[ CAS No. 22510-08-3 ] {[proInfo.proName]}

Name: 22510-08-3|2-Fluoro-5-nitrophenol|98%
Brand: Ambeed
SKU: A348054
Price: 5.0 USD
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Quality Control of [ 22510-08-3 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 22510-08-3 ]

CAS No. :	22510-08-3	MDL No. :	MFCD09054718
Formula :	C₆H₄FNO₃	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	WFRLFZAMCVAQLN-UHFFFAOYSA-N
M.W :	157.10	Pubchem ID :	23498100
Synonyms :

Calculated chemistry of [ 22510-08-3 ]

Physicochemical Properties

Num. heavy atoms :	11
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	1.0
Molar Refractivity :	37.24
TPSA :	66.05 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.75 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.13
Log Po/w (XLOGP3) :	2.12
Log Po/w (WLOGP) :	1.86
Log Po/w (MLOGP) :	0.7
Log Po/w (SILICOS-IT) :	-0.35
Consensus Log Po/w :	1.09

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.49
Solubility :	0.512 mg/ml ; 0.00326 mol/l
Class :	Soluble
Log S (Ali) :	-3.14
Solubility :	0.114 mg/ml ; 0.000727 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-1.47
Solubility :	5.34 mg/ml ; 0.034 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	2.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.8

Safety of [ 22510-08-3 ]

Signal Word:	Danger	Class:	9
Precautionary Statements:	P261-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352-P305+P351+P338+P310-P333+P313-P391-P501	UN#:	3077
Hazard Statements:	H302-H315-H317-H318-H410	Packing Group:	Ⅲ
GHS Pictogram:

Application In Synthesis of [ 22510-08-3 ]

* 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 [ 22510-08-3 ]
Downstream synthetic route of [ 22510-08-3 ]

[ 22510-08-3 ] Synthesis Path-Upstream 1~8

1
[ 22510-08-3 ]
[ 74-88-4 ]
[ 454-16-0 ]

Yield	Reaction Conditions	Operation in experiment
73.5%	Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: at 20℃; for 2 h;	To a solution of 2-fluoro-5-nitrophenol (5.0 g, 31.84 mmol) in DMF(50 mL) was added K2C03 (5.27 g, 38.1 mmol), after stirring at room temperature for 15 mm was added methyliodide (3 mL, 47.7 mmol) and the reaction mixture stirred at room temperature for 2h. Reaction mixture was poured into ice water, separated solids were filtered, washed the solid thoroughly with water and vacuum dried to afford an off white solid (4.0 g, 73.5percent). 1H NMR (300 MHz, CDC13) 7.89-7.84 (m, 2H), 7.25-7. 17 (m, 1H), 3.98 (s, 3H).
73.5%	Stage #1: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25 h; Stage #2: at 20℃; for 2 h;	Step-a Synthesis of 1-fluoro-2-methoxy-4-nitrobenzene To a solution of 2-fluoro-5-nitrophenol (5.0 g, 31.84 mmol) in DMF (50 mL) was added K₂CO₃ (5.27 g, 38.1 mmol), after stirring at room temperature for 15 min was added methyl iodide (3 mL, 47.7 mmol) and the reaction mixture stirred at room temperature for 2 h. Reaction mixture was poured into ice water, separated solids were filtered, washed the solid thoroughly with water and vacuum dried to afford an off white solid (4.0 g, 73.5percent). ¹H NMR (300 MHz, CDCl3): 7.89-7.84 (m, 2H), 7.25-7.17 (m, 1H), 3.98 (s, 3H).

Reference： [1] Patent: WO2015/104653, 2015, A1, . Location in patent: Page/Page column 57
[2] Patent: US2016/368906, 2016, A1, . Location in patent: Paragraph 0229
[3] Patent: US2014/57911, 2014, A1, . Location in patent: Paragraph 0635

2
[ 454-16-0 ]
[ 22510-08-3 ]

Yield	Reaction Conditions	Operation in experiment
30%	Stage #1: With boron tribromide In dichloromethane at -10 - 0℃; for 6 h; Stage #2: With water In dichloromethaneCooling with ice	116 ml (116 mmol) of boron tribromide (1 molar solution in dichloromethane) are added dropwise at -10° C. over a period of 1 h to a solution of 5.00 g (29.2 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene at such a rate that the temperature does not exceed -5° C. The solution is left at 0° C. for 5 h, then added slowly to 600 ml of ice-water and diluted with 100 ml of ethyl acetate. After phase separation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (10:1 cyclohexane/ethyl acetate). This affords 1.45 g (30percent of theory) of the desired compound. ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): 10.99 (s, 1H), 7.78 (dd, 1H), 7.73 (ddd, 1H), 7.44 (dd, 1H). HPLC (Method 1): R_t=3.60 min. MS (DCI, m/z): 174 (M+NH₄)⁺.

Reference： [1] Patent: US2010/298293, 2010, A1, . Location in patent: Page/Page column 39

3
[ 369-36-8 ]
[ 22510-08-3 ]

Reference： [1] Patent: US5658952, 1997, A,
[2] Patent: US4044049, 1977, A,

4
[ 67-63-0 ]
[ 360053-70-9 ]
[ 22510-08-3 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2, 2001, # 8, p. 1340 - 1345

5
[ 67-63-0 ]
[ 161518-24-7 ]
[ 22510-08-3 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 2, 2001, # 8, p. 1340 - 1345

6
[ 22510-08-3 ]
[ 100367-48-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24 h;	At room temperature, 2-fluoro-5-nitrophenol (1.0 g, 6.37 mmol) Was dissolved in methanol (25 mL) 10percent by weight palladium on charcoal (Pd / C) (50 mg) was added. The reaction mixture was stirred under hydrogen gas for 24 hours, 10percent by weight of palladium / charcoal was filtered through celite. The filtrate was concentrated in vacuo to give the desired compound (809 mg, 99percent yield) as a solid
72.4%	With 5% Pd/C; hydrogen In methanol at 20℃; for 6 h;	3.14 g (20 mmol) of 2-fluoro-5-nitrophenol (I1) was dissolved in 20 mL of CH3OH, 0.2 g (7percent) of Pd / C (chemical name: palladium on carbon) Through hydrogen, Stirred at room temperature for 6 h, TLC detection reaction is complete. Reaction solution suction filter, The filtrate was evaporated to dryness to a black solid, Column chromatography separation, Petroleum ether-ethyl acetate gradient elution, A light brown solid, 1.84 g, was obtained in a yield of 72.4percent. To confirm that 2-fluoro-5-aminophenol, Compounds Code I2.

Reference： [1] Patent: KR2017/31307, 2017, A, . Location in patent: Paragraph 0197-0199
[2] RSC Advances, 2018, vol. 8, # 55, p. 31803 - 31821
[3] Patent: CN104211632, 2016, B, . Location in patent: Paragraph 0075; 0076
[4] Patent: WO2007/45861, 2007, A1, . Location in patent: Page/Page column 66-67

7
[ 75-03-6 ]
[ 22510-08-3 ]
[ 1093656-34-8 ]

Yield	Reaction Conditions	Operation in experiment
89%	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5 h;	1.00 g (6.37 mmol) of example 88A are dissolved in 15 ml of DMF and admixed with 1.76 g (12.7 mmol) of potassium carbonate. Subsequently, 1.19 g (7.64 mmol) of iodoethane are added and the mixture is stirred at RT. After 1.5 h, it is admixed with 100 ml each of toluene and water, the phases are separated and the aqueous phase is extracted twice with 150 ml each time of toluene. The combined organic phases are washed with saturated aqueous sodium hydrogencarbonate solution and then dried over sodium sulfate. The mixture is freed of the solvent under reduced pressure, and the resulting solid is dried under high vacuum. This affords 1.06 g (89percent of theory) of the desired product. ¹H NMR (400 MHz, DMSO-d₆, δ/ppm): δ=7.95 (dd, 1H), 7.89 (ddd, 1H), 7.52 (dd, 1H), 4.25 (q, 2H), 1.38 (t, 3H). GC/MS (Method 9): R_t=6.42 min. MS (EI-pos): m/z=185 (M+H)⁺.

Reference： [1] Patent: US2010/298293, 2010, A1, . Location in patent: Page/Page column 40

8
[ 22510-08-3 ]
[ 1159825-08-7 ]

Reference： [1] Patent: US2014/57911, 2014, A1,

[ 22510-08-3 ] Synthesis Path-Downstream 1~88

1
[ 6482-24-2 ]
[ 22510-08-3 ]
[ 221198-59-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 70℃; for 4h;	A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (10.0 g , 63.7 mmol), 2-bromoethyl methyl ether (15.0 g, 107.9 mmol) and potassium carbonate (26.5 g, 192 mmol) in 40 mL of N, N'-dimethylformamide is heated at 70 C. for 4 hours then cooled to room temperature and poured onto ice. The solid is collected by filtration washed with water and dried to provide 12.0 g of 2-fluoro-1-(2-methoxyethoxy)-4-nitrobenzene, mp 62-63 C. [0225] MS 216.02 (M+H)+[0226] Analysis for C9H10FNO4 [0227] Calcd: C, 50.24; H, 4.68; N, 6.51. [0228] Found: C, 50.24; H, 4.67; N, 6.49.

Reference： [1]Patent: US2003/212276,2003,A1 .Location in patent: Page/Page column 13

2
[ 369-36-8 ]
[ 22510-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium nitrite; In sulfuric acid; water;	EXAMPLE 1 2-(2-Fluoro-5-nitrophenyloxy)tetrahydropyran 2-Fluoro-5-nitroaniline (3.2 g) is dissolved in 30 mL H2 SO4 and 80 mL H2 O is mixed with 1.5 g NaNO2 in water below 5 C. After 10 minutes the mixture is filtered, the filtrate added to 400 mL of boiling 50% H2 SO4, and the mixture heated for 15 min., then cooled and the phenol thus obtained, filtered, washed and recrystallized (hexane) to yield 2-fluoro-5-nitrophenol.
	With sulfuric acid; sodium nitrite; In water;	A. 2-Fluoro-5-nitrophenol A solution of 3.2 grams of 2-fluoro-5-nitroaniline, sulfuric acid (3 cc., d 1.84) and 8 ml. of water is stirred into a solution of 1.5 grams of sodium nitrite in water, maintained below 5 C. After 10 minutes, the excess nitrous acid is destroyed by urea, the reaction mixture filtered, and the filtrate added to 40 ml. of boiling 50% sulfuric acid. After complete addition, the mixture is boiled an additional 15 minutes, cooled, and the separated phenol filtered and washed with water. It is then purified by recrystallization from hexane.

Reference： [1]Patent: US5658952,1997,A
[2]Patent: US4044049,1977,A

3
[ 22510-08-3 ]
[ 100367-48-4 ]

Yield	Reaction Conditions	Operation in experiment
99%	With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; for 24h;	At room temperature, <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (1.0 g, 6.37 mmol) Was dissolved in methanol (25 mL) 10% by weight palladium on charcoal (Pd / C) (50 mg) was added. The reaction mixture was stirred under hydrogen gas for 24 hours, 10% by weight of palladium / charcoal was filtered through celite. The filtrate was concentrated in vacuo to give the desired compound (809 mg, 99% yield) as a solid
72.4%	With 5% Pd/C; hydrogen; In methanol; at 20℃; for 6h;	3.14 g (20 mmol) of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (I1) was dissolved in 20 mL of CH3OH, 0.2 g (7%) of Pd / C (chemical name: palladium on carbon) Through hydrogen, Stirred at room temperature for 6 h, TLC detection reaction is complete. Reaction solution suction filter, The filtrate was evaporated to dryness to a black solid, Column chromatography separation, Petroleum ether-ethyl acetate gradient elution, A light brown solid, 1.84 g, was obtained in a yield of 72.4%. To confirm that 2-fluoro-5-aminophenol, Compounds Code I2.
	With hydrogen;5% palladium over charcoal; In methanol; toluene; under 38002.6 Torr;	To a solution of <strong>[22510-08-3]1-fluoro-2-(methyloxy)-4-nitrobenzene</strong> (32.6g) (for example as prepared for Intermediate 46) in methanol (300ml) in an autoclave was added 5% palladium on carbon (1g) in toluene (2ml). The autoclave was purged with argon, then stirred under 50 atmospheres of hydrogen overnight. The mixture was filtered through celite and the filtrate evaporated. The residue was dissolved in ethyl acetate (250ml), then filtered. The filtrate was extracted with 2M hydrochloric acid (200ml). The aqueous phase was made basic by the addition of 2M sodium hydroxide (300ml) and extracted with ethyl acetate (250ml). The organic layer was washed with water (100ml) and brine (100ml) (with filtering), further washed with brine (200ml) and evaporated to give the title compound as a red liquid (18.3g).NMR (300 MHz, CDCI3) delta 6.84 (J = 9,11 Hz; lH,dd), delta 6.30 CLH,m), delta 6.15 (J = 3,9Hz; lH,dt), delta 3.82 (3H,s).

Reference： [1]Patent: KR2017/31307,2017,A .Location in patent: Paragraph 0197-0199
[2]RSC Advances,2018,vol. 8,p. 31803 - 31821
[3]Patent: CN104211632,2016,B .Location in patent: Paragraph 0075; 0076
[4]Patent: WO2007/45861,2007,A1 .Location in patent: Page/Page column 66-67

4
2-methoxy-4-nitrobenzenediazonium tetrafluoroborate [ No CAS ]
[ 22510-08-3 ]

Yield	Reaction Conditions	Operation in experiment
	With silica gel;	2-Methoxy-4-nitrobenzenediazonium tetrafluoroborate (179.3g) (for example as prepared for Intermediate 45) and sand (15Og) were placed in a 11 round-bottomed-flask (RBF) that was fitted with a gas exhaust connected to a gas inlet which was placed into water (200ml) in a 3-necked 11 RBF that was cooled in ice. The exhaust from this flask led to a second 3-necked 500 ml RBF containing water (100ml). The flask containing Intermediate 45 was heated with a heat-gun. The mixture was allowed to cool. The flask containing the sand was extracted with diethyl ether (500ml) and ethereal extracts combined with the other flask contents. The mixture was filtered and the aqueous layer separated. The aqueous layer was extracted with diethylether (500ml). The combined organic extracts were evaporated and the residue solidified on standing to give the title compound as a red solid (29.8g). NMR: (300 MHz, CDCI3) delta 7.85 (2H1ITi)1 delta 7.20 (J = 8Hz; 1 H,t), delta 3.98 (3H,s).

Reference： [1]Patent: WO2007/45861,2007,A1 .Location in patent: Page/Page column 65-66

5
[ 75-03-6 ]
[ 22510-08-3 ]
[ 1093656-34-8 ]

Yield	Reaction Conditions	Operation in experiment
95.59%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	Dissolve <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (500mg, 3.18mmol) and potassium carbonate (878mg, 6.37mmol) in DMF (8mL), add iodoethane (595mg, 3.82mmol) to react at room temperature for 1.5h, the raw materials disappear . The reaction solution was poured into ice water to precipitate a solid, which was filtered and dried to obtain 563 mg of an off-white solid, the yield was 95.59%, and the melting point was 63-64 C.
89%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 1.5h;	1.00 g (6.37 mmol) of example 88A are dissolved in 15 ml of DMF and admixed with 1.76 g (12.7 mmol) of potassium carbonate. Subsequently, 1.19 g (7.64 mmol) of iodoethane are added and the mixture is stirred at RT. After 1.5 h, it is admixed with 100 ml each of toluene and water, the phases are separated and the aqueous phase is extracted twice with 150 ml each time of toluene. The combined organic phases are washed with saturated aqueous sodium hydrogencarbonate solution and then dried over sodium sulfate. The mixture is freed of the solvent under reduced pressure, and the resulting solid is dried under high vacuum. This affords 1.06 g (89% of theory) of the desired product. 1H NMR (400 MHz, DMSO-d6, delta/ppm): delta=7.95 (dd, 1H), 7.89 (ddd, 1H), 7.52 (dd, 1H), 4.25 (q, 2H), 1.38 (t, 3H). GC/MS (Method 9): Rt=6.42 min. MS (EI-pos): m/z=185 (M+H)+.

Reference： [1]Patent: CN110483366,2019,A .Location in patent: Paragraph 1478-1483
[2]Patent: US2010/298293,2010,A1 .Location in patent: Page/Page column 40

6
[ 454-16-0 ]
[ 22510-08-3 ]

Yield	Reaction Conditions	Operation in experiment
30%		116 ml (116 mmol) of boron tribromide (1 molar solution in dichloromethane) are added dropwise at -10° C. over a period of 1 h to a solution of 5.00 g (29.2 mmol) of 1-fluoro-2-methoxy-4-nitrobenzene at such a rate that the temperature does not exceed -5° C. The solution is left at 0° C. for 5 h, then added slowly to 600 ml of ice-water and diluted with 100 ml of ethyl acetate. After phase separation, the aqueous phase is extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. After filtration, the solvents are removed under reduced pressure. The residue is purified by chromatography on silica gel (10:1 cyclohexane/ethyl acetate). This affords 1.45 g (30percent of theory) of the desired compound. 1H NMR (400 MHz, DMSO-d6, delta/ppm): 10.99 (s, 1H), 7.78 (dd, 1H), 7.73 (ddd, 1H), 7.44 (dd, 1H). HPLC (Method 1): Rt=3.60 min. MS (DCI, m/z): 174 (M+NH4)+.

Reference： [1]Patent: US2010/298293,2010,A1 .Location in patent: Page/Page column 39

7
[ 22510-08-3 ]
[ 107922-43-0 ]

Reference： [1]Patent: US2014/57911,2014,A1

8
[ 64-17-5 ]
[ 22510-08-3 ]
[ 7260-32-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium; for 72h;Reflux;	690 mg Sodium (30 mmol) was dissolved in 40 ml ethanol and 786 mg <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (5 mmol) was added in one portion. The mixture was refluxed for 3 days. The mixture was poured onto 150 g ice, pH was set to 1-2 by addition of 2 M HCl solution and it was extracted three times with 50-50 ml ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and evaporated to dryness. Residue was used in the next step without any further purification. Yield: 820 mg (90%). Ret. time: 3.11 min., (M+H)-=182.

Reference： [1]Patent: US2014/57911,2014,A1 .Location in patent: Paragraph 0603; 0604

9
[ 22510-08-3 ]
[ 74-88-4 ]
[ 454-16-0 ]

Yield	Reaction Conditions	Operation in experiment
73.5%		To a solution of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (5.0 g, 31.84 mmol) in DMF(50 mL) was added K2C03 (5.27 g, 38.1 mmol), after stirring at room temperature for 15 mm was added methyliodide (3 mL, 47.7 mmol) and the reaction mixture stirred at room temperature for 2h. Reaction mixture was poured into ice water, separated solids were filtered, washed the solid thoroughly with water and vacuum dried to afford an off white solid (4.0 g, 73.5percent). 1H NMR (300 MHz, CDC13) 7.89-7.84 (m, 2H), 7.25-7. 17 (m, 1H), 3.98 (s, 3H).
73.5%		Step-a Synthesis of 1-fluoro-2-methoxy-4-nitrobenzene To a solution of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (5.0 g, 31.84 mmol) in DMF (50 mL) was added K2CO3 (5.27 g, 38.1 mmol), after stirring at room temperature for 15 min was added methyl iodide (3 mL, 47.7 mmol) and the reaction mixture stirred at room temperature for 2 h. Reaction mixture was poured into ice water, separated solids were filtered, washed the solid thoroughly with water and vacuum dried to afford an off white solid (4.0 g, 73.5percent). 1H NMR (300 MHz, CDCl3): 7.89-7.84 (m, 2H), 7.25-7.17 (m, 1H), 3.98 (s, 3H).
	With potassium carbonate; In acetonitrile; for 2h;Reflux;	1.57 g 2-Fluoro-5-nitrophenol (10 mmol) was dissolved in 50 ml dry acetonitrile. 2.07 g potassium carbonate (15 mmol) and 1.70 g iodomethane (12 mmol) were added. The mixture was refluxed for 2 hours. Then it was poured onto 100 g ice and the mixture was extracted three times with 40-40 ml ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4 and evaporated under reduced pressure. Residue was crystallized upon cooling and was used without any further purification or analytical investigation. Yield: 1.62 g (95percent).

Reference： [1]Patent: WO2015/104653,2015,A1 .Location in patent: Page/Page column 57
[2]Patent: US2016/368906,2016,A1 .Location in patent: Paragraph 0229
[3]Patent: US2014/57911,2014,A1 .Location in patent: Paragraph 0635

10
[ 22510-08-3 ]
[ 1616380-37-0 ]

Reference： [1]Patent: US2014/179720,2014,A1
[2]Patent: US2015/174128,2015,A1

11
[ 22510-08-3 ]
[ 1616380-60-9 ]

Reference： [1]Patent: US2014/179720,2014,A1
[2]Patent: US2015/174128,2015,A1

12
[ 22510-08-3 ]
[ 1616380-63-2 ]

Reference： [1]Patent: US2014/179720,2014,A1
[2]Patent: US2015/174128,2015,A1

13
[ 22510-08-3 ]
[ 1616380-66-5 ]

Reference： [1]Patent: US2014/179720,2014,A1
[2]Patent: US2015/174128,2015,A1

14
[ 22510-08-3 ]
[ 1616380-69-8 ]

Reference： [1]Patent: US2014/179720,2014,A1
[2]Patent: US2015/174128,2015,A1

15
[ 22510-08-3 ]
[ 1616380-71-2 ]

Reference： [1]Patent: US2014/179720,2014,A1
[2]Patent: US2015/174128,2015,A1

16
[ 100-39-0 ]
[ 22510-08-3 ]
[ 433226-25-6 ]

Yield	Reaction Conditions	Operation in experiment
88.2%	With copper diacetate; triethylamine; In dichloromethane; at 80℃; for 2.5h;	Dissolve <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (400 mg, 2.55 mmol) and potassium carbonate (527 mg, 3.82 mmol) in DMF (8 mL), stir at 50 C for 0.5 h, and add benzyl bromide (523 mg, 3.06 mmol) to warm up The reaction was continued at 80 C for 2.5 h, and the starting materials disappeared. The reaction solution was poured into ice water to precipitate a solid, which was filtered and dried to obtain 555 mg of a yellow solid, a yield of 88.2%, and a melting point: 127-129 C.
3.2 g		In a 50 mL 3-neck RBF equipped with reflux condenser, magnetic stirrer and thermo pocket were charged <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (2.4 g), K2CO3 (3.16 g) and dry DMF (20 mL). The reaction mixture was heated at 50 C. for 30 min. followed by addition of benzyl bromide (2.87 g) in DMF and the reaction mixture was heated to 80 C. for 18 hr. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. The reaction was complete after 30 minutes. After completion, the reaction mixture was poured into cold water. The solid precipitate was filtered and washed with water and dried under reduced pressure at 45 C. to give 3.20 g of 2-(benzyloxy)-1-fluoro-4-nitrobenzene. 1H NMR: DMSO-d6 (400 MHz): 5.35 (s, 2H), 7.358-7.397 (m, 1H), 7.415-7.454 (m, 2H), 7.448-7.530 (m, 2H), 7.553-7.579 (m, 1H), 7.900-7.939 (m, 1H), 8.091-8.116 (dd, 1H, J=2.8, 4.4).
3.20 g		In a 50 mL 3-neck RBF equipped with reflux condenser, magnetic stirrer and thermo pocket were charged <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (2.4 g), K2CO3 (3.16 g) and dry DMF (20 mL). The reaction mixture was heated at 50 C. for 30 min. followed by addition of benzyl bromide (2.87 g) in DMF and the reaction mixture was heated to 80 C. for 18 hr. The reaction was monitored on TLC using hexane:ethyl acetate (5:5) as mobile phase. The reaction was complete after 30 minutes. After completion, the reaction mixture was poured into cold water. The solid precipitate was filtered and washed with water and dried under reduced pressure at 45 C. to give 3.20 g of 2-(benzyloxy)-1-fluoro-4-nitrobenzene. 1H NMR: DMSO-d6 (400 MHz): 5.35 (s, 2H), 7.358-7.397 (m, 1H), 7.415-7.454 (m, 2H), 7.448-7.530 (m, 2H), 7.553-7.579 (m, 1H), 7.900-7.939 (m, 1H), 8.091-8.116 (dd, 1H, J=2.8, 4.4).

Reference： [1]Patent: CN110483366,2019,A .Location in patent: Paragraph 1560-1565
[2]Patent: US2014/179720,2014,A1 .Location in patent: Paragraph 0392; 0393
[3]Patent: US2015/174128,2015,A1 .Location in patent: Paragraph 0638-0639

17
[ 24595-58-2 ]
[ 22510-08-3 ]
[ 1620403-46-4 ]

Reference： [1]Organic Letters,2014,vol. 16,p. 3900 - 3903

18
[ 22510-08-3 ]
2-(2-fluoro-5-nitrophenoxy)acetic acid [ No CAS ]

Reference： [1]Patent: WO2014/149164,2014,A1

19
[ 22510-08-3 ]
2-(2-fluoro-5-nitrophenoxy)-N-methoxy-N-methylacetamide [ No CAS ]

Reference： [1]Patent: WO2014/149164,2014,A1

20
[ 22510-08-3 ]
1-(2-fluoro-5-nitrophenoxy)-4-methylpent-3-en-2-one [ No CAS ]

Reference： [1]Patent: WO2014/149164,2014,A1

21
[ 22510-08-3 ]
1-(5-amino-2-fluorophenoxy)-4-methylpent-3-en-2-one [ No CAS ]

Reference： [1]Patent: WO2014/149164,2014,A1

22
[ 105-36-2 ]
[ 22510-08-3 ]
ethyl 2-(2-fluoro-5-nitrophenoxy)acetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71.4%	With potassium carbonate; In acetone; for 16h;Reflux;	To a solution of <strong>[22510-08-3]2-fiuoro-5-nitrophenol</strong> (2.0g, 12.7mmol) in acetone (30.0mL), K2CO3 (2.12g, 15.3mmol) and ethyl 2-bromoacetate (2.54g, 15.2mmol) were added, and the resulting mixture was heated to reflux for 16h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (50.0mL) and extracted with ethyl acetate (50.0mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure. The residue was purified by silica gel column chromatography to obtain 1 (2.2g, 71.4%) as yellow liquid. 1H NMR (400 MHz, CDC13) delta 1.31 (t, J = 7.1 Hz, 3H), 4.30 (q, J = 7.1 Hz, 2H), 4.78 (s, 2H), 7.22-7.26 (dd, J = 9.6, 15.8 Hz, 1H), 7.79-7.81 (dd, J = 2.5, 7.1 Hz, 1H), 7.92 (m, 1H). MS m/z (M+H): 244

Reference： [1]Patent: WO2014/149164,2014,A1 .Location in patent: Paragraph 00872

23
[ 22510-08-3 ]
1-(4-nitro-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)-4-(oxetan-3-yl)piperazine [ No CAS ]

Reference： [1]Patent: US2015/175616,2015,A1

24
[ 22510-08-3 ]
4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)aniline [ No CAS ]

Reference： [1]Patent: US2015/175616,2015,A1
[2]Patent: WO2015/100217,2015,A1
[3]Patent: WO2016/10809,2016,A1
[4]Patent: WO2016/172117,2016,A1

25
[ 22510-08-3 ]
6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)imidazo[1,2-a]pyrazin-8-amine [ No CAS ]

Reference： [1]Patent: US2015/175616,2015,A1
[2]Patent: WO2015/100217,2015,A1
[3]Patent: WO2016/10809,2016,A1
[4]Patent: WO2016/172117,2016,A1

26
[ 17739-45-6 ]
[ 22510-08-3 ]
2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
21%	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;	[0300] 2-(2-(2-FIuoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII: A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H- pyran (4.4 niL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C for 16h. The reaction was cooled to room temperature, diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5x's to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes - 1 : 1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII (1.5 g, 21%).
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;	A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C. for 16 h. The reaction was cooled to room temperature, diluted with EtOAc and H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H2O (5*'s to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes-1:1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII.
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;	A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C for 16h. The reaction was cooled to room temperature, diluted with EtOAc and H20. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H20 (5x's to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes - 1: 1 hexanes:EtOAc to provide 2-(2-(2- fluoro-5-nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII.

With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 16h;

A mixture of <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (4 g, 25 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (4.4 mL, 28 mmol) and potassium carbonate (4.2 g 30 mmol) in DMF (50 mL) was stirred at 50 C for 16h. The reaction was cooled to room temperature, diluted with EtOAc and H20. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were washed with H20 (5x's to remove DMF) and brine and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (40 g column) eluting with a gradient of 100% hexanes - 1 : 1 hexanes:EtOAc to provide 2-(2-(2-fluoro-5- nitrophenoxy)ethoxy)tetrahydro-2H-pyran XXII.

Reference： [1]Patent: WO2016/10809,2016,A1 .Location in patent: Paragraph 0300
[2]Patent: US2015/175616,2015,A1 .Location in patent: Paragraph 0275; 0276
[3]Patent: WO2015/100217,2015,A1 .Location in patent: Page/Page column 115
[4]Patent: WO2016/172117,2016,A1 .Location in patent: Page/Page column 45-46

27
[ 22510-08-3 ]
4-(2-methoxy-4-nitrophenyl)-3,5-dimethyl-4H-1,2,4-triazole [ No CAS ]

Reference： [1]Patent: WO2015/104653,2015,A1
[2]Patent: US2016/368906,2016,A1

28
[ 22510-08-3 ]
4-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-3-methoxyaniline [ No CAS ]

Reference： [1]Patent: WO2015/104653,2015,A1
[2]Patent: US2016/368906,2016,A1

29
[ 22510-08-3 ]
N-(3-[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}-4-fluorophenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

30
[ 22510-08-3 ]
N-(4-fluoro-3-[(3R)-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

31
[ 22510-08-3 ]
N-(4-fluoro-3-[(3S)-1-(3,3,3-trifluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

32
[ 22510-08-3 ]
N-(4-fluoro-3-[(3S)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]oxy}phenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

33
[ 22510-08-3 ]
N-(3-[(3S)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}-4-fluorophenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

34
[ 22510-08-3 ]
N-(4-fluoro-3-[(3S)-1-(3,3,3-trifluoropropyl)piperidin-3-yl]methoxy}phenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

35
[ 22510-08-3 ]
N-(4-fluoro-3-[(3S)-1-(2,2,2-trifluoroethyl)piperidin-3-yl]methoxy}phenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

36
[ 22510-08-3 ]
tert-butyl (3R)-3-(2-fluoro-5-[(3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazol-4-yl)carbonyl]amino}phenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

37
[ 22510-08-3 ]
N-{4-fluoro-3-[(3R)-pyrrolidin-3-yloxy]phenyl}-3-methyl-5-[5-(trifluoromethyl)-pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

38
[ 22510-08-3 ]
tert-butyl (3S)-3-(2-fluoro-5-[(3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazol-4-yl)carbonyl]amino}phenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

39
[ 22510-08-3 ]
N-{4-fluoro-3-[(3S)-pyrrolidin-3-yloxy]phenyl}-3-methyl-5-[5-(trifluoromethyl)-pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide trifluoroacetate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

40
[ 22510-08-3 ]
tert-butyl (3S)-3-[(2-fluoro-5-[(3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]-amino}-1,2-thiazol-4-yl)carbonyl]amino}phenoxy)methyl]piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

41
[ 22510-08-3 ]
(x)C₂HF₃O₂*C₂₂H₂₂F₄N₆O₂S [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

42
[ 22510-08-3 ]
N-(4-fluoro-3-[(3R)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl]oxy}phenyl)-3-methyl-5-[5-(trifluoromethyl)pyrazin-2-yl]amino}-1,2-thiazole-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

43
[ 22510-08-3 ]
tert-butyl (3R)-3-(5-amino-2-fluorophenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

44
[ 22510-08-3 ]
tert-butyl (3R)-3-(5-[(5-amino-3-methyl-1,2-thiazol-4-yl)carbonyl]amino}-2-fluorophenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

45
[ 22510-08-3 ]
tert-butyl (3S)-3-(5-amino-2-fluorophenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

46
[ 22510-08-3 ]
tert-butyl (3S)-3-(5-[(5-amino-3-methyl-1,2-thiazol-4-yl)carbonyl]amino}-2-fluoro-phenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

47
[ 22510-08-3 ]
tert-butyl (3S)-3-[(5-amino-2-fluorophenoxy)methyl]piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

48
[ 22510-08-3 ]
tert-butyl (3S)-3-[(5-[(5-amino-3-methyl-1,2-thiazol-4-yl)carbonyl]amino}-2-fluoro-phenoxy)methyl]piperidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: WO2015/113920,2015,A1

49
tert-butyl (3R)-3-bromopyrrolidine-1-carboxylate [ No CAS ]
[ 22510-08-3 ]
tert-butyl (3R)-3-(2-fluoro-5-nitrophenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	2-f[uoro-5-nitrophenol. (CAS-RN: 22510-08-3) (2.lg, 13.6 mmo[, 1 eq), tert-butyl.(3R)-3-bromopyrro[idine-1-carboxy[ate (CAS-RN: 569660-97-5) (6.8g, 27.2 mmo[, 2 eq) and potassium carbonate (9.4 g, 68 mmo[, 5eq) were dissolved in 49 mL DMF and stirred at 120C overnight. The reaction mixture was diluted with ethyl acetate and the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with brine and dryed by the use of aWhatman filter. The volatile components of the organic phase were removed in vacuo. The final purification of this crude material was achieved via preparative MPLC (Biotage Isolera; 100 g cartridge: n-hexane/ethyl acetate) to give 2.7 mg (62% yield of theory) of the title compound.

Reference： [1]Patent: WO2015/113920,2015,A1 .Location in patent: Page/Page column 185

50
[ 569660-89-5 ]
[ 22510-08-3 ]
tert-butyl (3S)-3-(2-fluoro-5-nitrophenoxy)pyrrolidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	<strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (CAS-RN: 22510-08-3) (2 g, 12.8 mmol, 1 eq), tert-butyl (3S)-3-bromopyrrolidine-1-carboxylate (CAS-RN: 569660-89-5) (6.4 g, 25.6 mmol, 2 eq) and potassium carbonate (8.8 g, 68 mmol, Seq) were dissolved in 46 mL DMF and stirred at 120C overnight. The reaction mixture was diluted with ethyl acetateand the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with brine and dryed by the use of a Whatman filter. The volatile components of the organic phase were removed in vacuo. The final purification of this crude material was achieved via preparative MPLC (Biotage Isolera; 100 g cartridge: n-hexane/ethyl acetate) to give 2.5 mg (60% yield oftheory) of the title compound.

Reference： [1]Patent: WO2015/113920,2015,A1 .Location in patent: Page/Page column 187

51
[ 158406-99-6 ]
[ 22510-08-3 ]
tert-butyl (3S)-3-[(2-fluoro-5-nitrophenoxy)methyl]piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃;	2-f[uoro-5-nitrophenol. (CAS-RN: 22510-08-3) (2 g, 12.7 mmo[, 1 eq), tert-butyl. (3S)-3-(bromomethy[)piperidine-1-carboxy[ate (CAS-RN: 158406-99-6) (7.1 g, 25.5 mmo[,2 eq) and potassium carbonate (8.8 g, 64 mmo[, 5eq) were dissolved in 40 mL DMF and stirred at 120C overnight. The reaction mixture was diluted with ethyl acetate and the residue was partitioned between ethyl acetate and water. The combined organic phases were washed with brine and dryed by the use of aWhatman filter. The volatile components of the organic phase were removed in vacuo. The final purification of this crude material was achieved via preparative MPLC (Biotage Isolera; 340 g cartridge: n-hexane/ethyl acetate) to give 3.5 mg (78% yield of theory) of the title compound.UPLC-MS (Method 2): Rt = 1 .48 mm; MS (Elpos): m/z = 355 [M+H].1H-NMR (400 MHz, DMSO-d6) delta [ppm]: 1.146 (1.15), 1.164 (2.25), 1.182 (1.25),7.969 (1.64), 7.976 (1.64), 7.988 (1.80), 7.995 (1.55), 8.237 (0.59).1.224(0.63),1.226(0.62),1.344(16.00),1.374(10.71),1.386(1.99),1.396(1.15),1.414(0.59),1.612(0.41),1.625(1.05),1.635(1.05),1.644(0.75),1.657(0.71),1.661(0.64),1.668(0.55),1.794(0.79),1.809(0.83),1.822(0.91),1.915(0.68),1.937(0.83),1.977(4.29),2.513(1.21),2.857(0.41),3.934(0.40),3.987(0.41),3.992(0.56),4.010(1.38),4.014(1.44),4.028(1.32),4.035(1.91),4.038(2.57),4.045(0.83),4.059(2.22),4.088(1.77),4.101(1.95),4.112(1.12),4.126(0.95),7.500(2.29),7.522(2.90),7.526(2.60),7.548(2.61),7.870(1.18),7.876(1.64),7.880(1.57),7.887(1.46),7.892(1.27),7.899(1.63),7.902(1.46),7.909(1.38),

Reference： [1]Patent: WO2015/113920,2015,A1 .Location in patent: Page/Page column 190

52
[ 1895-39-2 ]
[ 22510-08-3 ]
[ 97963-50-3 ]

Yield	Reaction Conditions	Operation in experiment
4.1 g	With potassium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 2.5h;Inert atmosphere;	Step 1: 2-Difluoromethoxy-1-fluoro-4-nitro-benzene [118] A mixture of 2-fluoro-5-nitro-phenol (4.3 g; 27.38 mmol), K2CO3 (4.541 g; 32.85 mmol), sodium chlorodifluoroacetate (8.348 g; 54.76 mmol) in DMF (90 ml), and water (12 ml) was degassed by bubbling nitrogen into the suspension for 5 min., and was then heated to 1000C, under nitrogen, for 2.5h. [119] The heterogeneous mixture was allowed to cool to room temperature, and 12N HCI (8 ml; 96 mmol), and water (12 ml) were successively added, and this mixture was stirred at room temperature for 1 h. The resulting mixture was cooled to 00C, and aqueous 1 N NaOH (100 ml) was then added portion wise. Et2O (250 ml), and water (200 ml) were then added, and the yellow organic layer was further washed with water (150 ml), dried over anhydrous MgSO4, filtered, and concentrated to dryness under reduced pressure. [120] The crude material was purified by FC (DCM / heptane = 1 / 1 to give 4.1 g of 2- difluoromethoxy-1-fluoro-4-nitro-benzene.

Reference： [1]Patent: WO2016/25917,2016,A1 .Location in patent: Paragraph 118-120

53
[ 22510-08-3 ]
4,6-dimethyl-2-(5-nitro-2-(piperazin-1-yl)phenoxy)pyrimidine [ No CAS ]

Reference： [1]Patent: CN105461635,2016,A

54
[ 22510-08-3 ]
tertbutyl 4-(2-((4,6-dimethyl-pyrimidin-2-yl)oxy)-4-nitrophenyl)piperazine-1-carboxylate [ No CAS ]

Reference： [1]Patent: CN105461635,2016,A

55
[ 4472-44-0 ]
[ 22510-08-3 ]
2-(2-fluoro-5-nitrophenoxy)-4,6-dimethylpyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69.8%	With potassium carbonate; In dimethyl sulfoxide; at 110℃; for 2h;Inert atmosphere;	Under a nitrogen atmosphere, <strong>[22510-08-3]2-fluoro-5-nitrophenol</strong> (0.47g, 2.99mmol), 2- chloro-4,6-dimethyl-pyrimidine (0.43g, 3.05mmol) and carbonPotassium (0.83g, 5.98mmol) was added to DMSO (10mL), and then the reaction was heated to 110oC for 20 hours. After completion of the reaction,The reaction mixture was cooled to room temperature, and water (20 mL) and washed, and then (30mL × 3) and extracted with ethyl acetate. The combined organic phase was dried over anhydrousAfter drying over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by a silica gel column (petroleum ether / ethyl acetate (v / v) = 20/1) to give the title compound viaAs a white solid (0.55g, 69.8%).

Reference： [1]Patent: CN105461635,2016,A .Location in patent: Paragraph 0386; 0387; 0388; 0389

56
[ 22510-08-3 ]
(S)-tert-butyl 2-((3-((tert-butyldimethylsilyl)oxy)-4-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2017/31307,2017,A
[2]RSC Advances,2018,vol. 8,p. 31803 - 31821

57
[ 22510-08-3 ]
(S)-tert-butyl 2-((4-fluoro-3-((fluorosulfonyl)oxy)phenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2017/31307,2017,A
[2]RSC Advances,2018,vol. 8,p. 31803 - 31821

58
[ 22510-08-3 ]
di-tert-butyl 2,2'-((((sulfonylbis(oxy))bis(4-fluoro-3,1-phenylene))bis(azanediyl))bis(carbonyl))(2S,2'S)bis(pyrrolidine-1-carboxylate) [ No CAS ]

Reference： [1]Patent: KR2017/31307,2017,A
[2]Patent: KR2017/31307,2017,A
[3]RSC Advances,2018,vol. 8,p. 31803 - 31821
[4]RSC Advances,2018,vol. 8,p. 31803 - 31821

59
[ 22510-08-3 ]
tert-butyl (S)-2-((3-(((5-((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxamido)-2-fluorophenoxy)sulfonyl)oxy)-2-fluorophenyl)carbamoyl)pyrrolidine-1-carboxylate [ No CAS ]

Reference： [1]Patent: KR2017/31307,2017,A
[2]RSC Advances,2018,vol. 8,p. 31803 - 31821

60
[ 22510-08-3 ]
2-fluoro-3-((S)-1-((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)pyrrolidine-2-carboxamido)phenyl (2-fluoro-5-((S)-1-((R)-2-((methoxycarbonyl)amino)-2-phenylacetyl)pyrrolidine-2-carboxamido)phenyl) sulfate [ No CAS ]

Reference： [1]Patent: KR2017/31307,2017,A
[2]RSC Advances,2018,vol. 8,p. 31803 - 31821

61
[ 22510-08-3 ]
2-fluoro 3-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxamido)phenyl-2-fluoro-5-((S)-1-((R)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxamido)phenyl sulfate [ No CAS ]

Reference： [1]Patent: KR2017/31307,2017,A
[2]RSC Advances,2018,vol. 8,p. 31803 - 31821

62
[ 22510-08-3 ]
N-(3-hydroxy-4-fluorophenyl)formamide [ No CAS ]