Size	Price	VIP Price	US Stock	Global Stock	In Stock
{[ item.pr_size ]}		Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate,item.pr_is_large_size_no_price, item.vip_usd) ]}

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

{[ item.pr_size ]}

In Stock

- +

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

US Stock: ship in 0-1 business day
Global Stock: ship in 2 weeks

Quality Control of [ 111141-00-5 ] Purity: 95% SDS Specification

COA

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

NMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

CNMR

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

HPLC

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

LC-MS

Search for reports by entering the product batch number.
Batch number can be found on the product's label following the word 'Batch'.

1-2 Day Shipping
High Quality
Technical Support Online Technical Q&A

Product Details of [ 111141-00-5 ]

CAS No. :	111141-00-5
Formula :	C₉H₇FO₂
M.W :	166.15
SMILES Code :	O=C1CCOC2=C1C=CC=C2F
MDL No. :	MFCD09744011
InChI Key :	FKDMFDMYQZIZMI-UHFFFAOYSA-N
Pubchem ID :	13953817

Safety of [ 111141-00-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Calculated chemistry of [ 111141-00-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	40.97
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.3 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.79
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.48
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.21
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.47
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	2.83
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.17
Solubility	1.12 mg/ml ; 0.00672 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.64
Solubility	3.81 mg/ml ; 0.0229 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.13
Solubility	0.124 mg/ml ; 0.000745 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.26 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.92

Application In Synthesis of [ 111141-00-5 ]

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

Downstream synthetic route of [ 111141-00-5 ]

[ 111141-00-5 ] Synthesis Path-Downstream 1~28

1
[ 151-50-8 ]
[ 111141-00-5 ]
[ 111140-49-9 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 230 - 243.

2
[ 2967-72-8 ]
[ 111141-00-5 ]

Yield	Reaction Conditions	Operation in experiment
98%		8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluororhohenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C for 2 hours, then aluminum chloride (7.39g, 55.42mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.2Og, 98%).
98%		8-fluorochroman-4-one (37). Oxalyl chloride (8.79 mL) and one drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C. for two hours, aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at RT. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, dried, evaporated, and purified by column chromatography (eluding with 20% EtOAc/Hex) to give 8-fluorochroman-4-one (37) (8.20 g, 98%). 8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluting with 20% EtOAc/Hex) to give of the title compound (8.20 g, 98%).
53%	With polyphosphoric acid; at 100℃; for 2h;	A mixture of compound (174a) (3.7 g, 20.3 mmol) in polyphosphoric acid (59.5 g, 607.6 mmol) was stirred at 100 C for 2 hours. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated in diethyl ether and filtered. The filtrate was concentrated to provide compound (174b) (1.80 g, 10.8 mmol, 53%) which was used without further purification. 1H NMR (300 MHz, CDCl3) delta 2.83-2.90 (m, 2H), 4.60-4.68 (m, 2H), 6.95 (td, J = 8.0/4.4 Hz, 1H), 7.30 (ddd, J = 1.4/8.0/10.6 Hz, 1H), 7.67 (td, J = 1.4/8.0 Hz, 1H). MS m/z ([M+H]+) 167.

With polyphosphoric acid; at 100℃; for 3.5h;

Polyphosphoric acid (7.0 g) was added to the compound 1-2 (450 mg) , and the mixture was stirred at 100C for 3.5 hours. The heat source was turned off and the temperature was lowered to 75C. At that time, crushed ice was gradually added to the reaction mixture with vigorous stirring. When the temperature was returned to room temperature, the reaction solution was added to ice water. The aqueous layer was extracted with diethyl ether, and the organic layer was sequentially washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (273 mg) .IH NMR (400 MHz, CDCl3) (ppm) : 2.89 (t, J=6.4 Hz, 2H), 4.66 (t, J=6.4 HZ, 2H), 6.98 (td, J=4.4 , 8.0 Hz, IH), 7.29-7.34 (m, IH), 7.71 (dt, J=I.5, 8.0 Hz, IH)

References: [1]Patent: WO2006/108103,2006,A1 .Location in patent: Page/Page column 95; 96.
[2]Patent: US2008/119496,2008,A1 .Location in patent: Page/Page column 12; 30.
[3]Journal of Medicinal Chemistry,1988,vol. 31,p. 230 - 243.
[4]Patent: EP2913330,2015,A1 .Location in patent: Paragraph 0653.
[5]Patent: WO2006/66950,2006,A2 .Location in patent: Page/Page column 33-36.
[6]Patent: WO2010/13794,2010,A1 .Location in patent: Page/Page column 60-61.
[7]Patent: WO2006/27236,2006,A1 .Location in patent: Page/Page column 52-54.
[8]Patent: WO2008/60301,2008,A1 .

3
3-(2-fluorophenoxy)propanoic acid chloride [ No CAS ]
[ 111141-00-5 ]

Yield	Reaction Conditions	Operation in experiment
98%	With aluminum (III) chloride; In dichloromethane; at 20℃; for 16h;	8-Fluorochroman-4-one. Oxalyl chloride (8.79 mL) and 1 drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 C. for 2 hours, then aluminum chloride (7.39 g, 55.42 mM) was added and the solution was stirred for 16 hours at room temperature. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, then dried, evaporated, and purified by column chromatography (eluding with 20% EtOAc/Hex) to give of the title compound (8.20 g, 98%).
	aluminum (III) chloride; In dichloromethane; at 20℃; for 16h;	Oxalyl chloride (8.79 mL) and one drop of DMF were added to an ice cold solution of 3-(2-fluorophenoxy)propanoic acid (9.27 g) in DCM (50 mL). The solution was stirred at 0 0C for two hours, aluminum chloride (7.39g, 55.42mM) was added and the solution was stirred for 16 hours at RT. The mixture was poured onto ice water, and extracted three times with DCM. The combined organics were washed with 0.5M NaOH and brine, dried, evaporated, and purified by column <n="36"/>chromatography (eluting with 20% EtOAc/Hex) to give 8-fluorochroman-4-one (37) (8.2Og, 98%),

References: [1]Patent: US2008/85898,2008,A1 .Location in patent: Page/Page column 8.
[2]Patent: WO2008/60301,2008,A1 .Location in patent: Page/Page column 34-35; 71-72.

4
[ 111140-91-1 ]
[ 111141-00-5 ]

References: [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 230 - 243.

5
[ 111141-00-5 ]
8-fluoro-4-methylenechromane [ No CAS ]

References: [1]Patent: WO2006/66950,2006,A2 .Location in patent: Page/Page column 33-36.

6
[ 111141-00-5 ]
8-fluorochroman-4-one oxime [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; for 18h;Heating / reflux;	8-Fluorochroman-4-amine.; A round bottom flask was charged with <strong>[111141-00-5]8-fluorochroman-4-one</strong> (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate <strong>[111141-00-5]8-fluorochroman-4-one</strong> oxime, which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (4.69 g, 57%).
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; for 18h;Heating / reflux;	8-Fluorochroman-4-amine. A round bottom flask was charged with 8- fluorochroman-4-one (8.2g), hydroxylamine hydrochloride (3.78g) and sodium acetate (4.46g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate 8-fluorochroman-4- one oxime, which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (4.69g, 57%). EPO <DP n="99"/>
	With hydroxylamine hydrochloride; sodium acetate; In ethanol; for 18h;Heating / reflux;	8-fluorochroman-4-amine (39). A round bottom flask was charged with <strong>[111141-00-5]8-fluorochroman-4-one</strong> (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to RT, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate <strong>[111141-00-5]8-fluorochroman-4-one</strong> oxime (38), which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (39) (4.69 g, 57%).; 8-Fluorochroman-4-amine. A round bottom flask was charged with <strong>[111141-00-5]8-fluorochroman-4-one</strong> (8.2 g), hydroxylamine hydrochloride (3.78 g) and sodium acetate (4.46 g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to room temperature, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate <strong>[111141-00-5]8-fluorochroman-4-one</strong> oxime, which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (4.69 g, 57%).

With hydroxylamine hydrochloride; sodium acetate; In ethanol; for 18h;Heating / reflux;

A round bottom flask was charged with 8- fluorochroman-4-one (8.2g), hydro xylamine hydrochloride (3.78g) and sodium acetate (4.46g). A reflux condenser was added, the flask was purged with argon, dry EtOH (20 mL) was added, and the mixture was stirred at reflux for 18 hours. The solution was cooled to RT, diluted with EtOAc, and washed with water. The organic phase was dried, and evaporated to give the intermediate <strong>[111141-00-5]8-fluorochroman-4-one</strong> oxime (38), which was reduced with Raney Nickel in EtOH at 50 PSI to yield the titled amine (39) (4.69g, 57%).

References: [1]Patent: US2008/85898,2008,A1 .Location in patent: Page/Page column 8-9.
[2]Patent: WO2006/108103,2006,A1 .Location in patent: Page/Page column 95; 96.
[3]Patent: US2008/119496,2008,A1 .Location in patent: Page/Page column 12; 30.
[4]Patent: WO2008/60301,2008,A1 .Location in patent: Page/Page column 34-35; 71-72.

7
[ 111141-00-5 ]
[ 113209-68-0 ]
[ 917248-49-8 ]
[ 1092938-99-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium tetrahydroborate; In methanol; at 0 - 20℃; for 18h;	At a temperature of 0 0C, sodium borohydride (7.4 g, 195 mmol) was added portion-wise to a mixture of 7-fluoro-2,3-dihydro-4/-/-chromen-4-one and 8-fluoro-2,3-dihydro-4/-/-chromen-4-one (16.2 g, 97.5 mmol) in methanol (200 ml). After a period of 1 hour at 0 0C and 17 hours at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (400 ml) and water (200 ml), and extracted with dichloromethane (2 x). The combined organic phases were washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and the solvent was evaporated. The yellow residue crystallized slowly. The title compound was isolated as mixture with 8- fluorochroman-4-ol (16.28 g, 99 % yield).

References: [1]Patent: WO2008/151927,2008,A2 .Location in patent: Page/Page column 62-63.

8
[ 133077-42-6 ]
[ 111141-00-5 ]
[ 113209-68-0 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 3-(3-fluorophenoxy)propanoic acid (20.0 g, 108 mmol) in toluene (230 ml) and thionyl chloride (64.3 g, 0.54 mol) was refluxed for 17 hours. The reaction mixture was concentrated several times in the presence of toluene. A solution of the yellow oily residue in chloroform (200 ml) was cooled to -65 0C and treated with trifluoromethanesulfonic acid (48.0 ml, 0.54 mol, addition over 45 min). The brown solution was gradually warmed to room temperature. After a period of 17 h, the reaction mixture was poured on ice water (1 I) and the phases were separated. The aqueous phase was extracted with chloroform (200 ml). The combined organic phases were washed with 1 N sodium hydroxide solution (2 x 200 ml), water, and saturated sodium chloride solution, and dried over magnei- sum sulfate. Evaporation of the solvent afforded the title compound as mixture with 8-fluoro-2,3- dihydro-4/-/-chromen-4-one (16.26 g of a yellow solid, 91 % yield).

References: [1]Patent: WO2008/151927,2008,A2 .Location in patent: Page/Page column 62.

9
[ 4071-88-9 ]
[ 111141-00-5 ]
[ 1206837-17-3 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of N-butyllithium in hexane (1.6 N, 1.88 ml) was added to a solution of dicyclohexylamine (545.7 mg) in tetrahydrofuran (13.0 ml) , cooled to -78C in a dry ice-acetone bath. After stirring at the same temperature for 10 minutes, a solution of ethyl (trimethylsilyl) acetate (482.3 mg) in tetrahydrofuran (2.5 ml) was added. After stirring at -78C for 10 minutes, a solution of the compound 4-1 (250.0 mg) in tetrahydrofuran (2.5 ml) was added. The mixture was stirred at -78C for one hour, and then returned to room temperature and further stirred for three hours. After confirming disappearance of the raw material, the reaction mixture was added to brine. The aqueous layer was extracted with ethyl acetate . The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography to obtain the title compound (162 mg) . 1H NMR (400 MHz, CDCl3) (ppm) : 1.29 (t, J=7.1 Hz, 3H), 2.67 (td, J=I.3, 5.9 Hz, 2H), 4.22 (q, J=7.1 Hz, 2H), 4.44-4.49 (m, 2H), 5.76 (s, IH), 6.78 (td, J=5.1, 8.1 Hz, IH), 7.06 (ddd, J=I.5, 8.1, 10.9 Hz, IH), 7.57 (dt, J=I.5, 8.1 Hz, IH)

References: [1]Patent: WO2010/13794,2010,A1 .Location in patent: Page/Page column 69-70.

10
[ 111141-00-5 ]
[ 1018978-81-8 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 6788 - 6792.

11
[ 111141-00-5 ]
[ 74-95-3 ]
8-fluoro-4-methylenechromane [ No CAS ]

References: [1]Patent: WO2006/27236,2006,A1 .Location in patent: Page/Page column 52-54.

12
[ 1421130-32-6 ]
[ 111141-00-5 ]
[ 1421064-47-2 ]
[ 1421064-97-2 ]

Yield	Reaction Conditions	Operation in experiment
	With tetrabutoxytitanium; sodium tetrahydroborate; N-ethyl-N,N-diisopropylamine; In methanol; at 20℃; for 14h;	Example 148C[(2R,3aR,6aR)-2- [(4R)-8-fluoro-3,4-dihydro-2H-chromen-4- yl]amino } hexahydropentalen-3 a( 1 H)-yl] [3 -(trifluoromethyl)-7, 8-dihydro- 1 ,6- naphthyridin-6(5H)-yl]methanoneA mixture of Example 148B (85.1 mg, 0.51 mmol) and Example 79N (0.2 g, 0.51 mol) in Ti-(OiPr)4 (5 mL) was added N,N-diisopropylethylamine (0.196 g, 1.53 mmol) dropwise at room temperature. The mixture was stirred at room temperature for 12 hours. NaBH4 (0.197 g, 5.1 mmol) was added to the reaction mixture, followed by addition of methanol (10 mL) and stirred for 2 hours at room temperature. LC-MS indicated that the reaction was complete, the mixture was washed with aqueous NaHC(? (15 mL), the aqueous layer was extracted with ethyl acetate (3 x 50 mL). The organic layer was dried over Na2S04,concentrated in vacuum and purified by chromatography on silica and then SFC (Instrument: Berger MultiGram SFC, Mettler Toledo Co, Ltd; Column: Chiralcel OJ 250x30 mm ID, 5 muiotaeta; Mobile phase: A: Supercritical CO2, B: isopropanol (0.05% diethylamine as modifier), A:B =70:30 at 60 mL/min; Column Temp: 38 C; Nozzle Pressure: 100 Bar; Nozzle Temp: 60 C; Evaporator Temp: 20 C Trimmer Temp: 25 C; Flow rate: 60 mL/min; Wavelength: 220 nm.) to afford the title compound as a white solid (peak 1, retention time 6.5 minute, 2.31 mg), as well as Example 201 (peak 2, retention time 7.22 minute, 0.98 mg). NMR (400 MHz, CD3OD): delta 8.68 (s, 1H), 8.04 (s, 1H), 6.95 (m, 3H), 4.70 (m, 2H), 4.25 (m, 2H), 4.31 (m, 1H), 3.95 (m, 3H), 3.51 (m, 2H), 3.10 (m, 2H), 2.29 (m, 1H), 1.90 (m, 9H), 1.55 (m, 1H), 1.31 (m, 2H); MS (ESI) m/z 503 (M+H)+.

References: [1]Patent: WO2013/10453,2013,A1 .Location in patent: Page/Page column 213.

13
[ 367-12-4 ]
[ 111141-00-5 ]

References: [1]Patent: EP2913330,2015,A1 .
[2]Patent: US2008/119496,2008,A1 .
[3]Patent: WO2008/60301,2008,A1 .

14
[ 111141-00-5 ]
8-fluoro-3,4-dihydro-2H-1-benzopyran [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
67%	With acetic acid; zinc; at 100℃; for 16h;	To a mixture of zinc powder (30 g, 0.45 mol) in acetic acid (10 mL) at room temperature was added slowly a solution of <strong>[111141-00-5]8-fluorochroman-4-one</strong> (3.0 g, 18 mmol) in acetic acid (10 mL). The reaction mixture was stirred at 100 C for 16 hours, then diluted with ethyl acetate ( 100 mL) and filtered. The filtrate was concentrated in vacuo and purified by silica gel chromatography [petroleum ether: ethyl acetate = 50: 1] to give compound B-265 (2.1 g, 67% yield) as a yellow oil. -NMR (CDC13, 400 MHz): delta 6.94-6.89 (m, 1H), 6.84-6.82 (m, 1H), 6.79-6.76 (m, lH), 4.30-4.27 (t, J = 5.2 Hz, 2H), 2.85-2.81 (t, J = 6.4 Hz, 2H), 2.12-2.04 (m, 2H).
50%	With acetic acid; zinc; at 100℃; for 5h;	A solution of compound (174b) (1.80 g, 10.83 mmol) in acetic acid (14 mL) was added to a suspension of zinc dust (9.21 g, 140.8 mmol) in acetic acid (14 mL). The reaction mixture was heated at 100C for 5 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite and successively rinsed with ethyl acetate (80 mL) and toluene (80 mL). The filtrate was concentrated under reduced pressure. The residue was purified purification by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 95/5), to provide compound (174c) (827 mg, 5.43 mmol, 50%).

References: [1]Patent: WO2016/100184,2016,A1 .Location in patent: Paragraph 00591-00592.
[2]Patent: EP2913330,2015,A1 .Location in patent: Paragraph 0654.

15
[ 111141-00-5 ]
6-bromo-8-fluoro-3,4-dihydro-2H-1-benzopyran [ No CAS ]

References: [1]Patent: EP2913330,2015,A1 .

16
[ 111141-00-5 ]
2-(8-fluoro-3,4-dihydro-2H-1-benzopyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ No CAS ]

References: [1]Patent: EP2913330,2015,A1 .

17
[ 111141-00-5 ]
8-fluorochroman-7-carbaldehyde [ No CAS ]

References: [1]Patent: WO2016/100184,2016,A1 .

18
[ 111141-00-5 ]
methyl 3,4-dihydro-2H-thieno[3,2-h]chromene-8-carboxylate [ No CAS ]

References: [1]Patent: WO2016/100184,2016,A1 .

19
[ 111141-00-5 ]
3,4-dihydro-2H-thieno[3,2-h]chromene-8-carboxylic acid [ No CAS ]

References: [1]Patent: WO2016/100184,2016,A1 .

20
[ 111141-00-5 ]
2-(1H-benzo[d]imidazol-1-yl)-9-((R)-8-fluorochroman-4-yl)-7H-purin-8(9H)-one [ No CAS ]