Name: 261951-70-6|4-(Bromomethyl)-1-fluoro-2-methylbenzene|98%
Brand: Ambeed
SKU: A720825
Rating: 90 (27 reviews)

1
[ 261951-66-0 ]
[ 261951-70-6 ]

Yield	Reaction Conditions	Operation in experiment
	With carbon tetrabromide; triphenylphosphine In dichloromethane for 1h;	51 Preparation 51; Carbon tetrabromide (3.08 g) was added portion wisely to a solution of 4-fluoro-3-methylbenzylalcohol (1.3 g) and triphenylphosphine (2.9 g) in methylene chloride (50 ml) and the mixture was stirred for 1 hour. The solution was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was triturated with hexane and the resulting precipitate was removed by filtration. The filtrate was evaporated in vacuo and the residue was purified by column chromatography on silica gel with hexane as eluent to give 4-fluoro-3-methylbenzylbromide (1.28 g) as an oil. IR (Neat): 1500, 1250, 1200 cm-1 NMR (CDCl3, δ): 2.26 (3H, s), 4.45 (2H, s), 6.91-7.26 (3H, m)

Reference： [1]Current Patent Assignee: ASTELLAS PHARMA INC. - US2006/14948, 2006, A1 Location in patent: Page/Page column 25

2
[ 261951-70-6 ]
[ 877142-72-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 5-fluoroisatoic anhydride With sodium hydride In N,N-dimethyl acetamide for 0.166667h; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In N,N-dimethyl acetamide at 70℃; for 2h;	25.B 6-fluoroisatoic anhydride (79, 0.6 g, 3.3 mmol) was dissolved in anhydrous N,N-dimethylacetamide (16 mL). The solution was stirred under an N2 atmosphere and NaH (0.146 g, 3.64 mmol, 60% dispersion in mineral oil) was added. The mixture was stirred for 10 min and then 4-fluoro-3-methylbenzyl bromide (0.74 g, 3.64 mmol) was added. The reaction was heated to 70° C. for 2 h, cooled to RT, and then in an ice bath. The cold reaction mixture was poured into a cold saturated NH4Cl solution (100 mL) and extracted twice with Et2O/EtOAc (100 mL). The combined ether solutions were washed with water (30 mL), saturated NaCl solution and dried (Na2SO4). The extracts were filtred and evaporated and the solid was triturated with 10% Et2O/hexanes and vacuum dried to afford 900 mg (90%) of 80: ms [M]+=303; 1H NMR (300 MHz, DMSO-d6):δ 7.84 ppm (1H, dd, J=7.4, 3 Hz); 7.37 ppm (1H, m); 7.1 ppm (3H, m); 6.99 ppm (1H, dd, J9 Hz); 5.22 ppm (2H, s); 2.26 ppm (3H, s).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2006/40927, 2006, A1 Location in patent: Page/Page column 40

3
[ 261951-70-6 ]
[ 180516-87-4 ]
[ 1029438-21-8 ]

Yield	Reaction Conditions	Operation in experiment
43%	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;	16 Boronate ester 32 (500 mg, 1.0 eq), benzyl bromide 33 (450 mg, 1.1 eq) and cesium carbonate(920 mg, 1.4 eq) were dissolved in anhydrous DMF and stirred for 3 h at rt. The reaction was diluted with EtOAc (25 mL). The solution was then washed with water, 5% NaHCO3, water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to a white solid which was purified via column chromatography (hexanes) to give 34 (320 mg, 43% yield) as a white solid.

Reference： [1]Current Patent Assignee: INFINITY PHARMACEUTICALS INC - WO2008/63300, 2008, A2 Location in patent: Page/Page column 178

4
[ 261951-70-6 ]
1,4-butenediol [ No CAS ]
[ 1043450-47-0 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran at 20℃; for 8h;	To a suspension of NaH (1.0 g, 60% oil dispersion) in 80 mL THF was slowly added but-2-ene-1,4-diol (2.0 g, 22 mmol) as a solution in 5 mL THF at room temperature. To this mixture was added dropwise 4-bromomethyl-1-fluoro-2-methyl-benzene (5.0 g, 24 mmol) and the resulting stirred for 8 h at room temperature. The reaction was quenched by the slow addition of 50 mL of saturated NH4Cl and the mixture extracted with ethyl acetate (380 mL). The combined organic layers were washed with brine (260 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the product isolated by Flash column chromatography eluding with 0% to 50% ethyl acetate/hexane to give 2.3 g of the title compound as a light yellow oil.

Reference： [1]Current Patent Assignee: PAN THERA BIOPHARMA - US2008/188565, 2008, A1 Location in patent: Page/Page column 16-17

5
[ 502-44-3 ]
[ 261951-70-6 ]
[ 1043453-91-3 ]

Yield	Reaction Conditions	Operation in experiment
94%	Stage #1: hexahydro-2H-oxepin-2-one; 4-(bromomethyl)-1-fluoro-2-methylbenzene With potassium hydroxide In toluene for 86h; Heating / reflux; Stage #2: With hydrogenchloride In water at 20℃;	4.a 6-(4-fluoro-3-methylbenzyloxy)hexanoic acid (A4) To a solution of oxepan-2-one (0.562 g, 4.925 mmol) and 4-fluoro-3-methylbenzyl bromide (3.000 g, 14.774 mmol) in 20 mL of toluene, was added KOH (1.382 g, 24.625 mmol). The mixture was refluxed for 86 h and after cooling to room temperature, the reaction mixture was diluted with water (80 mL) and washed with ether. The aqueous layer was acidified with concentrated HCl to pH=2 and extracted with ether (50 mL×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as colorless oil which was used directly in the next step without further purification (1.173 g, 94% yield). LC-MS: tR=8.0 min, m/z 277 (M+H)+.
94%	Stage #1: hexahydro-2H-oxepin-2-one; 4-(bromomethyl)-1-fluoro-2-methylbenzene With potassium hydroxide In toluene for 86h; Heating / reflux; Stage #2: With hydrogenchloride In water	6.a To a solution of oxepan-2-one (0.562 g, 4.925 mmol) and 4-fluoro-3- methylbenzyl bromide (3.000 g, 14.774 mmol) in 20 mL of toluene, was added KOH (1.382 g, 24.625 mmol). The mixture was refluxed for 86 h. After cooling to room temperature, the reaction mixture was diluted with water (80 mL) and washed with ether. The aqueous layer was acidified with concentrated HCl to pH = 2 and extracted with ether (50 mL X 3). The combined organic extracts dried (Na2SO4), filtered, and concentrated under reduced pressure to give the title compound as colorless oil which was used directly in the next step without further purification (1.173 g, 94% yield). LC-MS: tR = 8.0 min, m/z 277 (M+H)+.
	With potassium hydroxide In toluene Reflux;

Reference： [1]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - US2008/188566, 2008, A1 Location in patent: Page/Page column 14-15
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1 Location in patent: Page/Page column 47-48
[3]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]

6
[ 261951-70-6 ]
C₂₃H₂₈F₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide / toluene / Reflux 2: lithium hexamethyldisilazane / tetrahydrofuran / -78 - 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]

7
[ 261951-70-6 ]
[ 1043890-81-8 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 8 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C 3: 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane; acetic acid / tetrahydrofuran; toluene / -78 - 20 °C 4: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran; water / 0 °C 5: methanol; dichloromethane 6: 50% Pd-BaSO4; hydrogen / ethyl acetate 7: oxygen; copper diacetate; triethylamine / dichloromethane / 20 °C / Molecular sieve 8: potassium cyanide; hydroxylamine monohydrate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 8 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 0.02 - 0.03 h / -78 °C 3.3: -78 - 20 °C 4.1: lithium hydroxide; water; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.2: pH 2 5.1: methanol; dichloromethane / 0.5 h / 20 °C 6.1: hydrogen / rosenmund catalyst / ethyl acetate / 1.25 h / 20 °C 7.1: oxygen; copper diacetate; triethylamine / dichloromethane / 44 h / 20 °C / Molecular sieves 4Å 8.1: hydroxylamine; potassium cyanide / tetrahydrofuran; methanol; water / 15 h / 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

8
[ 261951-70-6 ]
[ 1043453-94-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium hydroxide / toluene / Reflux 2: lithium hexamethyldisilazane / tetrahydrofuran / -78 - 20 °C 3: hydroxylamine monohydrate / tetrahydrofuran; methanol / 20 °C
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: 20 °C / pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 3 h / -78 - 20 °C 4.1: hydroxylamine / potassium cyanide / tetrahydrofuran; methanol; water / 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - US2008/188566, 2008, A1

9
[ 261951-70-6 ]
C₂₀H₂₈FNO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]

10
[ 261951-70-6 ]
C₂₀H₂₇FN₄O₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C 3: 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane; acetic acid / tetrahydrofuran; toluene / -78 - 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]

11
[ 261951-70-6 ]
[ 1043890-93-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C 3: 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane; acetic acid / tetrahydrofuran; toluene / -78 - 20 °C 4: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran; water / 0 °C
	Multi-step reaction with 4 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 0.02 - 0.03 h / -78 °C 3.3: -78 - 20 °C 4.1: lithium hydroxide; water; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.2: pH 2

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

12
[ 261951-70-6 ]
[ 1043890-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C 3: 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane; acetic acid / tetrahydrofuran; toluene / -78 - 20 °C 4: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran; water / 0 °C 5: methanol; dichloromethane
	Multi-step reaction with 5 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 0.02 - 0.03 h / -78 °C 3.3: -78 - 20 °C 4.1: lithium hydroxide; water; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.2: pH 2 5.1: methanol; dichloromethane / 0.5 h / 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

13
[ 261951-70-6 ]
[ 1043890-95-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C 3: 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane; acetic acid / tetrahydrofuran; toluene / -78 - 20 °C 4: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran; water / 0 °C 5: methanol; dichloromethane 6: 50% Pd-BaSO4; hydrogen / ethyl acetate
	Multi-step reaction with 6 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 0.02 - 0.03 h / -78 °C 3.3: -78 - 20 °C 4.1: lithium hydroxide; water; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.2: pH 2 5.1: methanol; dichloromethane / 0.5 h / 20 °C 6.1: hydrogen / rosenmund catalyst / ethyl acetate / 1.25 h / 20 °C

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

14
[ 261951-70-6 ]
[ 1043890-96-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 7 steps 1: potassium hydroxide / toluene / Reflux 2: pivaloyl chloride; triethylamine; lithium chloride / tetrahydrofuran / -10 - 20 °C 3: 2,4,6-Triisopropylbenzenesulfonyl azide; potassium hexamethylsilazane; acetic acid / tetrahydrofuran; toluene / -78 - 20 °C 4: dihydrogen peroxide; lithium hydroxide / tetrahydrofuran; water / 0 °C 5: methanol; dichloromethane 6: 50% Pd-BaSO4; hydrogen / ethyl acetate 7: oxygen; copper diacetate; triethylamine / dichloromethane / 20 °C / Molecular sieve
	Multi-step reaction with 7 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 0.02 - 0.03 h / -78 °C 3.3: -78 - 20 °C 4.1: lithium hydroxide; water; dihydrogen peroxide / tetrahydrofuran / 0 - 20 °C 4.2: pH 2 5.1: methanol; dichloromethane / 0.5 h / 20 °C 6.1: hydrogen / rosenmund catalyst / ethyl acetate / 1.25 h / 20 °C 7.1: oxygen; copper diacetate; triethylamine / dichloromethane / 44 h / 20 °C / Molecular sieves 4Å

Reference： [1]Kim, Seongjin; Jiao, Guan-Sheng; Moayeri, Mahtab; Crown, Devorah; Cregar-Hernandez, Lynne; McKasson, Linda; Margosiak, Stephen A.; Leppla, Stephen H.; Johnson, Alan T. [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 7, p. 2030 - 2033]
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

15
[ 261951-70-6 ]
[ 1418720-62-3 ]
[ 1418717-98-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.25h;	25.B Step B methyl 2-(tert-butoxy)-2-(1-(4-fluoro-3-methylbenzyl)-6-methyl-4-(p-tolyl)-^b ]pyridin-5-yl) acetate Methyl 2-(tert-butoxy)-2-(6-methyl-4-(p-tolyl)-1 H-pyrrolo[2,3-b]pyridin-5-yl)acetate (15 mg, 0.036 mmol) was dissolved in DMF (2 mL) and cooled to 0°C. Sodium hydride (0.175 mmol, 7 mg, 60% dispersion in oil) was added followed by dropwise addition of 4- (bromomethyl)-1-fluoro-2-methylbenzene. The reaction was stirred at ambient temperature 15 minutes, diluted with water and extracted with ethyl acetate, dried over sodium sulfate and purified by silica-gel chromatography (0-50% ethyl acetate/hexanes gradient elution) to give the title compound as a colorless oil 17 mg, 85%). 1H NMR (400MHz ,CHLOROFORM-c/) δ ppm = 7.52 - 7.46 (m, 1 H), 7.42 - 7.35 (m, 1 H), 7.34 - 7.26 (m, 2 H), 7.16 (d, J = 7.2 Hz, 1 H), 7.1 1 (td, J = 2.3, 5.3 Hz, 1 H), 7.02 - 6.92 (m, 2 H), 6.15 (d, J = 3.5 Hz, 1 H), 5.44 - 5.39 (m, 2 H), 3.77 (s, 3 H), 2.74 (s, 3 H), 2.47 (s, 3 H), 2.26 (d, J = 1.4 Hz, 3 H), 1.67 (s, 1 H), 0.93 (s, 9 H); LCMS (m/z) ES+= 489 (M+1 ).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/12649, 2013, A1 Location in patent: Paragraph 00209

16
[ 261951-70-6 ]
N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]
1-(4-fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
150 mg	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5h;	6 1-(4-Fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide To a mixture of N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 4), (100 mg), 4-(bromomethyl)-1-fluoro-2-methylbenzene (86 mg) and cesium carbonate (289 mg) was added DMF (4 mL) and left to stir at rt for 90 min. The crude product was diluted with MeOH and purified using an SCX-2 cartridge (washed sequentially with MeOH, H2O, MeOH and product eluted using 2 M methanolic ammonia). The solution was evaporated under vacuum to give the desired compound (150 mg). LCMS: m/z 382.64 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.12-1.90 (m, 6H) 2.07-2.19 (m, 2H) 2.23 (d, J=1.5 Hz, 3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.78-4.03 (m, 1H) 4.49 (br. s., 1H) 5.27 (s, 2H) 6.86-7.07 (m, 3H) 7.18 (dd, J=8.3, 4.8 Hz, 1H) 7.52-7.73 (m, 1H) 8.08 (s, 1H) 8.50 (dd, J=4.7, 1.0 Hz, 1H) 9.04 (d, J=6.0 Hz, 1H)
150 mg	With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 1.5h;	6 1-(4-Fluoro-3-methylbenzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide To a mixture of N-((1S,2S)-2-hydroxycyclohexyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide (Intermediate 4), (100 mg), 4-(bromomethyl)-1-fluoro-2-methylbenzene (86 mg) and cesium carbonate (289 mg) was added DMF (4 mL) and left to stir at rt for 90 min. The crude product was diluted with MeOH and purified using an SCX-2 cartridge (washed sequentially with MeOH, H2O, MeOH and product eluted using 2 M methanolic ammonia). The solution was evaporated under vacuum to give the desired compound (150 mg). LCMS: m/z 382.64 [M+H]+. 1H NMR (400 MHz, CDCl3) ppm 1.12-1.90 (m, 6H) 2.07-2.19 (m, 2H) 2.23 (d, J=1.5 Hz, 3H) 3.57 (td, J=9.9, 4.5 Hz, 1H) 3.78-4.03 (m, 1H) 4.49 (br. s., 1H) 5.27 (s, 2H) 6.86-7.07 (m, 3H) 7.18 (dd, J=8.3, 4.8 Hz, 1H) 7.52-7.73 (m, 1H) 8.08 (s, 1H) 8.50 (dd, J=4.7, 1.0 Hz, 1H) 9.04 (d, J=6.0 Hz, 1H)

Reference： [1]Current Patent Assignee: EISAI CO LTD - US2015/94328, 2015, A1 Location in patent: Paragraph 0592-0594
[2]Current Patent Assignee: EISAI CO LTD - WO2015/49574, 2015, A1 Location in patent: Page/Page column 73

17
[ 261951-70-6 ]
cinchonidine [ No CAS ]
C₂₇H₃₀FN₂O⁽¹⁺⁾*Br^(1-) [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile at 20℃; Inert atmosphere;

Reference： [1]Denmark, Scott E.; Cullen, Lindsey R. [Journal of Organic Chemistry, 2015, vol. 80, # 23, p. 11818 - 11848]

18
[ 261951-70-6 ]
cinchonidine [ No CAS ]
cinconidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; isopropyl alcohol at 20 - 70℃; for 12h; Schlenk technique;

Reference： [1]Denmark, Scott E.; Cullen, Lindsey R. [Journal of Organic Chemistry, 2015, vol. 80, # 23, p. 11818 - 11848]

19
[ 261951-70-6 ]
[ 26621-44-3 ]
1-(4-fluoro-3-methylbenzyl)-3-nitro-1H-pyrazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutylammomium bromide; potassium carbonate; In acetone; at 20℃; for 8h;	Prepared according to general procedure 4 with K2CO3 (3.51 g, 25.4 mmol), 4-fluoro-3-methylbenzyl bromide (1.03 g, 5.08 mmol), 5-nitro-1 H-pyrazole (574 mg, 5.08 mmol), and Bu4NBr (334 mg, 1.02 mmol) in acetone (45 mL). The reaction is complete after 8 h at rt. Purification of the crude by automated FC (Buchi, EtOAc / heptane 1 :99? 5:95? 10:90? 15:85? 25:75 ? 35:65, 20 g silicagel, flow 20 mL/min) yields the title compound. LC-MS: tR = 0.86 min (conditions 3). General procedure 4 for the N-alkylation of 5-nitro-1H-pyrazole. K2CO3 or NaH is added to a sol. of 5-nitro-1 H- pyrazole in acetone or DMF or THF. The mixture is stirred for 15-30 min. The desired electrophile and Bu4NBr are added. The mixture is stirred efficiently at rt until the reaction is complete. The mixture is optionally filtered (if K2CO3 is used) or quenched with water (if NaH is used), and the filtrate is evaporated under reduced pressure. The residue is partitioned between water and EtOAc. The org. layer is dried over MgS04, filtered, and the solvents are removed under reduced pressure. Purification of the crude by automated FC or by HPLC yields the desired product.

Reference： [1]Patent: WO2015/186056,2015,A1 .Location in patent: Page/Page column 53

20
[ 261951-70-6 ]
(E)-N-((4-fluoro-3-methylbenzyl)(methyl)-λ⁴-sulfanylidene)-4-nitrobenzenesulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: N,N-dimethyl-formamide / 16 h / 20 °C 2: [bis(acetoxy)iodo]benzene / acetonitrile / 16 h / 90 °C

Reference： [1]Current Patent Assignee: JW PHARMACEUTICAL DO.,LTD. - WO2016/89060, 2016, A2

21
[ 261951-70-6 ]
N-((4-fluoro-3-methylbenzyl)(methyl)(oxo)-λ⁶-sulfanylidene)-4-nitrobenzene sulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: N,N-dimethyl-formamide / 16 h / 20 °C 2: [bis(acetoxy)iodo]benzene / acetonitrile / 16 h / 90 °C 3: ruthenium(III) trichloride hydrate; sodium periodate / water; dichloromethane / 16 h / 20 °C

Reference： [1]Current Patent Assignee: JW PHARMACEUTICAL DO.,LTD. - WO2016/89060, 2016, A2

22
[ 261951-70-6 ]
[ 5188-07-8 ]
(4-fluoro-3-methylbenzyl)(methyl)sulfane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	In N,N-dimethyl-formamide at 20℃; for 16h;	a (a) Synthesis of (4-fluoro-3-methylbenzyl)(methyl)sulfane Intermediate 13) Synthesis of 5-((S- methyIsulfonimidoyl)methyI)benzo[6]thiophene-2-carboxylic acid (a) Synthesis of (4-fluoro-3-methylbenzyl)(methyl)sulfane 4-(Bromomethyl)-l-fluoro-2-methylbenzene (1.0 g, 4.92 mmol) and sodium methanethiolate (380.0 mg, 5.42 mmol) were dissolved in DMF (24.6 mL). The reaction mixture was stirred at room temperature for 16 hours, H20 was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n- ex : CH2C12 = 4 : 1) to obtain (4-fluoro-3- methylbenzyl)(methyl)sulfane (709.0 mg, 85%) as a colorless liquid. 1H-NMR (400MHz, CDC13): δ 7.12 (d, 1H, J=7.3Hz), 7.06 (m, 1H), 6.93 (m, 1H), 3.61 (s, 2H), 2.26 (s, 3H), 1.99 (s, 3H)

Reference： [1]Current Patent Assignee: JW PHARMACEUTICAL DO.,LTD. - WO2016/89060, 2016, A2 Location in patent: Page/Page column 42

23
[ 261951-70-6 ]
butyl 5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate [ No CAS ]
butyl 1-(4-fluoro-3-methylbenzyl)-5-(methylcarbamoyl)-6-oxo-1,6-dihydropyridine-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
900 mg	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	Intermediate 128: Butvl 1-(4-fluoro-3-methvlbenzvl)-5-(methvlca rba movl)-6- oxo- 1,6-d ihyd ropyridine-3-ca rboxylate 4-(Bromomethyl)-1-fluoro-2-methylbenzene (0.805 g, 3.96 mmol) was added to a solution of butyl 5-(methylcarbamoyl)-6-oxo- 1,6-dihydropyridine-3-carboxylate (1 g, 3.96 mmol) and potassium carbonate (1.096 g, 7.93 mmol) in DMF (20 mL). The reaction mixture was left to stir atrt for 2 h. The reaction mixture was concentrated under vacuum and partitioned between DCM (20 mL) and water (20 mL). The organic layer was concentrated under vacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silica flash chromatography using a gradient of O-60% cyclohexane/ethyl acetate. The appropriate fractions were combined and concentrated under vacuum to give the product (900 mg) as a white solid.LCMS (2 mm Formic): Rt = 1.24 mi [MH] = 375.1.
900 mg	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2h;	Intermediate 24: Butvl 1-(4-fluoro-3-methvlbenzvl)-5-(methvlca rba movl)-6-oxo- 1,6-dihyd ronyridi ne-3-ca rboxvlate 4-(Bromomethyl)-1-fluoro-2-methylbenzene (0.805 g, 3.96 mmol) was added to a solution of butyl 5-(methylcarbamoyl)-6-oxo- 1,6-dihydropyridine-3-carboxylate (1 g, 3.96 mmol) and potassium carbonate (1.096 g, 7.93 mmol) in DMF (20 mL). The reaction mixture was left to stir at rt for 2 h. The reaction mixture was concentrated under vacuum and partitioned between DCM (20mL) and water (20 mL). The organic layer was concentrated under vacuum, loaded in DCM (3 mL) and purified by Biotage Isolera SNAP 25 g silica flash chromatography using a gradient of O-6O% cyclohexane/ethyl acetate. The appropriate fractions were combined and concentrated under vacuum to give the product (900 mg) as a white solid.LCMS (2 mm Formic):Rt = 1.24 mins, [MH] = 375.1

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/37116, 2017, A1 Location in patent: Page/Page column 123; 124
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/50714, 2017, A1 Location in patent: Page/Page column 63

24
[ 261951-70-6 ]
5-bromo-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]
5-bromo-1-(4-fluoro-3-methylbenzyl)-N-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
188 mg	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;	Intermediate 117: 5-Bromo-1-(4-fluoro-3-methvlbenzvfl-N-methvl-2-oxo-1,2- dihydropyridi ne-3-ca rboxa mide 5-Bromo-N-methyl-2-oxo- 1,2-dihydropyridine-3-carboxamide (195 mg, 0.844 mmol), potassium carbonate (233 mg, 1.688 mmol) in a solution of DMF (5 mL) were stirred at rt and 4- (bromomethyl)-1-fluoro-2-methylbenzene (257 mg, 1.266 mmol) was added dropwise. The reaction mixture was allowed to stir at rt for 3 h. The reaction mixture was concentrated under vacuum,redissolved in ethyl acetate (30 mL) and washed with water (30 mL). The solution was concentrated under vacuum, loaded in DCM and purified by Biotage Isolera SNAP 25g silica flash chromatography using a gradient of O-55% cyclohexane/ethyl acetate. The appropriate fractions were combined and concentrated under vacuum to give the product (188 mg).LCMS (2 mm Formic):Rt = 1.07 mi [MH] = 353.0 & 355.0.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2017/37116, 2017, A1 Location in patent: Page/Page column 118

25
[ 261951-70-6 ]
methyl 1-(7-hydroxychroman-3-yl)azetidine-3-carboxylate [ No CAS ]
1-[7-[(4-fluoro-3-methylphenyl)methoxy]chroman-3-yl]azetidine-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
38.7%	Stage #1: 4-(bromomethyl)-1-fluoro-2-methylbenzene; methyl 1-(7-hydroxychroman-3-yl)azetidine-3-carboxylate With potassium carbonate In N,N-dimethyl-formamide at 20℃; Sealed tube; Stage #2: With water; lithium hydroxide In methanol at 60℃; for 1h;	84 84. 84. 1-[7-[(4-fluoro-3-methyl-phenyl)methoxy]chroman-3-yl]azetidine-3-carboxylic Acid A vial was charged with a stir bar, a 500 μL solution of methyl 1-(7-hydroxychroman-3-yl)azetidine-3-carboxylate in DMF (22.2 mg, 0.08 mmol), 170 μL of a 0.6 mmol pre-weighed solution of 4-(bromomethyl)-1-fluoro-2-methylbenzene in 1000 μL of DMF (1.2 eq, 20.5 mg, 0.10 mmol), and ground K2CO3 (2 eq, 23.3 mg, 0.16 mmol). The vial was capped and placed to stir overnight at room temperature. Upon completion the vial was concentrated to dryness and the crude material was re-dissolved with 1000 μL of a 1M aqueous solution of LiOH in 75% MeOH. This was place capped once more and placed to stir with heating at 60° C. for 1 hour. Upon completion the compound was concentrated to dryness and re-dissolved in 1.4 mL of DMSO/Acetonitrile (1:1 v/v). The crude material was filtered using a 3 mL disposable syringe with filter. The crude material was submitted to APS for reverse phase HPLC purification where 1-[7-[(4-fluoro-3-methyl-phenyl)methoxy]chroman-3-yl]azetidine-3-carboxylic acid was afforded (14.3 mg, 38.7%). 1H NMR (400 MHz, DMSO-d6) δ 7.31 (dd, J=7.6, 2.2 Hz, 1H), 7.25 (ddd, J=7.7, 5.0, 2.3 Hz, 1H), 7.11 (dd, J=9.9, 8.4 Hz, 1H), 6.93 (d, J=8.4 Hz, 1H), 6.47 (dd, J=8.4, 2.6 Hz, 1H), 6.33 (d, J=2.6 Hz, 1H), 4.95 (s, 2H), 3.95 (ddd, J=11.1, 2.9, 1.4 Hz, 1H), 3.66 (dd, J=10.9, 6.6 Hz, 1H), 3.38 (dt, J=15.1, 7.3 Hz, 2H), 3.19 (td, J=7.1, 4.3 Hz, 2H), 2.95 (p, J=7.8 Hz, 1H), 2.72 (dd, J=15.5, 4.6 Hz, 1H), 2.59 (qd, J=7.0, 3.0 Hz, 1H), 2.33 (dd, J=15.9, 6.7 Hz, 1H), 2.22 (d, J=1.9 Hz, 3H).

Reference： [1]Current Patent Assignee: ABBVIE INC - US2017/174672, 2017, A1 Location in patent: Paragraph 1011-1012

26
[ 261951-70-6 ]
[ 1043453-92-4 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: 20 °C / pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C
	Multi-step reaction with 2 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C

Reference： [1]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - US2008/188566, 2008, A1
[2]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

27
[ 261951-70-6 ]
[ 1043453-93-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: 20 °C / pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 3 h / -78 - 20 °C

Reference： [1]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - US2008/188566, 2008, A1

28
[ 261951-70-6 ]
[ 1043450-51-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran / 8 h / 20 °C 2.1: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / 0 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -70 °C 3.2: 1 h / -70 °C 4.1: hydrogen / Wilkinson's catalyst / benzene / 8 h / 20 °C 5.1: hydroxylamine / potassium cyanide / tetrahydrofuran; methanol; water / 72 h / 20 °C

Reference： [1]Current Patent Assignee: PAN THERA BIOPHARMA - US2008/188565, 2008, A1

29
[ 261951-70-6 ]
[ 1043450-50-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydride / tetrahydrofuran / 8 h / 20 °C 2.1: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / 0 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -70 °C 3.2: 1 h / -70 °C 4.1: hydrogen / Wilkinson's catalyst / benzene / 8 h / 20 °C

Reference： [1]Current Patent Assignee: PAN THERA BIOPHARMA - US2008/188565, 2008, A1

30
[ 261951-70-6 ]
[ 1043450-48-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydride / tetrahydrofuran / 8 h / 20 °C 2: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / 0 °C

Reference： [1]Current Patent Assignee: PAN THERA BIOPHARMA - US2008/188565, 2008, A1

31
[ 261951-70-6 ]
[ 1043450-49-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / tetrahydrofuran / 8 h / 20 °C 2.1: 1H-imidazole; iodine; triphenylphosphine / dichloromethane / 2.5 h / 0 °C 3.1: lithium hexamethyldisilazane / tetrahydrofuran / 0.5 h / -70 °C 3.2: 1 h / -70 °C

Reference： [1]Current Patent Assignee: PAN THERA BIOPHARMA - US2008/188565, 2008, A1

32
[ 261951-70-6 ]
[ 1043890-92-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: potassium hydroxide / toluene / 86 h / Heating / reflux 1.2: pH 2 2.1: pivaloyl chloride; triethylamine / tetrahydrofuran / 1 h / -10 °C 2.2: -10 - 20 °C 3.1: potassium hexamethylsilazane / tetrahydrofuran / 1 h / -78 °C 3.2: 0.02 - 0.03 h / -78 °C 3.3: -78 - 20 °C

Reference： [1]Current Patent Assignee: PANTHERA BIOPHARNA; PAN THERA BIOPHARMA - WO2008/94592, 2008, A1

33
[ 261951-70-6 ]
[ 39791-96-3 ]
C₁₇H₁₆ClFN₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 16h;

Reference： [1]Hodges, Timothy R.; Abbott, Jason R.; Little, Andrew J.; Sarkar, Dhruba; Salovich, James M.; Howes, Jennifer E.; Akan, Denis T.; Sai, Jiqing; Arnold, Allison L.; Browning, Carrie; Burns, Michael C.; Sobolik, Tammy; Sun, Qi; Beesetty, Yugandhar; Coker, Jesse A.; Scharn, Dirk; Stadtmueller, Heinz; Rossanese, Olivia W.; Phan, Jason; Waterson, Alex G.; McConnell, Darryl B.; Fesik, Stephen W. [Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8875 - 8894]

34
[ 261951-70-6 ]
[ 39791-96-3 ]
1-(4-fluoro-3-methylbenzyl)-5,6-dimethyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 16 h / 20 °C 2: N,N-dimethyl acetamide / 0.75 h / 165 °C

Reference： [1]Hodges, Timothy R.; Abbott, Jason R.; Little, Andrew J.; Sarkar, Dhruba; Salovich, James M.; Howes, Jennifer E.; Akan, Denis T.; Sai, Jiqing; Arnold, Allison L.; Browning, Carrie; Burns, Michael C.; Sobolik, Tammy; Sun, Qi; Beesetty, Yugandhar; Coker, Jesse A.; Scharn, Dirk; Stadtmueller, Heinz; Rossanese, Olivia W.; Phan, Jason; Waterson, Alex G.; McConnell, Darryl B.; Fesik, Stephen W. [Journal of Medicinal Chemistry, 2018, vol. 61, # 19, p. 8875 - 8894]

35
[ 261951-70-6 ]
6-(4-fluoro-3-methylbenzyl)-1,4-dimethyl-6-(trityldisulfaneyl)piperazine-2,3,5-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1.1: lithium hexamethyldisilazane; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / tetrahydrofuran / 1 h / Cooling 1.2: 18 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 20 °C

Reference： [1]Snaddon, Thomas N.; Scaggs, Toya D.; Pearson, Colin M.; Fyfe, James W. B. [Organic Letters, 2019, vol. 21, # 12, p. 4873 - 4877]

36
[ 261951-70-6 ]
1-(4-fluoro-3-methylbenzyl)-4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo[2.2.2]octane-6,8-dione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: lithium hexamethyldisilazane; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / tetrahydrofuran / 1 h / Cooling 1.2: 18 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 20 °C 3.1: tetrahydrofuran; diethyl ether / 0.5 h / -78 °C 4.1: hafnium tetrakis(trifluoromethanesulfonate) / acetonitrile / 0.5 h

Reference： [1]Snaddon, Thomas N.; Scaggs, Toya D.; Pearson, Colin M.; Fyfe, James W. B. [Organic Letters, 2019, vol. 21, # 12, p. 4873 - 4877]

37
[ 261951-70-6 ]
C₃₄H₃₃FN₂O₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: lithium hexamethyldisilazane; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone / tetrahydrofuran / 1 h / Cooling 1.2: 18 h / 20 °C 2.1: tetrabutyl ammonium fluoride / tetrahydrofuran / 1 h / 20 °C 3.1: tetrahydrofuran; diethyl ether / 0.5 h / -78 °C

Reference： [1]Snaddon, Thomas N.; Scaggs, Toya D.; Pearson, Colin M.; Fyfe, James W. B. [Organic Letters, 2019, vol. 21, # 12, p. 4873 - 4877]

38
[ 261951-70-6 ]
6-((((tert-butyldimethylsilyl)oxy)methyl)thio)-1,4-dimethylpiperazine-2,3,5-trione [ No CAS ]
6-((((tert-butyldimethylsilyl)oxy)methyl)thio)-6-(4-fluoro-3-methylbenzyl)-1,4-dimethylpiperazine-2,3,5-trione [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	Stage #1: 6-((((tert-butyldimethylsilyl)oxy)methyl)thio)-1,4-dimethylpiperazine-2,3,5-trione With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; lithium hexamethyldisilazane In tetrahydrofuran for 1h; Cooling; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In tetrahydrofuran at 20℃; for 18h;

Reference： [1]Snaddon, Thomas N.; Scaggs, Toya D.; Pearson, Colin M.; Fyfe, James W. B. [Organic Letters, 2019, vol. 21, # 12, p. 4873 - 4877]

39
[ 261951-70-6 ]
[ 27048-04-0 ]
6-chloro-N-(4-fluoro-3-methylbenzyl)-3-nitropyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃;	258.A Example 258 Step A: To a stirred solution of 2-amino-6-chloro-3-nitropyridine (535 mg, 3.1 mmol) in DMF (5 mL) was added 4-fluoro-3-methylbenzyl bromide (657 mg, 3.2 mmol). The mixture was cooled to 0° C. and NaH 78 mg, 3.2 mmol) was added in 3 portions 5 min apart. The reaction was allowed to warm slowly to RT and stirred overnight. The reaction was diluted with EtOAc and water. The aqueous layer was separated and extracted with EtOAc (3). The combined organics were washed with water (2), brine (2*), dried over Na2SO4 and concentrated under vacuum. The residue was chromatographed on silica gel (80 g), eluting with a 1-to-5% EtOAc/hexane gradient to give 6-chloro-N-(4-fluoro-3-methylbenzyl)-3-nitropyridin-2-amine, 808 mg (89%) as a yellow solid. MS (ESI) (M+H+) m/z=296. LCMS Ret time (UV 215/254): 1.24 min.

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - US10501421, 2019, B1 Location in patent: Page/Page column 240-241

40
[ 261951-70-6 ]
[ 512-04-9 ]
C₃₅H₄₉FO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
3.6 g	With potassium carbonate In isopropyl alcohol at 110℃; for 12h;	15 Example 15 Weigh 4.2g of Diosgenin,1.5 g of potassium carbonate was dissolved in 100 mL of isopropanol in a 500 mL three-necked flask.Add 2.6 g of 3-methyl-4-fluorobenzyl bromide and heat and stir at 110 ° C.And incubate for 12h.TLC (developing solvent: petroleum ether-ethyl acetate (7: 3), developer: 5% phosphomolybdic acid ethanol solution) to detect all reactions of diosgenin, evaporate the solvent under reduced pressure, cool to room temperature, add 50 mL of water,Extracted three times with acetone (50mL × 3), followed by TLC to track the separation and purification process of the product. The extract was dried over anhydrous Na2SO4 for 8h, filtered, and the filtrate was recovered to obtain a solid, which was dried at 60 ° C for 4h to obtain 3.6 g of light yellow powder.

Reference： [1]Current Patent Assignee: SHANDONG UNIVERSITY - CN110642918, 2020, A Location in patent: Paragraph 0084; 0085

41
[ 261951-70-6 ]
N-(4-fluoro-3-methylbenzyl)-3-nitro-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 2: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - US10501421, 2019, B1

42
[ 261951-70-6 ]
N<SUP>2</SUP>-(4-fluoro-3-methylbenzyl)-6-((1,1,1-trifluoropropan-2-yl)oxy)pyridine-2,3-diamine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 2: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 3: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 1 h / 20 °C / 760.05 Torr

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - US10501421, 2019, B1

43
[ 261951-70-6 ]
3-(4-fluoro-3-methylbenzyl)-5-((1,1,1-trifluoropropan-2-yl)oxy)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 2: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 3: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 1 h / 20 °C / 760.05 Torr 4: formic acid / 0.75 h / 90 °C

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - US10501421, 2019, B1

44
[ 261951-70-6 ]
2-chloro-3-(4-fluoro-3-methylbenzyl)-5-((1,1,1-trifluoropropan-2-yl)oxy)-3H-imidazo[4,5-b]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 3.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 1 h / 20 °C / 760.05 Torr 4.1: formic acid / 0.75 h / 90 °C 5.1: N-ethyl-N,N-diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - US10501421, 2019, B1

45
[ 261951-70-6 ]
3-(4-fluoro-3-methylbenzyl)-2-(piperazin-1-yl)-5-((1,1,1-trifluoropropan-2-yl)oxy)-3H-imidazo[4,5-b]pyridine trifluoroacetate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 6 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 2.1: sodium hydride / N,N-dimethyl-formamide / 0 - 20 °C 3.1: hydrogen; palladium 10% on activated carbon / methanol; tetrahydrofuran / 1 h / 20 °C / 760.05 Torr 4.1: formic acid / 0.75 h / 90 °C 5.1: N-ethyl-N,N-diisopropylamine; n-butyllithium / tetrahydrofuran; hexane / 1 h / -78 °C / Inert atmosphere 5.2: -78 - 20 °C 6.1: 1-methyl-pyrrolidin-2-one / 4.45 h / 90 - 125 °C / Sealed tube

Reference： [1]Current Patent Assignee: VANDERBILT UNIVERSITY - US10501421, 2019, B1

46
[ 261951-70-6 ]
[ 1416819-91-4 ]
cobalt(II) bromide [ No CAS ]
C₂₁H₂₃Br₂CoF₄N₂O [ No CAS ]

Reference： [1]Journal of the American Chemical Society,2019,vol. 141,p. 18877 - 18889

47
[ 261951-70-6 ]
methyl 5-(4-fluoro-2-methylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate [ No CAS ]
methyl 5-(4-fluoro-2-methylphenyl)-2-(4-fluoro-3-methylbenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: methyl 5-(4-fluoro-2-methylphenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In N,N-dimethyl-formamide; mineral oil

Reference： [1]Tian, Jianhua; Teuscher, Kevin B.; Aho, Erin R.; Alvarado, Joseph R.; Mills, Jonathan J.; Meyers, Kenneth M.; Gogliotti, Rocco D.; Han, Changho; Macdonald, Jonathan D.; Sai, Jiqing; Shaw, J. Grace; Sensintaffar, John L.; Zhao, Bin; Rietz, Tyson A.; Thomas, Lance R.; Payne, William G.; Moore, William J.; Stott, Gordon M.; Kondo, Jumpei; Inoue, Masahiro; Coffey, Robert J.; Tansey, William P.; Stauffer, Shaun R.; Lee, Taekyu; Fesik, Stephen W. [Journal of Medicinal Chemistry, 2020, vol. 63, # 2, p. 656 - 675]

48
[ 261951-70-6 ]
1-(benzyloxy)but-3-en-2-yl (1,1,1,3,3,3-hexafluoropropan-2-yl) carbonate [ No CAS ]
4-(2-((benzyloxy)methyl)but-3-en-1-yl)-1-fluoro-2-methylbenzene [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	Stage #1: 4-(bromomethyl)-1-fluoro-2-methylbenzene With magnesium In diethyl ether; ethylene dibromide at 20℃; for 0.5h; Inert atmosphere; Stage #2: With rhodium(III) chloride trihydrate; zinc(II) iodide In diethyl ether at 20℃; for 0.5h; Stage #3: 1-(benzyloxy)but-3-en-2-yl (1,1,1,3,3,3-hexafluoropropan-2-yl) carbonate In diethyl ether at 0 - 20℃; for 16h;

Reference： [1]Pal, Debasis; Wright, Timothy B.; O'Connor, Ryan; Evans, P. Andrew [Angewandte Chemie - International Edition, 2021, vol. 60, # 6, p. 2987 - 2992][Angew. Chem., 2021, vol. 133, # 6, p. 3024 - 3029,6]

49
[ 261951-70-6 ]
[ 143900-44-1 ]
tert-butyl (S)-3-((4-fluoro-3-methylbenzyl)oxy)piperidine-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	Stage #1: (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In N,N-dimethyl-formamide at 60℃; for 48h;	General procedure A General procedure: Totert-butyl (S)-3-hydroxypiperidine-1-carboxylate,4, (213 mg, 1.04 mmol) dissolved in dimethylformamide (DMF) (10 mL) was added sodium hydride (125 mg, 3.00 mmol, 3 eq) at room temperature and stirred for 1h then 4-methylbenzyl bromide (195 mg, 1.03 mmol) was added and the reaction mixture was stirred at 60 C for 48h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), organic phase washed with brine (20 mL), dried with magnesium sulfate and concentrated in vacuo. The product,4’, was purified via Biotage in hexane/ethyl acetate (15-17%).
43%	Stage #1: (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In N,N-dimethyl-formamide at 60℃; for 48h;	General procedure A General procedure: Totert-butyl (S)-3-hydroxypiperidine-1-carboxylate,4, (213 mg, 1.04 mmol) dissolved in dimethylformamide (DMF) (10 mL) was added sodium hydride (125 mg, 3.00 mmol, 3 eq) at room temperature and stirred for 1h then 4-methylbenzyl bromide (195 mg, 1.03 mmol) was added and the reaction mixture was stirred at 60 C for 48h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), organic phase washed with brine (20 mL), dried with magnesium sulfate and concentrated in vacuo. The product,4’, was purified via Biotage in hexane/ethyl acetate (15-17%).

Reference： [1]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]
[2]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]

50
[ 261951-70-6 ]
[ 143900-43-0 ]
C₁₈H₂₆FNO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In N,N-dimethyl-formamide at 60℃; for 48h;	General procedure A General procedure: Totert-butyl (S)-3-hydroxypiperidine-1-carboxylate,4, (213 mg, 1.04 mmol) dissolved in dimethylformamide (DMF) (10 mL) was added sodium hydride (125 mg, 3.00 mmol, 3 eq) at room temperature and stirred for 1h then 4-methylbenzyl bromide (195 mg, 1.03 mmol) was added and the reaction mixture was stirred at 60 C for 48h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), organic phase washed with brine (20 mL), dried with magnesium sulfate and concentrated in vacuo. The product,4’, was purified via Biotage in hexane/ethyl acetate (15-17%).
	Stage #1: (R)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester With sodium hydride In N,N-dimethyl-formamide at 20℃; for 1h; Stage #2: 4-(bromomethyl)-1-fluoro-2-methylbenzene In N,N-dimethyl-formamide at 60℃; for 48h;	General procedure A General procedure: Totert-butyl (S)-3-hydroxypiperidine-1-carboxylate,4, (213 mg, 1.04 mmol) dissolved in dimethylformamide (DMF) (10 mL) was added sodium hydride (125 mg, 3.00 mmol, 3 eq) at room temperature and stirred for 1h then 4-methylbenzyl bromide (195 mg, 1.03 mmol) was added and the reaction mixture was stirred at 60 C for 48h. The reaction was quenched with distilled water (100 mL), extracted with ethyl acetate (30 mL x 3), organic phase washed with brine (20 mL), dried with magnesium sulfate and concentrated in vacuo. The product,4’, was purified via Biotage in hexane/ethyl acetate (15-17%).

Reference： [1]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]
[2]Hopkins, Corey R.; Mashinson, Viktoriya; Tolentino, Kirsten T.; Vadukoot, Anish K. [Bioorganic and Medicinal Chemistry Letters, 2022, vol. 61]

51
[ 261951-70-6 ]
(S)-3-((4-fluoro-3-methylbenzyl)oxy)-1-(3-fluoro-4-methoxybenzyl)piperidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1 h / 20 °C 1.2: 48 h / 60 °C 2.1: hydrogenchloride / 1,4-dioxane / 60 °C 3.1: Cs₂CO₃ / N,N-dimethyl-formamide / 1 h / 120 °C / Microwave irradiation