131747-63-2|4-Bromopicolinaldehyde| Ambeed

Structure of 4-Bromopyridine-2-carbaldehyde
CAS No.: 131747-63-2

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Quality Control of [ 131747-63-2 ] Purity: 97% SDS Specification

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Extended shortwave infrared absorbing antiaromatic fluorenium-indolizine chromophores

Meador, William E ; Saucier, Matthew A ; Tucker, Max R ; Kruse, Nicholas A ; Mobley, Alexander J ; Brower, Connor R , et al.

DOI: 10.1039/D4SC00733F Chem. Sci.,2024,15,12349-12360.

Abstract: Shortwave infrared (SWIR, 1000-1700 nm) and extended SWIR (ESWIR, 1700-2700 nm) absorbing materials are valuable for applications including fluorescence based biological imaging, photodetectors, and light emitting diodes. Currently, ESWIR absorbing materials are largely dominated by inorganic semiconductors which are often costly both in raw materials and manufacturing processes used to produce them. The development of ESWIR absorbing organic molecules is thus of interest due to the tunability, solution processability, and low cost of organic materials compared to their inorganic counterparts. Herein, through the combination of heterocyclic indolizine donors and an antiaromatic fluorene core, a series of organic chromophores with absorption maxima ranging from 1470-2088 nm (0.84-0.59 eV) and absorption onsets ranging from 1693-2596 nm (0.73-0.48 eV) are designed and synthesized. The photophysical and electrochemical properties of these chromophores, referred to as FluIndz herein, are described via absorption spectroscopy in 17 solvents, cyclic voltammetry, solution photostability, and transient absorption spectroscopy. Molecular orbital energies, predicted electronic transitions, and antiaromaticity are compared to higher energy absorbing chromophores using density functional theory. The presence of thermally accessible diradical states is demonstrated using density functional theory and EPR spectroscopy, while XRD crystallography confirms structural connectivity and existence as a single molecule. Overall, the FluIndz chromophore scaffold exhibits a rational means to access organic chromophores with extremely narrow optical gaps.

Purchased from AmBeed: 131747-63-2 ; 3375-31-3 ; 14221-01-3 ; 53358-54-6

Product Details of [ 131747-63-2 ]

CAS No. :	131747-63-2
Formula :	C₆H₄BrNO
M.W :	186.01
SMILES Code :	O=CC1=NC=CC(Br)=C1
MDL No. :	MFCD08690697
InChI Key :	CKVQWOKUEZYWRQ-UHFFFAOYSA-N
Pubchem ID :	14761472

Safety of [ 131747-63-2 ]

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

Computational Chemistry of [ 131747-63-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	37.32
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.96 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.11
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	1.34
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.66
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.	0.56
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	2.2
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.37

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.26
Solubility	1.01 mg/ml ; 0.00544 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.	-1.57
Solubility	5.0 mg/ml ; 0.0269 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	-2.83
Solubility	0.278 mg/ml ; 0.00149 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.	-6.48 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	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)	1.37

Application In Synthesis of [ 131747-63-2 ]

* 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 [ 131747-63-2 ]

[ 131747-63-2 ] Synthesis Path-Downstream 1~35

1
[ 131747-45-0 ]
[ 131747-63-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With manganese(IV) oxide; In chloroform; for 0.75h;Reflux;	Example 29i 4-Bromopicolinaldehyde Manganese(IV) oxide (22.19 g, 255.29 mmol) was added to a solution of (4-bromopyridin-2-yl)methanol (4.00 g, 21.27 mmol) in chloroform (80 mL) and the reaction mixture was stirred under reflux for 45 min. After the mixture had cooled to room temperature the solids were removed by filtration through a pad of Celite.(R).. The solvent was removed in vacuo and the residue (3.96 g, quant.) was used without further purification in the next step. 1H NMR (500 MHz, DMSO-d6) delta ppm 9.97 (s, 1H) 8.80 (d, 1H) 7.98 (d, 1H) 7.88 (dd, 1 H); MS (APCI+): m/z 186, 188 [M+H]+.
75%	With oxalyl dichloride; dimethyl sulfoxide; triethylamine; In dichloromethane; at -65 - -60℃; for 1.5h;Inert atmosphere;	Under the protection of nitrogen,Add 3L DCM to the 5L three-neck bottle to cool down.240g of oxalyl chloride was added dropwise during cooling;At -60 ° C,295.6 g of Dimethyl sulfoxide (DMSO) was added dropwise to the reaction solution.Keep warm for 30min;At -60 ° C,237.5 g of Cpd 3 was added dropwise to the reaction solution.The reaction was carried out at -65 ° C for 1 hour;At this temperature, 3.5 eq of triethylamine (TEA) was added dropwise.After the solution was allowed to stand, the plate was measured.Through the column, the product 4-bromopyridine-2-carbaldehyde is obtained.(Cpd 4) 177.2g,The yield was 75percent.
		Description 5: 4-Bromo-2-pyridinecarbaldehyde (D5); To a solution of the oxalyl chloride (0.364 mL, 4.09 mmol) in dry DCM (30 mL) at -780C was added DMSO (0.634 mL, 8.93 mmol) in dry DCM (5 mL) dropwise. The mixture was stirred at this temperature under argon atmosphere for 10 minutes <n="29"/>before a solution of (4-bromo-2-pyridinyl)methanol (D4) (700 mg, 3.72 mmol) in dry DCM (15 ml.) was added dropwise. After circa 30 minutes, triethylamine (2.6 mL, 18.6 mmol) was added and the cooling bath was removed. The reaction mixture was allowed to stir at room temperature for 1 h after which water was added and it was extracted 3 times with DCM. The combined organics were dried over MgSO4. The crude material (700 mg) was purified by flash chromatography (Biotage SP4, 25+M column) with a gradient of EtOAc in hexane to afford 425 mg (61 percent) of the desired product D5.1H-NMR (CDCI3): delta 7.70 (1 H, dd), 8.12 (1 H1 d), 8.61 (1 H, d), 10.05 (1 H, s); Description 5 - alternative procedure: 4-Bromo-2-pyridinecarbaldehyde (D5); To a solution of oxalyl chloride (13.2 mL, 0.149 mol) in dry dichloromethane (1 L) at - 78 0C under argon was added a solution of DMSO (23 mL, 0.324 mol) in dry dichloromethane (180 mL) dropwise over 20 minutes. The mixture was stirred at -78 0C under argon for 15 minutes and then a solution of (4-bromo-2-pyridinyl)methanol (D4) (25.4 g, 0.135 mol) in dry dichloromethane (500 mL) was added dropwise over 30 minutes. The resulting white suspension was stirred at -78 CC for 40-45 minutes and then triethylamine (95 mL, 0.676 mol) was added dropwise over 15 minutes. After stirring at -78 0C for 15 minutes, the mixture was allowed to reach room temperature over -1.5 h and then poured into water (400 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3x, ~1 L total solvent). The combined organic layers were washed with brine (20OmL), dried over MgSO4 and concentrated. The crude material was purified by flash chromatography on silica gel with a gradient of 0 to 30 percent ethyl acetate in hexane to afford 20.5 g (82percent) of the desired product D5, with NMR data consistent with those previously obtained.

References: [1]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 24.
[2]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[3]Patent: CN108516953,2018,A .Location in patent: Paragraph 0067-0068; 0074-0075; 0076-0083.
[4]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.
[5]MedChemComm,2015,vol. 6,p. 1252 - 1259.
[6]Patent: WO2008/17691,2008,A1 .Location in patent: Page/Page column 27-28.
[7]Chemical Science,2013,vol. 4,p. 3269 - 3274.

2
[ 54527-68-3 ]
[ 131747-63-2 ]
[ 14205-39-1 ]
[ 131747-73-4 ]

References: [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.

3
[ 131747-63-2 ]
[ 1576-35-8 ]
[ 192642-79-8 ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.

4
[ 128796-39-4 ]
[ 131747-63-2 ]
[ 1005189-47-8 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 130℃; for 0.25 - 0.333333h;Microwave irradiation;Product distribution / selectivity;	Description 6: 4-[4-(Trifluoromethyl)phenyl]-2-pyridinecarbaldehyde (D6); A mixture of 4-trifluoromethylphenylboronic acid (644 mg, 3.39 mmol), 4-bromo-2- pyridinecarbaldehyde (D5) (420 mg, 2.26 mmol) and 2M Na2CO3 (4 mL, 7.91 mmol) in dimethoxyethane (12 mL) was degassed for 5-10 minutes in an ultrasonic bath <n="30"/>under a flow of argon. Pd(dppf)CI2 (92 mg, 0.113 mmol) was added and the resulting mixture was heated with stirring at 130 0C for 10 minutes in a microwave reactor. TLC (EtOAc/hexane 1:1) after 10 minutes showed the reaction went to completion . The mixture was filtered through a pad of celite, washed with EtOAc and concentrated to afford 1 g of crude material which was purified by flash chromatography (Biotage SP4, 40+S column) with a gradient 0 to 50percent of EtOAc in hexane to yield 340 mg (60percent) of desired product D6.1H-NMR (CDCI3): delta 7.76 (1 H, m), 7.81 (4H, s), 8.2 (1 H, s), 8.89 (1 H, d), 10.18 (1 H, s)
	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In water; toluene; at 90℃; for 18.25h;Product distribution / selectivity;	Description 6 - alternative procedure: 4-[4-(Trifluoromethyl)phenyl]-2- pyridinecarboxaldehyde. (D6); A mixture of <strong>[131747-63-2]4-bromo-2-pyridinecarboxaldehyde</strong> (D5) (18.33 g, 98.5 mmol), 4-trifluoromethylphenylboronic acid (20.6 g, 108.4 mmol) and sodium bicarbonate(41.4 g, 492.7 mmol) in toluene (550 ml_) and water (55 mL) was degassed with argon for 15 minutes. To this suspension under argon was added tetrakis(triphenylphosphine) palladium(O) (3.42 g, 2.96 mmol) in one portion and the reaction was heated to 90 0C for 18 h. After cooling the solvent was evaporated and the residue suspended in ethyl acetate (1 L). This was filtered and the filter cake washed with ethyl acetate (4 chi 100 mL). The combined organics were evaporated to afford a yellow solid which was purified by flash chromatography (Biotage Flash 75L, silica gel, 3:1 --> 2:1 40-60 petroleum ether / ethyl acetate) to afford the title compound as a yellow solid (22.46 g) (D6), with NMR data consistent with those previously obtained.LC-MS: [MH+] = 252, C13H8F3NO requires 251.

References: [1]Patent: WO2008/17691,2008,A1 .Location in patent: Page/Page column 28-29.
[2]Patent: WO2008/17691,2008,A1 .Location in patent: Page/Page column 29.

5
[ 17704-74-4 ]
[ 131747-63-2 ]
C₁₀H₁₂BrN₃O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium acetate; In 1,2-dichloro-ethane; at 20℃; for 18h;Molecular sieve;	Description 11 : lambda/2-[(4-Bromo-2-pyridinyl)methyl]-2-methylalaninamide (D11); To a solution of <strong>[131747-63-2]4-bromo-2-pyridinecarbaldehyde</strong> (4 g, 21.5 mmol) (D5) in DCE (160 mL) was added 2-methylalaninamide hydrochloride (D2) (4.47 g, 32.25 mmol),NaOAc (2.65 g, 32.25 mmol) and 4 A molecular sieves (activated in the vacuum oven at 70 0C for 1 day, 20 g) and the resulting mixture was stirred under argon at room temperature. The imine formation was checked by 1H-NMR and after 18 h,NaBH(OAc)3 (6.84 g, 32.25 mmol) and acetic acid (1.94 mL, 32.25 mmol) were added. After stirring for 6 h a NMR sample showed reduction of the imine; saturated aqueous sodium bicarbonate solution (110 mL) was added slowly and the solution was stirred at room temperature for 1 hour after which it was filtered through a pad ofCelite, washed with DCM (100 mL) and the organic layer was separated. The aqueous phase was extracted with DCM (50 mL) and the combined organics were washed with brine (50 mL), dried over MgSO4 and concentrated to afford 5.4 g of <n="33"/>crude material. This was purified by flash chromatography using the Biotage SP4 (40+M silica cartridge), eluting with a gradient of 0 to 10percent MeOH in DCM to yield 5.4 g of the title compound D11.NMR deltaH (CDCI3): 1.43 (6H, s), 1.95 (1 H, broad s), 3.84 (2H, s), 5.36 (1H, broad s), 7.37 (1 H, dd, J = 5.2, 1.6 Hz), 7.47 (1 H, d, J = 1.6 Hz), 7.48 (1 H, broad s), 8.39 (1 H, d, J = 5.2 Hz).LC-MS: MH+ = 272/274, C10H14BrN3O requires 271/273.

References: [1]Patent: WO2008/17691,2008,A1 .Location in patent: Page/Page column 31-32.

6
[ 110-89-4 ]
[ 131747-63-2 ]
[ 956593-44-5 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5325 - 5329.

7
[ 100367-74-6 ]
[ 131747-63-2 ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[2]Chemical Science,2013,vol. 4,p. 3269 - 3274.

8
[ 131747-63-2 ]
[ 87838-47-9 ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[2]Tetrahedron,1997,vol. 53,p. 8257 - 8268.

9
[ 131747-63-2 ]
[ 192642-77-6 ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[2]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[3]Patent: WO2014/8197,2014,A1 .
[4]Patent: WO2015/95767,2015,A1 .

10
[ 131747-63-2 ]
5-Piperidin-1-yl-[1,2,3]triazolo[1,5-a]pyridine [ No CAS ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[2]Tetrahedron,1997,vol. 53,p. 8257 - 8268.

11
[ 131747-63-2 ]
4-([1,2,3]triazolo[1,5-a]pyridin-5-yl)morpholine [ No CAS ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[2]Tetrahedron,1997,vol. 53,p. 8257 - 8268.

12
[ 131747-63-2 ]
5-(4-Methoxy-phenoxy)-[1,2,3]triazolo[1,5-a]pyridine [ No CAS ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.
[2]Tetrahedron,1997,vol. 53,p. 8257 - 8268.

13
[ 192642-94-7 ]
[ 131747-63-2 ]

References: [1]Tetrahedron,1997,vol. 53,p. 8257 - 8268.

14
[ 931-19-1 ]
[ 131747-63-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.
[2]Inorganic Chemistry,2013,vol. 52,p. 6481 - 6501.

15
[ 22282-99-1 ]
[ 131747-63-2 ]

References: [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1239 - 1245.
[2]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.
[3]Chemical Science,2013,vol. 4,p. 3269 - 3274.

16
[ 13508-96-8 ]
[ 131747-63-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.

17
[ 5470-66-6 ]
[ 131747-63-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.
[2]Inorganic Chemistry,2013,vol. 52,p. 6481 - 6501.

18
[ 131747-63-2 ]
[ 108337-74-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.

19
[ 30766-03-1 ]
[ 131747-63-2 ]

References: [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2446 - 2458.

20
[ 1885-14-9 ]
[ 131747-63-2 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 5 Preparation of 4-Bromo-2-methylpyridine To a cooled (-78° C.) suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol) in anhydrous THF (90 mL) was added dropwise a solution of MeMgCl (3.0 M in THF, 21 mL, 63.0 mmol). After addition, the reaction mixture was stirred at -78° C. for 15 min. Phenyl chloroformate (3.8 mL, 30 mmol) in THF (10 mL) was added slowly and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl at 0° C. and extracted with Et2O. The combined organic extracts were washed successively with H2O, aqueous 1 N HCl and H2O, dried (MgSO4) and concentrated. The residue was dissolved in andydrous toluene (100 mL) and a solution of o-chloranil (7.8 g, 32 mmol) in glacial AcOH (60 mL) was added dropwise and the mixture was stirred for 22 h. a red suspension was formed and was made basic using 10percent NaOH until a black emulsion was obtained. The mixture was filtered through Celite and washed with H2O. The organic layer was extracted three times with aqueous 1 N HCl. The aqueous layers were basified with aqueous 50percent NaOH and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and the solvent was removed under vacuum to give the title compound (2.35 g, 53percent) as an oil. MS (+) EI: 171 M+.

References: [1]Patent: US2007/4730,2007,A1 .Location in patent: Page/Page column 12.

21
[ 131747-63-2 ]
[ 22282-99-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 5 Preparation of 4-Bromo-2-methylpyridine To a cooled (-78° C.) suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol) in anhydrous THF (90 mL) was added dropwise a solution of MeMgCl (3.0 M in THF, 21 mL, 63.0 mmol). After addition, the reaction mixture was stirred at -78° C. for 15 min. Phenyl chloroformate (3.8 mL, 30 mmol) in THF (10 mL) was added slowly and the mixture was allowed to warm to room temperature. The reaction was quenched with saturated NH4Cl at 0° C. and extracted with Et2O. The combined organic extracts were washed successively with H2O, aqueous 1 N HCl and H2O, dried (MgSO4) and concentrated. The residue was dissolved in andydrous toluene (100 mL) and a solution of o-chloranil (7.8 g, 32 mmol) in glacial AcOH (60 mL) was added dropwise and the mixture was stirred for 22 h. a red suspension was formed and was made basic using 10percent NaOH until a black emulsion was obtained. The mixture was filtered through Celite and washed with H2O. The organic layer was extracted three times with aqueous 1 N HCl. The aqueous layers were basified with aqueous 50percent NaOH and extracted with CH2Cl2. The combined organic extracts were dried (MgSO4) and the solvent was removed under vacuum to give the title compound (2.35 g, 53percent) as an oil. MS (+) EI: 171 M+.

References: [1]Patent: US2007/4730,2007,A1 .Location in patent: Page/Page column 12.

22
[ 108338-19-8 ]
[ 131747-63-2 ]

References: [1]Inorganic Chemistry,2013,vol. 52,p. 6481 - 6501.
[2]Tetrahedron Letters,2008,vol. 49,p. 7274 - 7275.

23
phthalazin-5-ylboronic acid hydrochloride [ No CAS ]
[ 131747-63-2 ]
[ 1225280-54-5 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 120℃; for 0.333333h;Sealed tube; Microwave irradiation;	INTERMEDIATE 104-(Quinoxalin-6-yl)pyridine-2-carbaldehydeA mixture of 4-bromo-2-formylpyridine (186 mg, 1 mmol), benzopyrazine-6- boronic acid hydrochloride (21 1 mg, 0.3 mmol), 2M aqueous sodium carbonate solution (1.5 mL, 3 mmol) and Pd(PPh3)4 (35 mg, 0.03 mmol) in DME (3 mL) was heated to 12O0C in a sealed tube, under microwave irradiation, for 20 minutes. The mixture was partitioned between water/brine (1 :1, 30 mL) and EtOAc (30 itiL). The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was purified by column chromatography (SiO2, 10-100percent EtOAc in heptane) to give the title compound (120 mg, 51percent) as a cream solid. deltaH (CDCl3) 10.20 (s, IH), 8.92-8.96 (m, 3H), 8.46 (d, IH), 8.36 (d, IH), 8.28 (d, IH), 8.11 (dd, IH), 7.92 (dd, IH). LCMS (ES+) 236 (M+H)+, RT 2.48 minutes.

References: [1]Patent: WO2010/52448,2010,A2 .Location in patent: Page/Page column 37-38.

24
[ 131747-63-2 ]
[ 1211580-54-9 ]

Yield	Reaction Conditions	Operation in experiment
54%	With diethylamino-sulfur trifluoride; at 20℃; for 16h;	[0207] Step 1: 4-Bromo-2-(difluoromethyl)pyridine : To a 4- bromopicolinaldehyde (5.0 g, 26.88 mmol) was added diethylaminosulfur trifluoride (7.03 mL, 53.7 mmol), and the mixture was stirred at rt for 16 h. The reaction was quenched with aq. sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (3 X 100 mL). The combined organic layers were washed with brine (2 X 50 mL), dried over sodium sulfate, filtered, concentrated and purified by column chromatography (100- 200 silica) using 5% ethyl acetate in hexane as eluent to afford 4-bromo-2- (difluoromethyl)pyridine (3.0 g, 14.492 mmol, 54% yield ). lH NMR (400 MHz, CDC13) delta = 8.48 (d, J = 4.9 Hz, 1H), 7.82 (d, J = 1.5 Hz, 1H), 7.66-7.50 (m, 1H), 6.60 (t, 1H). LCMS: 207.9 [M+H]+.
49.7%	With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃; for 12h;	DAST (0.620 mL, 4.69 mmol) was added dropwise to a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (700 mg, 3.76 mmol) in Chloroform (21 mL) at 0 C. The reaction mixture was stirred at 20 C. for 12 h. The reaction mixture was poured in to saturated NaHCO3 solution (20 mL), and was extracted with DCM (2×20 mL). The DCM layer was dried over anhydrous Na2SO4, filtered and filtrate was evaporated to afford 4-bromo-2-(difluoromethyl)pyridine (400 mg, 1.870 mmol, 49.7% yield) as light yellow solid, LCMS (m/z) 208.0 [M+H]+.
49.7%	With N,N-diethyltrifluoromethanesulfenamide; In chloroform; at 0 - 20℃; for 12h;	DAST (0.620 mL, 4.69 mmol) was added dropwise to a solution of 4- bromopicolinaldehyde (700 mg, 3.76 mmol) in Chloroform (21 mL) at 0 C. The reaction mixture was stirred at 20 C for 12h. The reaction mixture was poured in to saturated NaHC03 solution (20 mL), and was extracted with DCM (IX 20 mL). The DCM layer was dried over anhydrous Na2S04, filtered and filtrate was evaporated to afford 4-bromo- 2-(difluoromethyl)pyridine (400 mg, 1.870 mmol, 49.7 % yield) as light yellow solid, LCMS (m/z) 208.0 [M+H]+.

32%	With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃;Inert atmosphere;	Example 30i 4-Bromo-2-(difluoromethyl)pyridine Diethylaminosulphur trifluoride (4.08 mL, 33.31 mmol) was added to <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (0.267 M in chloroform) (100 mL, 26.7 mmol) at 0 C. under an atmosphere of argon. The reaction mixture was stirred over night while the temperature was raised to room temperature. The reaction was quenched by addition of aqueous sodium bicarbonate (sat.) and was further diluted with dichloromethane. The solids were filtered off through a pad of Celite. The organic layer was collected and the water phase was extracted with dichloromethane (*3). The organic layers were pooled, dried (Na2SO4), filtered and concentrated. Purification by silica chromatography using 0 to 60% diethyl ether in pentane gave the title compound (1.78 g, 32%). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.59 (d, 1H) 7.98 (d, 1H) 7.90 (dt, 1H) 6.98 (t, 1 H); MS (APCI+) m/z 208, 210 [M+H]+.
32%	With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃;Inert atmosphere;	To a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (10 g, 53.76 mmol) in CHCI3 (200.0 mL) was added diethylaminosulfur trifluoride (8.5 mL, 64.51 mmol) at 0C under argon. The reaction mixture was stirred overnight while the temperature was raised to room temperature. The reaction was quenched by addition of aqueous NaHC03 and further diluted with CH2CI2. The solids were filtered off through a pad of celite. The organic layer was separated and aqueous phase was extracted with CH2CI2 (3x). The organic phase dried over Na2S04. The suspension was concentrated to dryness and the resulting crude product was purified by Teledyne-Isco flash system by using Hexane/EtOAc, 0 to 20% of ethyl acetate in hexane to provide compound 16 as light yellow liquid (3.5 g, 32% yield). lH NMR (400 MHz, DMSO-d6) delta (ppm): 8.79 (d, 1H), 7.98 (s, 1H), 7.80 (d, 1H), 4.86 (s, 1H).
800 mg	With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃;Inert atmosphere;	Description 1284-Bromo-2-(difluoromethyl)pyridine (D128)To a solution of <strong>[131747-63-2]4-bromopicolinaldehyde</strong> (1 g) in DCM (20 mL) stirred under nitrogen atmosphere at 0C was added DAST (1.065 mL). The reaction mixture was stirred at RT overnight. To the mixture was added water, and then extracted with DCM (3 x50 mL). The organic phase was washed with saturated NaHCO3, water, and brine, then dried over MgSO4 and filtered to give the titlecompound (800 mg) as yellow oil. MS (ESI): C6H4BrF2N requires 207; found no mass.

References: [1]Patent: WO2016/161160,2016,A1 .Location in patent: Paragraph 0207.
[2]Patent: US2015/152108,2015,A1 .Location in patent: Paragraph 0480; 0481.
[3]Patent: WO2016/79709,2016,A1 .Location in patent: Page/Page column 179.
[4]Patent: US2010/125082,2010,A1 .Location in patent: Page/Page column 24; 25.
[5]Patent: WO2019/5297,2019,A1 .Location in patent: Page/Page column 33-34.
[6]Patent: WO2015/180612,2015,A1 .Location in patent: Page/Page column 78.

25
[ 1005342-94-8 ]
[ 131747-63-2 ]

Yield	Reaction Conditions	Operation in experiment
89%	With lithium aluminium tetrahydride; In tetrahydrofuran; at -78℃; for 1h;	4-bromo-N-methoxy-N-methylpicolinamide (42; 5.84 g, 23.8 mmol) was dissolved in anhydrous THF (100 ml) and cooled to -78° C and 1.0 M lithium aluminum hydride in THF (14.3 ml, 14.3 mmol) was added via syringe and then the resulting mixture was stirred for 1 hour. 1 M NaOH (20 ml) and water (20 ml) was added carefully to the reaction mixture, and then the resulting solution was stirred for 30 minutes. Ethyl acetate and water was added, the organic phase was washed with water and brine, dried over Na2SO4 and concentrated to give A- bromopicolinaldehyde 43 as a yellow oil (3.95 g, yield: 89percent). MS calcd for C6H4BrNO: 186; found: 187 [M+l].

References: [1]Patent: WO2010/101949,2010,A1 .Location in patent: Page/Page column 124.

26
[ 131747-63-2 ]
[ 67-64-1 ]
[ 1357287-76-3 ]

References: [1]Organic and Biomolecular Chemistry,2012,vol. 10,p. 1239 - 1245.

27
[ 131747-63-2 ]
C₂₂H₃₀N₄O₂ [ No CAS ]