1480-65-5|5-Chloro-2-fluoropyridine| Ambeed

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Structure of 1480-65-5

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Quality Control of [ 1480-65-5 ] Purity: 97% SDS Specification

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Product Details of [ 1480-65-5 ]

CAS No. :	1480-65-5
Formula :	C₅H₃ClFN
M.W :	131.54
SMILES Code :	FC1=NC=C(Cl)C=C1
MDL No. :	MFCD04112513
InChI Key :	ZULRQGBHWBQPFE-UHFFFAOYSA-N
Pubchem ID :	345817

Safety of [ 1480-65-5 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H225-H302-H315-H318-H335
Precautionary Statements:	P261-P280-P305+P351+P338
Class:	3(8)
UN#:	2924
Packing Group:	Ⅲ

Computational Chemistry of [ 1480-65-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	8
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	29.2
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	12.89 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.63
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	1.87
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.29
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.	1.51
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	2.51
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.96

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.39
Solubility	0.538 mg/ml ; 0.00409 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.	-1.76
Solubility	2.27 mg/ml ; 0.0173 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	-2.88
Solubility	0.172 mg/ml ; 0.00131 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.	-5.77 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	2.0
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	1.0 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)	1.49

Application In Synthesis of [ 1480-65-5 ]

* 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 [ 1480-65-5 ]

[ 1480-65-5 ] Synthesis Path-Downstream 1~35

Yield	Reaction Conditions	Operation in experiment
		By following the above procedures, and employing the appropriate starting pyridine compounds, the following compounds are prepared:2,5-Difluoropyridine; 2,5-dibromopyridine; 2-chloro-5-bromopyridine; 2-chloro-5-fluoropyridine; 2-fluoro-5-chloropyridine; 2-bromo-5-chloropyridine; and 2-bromo-5-fluoropyridine.
		Representative halopyridine compounds which can be prepared by the method of the present invention include:...2,5-difluoropyridine; 2,5-dibromopyridine; 2-chloro-5-bromopyridine; 2-chloro-5-fluoropyridine; 2-fluoro-5-chloropyridine; 2-fluoro-5-bromopyridine; 2-bromo-5-chloropyridine; 2-bromo-5-fluoropyridine; ...

2
(5R)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diaza-spiro[4.5]decan-1-one hydrochloride [ No CAS ]
[ 1480-65-5 ]
(5R)-7-(5-chloropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diaza-spiro[4.5]decan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 5h;	Example 116 EPO <DP n="90"/>(5R)-7-(5-ChIoropyridin-2-yl)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one A mixture of (5R)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-l-one hydrochloride (29.4 mg, 0.000107 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 1, steps 1-5), <strong>[1480-65-5]5-chloro-2-fluoropyridine</strong> (17 mg, 0.00013 mol) and potassium carbonate (0.029 mL, 0.00032 mol) in N,N-dimethylformamide (0.6 mL, 0.008 mol) was heated at 120 0C for 5 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 350.2 (M+H)+.

References: [1]Patent: WO2006/53024,2006,A2 .Location in patent: Page/Page column 88-89.

3
[ 1480-65-5 ]
[ 659731-48-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step A 5-Chloro-2-fluoro-4-iodopyridine (4-2); <strong>[1480-65-5]5-Chloro-2-fluoropyridin</strong>e (4-1, 1Og, 76.0 mmol) was adde dropwise at -78 0C to the solution of LDA (2.1M, 400 mL). The reaction mixture was stirred at the same temperature for 7 h, treated with solid I2, (19.3 g, 76.0 mmol) stirred for 2 h, quenched with water, and partitioned between hexanes and water. The organic layer was washed with IN-HCl and then with brine, separated, dried (MgSO4) and concentrated in vacuo to give the crude product. Chromatography (SiO2, hexanes only) afforded the desired isomer (4-2) as a minor product.

References: [1]Patent: WO2007/16358,2007,A1 .Location in patent: Page/Page column 38.

4
[ 1480-65-5 ]
[ 1040745-70-7 ]
[ 1041642-20-9 ]

References: [1]Journal of the American Chemical Society,2008,vol. 130,p. 9257 - 9259.

5
[ 1480-65-5 ]
potassium 1-trifluoroborato-5-phenylpentan-3-one [ No CAS ]
[ 1112788-71-2 ]

References: [1]Journal of Organic Chemistry,2009,vol. 74,p. 1297 - 1303.

6
potassium (4-(benzoyloxy)butyl)trifluoroborate [ No CAS ]
[ 1480-65-5 ]
[ 1137726-28-3 ]

References: [1]Journal of Organic Chemistry,2009,vol. 74,p. 3626 - 3631.

7
[ 1480-65-5 ]
potassium 3-trifluoroboratopropionic acid N,N-dimethyl amide [ No CAS ]
[ 1174066-62-6 ]

References: [1]Journal of Organic Chemistry,2009,vol. 74,p. 5446 - 5450.

8
[ 71-23-8 ]
[ 1480-65-5 ]
[ 1160018-61-0 ]

Yield	Reaction Conditions	Operation in experiment
98%		A 12 L three-neck round-bottom flask with a mechanical stirrer, thermocouple, addition funnel, nitrogen inlet, and a drying tube were equipped and placed into a cooling bath. An oversized flask was used due to the large amount of foaming and effervescence during the additions. The flask was charged with tetrahydrofuran (THF, 1.8 L), and stirring was initiated. Sodium hydride was added in portions. A mild exotherm was observed initially due to residual moisture in the solvent. After this had subsided the bulk of the material was added. The reaction mixture was cooled to 0-5° C. using an ice/water bath, and a solution of propanol (103 mL) in THF (350 mL) was added slowly over a 1 hour period at a rate to keep the internal temperature below 5° C. The addition was strongly exothermic and accompanied by the evolution of hydrogen gas. There was a significant delay (45 mins) to the hydrogen release, which was sudden and caused foaming. After the complete addition of propanol, the reaction was stirred for a further 1 h. A solution of <strong>[1480-65-5]5-chloro-2-fluoropyridine</strong> (22, 86 g) in tetrahydrofuran (THF, 350 mL) was added slowly over a 1.5 hour period at a rate to keep the internal temperature below 5° C. The addition was strongly exothermic and accompanied by the evolution of hydrogen gas. There was a significant delay (45 mins) to the hydrogen release, which was sudden and caused foaming. The cooling bath was allowed to expire naturally overnight. Stirring was continued at ambient temperature until the reaction was complete, i.e., typically after overnight stirring without the requirement for additional reagents and when no starting material was observed. If reaction was not complete, it was cooled back to 0-5° C. and treated with fresh sodium hydride (0.5 eq.), the reaction was stirred at ambient temperature overnight, resampled, and the reaction was continued until deemed to be complete. The reaction was monitored by TLC (SiO2, 25percent ethyl acetate in heptanes, UV) by diluting an aliquot of reaction mixture (1 mL) with water (2 mL), extracting with ethyl acetate, and spotting the organic layer. The starting material had retention factor (RF)=0.38; the product had RF=0.45. Materials used in the synthesis are detailed in Table 3. To isolate 5-chloro-2-propoxypyridine (23), the reaction mixture was cooled to 0-5° C. using an ice/water bath. The reaction was quenched by the addition of a slow stream of saturated aqueous ammonium chloride solution (1 L). The addition was exothermic and may be accompanied by hydrogen gas evolution. The mixture was extracted with ethyl acetate (2.x.2 mL). The combined organic extracts were washed with saturated brine solution (1 L), dried over magnesium sulfate and charcoal, and filtered through a glass fiber filter. The filtrate was concentrated under reduced pressure to give a pale yellow liquid.The reaction was successfully carried out on multi-gram scale giving both excellent yield and purity, and the results are shown in Table 4. 5-Chloro-2-propoxypyridine (23) (lot No. 1357-96-1) was a pale yellow liquid, synthesized with a yield of 110 g/98percent. 5-Chloro-2-propoxypyridine (23) was analyzed using HPLC, and according to results, it was 99.0percent pure. 1H-NMR (300 MHz, CDCl3) was also used to analyze 5-chloro-2-propoxypyridine (23), confirming the identity of the compound.

References: [1]Patent: US2009/306121,2009,A1 .Location in patent: Page/Page column 7-8; sheet 12.

9
[ 1480-65-5 ]
[ 1204336-54-8 ]
[ 1204336-04-8 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 70 - 100℃; for 88h;	To a solution of N-(2-hydroxy-l-hydroxymethylethyl)-2-methyl-6-(3-prperidin-4-yl- propoxy)nicotmamide hydrochloride (Preparation 50, 125 mg, 320 mumol) in DMSO (5 mL) was added <strong>[1480-65-5]5-chloro-2-fluoropyridine</strong> (70.2 mg, 533 mumol) and DBU (133 muL, 889 mumol) and the resulting solution was stirred at 1000C for 16 h. Further 5-chloro-2-fluoropyndine (93.7 mg,712 mumol) was added to the reaction mixture and heating at 7O0C was continued for 72 h The reaction mixture was diluted with EtOAc, then washed with H2O and brme, before being dried (MgSO4), filtered and concentrated in vacuo to afford the title compound: RT = 2.90 mm; mlz (ES+) = 463 22 [M + U]+ (Method A).

References: [1]Patent: WO2010/4343,2010,A1 .Location in patent: Page/Page column 65.

10
[ 1480-65-5 ]
[ 1204310-22-4 ]
[ 1204310-23-5 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene;water; In dimethyl sulfoxide; at 130℃; for 3h;Microwave irradiation;	To 2-methyl-4-(3-pipendin-4-ylpropoxy)benzoic acid hydrochloride (Preparation 22, 574 mg, 1.83 mmol) in DMSO (850 muL) was added 5-chloro-2-fluoropyndine (288 mg, 2.20 mmol), DBU (960 muL, 6 41 mmol) and H2O (6 drops) The resulting suspension was heated in a sealed tube in the microwave at 13O0C for 3 h The reaction mixture was diluted with H2O, acidified to pH 5 with 2M HCl and extracted with EtOAc (3x), then the combined organic extracts were washed with brine, before being dried (MgSO4). Filtration, removal of solvent under reduced pressure and purification by column chromatography (EtOAc-IH, 2 3 to 3:2) afforded the title compound: RT = 3.87 min; mlz (ES+) = 403.11 [M + H]+ (Method A).
	With 1,8-diazabicyclo[5.4.0]undec-7-ene;water; In dimethyl sulfoxide; at 130℃; for 3h;Microwave irradiation;	To 2-methyl-4-(3-piperidin-4-ylpropoxy)benzoic acid hydrochloride (Preparation 21, 574 mg, 1.83 mmol) in DMSO (850 muL) was added <strong>[1480-65-5]5-chloro-2-fluoropyridine</strong> (288 mg, 2.20 mmol), DBU (960 muL, 6.41 mmol) and H2O (6 drops). The resulting suspension was heated in a sealed tube in the microwave at 13O0C for 3 h. The reaction mixture was diluted with H2O, acidified to pH 5 with 2M HCl and extracted with EtOAc (3x), then the combined organic extracts were washed with brine, before being dried (MgSO4). Filtration, removal of solvent under reduced pressure and purification by column chromatography (EtOAc-IH, 2:3 to 3:2) afforded the title compound: RT = 3.87 min; mlz (ES+) = 403.11 [M + H]+ (Method A).

References: [1]Patent: WO2010/4344,2010,A1 .Location in patent: Page/Page column 22.
[2]Patent: WO2010/4347,2010,A1 .Location in patent: Page/Page column 26-27.

11
[ 1480-65-5 ]
3-(piperidin-4-yl)propan-1-ol hydrochloride [ No CAS ]
[ 1204310-31-5 ]

Yield	Reaction Conditions	Operation in experiment
		A stirred solution of 3-piperidin-4-ylpropan-l-ol hydrochloride (15.0 g, 84 mmol) in DMSO (120 mL) was cooled to O0C, before being treated dropwise with DBU (30.0 mL, 201 mmol) over 5 min. 2,5-dichloropyrimidine (17.4 g, 117 mmol) was added portionwise, then the reaction was heated to 11O0C for 4 h. After cooling to 2O0C, the reaction was poured into H2O (200 mL) and extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with IM HCl (2 x 200 mL), before being dried (MgSO4) and concentrated. The residue was purified by column chromatography (EtOAc-IH, 4:6) to provide the title compound: 1H NMR (CDCl3) delta 1.10-1.23 (m, 2H), 1.30-1.38 (m, 2H), 1.48-1.57 (m, IH), 1.58-1.66 (m, 2H), 1.78 (d, 2H), 2.86 (m, 2H), 3.66 (t, 2H), 4.67 (d, 2H), 8.20 (s, 2H).

References: [1]Patent: WO2010/4347,2010,A1 .Location in patent: Page/Page column 29.

12
[ 1480-65-5 ]
[ 1227471-85-3 ]
[ 1227471-97-7 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃;	tert-butyl (3R)-3-(3-[(5-chloropyridin-2-yl)oxylphenyl)-1-oxa-8-azaspiro[4.5ldecane-8-carboxylate To a mixture of tert-butyl (3R)-3-(3-hydroxyphenyl)-1-oxa-8-azaspiro[4.5]decane-8-carboxylate (2.82 g, 8.47 mmol) and cesium carbonate (5.52 g, 16.9 mmol) in DMF (5 ml_) was added <strong>[1480-65-5]5-chloro-2-fluoropyridine</strong> (1.5 ml_, 15 mmol) and stirred at RT over several nights. Water (50 ml_) and ethyl acetate (150 ml_) were added and the layers were separated. The organic was washed with saturated ammonium chloride (3x50 ml_), dried over magnesium sulfate, filtered, and concentrated to give ~5 g of the crude oil. The oil was purified by flash chromatography (5-30percent EA/Heptane) to give the title compound as a gum (3.80 g, 96.4percent). m/z 389 (MH+ minus t-Bu). 1H NMR (400 MHz, CDCI3) delta ppm 1.47 (s, 9 H), 1.53 - 1.59 (m, 1 H), 1.65 - 1.77 (m, 3 H), 1.82 (dd, J=12.63, 10.24 Hz, 1 H), 2.27 (dd, J=12.63, 8.19 Hz, 1 H), 3.30 - 3.41 (m, 2 H), 3.48 - 3.58 (m, 1 H), 3.62 (br. s., 2 H), 3.80 (t, J=8.88 Hz, 1 H), 4.23 (t, J=8.02 Hz, 1 H), 6.89 (d, J=8.88 Hz, 1 H), 6.96 - 7.02 (m, 2 H), 7.10 (d, J=7.85 Hz, 1 H), 7.35 (t, J=7.68 Hz, 1 H), 7.66 (dd, J=8.53, 2.73 Hz, 1 H), 8.13 (d, J=2.73 Hz, 1 H).

References: [1]Patent: WO2010/58318,2010,A1 .Location in patent: Page/Page column 34-35.

13
[ 1480-65-5 ]
[ 1011-65-0 ]
[ 1252779-91-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 200℃; for 2h;Microwave irradiaition;	A mixture of Ij (1.14 mmol, 200 mg), laa (1.14 mmol, 150 mg), K2CO3 (2.28 mmol, 315 mg) and NMP (1.5 mL) was heated at 200 0C in a microwave reactor for 2 h. The mixture was poured into water (50 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under vacuo. Purification was carried by flash column chromatography (silica gel, 15percent EtO Ac/heptane) to give 290 mg of lbb (290 mg).

References: [1]Patent: WO2010/124082,2010,A1 .Location in patent: Page/Page column 78.

14
[ 1480-65-5 ]
potassium (R)-3-(trifluoroborato)-N-((1S,2S)-1-hydroxy-1-phenylpropan-2-yl)-N,2-dimethylpropanamide [ No CAS ]
[ 1243333-41-6 ]

References: [1]Organic Letters,2010,vol. 12,p. 4384 - 4387.

15
[ 1480-65-5 ]
[ 108-46-3 ]
[ 1182818-78-5 ]

Yield	Reaction Conditions	Operation in experiment
37%	With caesium carbonate; In dimethyl sulfoxide; at 40℃; for 22h;	Intermediate 12: 3-(5-Chloro-pyridin-2-yloxy)-phenol. To a solution consisting of <strong>[1480-65-5]5-chloro-2-fluoropyridine</strong> (1.3 ml_, 13 mmol) and resorcinol (2.1 g, 19 mmol) and DMSO (30 ml_) was added Cs2CO3 (6.3 g, 19 mmol). The reaction vessel was heated at 40 °C for 22 hours then diluted with CH2CI2 (60 ml_) and washed with saturated aq. NH4CI (100 ml_). The organic layer was dried (MgSO4) and concentrated. The crude residue was purified (FCC) to give the title compound (1.0 g, 37percent). MS (ESI+): calcd. for CH H8CINO2, 221.02; m/z found, 222.1 (M+H)+. 1H NMR (CDCI3): 8.14 (d, J = 2.6 Hz, 1 H), 7.65 (dd, J = 8.7, 2.7 Hz, 1 H), 7.26-7.22 (m, 1 H), 6.89 (dd, J = 8.7, 0.5 Hz, 1 H), 6.69-6.65 (m, 2H), 6.60 (t, J = 2.3 Hz, 1 H).

References: [1]Patent: WO2010/141809,2010,A1 .Location in patent: Page/Page column 33-34.

16
[ 1480-65-5 ]
[ 1286686-17-6 ]
[ 1273318-21-0 ]

References: [1]Organic Letters,2011,vol. 13,p. 1694 - 1697.

17
[ 1480-65-5 ]
[ 1268340-93-7 ]
[ 1281677-24-4 ]

References: [1]Journal of Organic Chemistry,2011,vol. 76,p. 2762 - 2769.

18
[ 1480-65-5 ]
[ 1314538-55-0 ]
[ 1314538-84-5 ]

References: [1]Organic Letters,2011,vol. 13,p. 3956 - 3959.

19
[ 1480-65-5 ]
[ 124-38-9 ]
[ 121219-03-2 ]
[ 1335218-46-6 ]

Yield	Reaction Conditions	Operation in experiment
		Synthesis of Intermediate 7A solution of "-butyllithium (2.7N in heptanes; 165 mL, 445 mmol) in THF (300 mL) was cooled to -78°C and treated with 2,2,6,6-tetramethylpiperidine (77 mL, 456 mmol). The reaction mixture was allowed to stir for 30 minutes. A solution of 5-chloro-2- fluoropyridine (50.0 g, 380 mmol) in THF (200 mL) was added drop wise over 30 minutes. After stirring for an additional 30 minutes, the reaction mixture was quenched by bubbling CO2 through the reaction mixture for 10 minutes. The reaction mixture was allowed to warm to RT, and CO2 was bubbled through for an additional 30 minutes. The reaction mixture was then concentrated under reduced pressure and dissolved in DMF (400 mL). 4-Bromo-3-fluorophenol (72.6 g, 380 mmol) was added, followed by potassium carbonate (68.3 g, 494 mmol). The reaction mixture was heated to 120 °C overnight. The reaction mixture was diluted with EtOAc and washed with 4N HC1. The organic layer was separated, washed with water and dried over MgS04. The solvent was removed under reduced pressure. The crude residue was dissolved in Eaton's Reagent (700 mL, 54.0 g, 380 mmol) and the reaction mixture was heated to 120 °C overnight. The reaction mixture was poured onto a mixture of ice and MeOH. The resulting solid was filtered off and washed with water. The solid was suspended in a mixture of MeOH (100 mL) and cyclopropyl methyl ether (200 mL) and filtered off. The grey solid was washed with hexanes and dried yielding 7-bromo-3-chloro-8-fluoro-5H-chromeno[2,3- b]pyridin-5-one (53.76 g, 164 mmol, 43.0 percent yield) as a ~4:1 mixture of isomers.

References: [1]Patent: WO2011/115928,2011,A1 .Location in patent: Page/Page column 61-62.

20
[ 1480-65-5 ]
[ 1335218-52-4 ]

References: [1]Patent: WO2011/115928,2011,A1 .
[2]Patent: WO2013/44092,2013,A1 .

21
[ 1480-65-5 ]
[ 1335218-53-5 ]

References: [1]Patent: WO2011/115928,2011,A1 .
[2]Patent: WO2013/44092,2013,A1 .

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[ 1480-65-5 ]
[ 1335218-54-6 ]

References: [1]Patent: WO2011/115928,2011,A1 .
[2]Patent: WO2013/44092,2013,A1 .

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[ 368-47-8 ]
2-fluoro-5-phenyl-pyridine [ No CAS ]

References: [1]Journal of Organic Chemistry,2011,vol. 76,p. 9182 - 9187.

24
[ 1480-65-5 ]
[ 13688-78-3 ]
[ 1337563-01-5 ]

References: [1]Journal of Organic Chemistry,2011,vol. 76,p. 9182 - 9187.

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[ 1480-65-5 ]
[ 1383446-21-6 ]

References: [1]Patent: WO2012/83117,2012,A1 .
[2]Patent: WO2017/133664,2017,A1 .

26
[ 1480-65-5 ]
[ 1240725-66-9 ]

References: [1]Patent: WO2012/83117,2012,A1 .
[2]Patent: WO2017/133664,2017,A1 .
[3]Patent: WO2017/133667,2017,A1 .

27
[ 1480-65-5 ]
[ 1352395-64-2 ]

References: [1]Patent: WO2012/83117,2012,A1 .
[2]Patent: WO2017/133664,2017,A1 .
[3]Patent: WO2017/133667,2017,A1 .

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[ 1480-65-5 ]
[ 1383446-23-8 ]