yield (4) (141mg, 24%) as a brown oil.1H NMR (500 MHz, Chloroform-d), OH ppm: 8.85 (dd, J=4.6, 1.3 Hz, 1H), 8.59 (d, J=1.4 Hz, 1H), 8.23 (dd, J=2.6, 1.5 Hz, 1H), 8.18 (d, J=2.6 Hz, 1H), 7.61-7.71 (m, 2H), 7.50 (dd, J=9.1, 1.3 Hz, 1H), 7.32-7.42 (m, 2H), 5.64 (5, 2H), 3.86 (5, 3H).LCMS (ES): Found 339.9 [M+H].
24%		NaH (60%, 73mg, 1.82mmol) was added to a solution of (3) (300mg, 1 .73mmol) in DMF (1 1 mL) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (556mg, 2.25mmol) in DMF (4ml_) was added. The stirring was continued at 70C under N2(g) for 1 h. The reaction was cooled to rt and poured onto water (150ml_) and brine (25ml_) and the aqueous extracted with EtOAc (150+100ml_). Combined organic were dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1 :0-0:1 ) then EtOAc/MeOH (1 :0- 4:1 ) to yield (4) (141 mg, 24%) as a brown oil. 1H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.85 (dd, J=4.6, 1 .3 Hz, 1 H), 8.59 (d, J=1 .4 Hz, 1 H), 8.23 (dd, J=2.6, 1.5 Hz, 1 H), 8.18 (d, J=2.6 Hz, 1 H), 7.61-7.71 (m, 2H), 7.50 (dd, J=9.1 , 1 .3 Hz, 1 H), 7.32-7.42 (m, 2H), 5.64 (s, 2H), 3.86 (s, 3H). LCMS (ES): Found 339.9 [M+H]+.
24%		Example NN (0536) 3-Fluoro-N-hydroxy-4-[(pyrazin-2-yl)(pyridazin-3-yl)amino]m (0537) (0538) NN NaH (60%, 73mg, 1.82mmol) was added to a solution of (3) (300mg, 1.73mmol) in DMF (1 1 ml_) at 5C under N2(g). The reaction mixture was stirred for 20min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (556mg, 2.25mmol) in DMF (4ml_) was added. The stirring was continued at 70C under N2(g) for 1 h. The reaction was cooled to rt and poured onto water (150ml_) and brine (25ml_), and the aqueous layer was extracted with EtOAc (150+100ml_). Combined organics were dried over Na2S04, filtered and concentrated. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1 :0-0: 1) then EtOAc/MeOH (1 :0-4:1) to yield (4) (141 mg, 24%) as a brown oil. (0539) 1 H NMR (500 MHz, Chloroform-d), δΗ ppm: 8.85 (dd, J=4.6, 1.3 Hz, 1 H), 8.59 (d, J=1.4 Hz, 1 H), 8.23 (dd, J=2.6, 1.5 Hz, 1 H), 8.18 (d, J=2.6 Hz, 1 H), 7.61-7.71 (m, 2H), 7.50 (dd, J=9.1 , 1.3 Hz, 1 H), 7.32-7.42 (m, 2H), 5.64 (s, 2H), 3.86 (s, 3H). (0540) LCMS (ES): Found 339.9 [M+H]+.

Reference： [1]Patent: WO2014/181137,2014,A1 .Location in patent: Page/Page column 71; 72
[2]Patent: WO2017/29514,2017,A1 .Location in patent: Page/Page column 104
[3]Patent: WO2017/208032,2017,A1 .Location in patent: Page/Page column 80

16
C₁₀H₁₀N₄O [ No CAS ]
[ 128577-47-9 ]
C₁₉H₁₈N₄O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%		NaH (60%, 42mg, 1.O4mmol) was added to a solution of (3) (200mg, 0.99mmol) inDMF (7mL) at rt under N2(g). The reaction mixture was stirred for 30mm then methyl4-(bromomethyl)-3-fluorobenzoate (249mg, 1.O9mmol) in DMF (2mL) was added.The reaction was heated up to 70C under N2(g) for 2h, then at rt overnight. The reaction was cooled to rt and partitioned between H20 (l5OmL) and EtOAc (2 x lOOmL). Combined organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1:0-0:1) to yield (4) (1 73mg, 50%) as a viscous oil.1H NMR (300 MHz, Chloroform-d), OH ppm: 8.63 (dd, ...&-1.4 Hz, 1H), 8.14-8.22 (m,2H), 8.01 (d, J=2.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 6.61 (d, J=2.1 Hz, 1H), 6.54 (dd, J=5.8, 2.2 Hz, 1H), 5.46 (5, 2H), 3.85 (5, 3H), 3.75 (5, 3H). LCMS (ES): Found 350.9 [M+H].
50%		NaH (60%, 42mg, 1 .04mmol) was added to a solution of (3) (200mg, 0.99mmol) in DMF (7ml_) at rt under N2(g). The reaction mixture was stirred for 30min then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (249mg, 1 .09mmol) in DMF (2ml_) was added. The reaction was heated up to 70C under N2(g) for 2h, then at rt overnight. The reaction was cooled to rt and partitioned between H20 (150ml_) and EtOAc (2 x 100ml_). Combined organics were dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash column chromatography with CH2CI2/EtOAc (1 :0-0: 1 ) to yield (4) (173mg, 50%) as a viscous oil. 1 H NMR (300 MHz, Chloroform-d), δΗ ppm: 8.63 (dd, J=1 .4 Hz, 1 H), 8.14-8.22 (m, 2H), 8.01 (d, J=2.6 Hz, 1 H), 7.92 (d, J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 6.61 (d, J=2.1 Hz, 1 H), 6.54 (dd, J=5.8, 2.2 Hz, 1 H), 5.46 (s, 2H), 3.85 (s, 3H), 3.75 (s, 3H). LCMS (ES): Found 350.9 [M+H]+.

Reference： [1]Patent: WO2014/181137,2014,A1 .Location in patent: Page/Page column 74; 75
[2]Patent: WO2017/29514,2017,A1 .Location in patent: Page/Page column 106; 107

17
[ 142-08-5 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((2-oxopyridin-1(2H)-yl)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With potassium carbonate; In acetonitrile; at 85℃;	A mixture of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (500 mg, 2.02 mmol, 1.0 eq), pyridin-2(lH)-one (384 mg, 4.04 mmol, 2.0 eq) and K2CO3 (836 mg, 6.06 mmol, 3.0 eq) in MeCN (5 mL) was stirred at 85 C overnight. The mixture was filtered and the filtrate was concentrated. The residue was purified via flash chromatography to afford methyl 3-fluoro-4-((2-oxopyridin-l(2H)-yl)methyl)benzoate as a yellow solid (430 mg, 82%).

Reference： [1]Patent: WO2015/103317,2015,A1 .Location in patent: Page/Page column 126

18
C₉H₇BrN₄ [ No CAS ]
[ 128577-47-9 ]
C₁₈H₁₄BrFN₄O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%		To a solution of (3) (3.96g, 13.7mmol) in dry DMF (90ml_) was added NaH (60%, 0.65g, 12.3mmol) portion-wise at 5C under N2(g). The reaction mixture was stirred for 20mins, then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (4.4g, 17.8mmol) was slowly added. The reaction mixture was stirred for an additional 1 h. It was then partitioned between H20 (400ml_) and EtOAc (3 x 250ml_). The combined organic extracts were washed with brine (300ml_), dried over Na2S04, filtered and concentrated in vacuo. Purification by flash column chromatography with heptane/EtOAc (1 :0-3:1) yielded (4) (4.2g, 73%) as an off-white solid. 1 H NMR (400 MHz, Chloroform-cO, δΗ ppm: 8.69 (d, J=1.4 Hz, 1 H), 8.24 (m, 1 H), 8.15 (m, 2H), 7.69-7.77 (m, 2H), 7.26-7.36 (m, 2H), 7.12 (dd, J^5.3, 1.5 Hz, 1 H), 5.52 (s, 2H), 3.89 (s, 3H). LCMS (ES): Found 417.0; 419.0 [M+H]+.

Reference： [1]Patent: WO2016/67038,2016,A1 .Location in patent: Page/Page column 43

19
tert-butyl 4-(N-phenylsulfamoyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-phenylsulfamoyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.6%		To a solution of tert-butyl 4-(N-phenylsulfamoyl)piperazine-1-carboxylate (2.440 g, 7.146 mmol) in N,N-dimethylformide (50 mL) was added NaH (60.00 %, 0.372 g, 9.290 mmol) at 0 C, and the mixture was stirred at the same temperature for 10 min. The reaction mixture was treated with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.942 g, 7.861 mmol), and stirred for additional 1 hr at the room room temperature. Then, saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturaed aqueous sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (SiO2, 40 g cartridge; ethyl acetate / hexane = 10 % to 30 %) to give tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-phenylsulfamoyl)piperazine-1-carboxylate as white solid (3.070 g, 84.6 %).

Reference： [1]Patent: WO2017/18805,2017,A1 .Location in patent: Paragraph 171-173

20
tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
98.5%		To a solution of tert-butyl 4-(N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate (1.950 g, 5.425 mmol) in N,N-dimethylformide (20 mL) was added sodium hydride (60.00 %, 0.282 g, 7.053 mmol) at the room temperature, and the mixture was stirred at the same temperature for 10 min. The reaction mixture was treated with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.474 g, 5.968 mmol), and stirred for additional 1 hr at the same temperature. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (SiO2, 40 g cartridge; ethyl acetate / hexane = 10 % to 30 %) to give tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-(3-fluorophenyl)sulfamoyl)piperazine-1-carboxylate as white solid (2.810 g, 98.5 %).

Reference： [1]Patent: WO2017/18805,2017,A1 .Location in patent: Paragraph 262-264

21
tert-butyl 4-(N-(pyridin-3-yl)sulfamoyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-(pyridin-3-yl)sulfamoyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.1%		To a solution of tert-butyl 4-(N-(pyridin-3-yl)sulfamoyl)piperazine-1-carboxylate (1.745 g, 5.096 mmol) in N,N-dimethylformide (20 mL) was added sodium hydride (60.00 %, 0.265 g, 6.625 mmol) at the room temperature, and the mixture was stirred at the same temperature for 10 min. The reaction mixture was treated with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.385 g, 5.606 mmol), and stirred for additional 1 hr at the same temperature. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (SiO2, 40 g cartridge; ethyl acetate / hexane = 20 % to 50 %) to give tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-(pyridin-3-yl)sulfamoyl)piperazine-1-carboxylate as beige solid (1.220 g, 47.1 %).

Reference： [1]Patent: WO2017/18805,2017,A1 .Location in patent: Paragraph 317-319

22
[ 128577-47-9 ]
[ 83922-51-4 ]
methyl 4-((N-(3-bromophenyl)methylsulfonamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.9%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of <strong>[83922-51-4]N-(3-bromophenyl)methanesulfonamide</strong> (0.500 g, 1.999 mmol), sodium hydride (60.00 %, 0.096 g, 2.399 mmol) and methyl 4-(bromomethyl)-3-fluorobenzoate (0.543 g, 2.199 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl4-((N-(3-bromophenyl)methylsulfonamido)methyl)-3-fluorobenzoate as yellow solid (0.490 g, 58.9 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 794; 795; 796

23
[ 50790-31-3 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(2-(trifluoromethyl)phenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72.0%	With sodium hydride; In dichloromethane; mineral oil; at 20℃; for 5h;	A solution of N-(2-(trifluoromethyl)phenyl)methanesulfonamide (0.500 g, 2.090 mmol), sodium hydride (60.00 %, 0.100 g, 2.508 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.568 g, 2.299 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl3-fluoro-4-((N-(2-(trifluoromethyl)phenyl)methylsulfonamido)methyl)benzoate asyellow solid (0.6 10 g, 72.0 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 812; 813; 814

24
[ 50790-32-4 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(4-(trifluoromethyl)phenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.4%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(4-(trifluoromethyl)phenyl)methanesulfonamide (0.500 g, 2.090 mmol), sodium hydride (60.00 %, 0.100 g, 2.508 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.568 g, 2.299 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer waswashed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl3-fluoro-4-((N-(4-(trifluoromethyl)phenyl)methylsulfonamido)methyl)benzoate as white solid (0.630 g, 74.4 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 852; 853; 854

25
[ 7022-17-5 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(o-tolyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.3%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(o-tolyl)methanesulfonamide (0.500 g, 2.699 mmol), sodium hydride (60.00 %, 0.130 g, 3.239 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.734g, 2.969 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl 3-fluoro-4-((N-(o-tolyl)methylsulfonamido)methyl)benzoate as yellow solid (0.610 g, 64.3 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 937; 938; 939

26
[ 7022-25-5 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(2-methoxyphenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(2-methoxyphenyl)methanesulfonamide (0.500 g, 2.485 mmol), sodium hydride (60.00 %, 0.119 g, 2.982 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.675 g, 2.733 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-((N-(2-methoxyphenyl)methylsulfonamido)methyl)benzoate as yellow solid (0.630 g, 69.0 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 962; 963; 964

27
N-(3-fluorophenyl)tetrahydro-2H-thiopyran-4-sulfonamide1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-(((N-(3-fluorophenyl)-1,1-dioxidotetrahydro-2H-thiopyran)-4-sulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.5%		Sodium hydride (60.00 %, 0.041 g, 1.032 mmol) was added to a solution of N(3-fluorophenyl)tetrahydro-2H-thiopyran-4-sulfonamide 1,1-dioxide (0.244 g, 0.794 mmol) in N,N-dimethylformide (6 mL) at 0 C, and stirred at the same temperature for 20 mm. The reaction mixture was treated with methyl4-(bromomethyl)-3-fluorobenzoate (0.2 16 g, 0.873 mmol), and stirred at the same temperature for 20 mm. Then, aqueous iN-hydrochloric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-(((N-(3-fluorophenyl)- 1,1 -dioxidotetrahydro-2H-thiopyran)-4- sulfonamido)methyl)benzoate as colorlessness oil (0.220 g, 58.5 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1019; 1020; 1021

28
[ 4284-51-9 ]
[ 128577-47-9 ]
methyl 4-((N-(4-chlorophenyl)methylsulfonamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.3%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(4-chlorophenyl)methanesulfonamide (0.500 g, 2.43 1 mmol), sodium hydride (60.00%, 0.117 g, 2.917 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.66 1 g, 2.674 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl4-((N-(4-chlorophenyl)methylsulfonamido)methyl)-3-fluorobenzoate as yellow solid (0.690 g, 76.3 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1037; 1038; 1039

29
N-(5-fluoropyridin-3-yl)methanesulfonamide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(5-fluoropyridin-3-yl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.6%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(5-fluoropyridin-3-yl)methanesulfonamide (0.380 g, 1.998 mmol), sodium hydride (60.00 %, 0.096 g, 2.398 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.543 g, 2.198 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl3-fluoro-4-((N-(5-fluoropyridin-3-yl)methylsulfonamido)methyl)benzoate as yellow solid (0.5 10 g, 71.6 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1051; 1052; 1053

30
[ 128577-47-9 ]
[ 98611-90-6 ]
methyl 3-fluoro-4-((N-(2-fluorophenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67.1%		A solution of N-(2-fluorophenyl)methanesulfonamide (0.500 g, 2.643 mmol), sodium hydride (60.00 %, 0.127 g, 3.17 1 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.7 18 g, 2.907 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-((N-(2-fluorophenyl)methylsulfonamido)methyl)benzoate as yellow solid (0.630 g, 67.1 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1065; 1066; 1067

31
[ 35980-24-6 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(4-fluorophenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.5%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(4-fluorophenyl)methanesulfonamide (0.500 g, 2.643 mmol), sodium hydride (60.00 %, 0.127 g, 3.17 1 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.7 18 g, 2.907 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-((N-(4-fluorophenyl)methylsulfonamido)methyl)benzoate as yellow solid (0.690 g, 73.5 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1090; 1091; 1092

32
[ 4284-50-8 ]
[ 128577-47-9 ]
methyl 4-((N-(4-bromophenyl)methylsulfonamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.7%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(4-bromophenyl)methanesulfonamide (0.500 g, 1.999 mmol), sodium hydride (60.00 %, 0.096 g, 2.399 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.543 g, 2.199 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl4-((N-(4-bromophenyl)methylsulfonamido)methyl)-3-fluorobenzoate as yellow solid (0.680 g, 81.7 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1115; 1116; 1117

33
[ 7022-20-0 ]
[ 128577-47-9 ]
methyl 4-((N-(2-chlorophenyl)methylsulfonamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(2-chlorophenyl)methanesulfonamide (0.500 g, 2.43 1 mmol), sodium hydride (60.00%, 0.117 g, 2.917 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.66 1 g, 2.674 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl4-((N-(2-chlorophenyl)methylsulfonamido)methyl)-3-fluorobenzoate as yellow solid (0.640 g, 70.8 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1140; 1141; 1142

34
[ 4284-47-3 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(p-tolyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.6%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(p-tolyl)methanesulfonamide (0.500 g, 2.699 mmol), sodium hydride (60.00 %, 0.130 g, 3.239 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.734 g, 2.969 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 3-fluoro-4-((N-(p-tolyl)methylsulfonamido)methyl)benzoate as white solid (0.660 g, 69.6 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1173; 1174; 1175

35
tert-butyl 4-(methylsulfonamido)piperidine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)methylsulfonamido)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.1%		Sodium hydride (60.00 %, 0.172 g, 4.3 11 mmol) was added to a solution of tert-butyl 4-(methylsulfonamido)piperidine-1-carboxylate (1.000 g, 3.592 mmol) in N,N-dimethylformide (8 mL) at 0 C, and the mixture was stirred at the same temperature for 20 mm. The reaction mixture was treated with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.932 g, 3.772 mmol), and stirred for additional 16hr at the room temperature. Then, aqueous 0. iN-hydrochloric acid solution was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and the aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 20 %) to give tertbutyl4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)methylsulfonamido)piperidine- 1 -carboxyla te as white solid (1.200 g, 75.1 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1269; 1270; 1271

36
[ 935845-18-4 ]
[ 128577-47-9 ]
tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-phenylsulfamoyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92.4%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.6 10 g, 2.467 mmol) and potassium iodide (0.039 g, 0.235 mmol) in N,N-dimethylfomiide (8 mL) was stirred at the room temperature for 30 mm, and mixed with tert-butyl 4-(N-phenylsulfamoyl)piperidine-1-carboxylate (0.800 g, 2.350 mmol) and potassium carbonate (0.422 g, 3.055 mmol). The reaction mixture was stirred at the same temperature for additional 24 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 70 %) to give tert-butyl 4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-N-phenylsulfamoyl)piperidine- 1 -carboxyl ate as white solid (1.100 g, 92.4 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1450; 1451; 1452

37
tert-butyl 4-(4-(ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.454 g, 1.836 mmol) and potassium iodide (0.055 g, 0.334 mmol) in N,N-dimethylfomiide (30 mL) was stirred at the room temperature for 30 mm, and mixed with tert-butyl 4-(4-(ethylsulfonamido)benzyl)piperazine- 1 -carboxylate (0.640 g, 1.669 mmol) and potassium carbonate (0.346 g, 2.503 mmol). The reaction mixture was stirred at 50 C for additional 12 hr, and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give tert-butyl 4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)benzyl)piperazine- 1-c arboxylate as yellow solid (0.780 g, 85.0 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1609; 1610; 1611

38
tert-butyl 4-(3-(ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(3-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.454 g, 1.836 mmol) and potassium iodide (0.055 g, 0.334 mmol) in N,N-dimethylfomiide (30 mL) was stirred at the room temperature for 30 mm, and mixed with tert-butyl 4-(3-(ethylsulfonamido)benzyl)piperazine- 1 -carboxylate (0.640 g, 1.669 mmol) and potassium carbonate (0.346 g, 2.503 mmol). The reaction mixture was stirred at 50 Cfor additional 12 hr, and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give tert-butyl 4-(3-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)benzyl)piperazine- 1-c arboxylate as yellow solid (0.780 g, 85.0 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1626; 1627; 1628

39
N-(3-((1,1-dioxidothiomorpholino)methyl)phenyl)ethanesulfonamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(3-((1,1-dioxidothiomorpholino)methyl)phenyl)ethylsulfonamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.3%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.53 1 g, 2.148 mmol) and potassium iodide (0.068 g, 0.409 mmol) in N,N-dimethylfomiide (8 mL) was stirred at the room temperature for 20 mm, and mixed with N(3-(( 1,1 -dioxidothiomorpholino)methyl)phenyl)ethanesulfonamide (0.680 g, 2.046 mmol) and potassium carbonate (0.368 g, 2.659 mmol). The reaction mixture was stilTed at the same temperature for additional 8 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 70 %) to give methyl4-((N-(3-(( 1,1 -dioxidothiomorpholino)methyl)phenyl)ethylsulfonamido)methyl)-3-fluo robenzoate as white solid (0.880 g, 86.3 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1598; 1599; 1600

40
tert-butyl 4-(3-(ethylsulfonamido)phenyl)piperidine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(3-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)phenyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.6%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.605 g, 2.448 mmol) and potassium iodide (0.074 g, 0.445 mmol) in N,N-dimethylfomiide (10 mL) was stirred at the room temperature for 30 mm, and mixed with tert-butyl 4-(3-(ethylsulfonamido)phenyl)piperidine- 1 -carboxylate (0.820 g, 2.225 mmol) and potassium carbonate (0.46 1 g, 3.338 mmol). The reaction mixture was stirred at 50 C for additional 12 hr and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give tert-butyl 4-(3-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)ethylsulfonamido)phenyl)piperidine- 1-c arboxylate as yellow solid (0.900 g, 75.6 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1714; 1715; 1716

41
tert-butyl 4-(N-(3-chloro-4-fluorophenyl)sulfamoyl)piperidine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(N-(3-chloro-4-fluorophenyl)-N-(2-fluoro-4-(methoxycarbonyl)benzyl)sulfamoyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.1%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20℃; for 16h;	A mixture of tert-butyl4-(N-(3-chloro-4-fluorophenyl) sulfamoyl)piperidine- 1 -carboxylate (1.500 g, 3.818 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.132 g, 4.582 mmol), potassium carbonate (0.792 g, 5.727 mmol) and potassium iodide (0.95 1 g, 5.727 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 16 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 20 % to 50 %) to give tertbutyl 4-(N-(3-chloro-4-fluorophenyl)-N-(2-fluoro-4-(methoxycarbonyl)benzyl)sulfamoyl)pi peridine- 1 -carboxylate as white solid (1.860 g, 87.1 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 1778; 1779; 1780

42
[ 1197-22-4 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-phenylmethylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.7%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 5h;	A solution of <strong>[1197-22-4]N-phenylmethanesulfonamide</strong> (0.800 g, 4.673 mmol), sodium hydride (60.00 %, 0.224 g, 5.607 mmol) and methyl 4-(bromomethyl)-3-fluorobenzoate (1.270 g, 5.140 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) togive methyl 3-fluoro-4-((N-phenylmethylsulfonamido)methyl)benzoate as yellow solid(0.752 g, 47.7 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 510; 511; 512; 513

43
N-(1-methyl-1H-indazol-4-yl)ethanesulfonamide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(1-methyl-1H-indazol-4-yl)ethylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.7%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.2 16 g, 0.873 mmol) and potassium iodide (0.066 g, 0.397 mmol) in N,N-dimethylfomiide (20 mL) was stirred at the room temperature for 30 mm, and mixed with N-(i-methyl-i H-indazol-4-yl)ethanesulfonamide (0.190 g, 0.794 mmol) and potassium carbonate (0.165 g, 1.191 mmol). The reaction mixture was stirred at 50 C for additional 12 hr and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl3-fluoro-4-((N-( i-methyl-i H-indazol-4-yl)ethylsulfonamido)methyl)benzoate as yellow solid (0.250 g, 77.7 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 2056; 2057; 2058

44
N-(1-methyl-1H-indazol-7-yl)ethanesulfonamide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(1-methyl-1H-indazol-7-yl)ethylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.8%		A solution of <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.227 g, 0.9 19 mmol) and potassium iodide (0.069 g, 0.4 18 mmol) in N,N-dimethylfomiide (10 mL) was stirred at the room temperature for 30 mm, and mixed with N-(i-methyl-i H-indazol-7-yl)ethanesulfonamide (0.200 g, 0.836 mmol) and potassium carbonate (0.173 g, 1.254 mmol). The reaction mixture was stirred at 50 C for additional 12 hr and cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl3-fluoro-4-((N-( i-methyl-i H-indazol-7-yl)ethylsulfonamido)methyl)benzoate asyellow oil (0.240 g, 70.8 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 2084; 2085; 2086

45
[ 90415-85-3 ]
[ 128577-47-9 ]
methyl 4-(((3-chloro-N-phenylpropyl)sulfonamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.8%	With potassium carbonate; potassium iodide; In N,N-dimethyl-formamide; at 20 - 50℃; for 12.5h;	A solution of 3-chloro-N-phenylpropane-1-sulfonamide (2.000 g, 8.558 mmol), potassium carbonate (1.774 g, 12.836 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (2.326 g, 9.413 mmol) and potassium iodide (0.7 10 g, 4.279 mmol) in N,N-dimethylformide (5 mL) was stirred at the room temperature for 30 mm and for additional 12 hr at 50 C, then, cooled down to the room temperature to terminate the reaction. Then, water was added to the reaction mixture, followed by extraction with ammonium chloride. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 24 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 4-(((3-chloro-N-phenylpropyl)sulfonamido)methyl)-3-fluorobenzoate as yellow oil (2.800 g, 81.8 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 2240; 2241; 2242

46
[ 90415-85-3 ]
[ 128577-47-9 ]
methyl 6-(((3-chloro-N-phenylpropyl)sulfonamido)methyl)nicotinate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%		A solution of 3-chloro-N-phenylpropane-i-sulfonamide (2.000 g, 8.558 mmol) and potassium carbonate (1.774 g, 12.836 mmol) in N,N-dimethylformide (100 mL) was stilTed at the room temperature for 30 mm, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (2.067 g, 8.985 mmol) and potassium iodide (0.710 g, 4.279 mmol). The reaction mixture was stirred at the same temperature for additional 12 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 24 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give methyl 6-(((3-chloro-N-phenylpropyl)sulfonamido)methyl)nicotinate as yellow solid (2.000 g, 61.0 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 2844; 2845; 2846

47
[ 3833-42-9 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(3-(trifluoromethyl)phenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.8%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(3-(trifluoromethyl)phenyl)methanesulfonamide (0.500 g, 2.090 mmol), sodium hydride (60.00 %, 0.100 g, 2.508 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.568 g, 2.299 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-((N-(3-(trifluoromethyl)phenyl)methylsulfonamido)methyl)benzoate as yellow solid (0.600 g, 70.8 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 579; 580; 581

48
[ 7022-18-6 ]
[ 128577-47-9 ]
methyl-3-fluoro-4-((N-(m-tolyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.4%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;	A solution of N-(m-tolyl)methanesulfonamide (0.500 g, 2.699 mmol), sodium hydride (60.00 %, 0.130 g, 3.239 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.734 g, 2.969 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-((N-(m-tolyl)methylsulfonamido)methyl)benzoate as yellow solid (0.630 g,66.4 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 607; 608; 609

49
[ 7022-24-4 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(3-methoxyphenyl)methylsulfonamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.3%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 5h;Microwave irradiation;	A solution of N-(3-methoxyphenyl)methanesulfonamide (0.700 g, 3.252 mmol), sodium hydride (60.00 %, 0.156 g, 3.902 mmol) and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.884 g, 3.577 mmol) in N,N-dimethylformide (10 mL) was stirred at the room temperature for 5 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated ammonium chloride solution, dried with anhydrous Mg504, filtered, and concentrated in vacuo. The residue was chromatographed (5i02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl3-fluoro-4-((N-(3-methoxyphenyl)methylsulfonamido)methyl)benzoate as yellow solid (0.900 g, 75.3 %).

Reference： [1]Patent: WO2017/18803,2017,A1 .Location in patent: Paragraph 629; 930; 931

50
[ 21397-08-0 ]
[ 128577-47-9 ]
methyl 4-(((3-chloro-2-fluorophenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44.4%	With potassium carbonate; In acetonitrile; at 20℃; for 12h;	[3406] -A solution of <strong>[21397-08-0]2-chloro-3-fluoroaniline</strong> ( 1.000 g, 6.870 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate (6.1 10 g, 24.732 mmol) and potassium carbonate ( 1.867 g, 7.557 mmol) in acetonitrile ( 10 mL) was stirred at the room temperature for 12 hr, and concentrated under the reduced pressure to remove the solvent. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 10 ) to give methyl 4-(((3-chloro-2-fluorophenyl)amino)methyl)-3-fluorobenzoate as pale yellow oil (0.950 g, 44.4 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3404-3406

51
[ 4519-40-8 ]
[ 128577-47-9 ]
methyl 4-(((2,3-difluorophenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39.5%	With potassium carbonate; In acetonitrile; at 20℃; for 15h;	[3525] A solution of <strong>[4519-40-8]2,3-difluoroaniline</strong> ( 1.000 g, 7.745 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate (2.105 g, 8.520 mmol) and potassium carbonate (2.141 g, 15.491 mmol) in acetonitrile ( 10 mL) was stirred at the room temperature for 15 hr, filtered to remove solids, and concentrated under the reduced pressure to remove the solvents. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 percent to 10 ) to give methyl 4-(((2,3-difluOrophenyl)amino)methyl)-3-fluorobenzoate as pale brown oil (0.904 g, 39.5 percent).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3523-3525

52
[ 656-64-4 ]
[ 128577-47-9 ]
methyl 4-(((3-bromo-4-fluorophenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.9%	With potassium carbonate; In acetonitrile; at 20℃; for 15h;	A solution of <strong>[656-64-4]3-bromo-4-fluoroaniline</strong> ( 1.000 g, 5.263 mmol), methyl 4-(bi momethyl)-3-fluoi benzoate ( 1.430 g, 5.789 mmol) and potassium carbonate ( 1.455 g, 10.525 mmol) in acetonitrile ( 10 mL) was stirred at the room temperature for 15 hr, filtered to remove solids, and concentrated under the reduced pressure to remove the solvents. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 10 %) to give methyl 4-(((3-bromo-4-fluorophenyl)amino)methyl)-3-fluorobenzoate as palw brown oil ( 1.104 g, 58.9 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3540-3542

53
[ 128577-47-9 ]
[ 95-74-9 ]
methyl 4-(((3-chloro-4-methylphenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47.9%	With potassium carbonate; In acetonitrile; at 20℃; for 15h;	[3559] A solution of 3-chloro-4-methylaniline ( 1.000 g, 7.062 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate ( 1.919 g, 7.768 mmol) and potassium carbonate ( 1.952 g, 14.124 mmol) in acetonitrile ( 10 mL) was stirred at the room temperature for 15 hr, filtered to remove solids, and concentrated under the reduced pressure to remove the solvents. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 10 %) to give methyl 4-(((3-chloro-4-methylphenyl)amino)methyl)-3-fluorobenzoate as pale yellow oil ( 1 .041 g, 47.9 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3557-3559

54
[ 41926-06-1 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-(((1-methyl-1H-indazol-7-yl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56.4%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18.0h;	[3695] A solution of 1 -methyl- l H-indazol-7-amine ( 1.472 g, 10.000 mmol), methyl 4-(bi momethyl)-3-fluorobenzoate (2.471 g, 10.000 mmol) and N,N-diisopropylethylamine (3.484 mL, 20.000 mmol) in acetonitrile (40 mL) was stirred at the room temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS0 ), filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 30 ) to give methyl 3-fluoro-4-((( l -methyl- l H-indazol-7-yl)amino)methyl)benzoate as white solid ( 1.768 g, 56.4 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3693-3695

55
[ 128577-47-9 ]
[ 77894-69-0 ]
methyl 3-fluoro-4-(((1-methyl-1H-indazol-4-yl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.7%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[3723] A solution of 1 -methyl- l H-indazol-4-amine (0.442 g, 3.000 mmol), methyl 4-(bromomethyl)-3-fluorobenzoate (0.741 g, 3.000 mmol) and N,N-diisopropylethylamine ( 1.045 mL, 6.001 mmol) in acetonitrile ( 12 mL) was stirred at the room temperature for 18 hr, and then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS0 ), filtered, and concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methy i 3-fluoro-4-((( l-methyl- l H-indazol-4-yl)amino)methyl)benzoate as pale brown oil (0.768 g, 81.7 %)

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3721-3723

56
[ 372-19-0 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-(((3-fluorophenyl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.0%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	3-Fluoroaniline (1.000 g, 8.999 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (2.446 g, 9.899 mmol)synthesized in step 1, and N,N-diisopropylethylamine (3.102 mL, 17.999 mmol) were dissolved in acetonitrile (50 mL) at room temperature, and the solution was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 24 g cartridge; ethyl acetate/hexane = from 0% to 80%) and concentrated to give the title compound (2.170 g, 87.0%) as colorless oil.
81.8%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[3787] A solution of 3-fluoroaniline (0.500 g, 4.500 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> ( 1.1 12 g, 4.500 mmol) and Ν,Ν-diisopropylethylamine ( 1.567 mL, 8.999 mmol) in acetonitrile ( 10 mL) was stirred at the room temperature for 18 hr, filtered through a plastic frit to remove solids, and concentrated under the reduced pressure to remove the solvents. The residue was chromatographed (Si02, 12 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give methyl 3-fluoro-4-(((3-fluorophenyl)amino)methyl)benzoate as pale brown oil ( 1 .021 g, 81.8 %).

Reference： [1]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0160; 0161; 0312; 0313
[2]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3785-3787

57
[ 128577-47-9 ]
[ 108-44-1 ]
methyl 3-fluoro-4-((m-tolylamino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.4%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[3801 ] A solution of m-toluidine (0.500 g, 4.666 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> ( 1.153 g, 4.666 mmol) and N,N-diisopropylethylamine ( 1.625 mL, 9.332 mmol) in acetonitrile ( 10 n L) was stirred at the room temperature for 18 nr. filtered through a plastic frit to remove solids, and concentrated under the reduced pressure. The residue was chromatographed (Si02, 12 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give methyl 3-fluoro-4-((m-tolylamino)methyl)benzoate as pale brown oil (0.885 g, 69.4 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3799-3802

58
N-(2,3-dihydro-1H-inden-5-yl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(2,3-dihydro-1H-inden-5-yl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.1%		[3863] A solution of N-(2,3-dihydl-lH-inden-5-yl)thiomo holine-4-carboxamide 1,1-dioxide (0.294 g, 1.000 mmol) and sodium hydride (60.00 %, 0.044 g, 1.100 mmol) in tetrahydrofuran (5 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.259 g, 1.050 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr, concentrated under the reduced pressure. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 ) to give methyl 4-(( -(2,3-dihydro-lH-inden-5-yl)-l,l-dioxidothiomoφholine-4-calboxamido)methyl) -3-fluorobenzoate as white solid (0.392 g, 85.1 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3861-3863

59
N-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-(((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.6%		[3880] A solution of N- (2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)thiomorpholine-4-caiboxamide 1 , 1 -dioxide (0.324 g, 1.000 mmol) and sodium hydride (60.00 %, 0.044 g, 1.100 mmol) in tetrahy- drofuran (5 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.259 g, 1 .050 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr, concentrated under the reduced pressure. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 4-(( -(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)- l , l-dioxidothiomoφholine-4-carbox amido)methyl)-3-fluorobenzoate as colorless oil (0.459 g, 93.6 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3878-3880

60
N-(1-methyl-1H-indol-5-yl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(1-methyl-1H-indol-5-yl)-1.1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85.7%		[3897] A solution of N-( l-methyl-l H-ndol-5-yl)thiomoφholne-4-carboxamide 1 , 1-dioxide (0.307 g, 1.000 mmol) and sodium hydride (60.00 %, 0.044 g, 1.100 mmol) in tetrahy- drofuran (5 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.259 g, 1.050 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr, concentrated under the reduced pressure. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 3-fluoro-4-((N-( l -methyl- l H-indol-5-yl)- l , l-dioxidothiomorpholine-4-carboxamido)m ethyl)benzoate as white solid (0.406 g, 85.7 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3895-3897

61
N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(3-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.1%		[3927] A solution of N-(3-fluorophenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide (0.300 g, 1. 102 mmol) and sodium hydride (60.00 %. 0.048 g, 1 .21 2 mmol) in N,N-dimethylformamide (5 mL) was stirred at 0 C for 2 hr, and mixed with methyl 4-(biOmomethyl)-3-fluorobenzoate (0.299 g, 1.2 12 mmol). The reaction mixture was stirred at the room temperature for additional 17 hr. quenched at the room temperature by the addition of water (2 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 4 g cartridge; ethyl acetate / hexane = 0 % to 40 ) to give methyl 3-fluoro-4-(( N-(3-fluorophenyl)- l , l-dioxidothiomoipholine-4-carboxamido)methyl)be nzoate as white solid (0.300 g, 62. 1 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3925-3927

62
[ 128577-47-9 ]
[ 65642-30-0 ]
methyl 4-(((1-ethyl-1H-indazol-6-yl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.5%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[3974] A solution of 1 -ethyl- l H-indazol-6-amine (0.322 g, 2.000 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.494 g, 2.000 mmol) and N,N-diisopropylethylamine (0.697 mL, 4.000 mmol) in acetonitrile (8 mL) was stirred at the room temperature for 18 hr, and concentrated under the reduced pressure to remove the solvent. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %). to give jnethyl 4-((( l -ethyl- l H-indazol-6-yl)amino)methyl)-3-fluorobenzoate as green oil (0.573 g, 87.5 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3972-3974

63
1-isopropyl-1H-indazol-6-amine [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-(((1-isopropyl-1H-indazol-6-yl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86.8%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[3991 ] A solution of l -isopropyl- l H-indazol-6-amine (0.35 1 g. 2.000 mmol). <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.494 g, 2.000 mmol) and N.N-diisopropylethylamine (0.697 mL. 4.000 mmol) in acetonitnle (8 mL) was stin ed at the room temperature for 18 hr, concentrated under the reduced pressure. Then, water was added to the reaction mixture, followed by extraction with dichloroniethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 3-fluoro-4-((( l -isopropyl- lH-indazol-6-yl)amino)methyl)benzoate as green oil (0.592 g, 86.8 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3989-3991

64
2-isopropylbenzo[d]thiazol-6-amine [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-(((2-isopropylbenzo[d]thiazol-6-yl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95.2%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[4008] A solution of 2-isopropylbenzo[d]thiazol-6-amine (0.385 g, 2.000 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.494 g, 2.000 mmol) and N,N-diisopropylethylamine (0.697 mL, 4.000 mmol) in acetonitrile (8 mL) was stirred at the room temperature for 18 hr, and concentrated under the reduced pressure to remove the solvent. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasie mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 3-fluoro-4-(((2-isopropylbenzo[d]thiazol-6-yl)amino)methyl)benzoate as orange oil (0.683 g, 95.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4006-4008

65
[ 84882-84-8 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(4-fluorophenyl)morpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.6%		[4122] To a stirred solution of N-(4-fluorophenyl)moφhol ne-4-caIboxamide (0.200 g, 0.892 mmol) in N,N-dimethylformamide (5 mL) was added at 0 C sodium hydride (60.00 %, 0.036 g, 0.892 mmol). The reaction mixture was stirred at the same temperature for I hr, treated at the room temperature with methyl 4-(bromomethyl)-3-fluoi benzoate (0.220 g, 0.892 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (SiO:, 4 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give methyl 3-fluoro-4-((N-(4-fluoiOphenyl )moi holine-4-carboxamido)methyl)benzoate as yel low oil (0.305 g, 87.6 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4120-4122

66
N-(3-fluorophenyl)morpholine-4-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(3-fluorophenyl)morpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94.2%		To a stirred solution of N-(3-fuorophenyl)mo holine-4-carbo amide (0.200 g, 0.892 mmol) in N,N-dimethylformamide (5 mL) was added at 0 C sodium hydride (60.00 %, 0.036 g, 0.892 mmol). The reaction mixture was stirred at the same temperature for 1 hr, added at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.220 g, 0.892 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 4 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give methyl 3-fluoro-4-((N-(3-Πuorophenyl)mo lloline-4-carboxamido)methyl)benzoate as yellow oil (0.328 g, 94.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4167-4169

67
[ 52625-27-1 ]
[ 128577-47-9 ]
methyl 4-((N-(4-chlorophenyl)morpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77.2%		[4216] To a stirred solution of N-(4-chlorophenyl)morpholine-4-carboxamide (0.200 g. 0.831 mmol) in N,N-dimethylformamide (5 mL) was added at 0 C sodium hydride (60.00 %, 0.033 g, 0.83 1 mmol). The reaction mixture was stirred at the same temperature for 1 hr, added at the room temperature with methyl 4-(bromomethyl )-3-fluorobenzoate (0.205 g. 0.8 1 mmol ). and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 4 g cartridge; methanol / dichloromethane = 0 % to 5 % ) to give methyl 4-((N-(4-chloiOphenyl)morpholine-4-carboxamido)methyl)-3-fluoi benzoate as yellow oil (0.261 g, 77.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4214-4216

68
[ 2302-14-9 ]
[ 128577-47-9 ]
methyl 4-((N-(3-chlorophenyl)morpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.2%		[4263] To a stirred solution of N-(3-chlorophenyl)n ^holine-4-carboxamide (0.200 g, 0.831 mmol) in Ν,Ν-dimethylformamide (5 mL) was added at 0 C sodium hydride (60.00 , 0.033 g, 0.831 mmol). The reaction mixture was stirred at the same temperature for I hr, treated at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.205 g, 0.831 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 4 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give methyl 4-(( -(3-chlorophenyl)mo holine-4-carboxamido)methyl)-3-fluorobenzoate as yellow oil (0.278 g, 82.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4261-4263

69
N-(2-fluoro-4-methylphenyl)morpholine-4-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(2-fluoro-4-methylphenyl)morpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		[4302] To a stirred solution of N-(2-fluoro-4-methylphenyl)moφholine-4-carbo amide (0.125 g, 0.525 mmol) in N,N-dimethylformamide (5 niL) was added at 0 C sodium hydride (60.00 %, 0.021 g, 0.525 mmol). The reaction mixture was stirred at the same temperature for 1 hr, added at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.130 g, 0.525 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 4 g cartridge: methanol / dichloromethane = 0 % to 5 %) to give methyl 3-fuol-4-((N-(2-fluoro-4-methylphenyl)mo holine-4-cal'boxamido methyl)benzoate as yellow oil (0.123 g, 58.0 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4300-4302

70
[ 349119-20-6 ]
[ 128577-47-9 ]
methyl 4-((N-(2,4-difluorophenyl)morpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.5%		To a stirred solution of N-(2,4-difluorophenyl )morpholine-4-carboxamide (0. 150 g, 0.619 mmol) in N,N-dimethylformamide (5 mL) was added at 0 C sodium hydride (60.00 %, 0.025 g, 0.619 mmol). The reaction mixture was stirred at the same temperature for 1 hr, added at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0. 153 g, 0.619 mmol), and stirred for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si0 . 4 g cartridge; methanol / dichloromethane = 0 % to 5 % ) to give methyl 4-((N-(2.4-difluoiOphenyl )morpholine-4-carboxamido)methyr)-3-tluoiObenzoate as yellow oil (0.191 g, 75.5 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4331-4333

71
4-ethyl-N-(3-fluorophenyl)piperazine-1-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((4-ethyl-N-(3-fluorophenyl)piperazine-1-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.1%		[4448] A solution of 4-ethyl-N-(3-fluorophenyl)piperazine- l -carboxamide (0.334 g, 1.330 mmol) and sodium hydride (60.00 %, 0.059 g, 1.463 mmol) in tetrahydrofuran (6 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.361 g, 1.463 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane.. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The title compound was used without further purification (methyl 4-((4-ethyl-N-(3-fluorophenyl)piperazine- l-carboxamido)methyl)-3-fluorobenzoate, 0.550 g, 99.1 %, pale yellow oil).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4446-4448

72
4-ethyl-N-(4-fluorophenyl)piperazine-1-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((4-ethyl-N-(4-fluorophenyl)piperazine-1-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.1%		[4493] A solution of 4-ethyl-N-(4-fluoiOphenyl)piperazine- l-carboxamide (0.334 g, 1.330 mmol) and sodium hydride (60.00 %, 0.059 g. 1.463 mmol) in tetrahydrofuran (6 niL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.361 g, 1.463 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The title compound was used without further purification (methyl 4-((4-ethyl-N-(4-fluorophenyl)piperazine- l-carboxamido)methyl)-3-fluorobenzoate, 0.550 g, 99.1 %, pale yellow oil).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4491-4493

73
4-ethyl-N-(3-methoxyphenyl)piperazine-1-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((4-ethyl-N-(3-methoxyphenyl)piperazine-1-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.8%		[4538] A solution of 4-ethyl-N-(3-methoxyphenyl)piperazine- l-carboxamide (0.350 g, 1.330 mmol) and sodium hydride (60.00 %, 0.059 g, 1.463 mmol) in tetrahydrofuran (6 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.361 g, 1.463 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The title compound was used without further purification (methyl 4-((4-ethyl-N-(3-methoxyphenyl)piperazine- l -carboxamido)methyl)-3-fluorobenzoate, 0.570 g, 99.8 %, pale yellow oil).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4536-4538

74
4-ethyl-N-(4-methoxyphenyl)piperazine-1-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((4-ethyl-N-(4-methoxyphenyl)piperazine-1-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.8%		[4583] A solution of 4-ethyl-N-(4-methoxyphenyl)piperazine- l -carboxainide (0.350 g, 1.330 mmol) and sodium hydride (60.00 %, 0.059 g, 1.463 mmol) in tetrahydrofuran (6 mL) was stirred at the room temperature for 30 min, and mixed with methyl 4-(bromomethyl)-3-fluoi benzoate (0.361 g, 1.463 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane'. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The title compound was used without further purification (methyl 4-((4-ethyl-N-(4-methoxyphenyl)piperazine- l -carboxamido)methyl)-3-fluorobenzoate, 0.570 g, 99.8 %, pale yellow oil).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4581-4583

75
tert-butyl 4-(4-(1,1-dioxidothiomorpholine-4-carboxamido)benzyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-1,1-dioxidothiomorpholine-4-carboxamido)benzyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.2%		[4767] A solution of tert-butyl 4-(4-( 1 , 1 -dioxidothiomoipholine-4-carboxamido)benzyl)piperazine- 1 -carboxylate ( 1.990 g, 4.397 mmol) and sodium hydride (60.00 %, 0.193 g, 4.837 mmol) in N.N-dimethylformamide (20 mL) was stirred at 0 C for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> ( 1.195 g, 4.837 mmol). The reaction mixture was stirred at the room temperature for additional 17 hr, quenched at the room temperature by the addition of water (50 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSOj, filtered, and concentrated in vacuo. The concentrate was purified and con- centrated by column chromatography (Si02, 24 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give tert-butyl 4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)- 1 , 1 -dioxidothiomorpholine-4-carboxa mido)benzyl)piperazine-l-carboxylate as yellow solid (2.700 g, 99.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4765-4767

76
N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(4-((4-ethylpiperazin-1-yl)methyl)phenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76.8%		[4820] A solution of N- (4-((4-ethylpiperazin- l -yl)methyl)phenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide (0.360 g, 0.946 mmol) and sodium hydride (60.00 %, 0.042 g, 1.041 mmol) in N,N-dimethylformamide ( 10 mL) was stirred at 0 C for 10 min, and mixed with methyl 4-(bromomethyl)-3-fluoi benzoate (0.257 g, 1.041 mmol). The reaction mixture was stiiTed at the room temperature for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSOj, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; methanol / dichloromethane = 0 % to 5 '%) to give methyl 4-((N-(4-((4-ethylpiperazin- 1 -yl)methyl)phenyl)- 1 , 1 -dioxidothiornorpholine-4-carboxa mido)methyl)-3-fluorobenzoate as pale yellow solid (0.397 g, 76.8 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4818-4820

77
N-(4-((4-benzylpiperazin-1-yl)methyl)phenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(4-((4-benzylpiperazin-1-yl)methyl)phenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.5%		[4837] A solution of N- (4-((4-benzylpiperazin- l -yl)methyl)phenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide (0.618 g, 1.396-mmol) and sodium hydride (60.00 %, 0.061 g, 1.536 mmol) in N.N-dimethylformamide (10 mL) was stirred at 0 C for 10 min, and mixed with methyl 4-(bromomethyl)-3-fluoi benzoate (0.379 g, 1.536 mmol). The reaction mixture was stirred at the room temperature for additional 2 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO_i, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; methanol / dichloromethane = 0 % to 5 % ) to give methyl 4-((N-(4-((4-benzylpiperazin- 1 -yl)rhethyl)phenyl)- 1 , 1 -dioxidothiomorpholine-4-carbo xamido)methyl)-3-fluorobenzoate as white solid (0.761 g, 89.5 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4835-4837

78
[ 128577-47-9 ]
[ 138227-63-1 ]
tert-butyl 4-(4-((2-fluoro-4-(methoxycarbonyl)benzyl)amino)phenoxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
1.81 g		[4970] A solution of tert-butyl 4-(4-aminophenoxy)piperidine- 1 -carboxylate ( 1.420 g, 4.857 mmol) and sodium hydride (60.00 %, 0.204 g, 5. 100 mmol) in N.N-dimethylformamide (20 mL) was stirred at 0 C for 30 min. and mixed with methyl 4-( bromomethyl)-3-fluorobenzoate ( 1 .260 g, 5. 100 mmol). The reaction mixture was stirred at the room temperature for additional 17 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSO^, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02. 24 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give tert-butyl 4-(4-((2-fluoro-4-(methoxycarbony I )benzy I )amino )phenoxy )piperidine- 1 -carboxylate as yellow oil ( 1.810 g, 8 1.3 ).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4968-4970

79
tert-butyl (3S,5R)-4-(4-(1,1-dioxidothiomorpholine-4-carboxamido)benzyl)-3.5-dimethylpiperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl (3R,5S)-4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-1,1-dioxidothiomorpholine-4-carboxamido)benzyl)-3,5-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.6%		[4993] A solution of tert-butyl (2S,6R)-4-(4-(l ,l-dioxidothiomorpholine-4-carboxamido)benzyl)-2,6-dimethylpiperaz ine-l-carboxylate (2.000 g.4.161 mmol) and sodium hydride (60.00 %, 0.183 g, 4.577 mmol) in N,N-dimethylfonnamide (100 mL) was stirred at 0 C for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.131 g, 4.577 mmol). The reaction mixture was stirred at the room temperature for additional 3 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 40 g cartridge; methanol / dichloromethane = 0 % to 10 %) to give tert-butyl (3R,5S)-4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)- 1 , 1 -dioxidothiomoφholine-4- carboxamido)benzyl)-3,5-dimethylpiperazine-l -carboxylate as yellow solid ( 1.980 g, 73.6 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 4991-4993

80
tert-butyl (2S,6R)-4-(4-(1.1-dioxidothiomorpholine-4-carboxamido)benzyl)-2,6-dimethylpiperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl (2S,6R)-4-(4-(N-(2-fluoro-4-(methoxycarbonyl)benzyl)-1,1-dioxidothiomorpholine-4-carboxamido)benzyl)-2,6-dimethylpiperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.9%		[5025] A solution of tert-butyl (2S,6R)-4-(4-( l , l -dio idothiomoφholine-4-carboxamido)benzyl)-2>6-dimethylpiperaz ine- 1 -carboxylate ( 1.450 g, 3.017 mmol) and sodium hydride (60.00 %, 0.133 g, 3.3 19 mmol) in N,N-dimethylfomiamide (30 mL) was stirred at 0 C for 10 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.820 g, 3.319 mmol). The reaction mixture was stirred at the same temperature for additional 1 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgSOj, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 10 % to 60 %) to give tert-butyl (2S,6R)-4-(4-(N-(2-fluoro-4-(methoxyca bonyl)benzy])- l , l-dioxidothiomo holine-4- carboxamido)benzyl)-2,6-dimethylpiperazine- l -carboxylate as yellow solid ( 1.950 g, 99.9 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 5023-5025

81
((3r,5r,7r)-adamantan-1-yl)methanamine [ No CAS ]
[ 128577-47-9 ]
methyl 4-(((((3r,5r,7r)-adamantan-1-yl)methyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82.3%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[5075] A solution of ((3r,5r,7r)-adamantan- l -yl)methanamine (1.500 g, 9.076 mmol), <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (2.466 g, 9.983 mmol) and N,N-diisopropylethylamine (3.162 mL, 18.151 mmol) in acetonitrile (30 mL) prepared at the room temperature was stirred at the same temperature for 18 hr. Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (SiCh, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give methyl 4-(((((3r,5r,7r)-adamantan- l-yl)methyl)amino)methyl)-3-fluorobenzoate as yellow solid (2.474 g, 82.3 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 5073-5075

82
[ 1326562-27-9 ]
[ 128577-47-9 ]
tert-butyl 4-((3-chlorophenyl)(2-fluoro-4-(methoxycarbonyl)benzyl)carbamoyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		[5250] A solution of tert-butyl 4-((3-chlorophenyl)carbamoyl)piperazine- l-carboxylate (0.453 g, 1.333 mmol) and sodium hydride (60.00 %, 0.080 g, 1.999 mmol) in tetrahy- drofuran (6 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.362 g, 1.466 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give tert-butyl 4-((3-chlorophenyl)(2-fluoro-4-(methoxycarbonyl)benzyl)carbamoyl)piperazine- l-carb oxylate as colorless oil (0.391 g, 58.0 ).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 5248-5250

83
tert-butyl 4-((3-methoxyphenyl)carbamoyl)piperazine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 4-((2-fluoro-4-(methoxycarbonyl)benzyl)(3-methoxyphenyl)carbamoyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
59.5%		[5358] solution of tert-butyl 4-((3-methoxyphenyl)carbamoyl)piperazine- l-carboxylate (0.447 g, 1.333 mmol) and sodium hydride (60.00 %, 0.080 g, 1.999 mmol) in tetrahy- drofuran (6 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.362 g, 1.466 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give tert-butyl 4-((2-fluoro-4-(methoxycarbonyl)benzyl)(3-methoxyphenyl)carbamoyl)piperazine- l-c arboxylate as colorless oil (0.397 g, 59.5 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 5356-5358

84
N-phenylthiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((1,1-dioxido-N-phenylthiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 18h;	[748] A solution of Ν-ρηεηγ1ιηιοιηο ηοηε-4-03ΛοχΗ(1ε 1 , 1-dioxide ( 1.000 g, 3.932 mmol) and sodium hydride (60.00 %, 0.1 89 g, 4.719 mmol) in N,N-dimethylformamide (30 mL) was mixed at 0 C with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> ( 1.020 g, 4. 129 mmol). and stirred at the room temperature for 18 hr. Then, saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (SiO . 40 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give the title compound methyl 4-(( l , l -dioxido-N-phenylthiomoipholine-4-carboxamido)methyl)-3-fluorobenzoate as white solid ( 1.240 g. 75.0 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 746-748

85
[ 295341-38-7 ]
[ 128577-47-9 ]
tert-butyl 4-((2-fluoro-4-(methoxycarbonyl)benzyl)(phenyl)carbamoyl)piperazine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.2%		[5466] A solution of tert-butyl 4-(phenylcarbamoyl )piperazine- 1 -carbox late (0.610 g. 1.998 mmol) and sodium hydride (60.00 %. 0. 120 g. 2.996 mmol ) in tetrahydrofuran (6 mL) was stirred at the room temperature for 30 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.543 g, 2. 197 mmol). The reaction mixture was stirred at the same temperature for additional 18 hr, and concentrated under the reduced pressure. The concentrate was purified and concentrated by column chromatography (Si02. 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give tert- butyl 4-((2-fluoro-4-(methoxycarbonyl)benzyl)(phenyl)carbamoyl)piperazine- l -carboxylate as colorless oil (0.699 g. 74.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 5464-5466

86
N-(4-methoxyphenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(4-methoxyphenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.3%		2163] To a stirred solution of N-(4-methoxyphenyl)thiomoi holine-4-carboxamide 1 , 1-dioxide ( 1.000 g, 3.5 17 mmol) in N,N-dimethylf rmamide (20 mL) was added at 0 C sodium hydride (60.00 %, 0.169 g, 4.220 mmol). The reaction mixture was stirred at the same temperature, treated at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.956 g, 3.869 mmol), and stirred for additional 1 hr. Then, aqueous lN-sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 40 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give the title compound methyl 3-fluoro-4-((N-(4-methoxyphenyl)- l , l-dioxidothiomorpholine-4-carboxamido)methyl) benzoate as bright yellow solid ( 1 . 130 g, 7 1.3 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2161-2163

87
N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(3-chlorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93.1%		[3963] A solution of N-(3-chlorophenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide (0.300 g, 1.039 mmol) and sodium hydride (60.00 %, 0.046 g, 1.143 mmol) in N.N-dimethylformamide (5 mL) was stirred at 0 C for 2 hr, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.282 g, 1.143 mmol). The reaction mixture was stirred at the room temperature for additional 1 7 hr, quenched at the room temperature by the addition of water (2 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatog aphed (Si02, 4 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl 4-((N-(3-chlorophenyl)- l . l -dioxidothiomorpholine-4-carboxamido)methyl )-3-fluoiObe nzoate as white solid (0.440 g, 93. 1 ).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3961-3963

88
N-(4-bromophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(4-bromophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58.5%		[2506] To a stirred solution of N-(4-bromophenyl)thiomoφholine-4-carboxamide 1 , 1-dioxide ( 1.500 g, 4.502 mmol) prepared in Step 1 in N,N-dimethylformamide ( 15 mL) was added at 0 C sodium hydride (60.00 %, 0.180 g, 4.502. mmol). The reaction mixture was stirred at the same temperature for 30 min. Methyl 4-(bromomethyl)-3-fluorobenzoate ( 1.1 12 g, 4.502 mmol) was added to the reaction mixture, and stirred at the room temperature for additional 4 hr. The precipitates were collected by filtration, washed by diethylether, and dried to give the title compound methyl 4-((N-(4-bromophenyl)- 1 , 1 -dio idothiomoφholine-4-carboxamido)methyl)-3-fuorobe nzoate as white solid (1.314 g, 58.5 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2504-2506

89
N-(2-methoxyphenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(2-methoxyphenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.9%		[2185] To a stirred solution of N-(2-methoxyphenyl)thiomorpholine-4-carboxamide 1, 1 -dioxide ( 1.000 g, 3.517 mmol) in N,N-dimethylformamide ( 10 mL) was added at 0 C sodium hydride (60.00 %, 0.169 g, 4.220 mmol). The reaction mixture was stirred at the same temperature, treated at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.956 g, 3.869 mmol), and stirred for additional 1 hr. Then. waier was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 40 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give the title compound methyl 3-fluoro-4-((N-(2-methoxypheny 1)- 1 , 1 -dio idothiomo holine-4-carboxamido)methyl) benzoateas white solid (1.582 g, 99.9 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2183-2185

90
[ 4559-92-6 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-phenylmorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
64.1%	With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 16h;	[319] A solution of N-phenylmorpholine-4-carboxamide (0.300 g. 1.455 mmol) and sodium hydride (60.00 %, 0.058 g, 1.455 mmol) in Ν,Ν-dimethylformamide ( 10 niL) was mixed at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.359 g. 1.455 mmol). The reaction mixture was stirred at the same temperature for 16 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (SiOi. 12 g cartridge; ethyl acetate / hexane - 10 % to 30 % ) to give the title compound methyl 3-fluoiO-4-((N-phenylmotpholine-4-carboxamido)methyl )benzoate as yellow solid (0.347 g, 64. 1 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 317-319

91
N-(3-methoxyphenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(3-methoxyphenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70.1%		[2207] To a stirred solution of N-(3-methoxyphenyl)thiomoi holine-4-carboxamide 1 , 1 -dioxide ( 1.000 g, 3.5 17 mmol) in N,N-dimethylformamide ( 10 mL) was added at 0 C sodium hydride (60.00 %, 0.169 g, 4.220 mmol). The reaction mixture was stirred at the same temperature, treated at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.956 g, 3.869 mmol), and stirred for additional 1 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 40 g cartridge; methanol / dichloromethane = 0 % to 5 %) to give the title compound methyl 3-fluoro-4-((N-(3-methoxyphenyl)- 1 , 1 -dio idothiomoφholine-4-carbo amido)methy 1) benzoate as white solid ( 1.1 10 g, 70.1 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2205-2207

92
N-(2-fluorophenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((N-(2-fluorophenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66.2%		[39381 A solution of N-(2-fluorophenyl)thiomorpholine-4-carboxamide 1 , 1 -dioxide (0.300 g, 1. 102 mmol) and sodium hydride (60.00 %, 0.048 g, 1 .212 mmol) in N.N-dimethylformamide (5 mL) was stirred at 0 C for 2 hr, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.299 g, 1 .2 12 mmol). The reaction mixture was stirred at the room temperature for additional 17 hr, quenched at the room temperature by the addition of water (2 mL, 10 min stirring ). Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove the solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The residue was chromatographed (Si02, 4 g cartridge; ethyl acetate / hexane = 0 % to 40 %) to give methyl 3-fluoro-4-((N-(2-fluorophenyl)-l , l-dioxidothiomoi holine-4-carboxamido)methyl)be nzoate as white solid (0.320 g, 66.2 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 3936-3938

93
N-(3-bromophenyl)-4-methylpiperazine-1-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(3-bromophenyl)-4-methylpiperazine-1-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75.4%		[ 1977] To a stirred solution of N-(3-bromophenyl)-4-methylpiperazine- l-carboxamide (5.280 g, 17.707 mmol) prepared in Step 1 in N,N-dimethylformamide (50 mL) was added at 0 C sodium hydride (60.00 %, 1.062 g, 26.561 mmol). The reaction mixture was stirred at the same temperature for 30 min, treated at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (4.812 g, 19.478 mmol), and stirred for additional 12 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried (anhydrous MgS04), filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give the title compound methyl 4-((N-(3-bromophenyl)-4-methylpiperazine- l-carboxamido)methyl)-3-fluorobenzoate as Yellow oil (6.200 g, 75.4 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 1975-1977

94
N-(4-bromophenyl)-4-methylpiperazine-1-carboxamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(4-bromophenyl)-4-methylpiperazine-1-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89.9%		[2735] To a stirred solution of N-(4-bromophenyl)-4-methylpiperazine- l -carboxamide (2.000 g, 6.707 mmol) in N.N-dimethylformamide (30 mL) was added at 0 C sodium hydride (60.00 %, 0.402 g, 10.061 mmol). The reaction mixture was stirred at the same temperature for 30 min. Methyl 4-(bromomethyl)-3-fluorobenzoate ( 1.823 g, 7.378 mmol) was added to the reaction mixture, and stirred at the room temperature for additional 5 hr. Then, water was added to the reaction mixture, followed by extraction ' with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 30 %) to give the title compound methyl 4-((N-(4-bromophenyl)-4-methylpiperazine- l-carboxamido)methyl)-3-fluorobenzoate as white solid (2.800 g, 89.9 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2733-2735

95
[ 128577-47-9 ]
[ 108-42-9 ]
methyl 4-(((3-chlorophenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.4%		[2008] A solution of 3-chloroaniline (0.498 mL, 4.703 mmol) and sodium hydride (60.00 %, 0.198 g, 4.938 mmol) in N,N-dimethylformamide ( 10 mL) was stirred at 0 C for 10 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> ( 1.278 g, 5.174 mmol)'. The reaction mixture was stirred at the same temperature for additional 1 hr, and quenched at the room temperature by the addition of saturated aqueous sodium bicarbonate solution ( 10 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The concentrate was purified arid - - concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 20 %) to give the title compound methyl 4-(((3-chlorophenyl)amino)methyl)-3-fluorobenzoate as orange oil ( 1.1 10 g, 80.4 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2006-2008

96
[ 20265-96-7 ]
[ 128577-47-9 ]
methyl 4-(((4-chlorophenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%		[2025] A solution of 4-chloroaniline hydrochloride (0.600 g, 3.658 mmol) and sodium hydride (60.00 %, 0.154 g, 3.841 mmol) in N,N-dimethylformamide ( 10 mL) was stirred at 0 C for 10 min, and mixed with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.994 g, 4.024 mmol). The reaction mixture was stirred at the same temperature for additional 1 hr, and quenched at the room temperature by the addition of saturated aqueous sodium bicarbonate solution ( 10 mL, 10 min stirring). Then, water was added to the reaction mixture, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 20 ) to give the title compound methyl 4-(((4-chlorophenyl)amino)methyl)-3-fluorobenzoate as pale yellow solid (0.623 g, 58.0 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2023-2025

97
N-(4-ethylphenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(4-ethylphenyl)-1,1-dioxidothiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.8%		[2429] To a stirred solution of N-(4-ethylphenyl)thiomoφholine-4-carboxamide 1 , 1 -dioxide ( 1.000 g, 3.542 mmol) prepared in Step 1 in N,N-dimethylformide (30 mL) was added at 0 C sodium hydride (60.00 %, 0.170 g, 4.250 mmol). The reaction mixture was stirred at the same temperature. Methyl 4-(bromomethyl)benzoate (0.884 g, 3.577 mmol) was added to the reaction mixture, and stirred for additional 3 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02. 40 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give the title compound methyl 4-((N-(4-ethylphenyl)- 1 , 1 -dioxidothiomo holine-4-carboxamido)methyl)-3-fluoroben zoate as white solid (1.300 g, 81.8 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2427-2429

98
N-(4-(trifluoromethoxy)phenyl)thiomorpholine-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((1,1-dioxido-N-(4-(trifluoromethoxy)phenyl)thiomorpholine-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99.3%		[2454] To a stirred solution of N- (4-(trifluoromethoxy)phenyl)thiomoipholine-4-carboxamide 1 , 1 -dioxide ( 1.000 g, 2.956 mmol) prepared in Step 1 in N,N-dimethylformide (30 mL) was added at 0 C sodium hydride (60.00 %, 0.142 g, 3.547 mmol). The reaction mixture was stirred at the same temperature. Methyl 4-(bi momethyl)-3-fluorobenzoate (0.738 g, 2.986 mmol) was added to the reaction mixture, and stirred at the room temperature for additional 3 hr-. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 40 g cartridge; ethyl acetate / hexane = 0 % to 50 ) to give the title compound methyl 4-(( 1 , l-dioxido-N-(4-(trifluoromethoxy)phenyl)thiomo holine-4-carboxamido)methyl )-3-fluorobenzoate as colorless oil ( 1.480 g, 99.3 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2452-2454

99
[ 128577-47-9 ]
[ 1535-73-5 ]
methyl 3-fluoro-4-(((3-(trifluoromethoxy)phenyl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65.8%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 16h;	[2598] A solution of 3-(trifluoromethoxy)aniline (0.500 g, 2.823 mmol) and N.N-diisopropylethylamine (0.739 mL, 4.234 mmol) in acetonitrile ( 10 mL) was mixed at the room temperature with methyl 4-(bromomethyl)-3-fliiorobenzoate (0.704 g, 2.851 mmol). The reaction mixture was stirred at the same temperature for 16 hr, concentrated under the reduced pressure to remove the solvent, and water was added to the concentrate, followed by extraction with dichloromethane. The bi-phasic mixture was passed through a plastic frit to remove solid residues and aqueous layer, and the organic layer collected was concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 24 g cartridge; ethyl acetate / hexane = 0 % to 10 %) to give the title compound methyl 3- fluoro-4-(((3-(trifluoromethoxy)phenyl)amino)methyl)benzoate as white solid (0.638 g, 65.8 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2596-2598

100
[ 367-21-5 ]
[ 128577-47-9 ]
methyl 4-(((3-chloro-4-fluorophenyl)amino)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88.1%	With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 18h;	[5042] A solution of 3-chloiO-4-fluoroaniline ( 0.500 g, 3.435 mmol), methyl 4-(bromoniethyl)-3-fluoiObenzoate (0.934 g. 3.779 mmol) and Ν,Ν-diisopropylethylamine ( 1 .197 mL, 6.870 mmol) in acetonitrile (5 mL) was stined at the room temperature for 1 8 hr. Then, water was added to the reaction mixture, fol lowed by extraction with dichloiomethane. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04. filtered, and concentrated i n vacuo. The concentrate was purified and concentrated by column chromatography (Si02. 24 g cartridge; ethyl acetate / hexane = 0 % to 30 % ) to give methyl 4-(((3-chloro-4-fluorophenyl)amino)methyl)-3-fluorobenzoate as orange solid (0.943 g, 88. 1 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 5040-5042

101
[ 135855-62-8 ]
[ 128577-47-9 ]
methyl 3-fluoro-4-(((1-methyl-1H-indazol-6-yl)amino)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	[2805] A solution of 1 -methyl- lH-indol-6-amine (0.300 g, 1.214 mmol) and N,N-diisopropylethylamine (0.254 mL, 1.457 mmol) in N,N-dimethylformide (3 mL) was mixed at the room temperature with <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.303 g, 1.226 mmol). The reaction mixture was stirred at the same temperature for 16 hr. Then, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, dried with anhydrous MgS04, filtered, and concentrated in vacuo. The concentrate was purified and concentrated by column chromatography (Si02, 12 g cartridge; ethyl acetate / hexane = 0 % to 50 %) to give the title compound methyl 3-fluoro-4-((( l -methyl- l H-indazol-6-yl)amino)methyl)benzoate as white solid (0.381 g, 100.0 %).

Reference： [1]Patent: WO2017/23133,2017,A2 .Location in patent: Paragraph 2803-2805

102
[ 49716-18-9 ]
[ 128577-47-9 ]
methyl 4-((6-chloro-3,4-dihydroquinolin-1(2H)-yl)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
30%	With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 5h;	To a round bottom flask charged with compound 3-1 (120 mg, 0.5 mmol) and 6-chloro- l,2,3,4-tetrahydroquinoline (55 mg, 0.32 mmol) in DMF (3 mL) was added K2CO3 (88 mg, 0.64 mmol). The resulting mixture was allowed to stir for 5 h at 80 C. The mixture was cooled to room temperature and after addition of water (15 mL) extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (0 - 80% EtOAc/hexanes) to afford as colorless oil (50 mg, 30%). 1H NMR (400 MHz, CDC13) delta 7.77 - 7.68 (m, 2H), 7.24 (dd, = 10.9, 4.5 Hz, 1H), 6.95 (d, = 2.5 Hz, 1H), 6.89 (dd, = 8.7, 2.5 Hz, 1H), 6.28 (d, = 8.7 Hz, 1H), 4.52 (s, 2H), 3.91 (s, 3H), 3.45 - 3.28 (m, 2H), 2.79 (t, = 6.3 Hz, 2H), 2.08 - 1.95 (m, 2H). 13C NMR (100 MHz, CDCI3) delta 165.9 (d, = 2.8 Hz), 160.5 (d, = 244.9 Hz), 143.6, 130.8 (d, = 7.0 Hz), 130.7 (d, = 14.4 Hz), 128.7, 128.0 (d, = 4.5 Hz), 126.9, 125.5 (d, = 3.3 Hz), 124.1, 120.9, 116. 5 (d, = 23.1 Hz), 111.8, 52.3, 50.1, 49. 5 (d, = 4.3 Hz), 28.0, 22.2.

Reference： [1]Patent: WO2017/142883,2017,A1 .Location in patent: Paragraph 0176; 0178

103
tert-butyl 3-((3-fluorophenyl)carbamoyl)azetidine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 3-((2-fluoro-4-(methoxycarbonyl)benzyl)(3-fluorophenyl)carbamoyl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81.4%		Tert-butyl 3-((3-fluorophenyl)carbamoyl)azetidine-1-carboxylate (0.550 g, 1.869 mmol) was dissolved in tetrahydrofuran (80 mL), and sodium hydride (60.00%, 0.149 g, 3.737 mmol) was added slowly to the solution while the temperature was maintained at 0C. The mixture was stirred for 20 minutes, and then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (0.508 g, 2.056 mmol) was added thereto. The reaction mixture was further stirred at 50C for 12 hours and cooled to room temperature. Then, water (20 mL) was added to the reaction mixture at 0C, followed by stirring for 5 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate/hexane = from 5% to 50%) and concentrated to give the title compound (0.700 g, 81.4%) as a white solid.

Reference： [1]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0280; 0281

104
[ 128577-47-9 ]
[ 162881-76-7 ]
tert-butyl 4-((2-fluoro-4-(methoxycarbonyl)benzyl)(phenyl)carbamoyl)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84.1%		Tert-butyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (2.000 g, 6.571 mmol) synthesized in step 1 of Example 9 was dissolved in tetrahydrofuran (80 mL), and sodium hydride (60.00 %, 0.526 g, 13.141 mmol) was added slowly to the solution while the temperature was maintained at 0C. The mixture was stirred for 20 minutes, and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.948 g, 7.885 mmol) was added thereto, followed by additional stirring at 50C for 12 hours. The reaction mixture was cooled down to room temperature, and then water (20 mL) was added to the reaction mixture at 0C, followed by stirring for 5 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate/hexane = from 5% to 50%) and concentrated to give the title compound (2.600 g, 84.1%) as colorless oil.

Reference： [1]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0174; 0175

105
2-(benzyloxy)-N-(3-chloro-4-fluorophenyl)acetamide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((2-(benzyloxy)-N-(3-chloro-4-fluorophenyl)acetamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60.5%	With calcium carbonate; In tetrahydrofuran; at 0 - 20℃; for 18h;	2-(Benzyloxy)-N-(4-chloro-3-fluorophenyl)acetamide (1.880 g, 6.401 mmol), synthesized in step 1, and calcium carbonate (1.327 g, 9.601 mmol) were dissolved in tetrahydrofuran (50 mL) at 0C, and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.898 g, 7.681 mmol) was added to the solution. The mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 40 g cartridge; ethyl acetate/hexane = from 0% to 50%) and concentrated to give the title compound (1.780 g, 60.5%) as yellow oil.

Reference： [1]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0404; 0405

106
N-(3-chloro-4-fluorophenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide [ No CAS ]
[ 128577-47-9 ]
methyl 4-((N-(3-chloro-4-fluorophenyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-carboxamido)methyl)-3-fluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80.3%	With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 18h;	N-(3-chloro-4-fluorophenyl)tetrahydro-2H-thiopyran-4-carboxamide 1,1-dioxide (1.000 g, 3.271 mmol), synthesized in step 1, and sodium hydride (60.00 %, 0.262 g, 6.541 mmol) were dissolved in N,N-dimethylformamide (50 mL) at room temperature, and <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (1.212 g, 4.906 mmol) was added to the solution. The mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 12 g cartridge; ethyl acetate/hexane = from 0% to 100%) and concentrated to give the title compound (1.240 g, 80.3%) as a white solid.

Reference： [1]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0430; 0431

107
tert-butyl 3-(phenylcarbamoyl)azetidine-1-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 3-((2-fluoro-4-(methoxycarbonyl)benzyl)(phenyl)carbamoyl)azetidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87.4%		Tert-butyl 3-(phenylcarbamoyl)azetidine-1-carboxylate (2.000 g, 7.237 mmol) synthesized in step 1 of Example 8 was dissolved in tetrahydrofuran (80 mL), and sodium hydride (60.00 %, 0.579 g, 14.475 mmol) was added slowly to the solution while the temperature was maintained at 0C. The mixture was stirred for 20 minutes, and then <strong>[128577-47-9]methyl 4-(bromomethyl)-3-fluorobenzoate</strong> (2.146 g, 8.685 mmol) was added thereto, followed by additional stirring at 50C for 12 hours. Then, the reaction mixture was cooled down to room temperature, and water (20 mL) was added to the reaction mixture at 0C, followed by stirring for 5 minutes. After completion of the reaction, water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate anhydrous, filtered, and then concentrated under reduced pressure. The concentrate was purified by column chromatography (SiO2, 80 g cartridge; ethyl acetate/hexane = from 5% to 50%) and concentrated to give the title compound (2.800 g, 87.4%) as colorless oil.

Reference： [1]Patent: EP3330259,2018,A1 .Location in patent: Paragraph 0223; 0224

108
4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidin-1-ium 2,2,2-trifluoroacetate [ No CAS ]
[ 128577-47-9 ]
methyl 3-fluoro-4-((4-((1-(4-fluorophenyl)-4-oxo-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)methyl)-4-hydroxypiperidin-1-yl)methyl)benzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	General procedure: A mixture of 5 (88 mg, 0.2 mmol), benzyl bromide (36 µL, 0.3 mmol) and K2CO3 (102 mg, 0.74 mmol) in DMF (4 mL) was stirred at ambient temperature for 2 h. The mixture was diluted with water (9 mL) and extracted with ethyl acetate (6 mL × 3). The combined organic layers were washed with water (10 mL × 3) and brine (10 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (silica gel, DCM : methanol = 20 : 1) to give compound L14 (27 mg, 31% yield) as a light yellow solid.

Reference： [1]European Journal of Medicinal Chemistry,2020,vol. 199

109
tert-butyl 9-[[(3-hydroxyphenyl)(phenyl)methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate [ No CAS ]
[ 128577-47-9 ]
tert-butyl 9-[[[[3-[[2-fluoro-4-(methoxycarbonyl)benzyl]oxy]phenyl](phenyl)methyl]carbamoyl]oxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;	9-[[(3-hydroxyphenyl)-phenyl-methyl]carbamoyloxy]-3-oxa-7-azabicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (Intermediate 2-a) (0.205g, 0.438mmol) was dissolved in 10ml DMF, and <strong>[128577-47-9]4-(bromomethyl)-3-fluorobenzoic acid methyl ester</strong> (0.163g, 0.656mmol) and potassium carbonate (0.182 g, 1.31 mmol), the reaction was stirred at room temperature overnight. Concentrate under reduced pressure to remove DMF. The residue was dissolved in 20 ml of ethyl acetate, 20 ml of water was added and stirred, and the layers were separated by standing. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, and then saturated brine (40 mL ) Wash, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate (v/v)=8:1-4:1) to obtain 9-[ [[[3-[[2-Fluoro-4-(methoxy-carbonyl)benzyl]oxy]phenyl]phenyl]methyl]carbamoyl]oxy]-3-oxa-7- Azabicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (18a) (0.243g, yield: 88%).

Reference： [1]Patent: CN111574529,2020,A .Location in patent: Paragraph 0939; 0942-0946

Recommend Products

Same Skeleton Products

Related Products

Isomers

Technical Information

• Acid-Catalyzed α -Halogenation of Ketones • Acidity of Phenols • Acyl Group Substitution • Addition of a Hydrogen Halide to an Internal Alkyne • Alcohols Convert Acyl Chlorides into Esters • Alcohols from Haloalkanes by Acetate Substitution-Hydrolysis • Alcohols React with PX3 • Alcoholysis of Anhydrides • Alkyl Halide Occurrence • Alkylation of an Alkynyl Anion • Amines Convert Esters into Amides • An Alkane are Prepared from an Haloalkane • Benzylic Halogenation • Benzylic Oxidation • Birch Reduction • Birch Reduction of Benzene • Blanc Chloromethylation • Bouveault-Blanc Reduction • Catalytic Hydrogenation • Chan-Lam Coupling Reaction • Claisen Condensations Produce β-Dicarbonyl Compounds • Claisen Condensations Produce β-Dicarbonyl Compounds • Complete Benzylic Oxidations of Alkyl Chains • Complete Benzylic Oxidations of Alkyl Chains • Complex Metal Hydride Reductions • Conjugate Additions of p-Benzoquinones • Conversion of Amino with Nitro • Convert Esters into Aldehydes Using a Milder Reducing Agent • Convert Haloalkanes into Alcohols by SN2 • Decarboxylation of 3-Ketoacids Yields Ketones • Decomposition of Arenediazonium Salts to Give Phenols • Deprotection of Cbz-Amino Acids • Deprotonation of Methylbenzene • Diazo Coupling • Directing Electron-Donating Effects of Alkyl • Electrophilic Chloromethylation of Polystyrene • Electrophilic Substitution of the Phenol Aromatic Ring • Ester Cleavage • Ester Hydrolysis • Etherification Reaction of Phenolic Hydroxyl Group • Friedel-Crafts Alkylation of Benzene with Acyl Chlorides • Friedel-Crafts Alkylation of Benzene with Carboxylic Anhydrides • Friedel-Crafts Alkylation of Benzene with Haloalkanes • Friedel-Crafts Alkylation Using Alkenes • Friedel-Crafts Alkylations of Benzene Using Alkenes • Friedel-Crafts Alkylations Using Alcohols • Friedel-Crafts Reaction • General Reactivity • Grignard Reaction • Grignard Reagents Transform Esters into Alcohols • Groups that Withdraw Electrons Inductively Are Deactivating and Meta Directing • Halogenation of Alkenes • Halogenation of Benzene • Halogenation of Phenols • Hantzsch Pyridine Synthesis • Hiyama Cross-Coupling Reaction • Hydrogenation to Cyclohexane • Hydrogenolysis of Benzyl Ether • Ketones Undergo Mixed Claisen Reactions to Form β-Dicarbonyl Compounds • Kinetics of Alkyl Halides • Kolbe-Schmitt Reaction • Kumada Cross-Coupling Reaction • Methylation of Ammonia • Methylation of Ammonia • Nitration of Benzene • Nucleophilic Aromatic Substitution • Nucleophilic Aromatic Substitution with Amine • Oxidation of Alkyl-substituted Benzenes Gives Aromatic Ketones • Oxidation of Phenols • Pechmann Coumarin Synthesis • Preparation of Aldehydes and Ketones • Preparation of Alkylbenzene • Reactions of Alkyl Halides with Reducing Metals • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Dihalides • Reactions with Organometallic Reagents • Reduction of an Ester to an Alcohol • Reduction of an Ester to an Aldehyde • Reductive Removal of a Diazonium Group • Reimer-Tiemann Reaction • Reverse Sulfonation——Hydrolysis • Specialized Acylation Reagents-Carbodiimides and Related Reagents • Stille Coupling • Substitution and Elimination Reactions of Alkyl Halides • Sulfonation of Benzene • Suzuki Coupling • The Acylium Ion Attack Benzene to Form Phenyl Ketones • The Claisen Rearrangement • The Cycloaddition of Dienes to Alkenes Gives Cyclohexenes • The Nitro Group Conver to the Amino Function • Transesterification • Vilsmeier-Haack Reaction • Williamson Ether Syntheses

Historical Records

Related Functional Groups of
[ 128577-47-9 ]

Fluorinated Building Blocks

[ 85070-57-1 ]

Methyl 4-(bromomethyl)-2-fluorobenzoate

Similarity: 0.97

[ 709-45-5 ]

Methyl 5-(bromomethyl)-2-fluorobenzoate

Similarity: 0.95

[ 87808-48-8 ]

Methyl 3-fluoro-4-methylbenzoate

Similarity: 0.86

[ 937636-18-5 ]

Methyl 3-fluoro-4-(hydroxymethyl)benzoate

Similarity: 0.85

[ 85070-58-2 ]

Methyl 2-fluoro-4-formylbenzoate

Similarity: 0.84

Aryls

[ 85070-57-1 ]

Methyl 4-(bromomethyl)-2-fluorobenzoate

Similarity: 0.97

[ 709-45-5 ]

Methyl 5-(bromomethyl)-2-fluorobenzoate

Similarity: 0.95

[ 87808-48-8 ]

Methyl 3-fluoro-4-methylbenzoate

Similarity: 0.86

[ 937636-18-5 ]

Methyl 3-fluoro-4-(hydroxymethyl)benzoate

Similarity: 0.85

[ 85070-58-2 ]

Methyl 2-fluoro-4-formylbenzoate

Similarity: 0.84

Bromides

[ 85070-57-1 ]

Methyl 4-(bromomethyl)-2-fluorobenzoate

Similarity: 0.97

[ 709-45-5 ]

Methyl 5-(bromomethyl)-2-fluorobenzoate

Similarity: 0.95

[ 57381-59-6 ]

Methyl 5-bromo-2-fluorobenzoate

Similarity: 0.83

[ 1206680-27-4 ]

Methyl 4-bromo-2-fluoro-3-methylbenzoate

Similarity: 0.83

[ 334792-52-8 ]

Methyl 3-bromo-5-fluorobenzoate

Similarity: 0.82

Esters

[ 85070-57-1 ]

Methyl 4-(bromomethyl)-2-fluorobenzoate

Similarity: 0.97

[ 709-45-5 ]

Methyl 5-(bromomethyl)-2-fluorobenzoate

Similarity: 0.95

[ 87808-48-8 ]

Methyl 3-fluoro-4-methylbenzoate

Similarity: 0.86

[ 937636-18-5 ]

Methyl 3-fluoro-4-(hydroxymethyl)benzoate

Similarity: 0.85

[ 85070-58-2 ]

Methyl 2-fluoro-4-formylbenzoate

Similarity: 0.84

Benzyl Bromides

[ 85070-57-1 ]

Methyl 4-(bromomethyl)-2-fluorobenzoate

Similarity: 0.97

[ 709-45-5 ]

Methyl 5-(bromomethyl)-2-fluorobenzoate

Similarity: 0.95

[ 2417-73-4 ]

Methyl 2-bromomethylbenzoate

Similarity: 0.76

[ 1129-28-8 ]

Methyl 3-(bromomethyl)benzoate

Similarity: 0.76

[ 2417-72-3 ]

Methyl 4-(bromomethyl)benzoate

Similarity: 0.76

Purity	Size	Price	VIP Price	USA Stock *0-1 Day	Global Stock *5-7 Days	Quantity
{[ item.p_purity ]}	{[ item.pr_size ]}	Inquiry	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ getRatePrice(item.pr_usd, 1,1,item.pr_is_large_size_no_price) ]}	Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate,item.pr_is_large_size_no_price) ]}	{[ item.pr_usastock ]}		{[ item.pr_chinastock ]}	{[ item.pr_remark ]}

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
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. 128577-47-9 ] {[proInfo.proName]}

Quality Control of [ 128577-47-9 ]

Related Doc. of [ 128577-47-9 ]

Product Details of [ 128577-47-9 ]

Calculated chemistry of [ 128577-47-9 ] Expand+

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 128577-47-9 ]

Application In Synthesis of [ 128577-47-9 ]

[ 128577-47-9 ] Synthesis Path-Upstream 1~15

[ 128577-47-9 ] Synthesis Path-Downstream 1~109

Technical Information

Related Functional Groups of [ 128577-47-9 ]

Fluorinated Building Blocks

Aryls

Bromides

Esters

Benzyl Bromides

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 128577-47-9 ]