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[ CAS No. 188582-62-9 ]

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CAS No. :	188582-62-9	MDL No. :	MFCD00143265
Formula :	C₇H₆BrFO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	N/A
M.W :	205.02 g/mol	Pubchem ID :	-
Synonyms :

Safety of [ 188582-62-9 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 188582-62-9 ]

Upstream synthesis route of [ 188582-62-9 ]
Downstream synthetic route of [ 188582-62-9 ]

[ 188582-62-9 ] Synthesis Path-Upstream 1~6

1
[ 188582-62-9 ]
[ 128577-47-9 ]

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

2
[ 188582-62-9 ]
[ 76283-09-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	at 100℃; for 0.166667 h;	The above compound (7.00 g, 34.1 mmol) was dissolved into 48percent hydrobromic acid (35 mL), and the resultant was caused to react at 100° for 10 minutes. After the end of the reaction, the resultant was neutralized with potassium carbonate. Thereafier, extraction with ethyl acetate was carried out, and this extraction layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to yield a compound (8.35 g, 91percent). 1H-NMR (CDC13): 4.46 (s, 2H, HnCH2), 7.25-7.29 (m, 3H, Ar).

Reference： [1] Patent: US2017/15684, 2017, A1, . Location in patent: Paragraph 0144; 0145; 0146

3
[ 188582-62-9 ]
[ 134057-95-7 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 9, p. 931 - 943

4
[ 188582-62-9 ]
[ 57848-46-1 ]

Reference： [1] Advanced Synthesis and Catalysis, 2014, vol. 356, # 8, p. 1741 - 1746

5
[ 188582-62-9 ]
[ 881189-74-8 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 9, p. 931 - 943

6
[ 73183-34-3 ]
[ 188582-62-9 ]
[ 1082066-29-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; potassium acetate In 1,4-dioxane at 90℃; Inert atmosphere	3.1.1. Preparation of (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) At 90° C. under N₂ atmosphere, to a stirred solution of 4-bromo-2-fluorophenylmethanol (500 mg, 2.44 mmol) in dioxane (5 mL) were added B₂Pin₂ (929 mg, 3.66 mmol), Pd(dppf)Cl₂.DCM (198 mg, 0.24 mmol) and KOAc (717 mg, 7.32 mmol). After being stirred at 90° C. overnight, the reaction mixture was cooled down to room temperature and partitioned between EA and H₂O. The layers were separated and the organic layer was washed with brine, dried over Na₂SO₄. Solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0˜20 ethyl acetate in petroleum ether) to provide (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) (300 mg, 48percent) as a yellow oil.

Reference： [1] Patent: US2018/194762, 2018, A1, . Location in patent: Paragraph 0740-0741
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 18, p. 4984 - 4995

[ 188582-62-9 ] Synthesis Path-Downstream 1~24

1
[ 57848-46-1 ]
[ 188582-62-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With methanol; sodium tetrahydroborate at -5 - 20℃;	6.6.8.b To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15 g, 79.36 mmol) in MeOH (100 ml.) at 00C to -5°C, added NaBH4 (6.0 g, 158.73 mmol) in equal portions and stirred at room temperature. The reaction mixture was diluted with ice cold water (100 mL) and concentrated under reduced pressure. The obtained aqueous residue was extracted with ethyl acetate (2*200 mL); the ethyl acetate layer was washed with brine solution (50 mL), dried over anhydrous NaSO4. filtered and concentrated to afford a colorless oil (15 g, 99%).
99%	With methanol; sodium tetrahydroborate at -5 - 23℃; for 1h;	A111.1; A118.3 Step 3: To a stirred solution of 4-Bromo-2-fluoro benzaldehyde (15 g, 79.36 mmol) in MeOH (100 mL) at -5 °C to 0 °C was added NaBH4 (6.0 g, 158.73 mmol) in equal portions and stirred at RT for 1 h until the starting material was completely consumed, as evidenced by TLC analysis. The reaction mixture was then diluted with ice cold water (100 mL) and concentrated under reduced pressure. The residue obtained on concentration was extracted with EtOAc (2x200 mL) and separated. The combined EtOAc layers were washed with brine solution (50 mL), dried over anhydrous NaS04, filtered and concentrated to afford (4-bromo-2-fluorophenyl)methanol (30 g, 99 % (from 2 batches))] as colorless oil (TLC solvent system: 30% EtOAc in PE; Rf: 0.3).
99%	With sodium tetrahydroborate In methanol at 20℃; for 0.5h;	2 Production of (4-bromo-2-fluorophenyl)methanol Into methanol (50 mL) was dissolved 4-bromo-2- fluorobenzaldehyde (10.0 g, 48.8 mmol), and thereafter the resultant was caused to react with NaBH4 (3.69 g, 97.6 mmol) at room temperature for 30 minutes. Thereafter, water (50 mL) was added thereto and, afier extraction with ethyl acetate, the extraction layer was washed with water. The obtained compound was subjected to the next step without purification.and a saturated saline solution, then dried over anhydrousmagnesium sulfate, and concentrated under a reduced pressure to yield a compound (12.9 g, 99%). The obtained compound was subjected to the next step without purification.

95%	With methanol; sodium tetrahydroborate at -5 - 20℃; for 1h;	Synthesis of (4-bromo-2-fluorophenyl)methanol Synthesis of (4-bromo-2-fluorophenyl)methanol To a stirred solution of 4-bromo-2-fluoro benzaldehyde (15 g, 79.4 mmol) in MeOH (100 mL) at -5X to OX was added NaBH4 (6.0 g, 9 mmol) in portions and stirred at RT for 1 h until the starting material was completely consumed, as evidenced by TLC analysis. The RM was then diluted with ice cold water (100 mL) and concentrated under reduced pressure. The residue obtained on concentration was extracted with EtOAc (2 x 200 mL) and separated. The EtOAc layer was washed with brine (50 mL), dried over anhydrous NaS04, filtered and concentrated to afford (4-bromo-2-fluorophenyl)methanol (29 g, from 2 batches each of 15 g of of 4-bromo-2-fluoro benzaldehyde, 95%) as colorless oil. TLC system: EtOAcPE (3:7), Rf: 0.3
	With hydrogenchloride; borane Ν,Ν-diethylaniline complex 1.) THF, 5 h, reflux; Yield given. Multistep reaction;
	With sodium tetrahydroborate In methanol at 20℃; for 2h;	R.i To a solution of 4-bromo-2-fluorobenzaldehyde (25 g, 0.123 mol) in methanol (250 ml) was added NaBH4 (7.02 g, 0.1847 mol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with 25 ml of water and solvent evaporated under reduced pressure. The compound was extracted with ethyl acetate, organic layer was washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (25 g) as an oil. This was directly taken for next step without further purification.
	Stage #1: 4-bromo-2-fluorobenzaldehyde With sodium tetrahydroborate In methanol at 0 - 20℃; for 1h; Stage #2: With water In methanol	D.i Sodium borohydride (4.63 g, 0.1219 mol) was added to a solution of 4-bromo-2- fluorobenzaldehyde (16.5 g, 0.0813 mol) in methanol (200 mL) at 00C. The resulting mixture was stirred for 1 h at RT before being quenched with water. Solvent (methanol) was concentrated under reduced pressure before the aqueous phase was extracted with DCM (3 times). The combined organic layers were washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure afforded the sub-title compound (15.3 g) as a pale yellow liquid.
16.8 g	With sodium tetrahydroborate In tetrahydrofuran; methanol at 0 - 20℃; for 5h; Inert atmosphere;	1-1 Sodium borohydride (9.4 g), methanol (8.0 g) and THF (55 mL) were mixed under dry nitrogen and cooled to 0 ° C. Under cooling,2-Fluoro-4-bromobenzaldehyde (16.8 g) and THF (30 mL) were slowly added, and the mixture was returned to room temperature and stirred for 5 hours. Subsequently, a solution of cyclopentanone (27.7 g) dissolved in THF (80 mL) was slowly added under cooling, and then the temperature was slowly raised to room temperature. The reaction solution was cooled to 0° C., 10% hydrochloric acid (200 mL) was slowly added, ethyl acetate (300 mL) was added for liquid separation, and the organic layer was washed 3 times with saturated brine (300 mL). After anhydrous sodium sulfate was added and dried, sodium sulfate was removed by filtration. The organic solvent was distilled off under reduced pressure to give 16.8 g of 2-fluoro-4-bromobenzbenzyl alcohol as a transparent liquid.Obtained.
	With methanol; sodium tetrahydroborate at 0℃;	1 Step 1: (4-bromo-2-fluorophenyl)methanol. A solution of 4-bromo-2- fluorobenzaldehyde (10.2 g, 50 mmol) in MeOH (500 mL) was cooled to 0°C and NaBH4 (5.70 g, 151 mmol) added over 10 min. The solution was stirred for 16h. The excess MeOH was removed and the crude mixture was partitioned between EtOAc (500 mL) and 1N NaOH (500 mL). The 1N NaOH was washed with an additional portion of EtOAc (300 mL). The combined organics were dried over Na2SO4 and concentrated to afford the title compound as a viscous oil to white solid which was in the next step without further purification.

Reference： [1]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2010/127856, 2010, A1 Location in patent: Page/Page column 92
[2]Current Patent Assignee: MEDIFRON DBT KR - WO2013/68461, 2013, A1 Location in patent: Page/Page column 115; 118; 119
[3]Current Patent Assignee: STELLA CHEMIFA CORPORATION; OSAKA CITY UNIVERSITY - US2017/15684, 2017, A1 Location in patent: Paragraph 0141; 0142; 0143
[4]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2016/82930, 2016, A1 Location in patent: Page/Page column 26
[5]Salunkhe, Ashok M.; Burkhardt, Elizabeth R. [Tetrahedron Letters, 1997, vol. 38, # 9, p. 1519 - 1522]
[6]Current Patent Assignee: ANIMEDA - WO2005/123748, 2005, A1 Location in patent: Page/Page column 92-93
[7]Current Patent Assignee: ASTRAZENECA PLC - WO2007/69986, 2007, A1 Location in patent: Page/Page column 73-74
[8]Current Patent Assignee: DIC CORP. - JP2020/66582, 2020, A Location in patent: Paragraph 0358-0359
[9]Current Patent Assignee: UNIVERSITY OF UTAH; CURZA GLOBAL LLC - WO2020/150385, 2020, A1 Location in patent: Paragraph 00669

2
[ 18162-48-6 ]
[ 188582-62-9 ]
[ 930785-23-2 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With 1H-imidazole In dichloromethane at 0 - 20℃; for 16.08h;	24 ((4-Bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane A mixture of (4-bromo-2-fluorophenyl)methanol (30.0 g, 146 mmol) and imidazole (14.9 g, 219 mmol) in dichloromethane (200 mL) was cooled to 0° C. and tert-butyl-chlorodimethylsilane (24.2 g, 161 mmol) was added. The mixture was stirred for 5 minutes, the cooling bath removed and the mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into chilled water (300 mL), mixed and the organic layer was separated. The aqueous layer was extracted with dichloromethane (30 mL3) and the combined organic layers were washed with saturated NaCl (20 mL3), dried over Na2SO4, filtered and concentrated under reduced pressure to give ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane (46.0 g, 98.5%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.40-7.34 (m, 1H), 7.31-7.28 (m, 1H), 7.19 (dd, J=1.8, 9.6 Hz, 1H), 4.74 (s, 2H), 0.97 (s, 9H), 0.16 (s, 6H).
98%	With 1H-imidazole In dichloromethane at 20℃; for 0.166667h;	1.1 A mixture of (4-bromo-2-fluorophenyl)methanol (20 g, 98 mmol) and imidazole (7.31 g, 107 mmol) in methylene chloride (100 mL) was treated with /tvV-butyl dimethyl silyl chloride (16.17 g, 107 mmol) in methylene chloride (100 mL) over 10 min. at rt. A white precipitate immediately formed which was removed by filtration. The filtrate was concentrated under reduced pressure and the remainder dissolved in heptane (100 mL). The organic phase was washed with water (2 x 40 mL), brine (2 x 40 mL), dried over NaSCri and concentrated under reduced pressure. The remainder was dissolved in c-hexane and passed through a silica pad (100 g) and then the solvent was removed under reduced pressure to afford Compound 1-B as a yellowish oil (30.51 g, 98% yield). NMR (400 MHz, CDCb) d ppm 0.12 (s, 6H), 0.95 (s, 9H), 4.74 (s, 2H), 7.14 - 7.22 (m, 1H), 7.28 - 7.32 (m, 1H), 7.34 - 7.42 (m, 1H).
97%	With 1H-imidazole; dmap at 20℃;	16a 16a (4-Bromo-2-fluoro-benzyloxy)-te/f-butyl-dimethyl-silaneTo 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) tert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated.Yield: 7.70 g (97% of theory)Rf-value: 0.9 (silica gel, mixture C).

97%	With 1H-imidazole; dmap In N,N-dimethyl-formamide at 20℃;	6.a To 5.10 g (24.9 mmol) (4-bromo-2-fluoro-phenyl)-methanol in 30 mL DMF is added subsequently 4.06 g (26.1 mmol) fert-butyl-chloro-dimethyl silane, 2.57 g (37.3 mmol) imidazole and 456 mg (3.73 mmol) DMAP. The reaction mixture is stirred overnight at RT and the solvent is evaporated. The residue is diluted with EtOAc, washed five times with water and the combined organic phase is dried over MgSO4, filtered and the solvent is evaporated. Yield: 7.70 g (97% of theory); Rrvalue: 0.9 (silica gel, mixture C).
75%	With 1H-imidazole In dichloromethane at 0 - 25℃;	(4-bromo-2-fluoro-phenyl)methoxy-tert-butyl-dimethyl-silane (SI-9) To a solution of compound SI-8 (12 g, 58.8 mmol) and imidazole (6.4 g, 94.1 mmol) inCH2Cl2 (200 mL) was added TBDMSCl (9.77 g, 64.8 mmol) at 0 oC over 1 hour and thenthe solution was stirred at room temperature overnight. Then, the reaction was quenchedwith water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography to obtain pure compound SI-9 (14 g, 75%) as a white solid. ESI-MS m/z 319 [M+H]+ calc. for C13H20BrFOSi. This intermediate was used in the next step without further characterization.
70%	With 1H-imidazole In dichloromethane at 20℃; for 1h;	Synthesis of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane Synthesis of ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane A stirred solution of 4-bromo-2-fluoro benzaldehyde (49 g, 239 mmol, 1 eq) in DCM (400 mL) was treated with imidazole (32.5 g, 478 mmol, 2 eq) followed by TBDMS chloride (39.6 g, 263 mmol, 1.1 eq). The resulting solution was stirred at RT for 1 h, quenched with water (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 χ 100 mL). The combined organic layer was washed with brine (100 mL), dried (Na2S04) and concentrated. The residue upon purification by column chromatography (silica gel 100-200, EtOAc/PE; 10:90) afforded ((4-bromo-2-fluorobenzyl)oxy)(tert- butyl)dimethylsilane (53 g, 70%) as a brown liquid. TLC system: EtOAc/ PE (1 :9), R,: 0.6
	With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 10h;	29.i Example 29; 2-Butoxy-7,8-dihydro-9-[3-fluoro-4-{4-[3-(methoxycarbonylmethyl)phenoxymethyl]piperidin-1 -yl}methylbenzyl]-8-oxoadenine; [Show Image] Step (i); 4-Bromo-1-(tert-butyldimethylsiloxymethyl)-2-fluorobenzene; [Show Image] 4-Bromo-2-fluoro-1-(methoxycarbonyl)benzene 3.0g (12.9mmol) was dissolved in THF (50ml) and thereto was added portion wise under ice cooling lithium aluminum hydride 732mg (19.3mmol). After 1.5 hours, the reaction was quenched with 1N aqueous sodium hydroxide. After filtration over Celite, the filtrate was concentrated and thereto was added water. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over Na2SO4, concentrated and dried in vacuo. The residue was dissolved in DMF (30ml) and thereto were added imidazole 871mg (12.8mmol) and TBSC1 1.93g (12.8mmol), followed by stirring at room temperature for 10 hours. After concentration, thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the titled compound 2.7 g (8.5mmol) as a colorless transparent oil. Yield 69% 1H NMR (DMSO-d6) δ 7.35 (1H, dd, J = 7.7, 7.7 Hz), 7.27 (1H, dd, J = 1.8, 8.3 Hz), 7.16 (1H, dd, J = 1.8, 9.6 Hz), 4.72 (2H, s), 0.92 (9H, s), 0.10 (6H, s).
	With 1H-imidazole In N,N-dimethyl-formamide for 16h;	2 Step 2: ((4-bromo-2-fluorobenzyl)oxy)(tert-butyl)dimethylsilane. To a crude solution of 4-bromo-2-fluorophenyl)methanol (10.1 g, 49.3 mmol) in DMF (250 mL) was added TBSCl (11.1 g, 73.9 mmol) followed by Imidizole (6.71 g, 98.5 mmol). The solution was stirred for 16h. The crude solution was partitioned between EtOAc (500 mL) and LiCl (500 mL). The LiCl was discarded and the organic layer was washed with additional LiCl (2x250 mL). The combined organics were dried over Na2SO4 and concentrated to afford a crude oil which was purified via colomn chromatagrohy (Hexanes:EtOAc) to afford the title compound as a clear oil.

Reference： [1]Current Patent Assignee: BRISTOL-MYERS SQUIBB CO - US2019/322647, 2019, A1 Location in patent: Paragraph 0254; 0255
[2]Current Patent Assignee: NEUROCRINE BIOSCIENCES INC - WO2021/62246, 2021, A1 Location in patent: Page/Page column 84-85
[3]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2008/22979, 2008, A1 Location in patent: Page/Page column 90
[4]Current Patent Assignee: C.H. Boehringer Sohn AG & Co. KG - WO2009/103478, 2009, A1 Location in patent: Page/Page column 42
[5]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524]
[6]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2016/82930, 2016, A1 Location in patent: Page/Page column 28
[7]Current Patent Assignee: ASTRAZENECA PLC; Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP1939202, 2008, A1 Location in patent: Page/Page column 56-57
[8]Current Patent Assignee: UNIVERSITY OF UTAH; CURZA GLOBAL LLC - WO2020/150385, 2020, A1 Location in patent: Paragraph 00669; 00670

3
[ 188582-62-9 ]
[ 219873-06-0 ]

Yield	Reaction Conditions	Operation in experiment
	With dicyanozinc In DMF (N,N-dimethyl-formamide) at 90℃;	R.ii A suspension of (4-bromo-2-fluoro-phenyl) -methanol_(25 g, 0.122 mol, from step (i) above), Zn (CN)2 g, 0.085 mol) and Pd (PPh3)4 g, 0.006 mol) in dry DMF (150 ml) was stirred at 90 °C overnight under nitrogen atmosphere. The reaction mixture was filtered and solvent concentrated under reduced pressure. The residue was purified by column chromatography over silica gel using 25 % ethyl acetate in petroleum ether, as eluent to the sub-title compound (13 g) as white solid.

Reference： [1]Current Patent Assignee: ANIMEDA - WO2005/123748, 2005, A1 Location in patent: Page/Page column 93

4
[ 124-63-0 ]
[ 188582-62-9 ]
[ 942282-43-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With triethylamine In tetrahydrofuran at 0℃; for 0.5h;
	With triethylamine In dichloromethane at 0 - 20℃;	S.ii Methanesulfonyl chloride (5.63 g, 0.0492 mol) was added, drop by drop at 00C, to a solution of (4-bromo-2-fluorophenyl)methanol (10.1 g, 0.0492 mol; see step (i) above) and triethylamine (5.47 g, 0.0541 mol) in dry DCM (25 mL). The resulting mixture was stirred at RT overnight under a nitrogen atmosphere. The reaction was quenched with water, extracted with DCM, washed with water and brine and then dried over sodium sulfate. Solvent evaporation under reduced pressure afforded 8.4 g of the sub-title compound as a red oil. This was employed directly in the next step without further purification.
	With triethylamine In dichloromethane at -30 - 20℃; for 5.5h; Inert atmosphere;

Reference： [1]Schwertz, Geoffrey; Witschel, Matthias C.; Rottmann, Matthias; Leartsakulpanich, Ubolsree; Chitnumsub, Penchit; Jaruwat, Aritsara; Amornwatcharapong, Watcharee; Ittarat, Wanwipa; Schäfer, Anja; Aponte, Raphael A.; Trapp, Nils; Chaiyen, Pimchai; Diederich, François [ChemMedChem, 2018, vol. 13, # 9, p. 931 - 943]
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2007/69986, 2007, A1 Location in patent: Page/Page column 94-95
[3]Lenstra, Danny C.; Lenting, Peter E.; Mecinović, Jasmin [Green Chemistry, 2018, vol. 20, # 19, p. 4418 - 4422]

5
[ 112704-79-7 ]
[ 188582-62-9 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 2-fluoro-4-bromobenzoic acid With borane In tetrahydrofuran at 0 - 85℃; Stage #2: With hydrogenchloride In methanol; water at 25℃; for 2h;	(4-bromo-2-fluoro-phenyl)methanol (SI-8) To a solution of commercially available 4-bromo-2-fluoro-benzoic acid (SI-7) (15 g, 68.5mmol) in THF (250 mL) was added BH3 (1.0 M in THF, 140 mL, 140 mmol) at 0 oC andthen the solution was stirred at 85 oC overnight. Then, the reaction was quenched withMeOH and 1 N HCl and stirred at room temperature for an additional 2 hours. The mixturewas extracted with EtOAc and the organic layer was washed with brine, dried overanhydrous Na2SO4, filtered and concentrated to give the crude product which was purifiedby column chromatography to obtain pure compound SI-8 (12 g, 86%) as a yellow oil. ESIMSm/z 205 [M+H]+ calc. for C7H6BrFO. This intermediate was used in the next stepwithout further characterization.
	Stage #1: 2-fluoro-4-bromobenzoic acid With borane-THF In tetrahydrofuran at 20℃; Stage #2: With citric acid In tetrahydrofuran; water at 0℃;	S.i BH3 (1 M, in THF, 205 mL) was added to 4-bromo-2-fluoro benzoic acid (15 g, 0.0684 mol) in dry THF (150 mL) under a nitrogen atmosphere. The resulting mixture was stirred at RT overnight, after which the reaction mixture was cooled to 0°C and quenched with aqueous citric acid. Solvents (THF) were evaporated from the reaction mixture and the resulting aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with 10% NaHCO3, water and brine, dried over sodium sulfate and then concentrated under reduced pressure to afforded 14.7 g of the sub-title compound as pale yellow liquid. This was employed directly in the next step without further purification.

Reference： [1]Rabal, Obdulia; Sánchez-Arias, Juan A.; Cuadrado-Tejedor, Mar; de Miguel, Irene; Pérez-González, Marta; García-Barroso, Carolina; Ugarte, Ana; Estella-Hermoso de Mendoza, Ander; Sáez, Elena; Espelosin, Maria; Ursua, Susana; Haizhong, Tan; Wei, Wu; Musheng, Xu; Garcia-Osta, Ana; Oyarzabal, Julen [European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524]
[2]Current Patent Assignee: ASTRAZENECA PLC - WO2007/69986, 2007, A1 Location in patent: Page/Page column 94

6
[ 557-21-1 ]
[ 188582-62-9 ]
[ 219873-06-0 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 95℃; for 17.25h;	D.ii A solution of (4-bromo-2-fluorophenyl)methanol (15.3 g, 0.0746 mol; see step (i) above) in DMF (80 mL) was purged with argon for 15 min. At this point, Zn(CN)2 (5.97 g, 0.0522 mol) and Pd(PPh3)4 (4.27 g, 0.0037 mol) were added, successively. The resulting suspension was stirred at 95°C for 17 h under an argon atmosphere, before being cooled to RT, quenched with water and extracted with ethyl acetate. The organic (ethyl acetate) layer was then washed with water and brine and dried over sodium sulfate. Solvent evaporation under reduced pressure, followed by column chromatography over silica gel (using 25% ethyl acetate in petroleum ether as eluent) afforded 8.9 g of the sub-title compound as a white solid.

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - WO2007/69986, 2007, A1 Location in patent: Page/Page column 74

7
[ 179232-29-2 ]
[ 188582-62-9 ]

Yield	Reaction Conditions	Operation in experiment
83%	With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 1h;	1.1 1.1 4-bromo-2-fluorobenzyl alcohol (1-1) At 0°C, lithium aluminum hydride (1.14 g, 30 mmol) was dropped into a solution of Methyl 4-Bromo-2-fluorobenzoate (4.66 g, 20 mmol) in tetrahydrofuran (100 mL) slowly. The ice-salt bath used was removed after that dropping. The reaction was complete (detected by LCMS and TLC) after stirred for 1 hour at room temperature. The mixture was cooled to 0°C again and the reaction was quenched with water (1.14 mL) and 10% NaOH solution (11.4 mL) respectively. After stirred for 15 min at room temperature, the mixture was filtered and then the filter cake was washed with tetrahydrofuran (50 mL2) and ethyl acetate EA (50 mL2). The filtrate was dried with anhydrous sodium sulfate, filtered, and then concentrated to obtain a colorless oil product (3.4 g, 83% yield).
	Stage #1: methyl 4-bromo-2-fluorobenzoate With lithium aluminium tetrahydride In tetrahydrofuran at 0℃; for 1.5h; Stage #2: With sodium hydroxide; water In tetrahydrofuran	29.i Example 29; 2-Butoxy-7,8-dihydro-9-[3-fluoro-4-{4-[3-(methoxycarbonylmethyl)phenoxymethyl]piperidin-1 -yl}methylbenzyl]-8-oxoadenine; [Show Image] Step (i); 4-Bromo-1-(tert-butyldimethylsiloxymethyl)-2-fluorobenzene; [Show Image] 4-Bromo-2-fluoro-1-(methoxycarbonyl)benzene 3.0g (12.9mmol) was dissolved in THF (50ml) and thereto was added portion wise under ice cooling lithium aluminum hydride 732mg (19.3mmol). After 1.5 hours, the reaction was quenched with 1N aqueous sodium hydroxide. After filtration over Celite, the filtrate was concentrated and thereto was added water. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over Na2SO4, concentrated and dried in vacuo. The residue was dissolved in DMF (30ml) and thereto were added imidazole 871mg (12.8mmol) and TBSC1 1.93g (12.8mmol), followed by stirring at room temperature for 10 hours. After concentration, thereto was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the titled compound 2.7 g (8.5mmol) as a colorless transparent oil. Yield 69% 1H NMR (DMSO-d6) δ 7.35 (1H, dd, J = 7.7, 7.7 Hz), 7.27 (1H, dd, J = 1.8, 8.3 Hz), 7.16 (1H, dd, J = 1.8, 9.6 Hz), 4.72 (2H, s), 0.92 (9H, s), 0.10 (6H, s).

Reference： [1]Current Patent Assignee: SUZHOU CONNECT BIOPHARMACEUTICALS - EP3048103, 2016, A1 Location in patent: Paragraph 0051; 0052
[2]Current Patent Assignee: ASTRAZENECA PLC; Sumitomo Pharma (in: Sumitomo Chemical); Sumitomo Chemical (w/o Dongwoo Fine-Chem); SUMITOMO CHEMICAL COMPANY LIMITED - EP1939202, 2008, A1 Location in patent: Page/Page column 56-57

8
[ 861931-87-5 ]
[ 76-05-1 ]
[ 188582-62-9 ]
6-(3-fluoro-4-hydroxymethyl-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol, trifluoroacetic acid salt [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 6-hydroxy-1-(4-(2-(piperidin-1-yl)ethoxy)phenoxy)naphthalen-2-ylboronic acid hydrochloride; 4-bromo-2-fluorobenzyl alcohol With sodium carbonate In 1,2-dimethoxyethane; water at 70℃; Stage #2: trifluoroacetic acid In acetonitrile	75 Add 6-boronic acid-5- [4- (2-piperidin-1-yl-ethoxy)-phenoxy]-naphthalen-2-ol hydrochloride salt (20 mg, 0.05 mmol) and freshly distilled dimethoxyethane and 2M sodium carbonate (9: 1,3 mL total volume) to a Quest210 under nitrogen. Add 3-fluoro-4- hydroxymethyl-bromobenzene (3 eq) followed by trans-dichlorobis (tri-o- tolylphosphine) palladium (10 mg, 0.01 mmol) and heat to 70 °C overnight under nitrogen. Cool reaction to room temperature and filter into tubes containing-400 mg TsOH-MP and agitate for 3 hours. Solvent filtered off and washed with DME. Add 3N ammonia in methanol and filter. Wash resin three times with 3N ammonia in methanol. Concentrate in vacuo and purify by reverse phase HPLC. Preparative HPLC's may be obtained, e. g. , on a Mass Guided Waters Preparative System using a 20 x 100 mm C18 Symmetry column. The eluent is a binary system of bottle and bottle A (0. 1 % trifluoroacetic acid in water) B (0. 1 % trifluoroacetic acid in acetonitrile). The standard method is a gradient of 10-95% B unless otherwise indicated. MS (IS+) tnle 488 (M + 1-TFA)

Reference： [1]Current Patent Assignee: ELI LILLY & CO - WO2005/73205, 2005, A1 Location in patent: Page/Page column 82

9
[ 188582-62-9 ]
[ 74-88-4 ]
[ 95068-02-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-bromo-2-fluorobenzyl alcohol With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.75h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃;	17 The title compound was prepared according to General Method 8. To a suspension of NaH (50-60 % mineral oil , 8 g, 0.33 mol) in Dry DMF ( 200 mL ) at 0 0C was added (4-bromo-2-fluorophenyl)methanol ( 27 g , 0.1317 mol). The reaction mixture was stirred for 15 min at 0 0C and then warmed to and stirred at RT for 30 min. The reaction mixture was again cooled to 0 0C and MeI (15 mL, 0.1975 mol) was added drop wise. After addition was complete, the reaction mixture was warmed to room temperature and stirred for Ih. Ice- water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate, and concentrated under reduced pressure to obtained 4-bromo-2- fluoro-l-(methoxymethyl)benzene (24 g).
14.8 g	Stage #1: 4-bromo-2-fluorobenzyl alcohol With sodium hydride In tetrahydrofuran at 0 - 20℃; for 2h; Stage #2: methyl iodide In tetrahydrofuran for 3h;	1-2 Sodium hydride and THF (20 mL) were mixed and cooled to 0°C. Under cooling, 2-fluoro-4-bromobenzbenzyl alcohol (16.8) obtained in (1-2) was obtained.g) and THF (80 mL) were slowly added, and the mixture was returned to room temperature and stirred for 2 hours. Subsequently, iodomethane (23.3 g) was slowly added, and the mixture was further stirred for 3 hours.The reaction solution was cooled to 0 ° C., water (50 mL) was slowly added, ethyl acetate (200 mL) was added for liquid separation, and the organic layer was washed with saturated brine (100 mL). After anhydrous sodium sulfate was added and dried, sodium sulfate was removed by filtration. The organic solvent was concentrated under reduced pressure. The obtained residue was dissolved in hexane and purified by silica gel column chromatography to give 14.8 g of 1-Fluoro-3-bromo-5-methoxymethylbenzene was obtained as a clear liquid.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2010/118354, 2010, A1 Location in patent: Page/Page column 38
[2]Current Patent Assignee: DIC CORP. - JP2020/66582, 2020, A Location in patent: Paragraph 0358-0359

10
[ 6482-24-2 ]
[ 188582-62-9 ]
[ 166960-01-6 ]

Yield	Reaction Conditions	Operation in experiment
47%	Stage #1: 4-bromo-2-fluorobenzyl alcohol With sodium hydride In tetrahydrofuran at 0 - 50℃; Stage #2: 2-Bromoethyl methyl ether In tetrahydrofuran at 20℃; for 20h;	6.6.8.c To a stirred solution of step-b product (10g, 49.02 mmol) in THF (250ml) at 00C1 added 60% NaH (2.93 g, 73.53 mmol) slowly in portions. After addition, the suspension was heated to 50°C for 30 minutes, cooled to room temperature, added 1-bromo-2-methoxy ethane (5 ml, 53.92 mmol) and stirred at room temperature for 20 h. The reaction mixture was diluted with ice cold water (100 ml_) and concentrated under reduced pressure. The obtained aqueous residue was extracted with ethyl acetate (2*150 mL); the combined ethyl acetate layer was washed with brine solution (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by column chromatography (100-200 mesh silica gel) using 5% ethyl acetate in petroleum ether as eluent to afford product as yellow liquid (6 g, 47%).
47%	Stage #1: 4-bromo-2-fluorobenzyl alcohol With sodium hydride In tetrahydrofuran at 0 - 50℃; for 0.5h; Stage #2: 2-Bromoethyl methyl ether In tetrahydrofuran at 23℃; for 20h;	A111.2 Step 2: To a stirred solution of (4-bromo-2-fluorophenyl)methanol (10 g, 49.02 mmol) in THF (250 mL) at 0°C, was added 60% NaH (2.93 g, 73.53 mmol) slowly in portions. After addition, the suspension was heated to 50 °C for 30 min, cooled to RT, then was added 1 -bromo-2-methoxy ethane (5 mL, 53.92 mmol) and the mixture was stirred at RT for 20 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was diluted with ice cold water (100 mL) and concentrated under reduced pressure. The obtained aqueous residue was extracted with EtOAc (2 χ 150mL); the combined EtOAc layers were washed with brine solution (50 mL), dried over anhydrous NaS04, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 4-bromo-2-fluoro-1 -((2-methoxyethoxy)methyl)benzene (6 g, 47%) as yellow liquid (TLC solvent system: 30% EtOAc-PE; Rf: 0.4).

Reference： [1]Current Patent Assignee: MEDIFRON DBT CO.,LTD. - WO2010/127856, 2010, A1 Location in patent: Page/Page column 92; 93
[2]Current Patent Assignee: MEDIFRON DBT KR - WO2013/68461, 2013, A1 Location in patent: Page/Page column 115

11
[ 188582-62-9 ]
[ 761446-44-0 ]
[ 1418201-67-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; sodium carbonate In 1,4-dioxane; water at 80℃; for 2.5h;	A.5.1 (2-fluoro-4-(l -methyl- lH-pyrazol-4-yl)phenyl)methanol To a mixture of (4-bromo-2-fluorophenyl)methanol (7.3 g, 34.9 mmol), l-methyl-4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (15.1 g, 71.3 mmol) and Ι,Γ- bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.42 g, 1.74 mmol) in dioxane (104 ml) were added water (83.4 ml) and a 2M sodium carbonate solution (52.3 ml, 105 mmol). The reaction mixture was heated at 80 °C, stirred for 2.5 hours, cooled to room temperature and filtered through a glass fiber paper. The solid was washed with a mixture of ethyl acetate and water. The filtrate was extracted with ethyl acetate and the organic phases were washed with water, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified on silica eluting with a gradient formed from n-heptane and ethyl acetate (10 to 80 ) to provide 7.07 g (98 ) of the title compound as an off-white solid. MS (m/e): 207.5 (M+H)+
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Sealed tube; Microwave irradiation;	1B; 3.1.a.1 a. STEP 1: PREPARATION OF (2-FLUORO-4-(l-METHYL-liZ-PYRAzoL-4- YL)PHENYL)METHANOL. a. STEP 1: PREPARATION OF (2-FLUORO-4-(l-METHYL-liZ-PYRAzoL-4- YL)PHENYL)METHANOL.(4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL)was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [l, -Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160 °C for 10 min. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the title compound as a beige, crystalline solid.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Microwave irradiation; Sealed tube;	Preparation of 4-(4-(chloromethyl)-3-fluorophenyl)-1-methyl-1H-pyrazole (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1′-bis(diphenylphosphino)ferrocene]-dichloro-palladium (II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160° C. for 10 min. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid. To a flame-dried round bottom flask equipped with a magnetic stir bar was added (2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)methanol (3.9 g, 19 mmol). Dichloro-methane (60 mL) was added, and to the suspension was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (5 mL, 38 mmol). The mixture was stirred at room temperature for 2 h, and then the solvent was removed by evaporation under reduced pressure. Residual volatiles were removed under high vacuum to afford the title compound as an amorphous beige solid. LCMS: RT=0.0.66 min, >99% (at) 254 nm, >99% (at) 220 nm; m/z (M+1)+=255. 1H NMR (400 MHz, CDCl3, δ (ppm)): 8.2 (s; 1H), 7.9 (s; 1H), 7.5-7.4 (m; 3H), 4.8 (s; 2H), 3.8 (s; 3H).

	With [1,1'-bis(diphenylphosphino)-ferrocene]palladium(II) chloride-dichlormethane complex; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Sealed tube;	3 (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1 -methyl-4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1 ‘-Bis(diphenylphosphino)ferrocene]dichloro-palladium(ll) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160 °C for 10 mm. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH₂Cl₂; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Microwave irradiation; Sealed tube;	3 j00630j (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1 -methyl-4-(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)- 1 Hpyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1 ‘-Bis(diphenylphosphino)ferrocene] dichloro-palladium (II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160 °C for 10 mm. The water layerwas removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate In tetrahydrofuran; water at 160℃; for 0.166667h; Microwave irradiation;	3. INTERMEDIATE 1: PREPARATION OF 4-(4-(CHLOROMETHYL)-3-FLUOROPHENYL)-1-METHYL-1H-PYRAZOLE (INTERMEDIATE 1) 3. INTERMEDIATE 1: PREPARATION OF 4-(4-(CHLOROMETHYL)-3-FLUOROPHENYL)-1-METHYL-1H-PYRAZOLE (INTERMEDIATE 1) The overall synthesis for the preparation of Intermediate 1 is shown below. (4-Bromo-2-fluorophenyl)methanol (2.5 g, 12.2 mmol) was added to a 20 mL microwave vial, followed by 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.54 g, 12.2 mmol), and cesium carbonate (7.9 g, 24.4 mmol). THF (5 mL) was added, and the mixture was stirred until all organics had dissolved, and then water (5 mL) was added. [1,1'-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (498 mg, 0.61 mmol) was added, and the vial was sealed and heated to 160° C. for 10 min. The water layer was removed and discarded, and the organic layer was dried, evaporated, and purified by silica gel chromatography (50-100% ethyl acetate in hexanes gradient) to afford the benzyl alcohol as a beige, crystalline solid. To a flame-dried round bottom flask equipped with a magnetic stir bar was added (2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl)methanol (3.9 g, 19 mmol). Dichloromethane (60 mL) was added, and to the suspension was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (5 mL, 38 mmol). The mixture was stirred at room temperature for 2 h, and then the solvent was removed by evaporation under reduced pressure. Residual volatiles were removed under high vacuum to afford the title compound as an amorphous beige solid. LCMS: RT=0.0.66 min, >99% 254 nm, >99% 220 nm; m/z (M+1)+=255. 1H NMR (400 MHz, CDCl3, δ (ppm)): 8.2 (s; 1H), 7.9 (s; 1H), 7.5-7.4 (m; 3H), 4.8 (s; 2H), 3.8 (s; 3H).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2015/28483, 2015, A1 Location in patent: Page/Page column 23; 24
[2]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2013/63549, 2013, A1 Location in patent: Paragraph 00490; 00663; 00664
[3]Current Patent Assignee: VANDERBILT UNIVERSITY - US2013/123236, 2013, A1 Location in patent: Paragraph 0673; 0674
[4]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2013/103931, 2013, A1 Location in patent: Paragraph 00307; 00445; 00446
[5]Current Patent Assignee: VANDERBILT UNIVERSITY - WO2013/106795, 2013, A1 Location in patent: Paragraph 00491; 00629; 00630
[6]Current Patent Assignee: VANDERBILT UNIVERSITY - US2014/194471, 2014, A1 Location in patent: Paragraph 0485; 0486

12
[ 1462-37-9 ]
[ 188582-62-9 ]
[ 1402585-62-9 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium hydride In N,N-dimethyl-formamide at 0 - 23℃; for 16h;	A118.4 Step 4: To a stirred solution of (4-bromo-2-fluorophenyl)methanol( 5 g, 24.509 mmol) in DMF (50 mL) at 0 °C NaH (60% suspension in mineral oil, 1 .96 g, 49.01 8 mmol) was added in portions. To the resulting suspension ((2-bromoethoxy)methyl)benzene (6.32 g, 29.41 mmol) was added at 0 °C, and the reaction mixture was allowed to stir at RT for 16 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was quenched with MeOH (5 mL), diluted with ice cold water (50 mL) and was extracted with EtOAc (3x 1 00 mL). The combined EtOAc layer was washed with water (50 mL), brine (50 mL), dried over anhydrous NaS04, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 1 -((2-(benzyloxy)ethoxy)methyl)-4-bromo-2-fluorobenzene (4.2 g, 51 %) as yellow liquid (TLC solvent system: 30% EtOAc in PE; Rf: 0.6).

Reference： [1]Current Patent Assignee: MEDIFRON DBT KR - WO2013/68461, 2013, A1 Location in patent: Page/Page column 118; 119

13
[ 188582-62-9 ]
[ 1541190-93-5 ]

Yield	Reaction Conditions	Operation in experiment
20%	With copper(l) iodide; sodium azide; sodium L-ascorbate; N,N`-dimethylethylenediamine In water; dimethyl sulfoxide at 60℃; Inert atmosphere;	VI.K.11; L.4.b 4-AZIDO-2-FLUOROBENZALDEHYDE, 26. [0339] 4-AZIDO-2-FLUOROBENZALDEHYDE, 26. 4-Bromo-2-fluorobenzyl alcohol (0.90 g, 4.4 mmol) was combined with sodium azide (572 mg, 8.8 mmol, 2 eq), copper iodide (84 mg, 0.44 mmol, 0.1 eq) and sodium ascorbate (44 mg, 0.22 mmol, 0.05 eq). This flask was evacuated and back-filled with Ar several times. 2 mL DMSO:H20 (5: 1; degassed with Ar) with N,A/ -dimethylethylenediamine (116 mg, 0.66 mmol, 0.15 eq) was added and the solution was stirred at 60° under Ar overnight. The solution was diluted in 10 mL of brine and extracted with EtOAc which was dried, passed through a plug of silica, and concentrated. 1H-NMR analysis indicated 28% conversion to 4-azido-2-fluorobenzylalcohol. Oxidation with PCC followed by silica gel chromatography gave 142 mg (20%) of 4-azido-2-fluorobenzaldehdye as a white solid. 1H-NMR (CDC13; 400 MHz): δ 10.26 (s, IH), 7.89 (dd, J= 8.4 Hz, J= 7.6 Hz, IH), 6.94 (dd, J= 8.4 Hz, J= 2.1 Hz, IH), 6.82 (dd, J= 11.0 Hz, J= 2.1 Hz) ppm. 19F-NMR (CDC13; 377 MHz): δ -119.8 (dd, J= 11.0 Hz, J= 7.6 Hz) ppm.
	Multi-step reaction with 2 steps 1: sodium azide; copper(l) iodide; N,N`-dimethylethylenediamine; sodium L-ascorbate / water; dimethyl sulfoxide / 60 °C / Inert atmosphere 2: pyridinium chlorochromate / dichloromethane / 1 h / 20 °C

Reference： [1]Current Patent Assignee: UNIVERSITY OF CALIFORNIA - WO2014/113607, 2014, A1 Location in patent: Paragraph 0339; 0359
[2]Jung, Michael E.; Chamberlain, Brian T.; Ho, Chi-Lee C.; Gillespie, Eugene J.; Bradley, Kenneth A. [ACS Medicinal Chemistry Letters, 2014, vol. 5, # 4, p. 363 - 367]

14
[ 188582-62-9 ]
[ 57848-46-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With tert.-butylhydroperoxide; tetrabutylammomium bromide In decane; benzene at 40℃; for 24h; Inert atmosphere; Sealed tube; chemoselective reaction;

Reference： [1]Ma, Xinyi; Li, Zhongfeng; Liu, Feijie; Cao, Shengli; Rao, Honghua [Advanced Synthesis and Catalysis, 2014, vol. 356, # 8, p. 1741 - 1746]

15
[ 557-21-1 ]
[ 188582-62-9 ]
[ 219873-06-0 ]

Yield	Reaction Conditions	Operation in experiment
30%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In N,N-dimethyl-formamide at 100℃; for 16h; Inert atmosphere;	1.2 1.2 3-fluoro-4-hydroxymethyl benzonitrile (1-2) Zinc cyanide (1.85 g, 15.85 mmol) and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 0.916 g, 0.79 mmol) were added into a solution of 4-bromo-2-fluorobenzyl alcohol (1-1, 3.25 g, 15.85 mmol) in DMF (35 mL). After deoxygenated via argon bubbling, the reaction mixture was heated at 100°C and reacted for 16 hours, cooled down to room temperature, diluted with ethyl acetate (100 mL), washed successively with water (100 mL3) and saturated brine (100 mL3), dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated to obtain a crude product. The crude product was then purified by column chromatography (elution system: petroleum ether: ethyl acetate = 15/1-4/1) to obtain a white solid product (0.72 g, 30% yield). The molecular ion peak shown by liquid chromatography-mass spectrometry was: MS (ESI): m/z 152.1 [M+H]+. NMR: 1HNMR (400 MHz, CDCl3) δ: 7.63 (t, J = 7.6 Hz, 8.0 Hz, 1 H), 7.48 (dd, J = 1.2 Hz, 8.0 Hz, 1 H), 7.48 (dd, J = 1.2 Hz, 9.2 Hz, 1 H), 4.83 (d, J = 10Hz, 2H), 2.00 (t, J = 10Hz, 1H).

Reference： [1]Current Patent Assignee: SUZHOU CONNECT BIOPHARMACEUTICALS - EP3048103, 2016, A1 Location in patent: Paragraph 0053; 0054

16
[ 188582-62-9 ]
[ 76283-09-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	With hydrogen bromide at 100℃; for 0.166667h;	3 Production of 4-bromo-2-fluorobenzyl bromide The above compound (7.00 g, 34.1 mmol) was dissolved into 48% hydrobromic acid (35 mL), and the resultant was caused to react at 100° for 10 minutes. After the end of the reaction, the resultant was neutralized with potassium carbonate. Thereafier, extraction with ethyl acetate was carried out, and this extraction layer was washed with water and a saturated saline solution, then dried over anhydrous magnesium sulfate, and concentrated under a reduced pressure to yield a compound (8.35 g, 91%). 1H-NMR (CDC13): 4.46 (s, 2H, HnCH2), 7.25-7.29 (m, 3H, Ar).

Reference： [1]Current Patent Assignee: STELLA CHEMIFA CORPORATION; OSAKA CITY UNIVERSITY - US2017/15684, 2017, A1 Location in patent: Paragraph 0144; 0145; 0146

17
[ 188582-62-9 ]
[ 244768-32-9 ]
C₁₈H₁₂BrFN₄O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With sodium hydroxide In dimethyl sulfoxide at 80℃;	4.1.4. Synthesis of target molecules 4a-ac General procedure: To a 100 mL two-necked flask was added substituted benzylalcohol or 4,6-dimethylpyrimidine-2-thiol (2.60 mmol), NaOH (6.40 g, 1.60 mmol) and dimethylsulfoxide (30 mL). The flask was vacuumed and flushed three times with nitrogen. Then the solutionof 8 (0.20 g, 0.87 mmol) in dimethylsulfoxide (510 mL) was added, and the resulting mixture was heated to 80 C and kept at that temperature for approximately 12 h until the completion of the reaction (monitored by TLC). Subsequently, the mixture was cooled to room temperature and diluted with ethyl acetate (100 mL). The mixture was washed with brine to pH 7, and the organic phase was dried with anhydrous sodium sulfate. The organic phase was concentrated to get crude product, which was purified by column chromatography (ethyl acetate/ petroleumether 1:30 as eluent) to get 4a-ac in yields of 27.3-75.1%.

Reference： [1]Lu, Huan-Huan; Xue, Ping; Zhu, Yuan-Yuan; Ju, Xiu-Lian; Zheng, Xiao-Jiao; Zhang, Xun; Xiao, Ting; Pannecouque, Christophe; Li, Ting-Ting; Gu, Shuang-Xi [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 8, p. 2491 - 2497]

18
[ 188582-62-9 ]
[ 134057-95-7 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 931 - 943

19
[ 188582-62-9 ]
[ 881189-74-8 ]

Reference： [1]ChemMedChem,2018,vol. 13,p. 931 - 943

20
[ 73183-34-3 ]
[ 188582-62-9 ]
[ 1082066-29-2 ]

Yield	Reaction Conditions	Operation in experiment
48%	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In 1,4-dioxane; at 90℃;Inert atmosphere;	3.1.1. Preparation of (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) At 90 C. under N2 atmosphere, to a stirred solution of 4-bromo-2-fluorophenylmethanol (500 mg, 2.44 mmol) in dioxane (5 mL) were added B2Pin2 (929 mg, 3.66 mmol), Pd(dppf)Cl2.DCM (198 mg, 0.24 mmol) and KOAc (717 mg, 7.32 mmol). After being stirred at 90 C. overnight, the reaction mixture was cooled down to room temperature and partitioned between EA and H2O. The layers were separated and the organic layer was washed with brine, dried over Na2SO4. Solvents were removed under vacuum and the residue was purified by flash chromatography (silica gel, 0?20 ethyl acetate in petroleum ether) to provide (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol (934-2) (300 mg, 48%) as a yellow oil.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 179,p. 449 - 469
[2]Patent: US2018/194762,2018,A1 .Location in patent: Paragraph 0740-0741
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 4984 - 4995
[4]Bioorganic Chemistry,2019,vol. 91

21
[ 58804-62-9 ]
[ 188582-62-9 ]
5-(3-fluoro-4-(hydroxymethyl)benzyl)-1-phenylpyrrolidin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With Ir(dF(CF₃)ppy)2(bpy)PF₆; Ni(4,4'-dimethoxy-2,2'-bipyridine)(H<SUB>2</SUB>O)<SUB>2</SUB>Br<SUB>2</SUB>; dibutylphosphoric acid tetrabutylammonium salt In toluene; <i>tert</i>-butyl alcohol at 20℃; for 48h; Inert atmosphere; Sealed tube; Irradiation;	General Procedure VI General procedure: An 8.0 mL screw-cap vial containing a stirring bar was charged with [Ni(dMeObpy)(H 2 O) 2 (Br) 2 ] (8.5 mg, 0.018 mmol, 6 mol %), [[Ir{dF(CF 3 ) 2 ppy} 2 (bpy)]PF 6 ] (9.0 mg, 0.009 mmol, 3 mol %), amide (0.36 mmol, 1.2 equiv), aryl bromide (if solid) (0.3 mmol, 1.0 equiv) and Bu 4 N[OP(O)(OBu) 2 ] (338.8 mg, 0.75 mmol, 2.5 equiv). Next, the vial was closed, and three vacuum/argon cycles were carried out. Under inert atmosphere, a 2:1 mixture of dry t-BuOH/PhCF 3 was added (6.0 mL, 0.05 M) followed by addition of the aryl bromide (if liquid). After further sealing with Parafilm, the reaction was placed in the blue LED bay and stirred at rt until completion (a fan was added to disperse any heat coming from the blue LEDs). When completed, the reactions were taken to dryness and purified by column chromatography using an automated system (hexanes/EtOAc gradient), delivering the corresponding pure product.

Reference： [1]Zheng, Shuai; Gutiérrez-Bonet, Álvaro; Molander, Gary A. [Chem, 2019, vol. 5, # 2, p. 339 - 352]

22
[ 188582-62-9 ]
[ 329214-79-1 ]
(2-fluoro-4-(pyridin-3-yl)phenyl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
69%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; potassium carbonate In 1,4-dioxane; water at 100℃; Inert atmosphere;	1 Step 1: (2-fluoro-4-(pyridin-3-yl)phenyl)methanol To a stirred solution of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine (350 mg, 1.68 mmol) and 4-bromo-2-fluorophenyl)methanol (340 mg, 1.85 mmol) in dry dioxane (4 ml_), a solution of potassium carbonate (700 mg, 5.04 mmol) in water (1 mL) was added at RT and the resulting solution was flushed with nitrogen for 10 min. Tetrakis (triphenylphosphine)palladium(O) (191 mg, 0.68 mmol) was added at RT. The reaction mixture was heated at 100 °C overnight. After completion of reaction, the reaction mixture was filtered through celite pad and the filtrate was concentrated under vacuum. The resulting crude product was purified by flash chromatography (Eluent: 50% EtOAc in pet ether) to afford the title compound. Yield: 69% (235 mg, pale yellow gummy solid). 1H NMR (400 MHz, DMSO-cfe): <5 8.93 (d, J = 2.4 Hz, 1 H), 8.59 (dd, J = 6.2, 1.6 Hz, 1 H), 8.58-8.09 (m, 1 H), 7.47-7.60 (m, 4H), 5.35 (t, J = 7.6 Hz, 1 H), 4.60 (d, J = 7.6 Hz, 2H). LCMS: (Method A) 204.2 (M+H), Rt. 0.74 min, 94.66% (max).

Reference： [1]Current Patent Assignee: ASCENEURON SA - WO2020/39027, 2020, A1 Location in patent: Page/Page column 147

23
[ 107-30-2 ]
[ 188582-62-9 ]
4-bromo-2-fluoro-1-((methoxymethoxy)methyl)benzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With N-ethyl-N,N-diisopropylamine In dichloromethane at 4℃; for 48.3333h;	2.1 A mixture of (4-bromo-2-fluorophenyl)methanol (20 g, 98 mmol) and DIPEA (25.5 mL, 107 mmol) in methylene chloride (100 mL) was treated with methoxymethyl chloride (8.17 mL, 107 mmol) in methylene chloride (20 mL) over 20 min. at 4 °C. The resulting mixture was stirred for 48 h. The mixture was washed with 5% aq. NaHCCh (50 mL), dried over NaSCri, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel 100 g, c-hexane/AcOEt 100:0 to 95:5) to afford Compound 1-D as a colorless oil (23.5 g, 88% yield). 'H NMR (400 MHz, DMSO-i) d ppm 1.40 (s), 3.28 (s, 3H), 4.54 (d, J= 1.32 Hz, 2H), 4.65 (s, 2H), 7.37 - 7.48 (m, 2H), 7.50 - 7.60 (m, 1H) residual solvent present.

Reference： [1]Current Patent Assignee: NEUROCRINE BIOSCIENCES INC - WO2021/62246, 2021, A1 Location in patent: Page/Page column 90-91

24
[ 111-34-2 ]
[ 188582-62-9 ]
1-[3-fluoro-4-(hydroxymethyl)phenyl]ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
25.36%	With 1,3-bis-(diphenylphosphino)propane; palladium diacetate; potassium carbonate In N,N-dimethyl-formamide at 120℃; for 2h; Inert atmosphere; Microwave irradiation;	1.1 (1) Preparation of compounds 1-1 Stirred to (4-bromo-2-fluorophenyl) methanol (500.00 mg, 2.439mmol, 1.00eq), Pd(OAc)2 (10.95mg, 0.049mmol, 0.02eq), DPPP (40.6mg, 0.09mmol, 0.04eq) and K at room temperature 2 CO 3 (404.45 mg, 2.926 mmol, 1.20 equivalent) in the mixture of DMF (5 mL) was added butyl vinyl ether (1.25 mL). Empty the flask and rinse three times with nitrogen. Irradiate the final reaction mixture with microwave radiation for 2 h at 120 °C and extract the resulting solution with ethyl acetate. Combine the organic layers, wash with sodium carbonate (aqueous solution) and brine, dry and concentrate in vacuo. The residue was purified by reversed-phase rapid chromatography to give 1-[3-fluoro-4-(hydroxymethyl)phenyl]ethanone (104 mg, 25.36%), which was a yellow solid.

Reference： [1]Current Patent Assignee: HUADONG MEDICINE CO., LTD. - WO2022/78152, 2022, A1 Location in patent: Page/Page column 39-40

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P378
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Ghs Hazard Statements

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H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
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Code	Phrase
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H420	Harms public health and the environment by destroying ozone in the upper atmosphere