[ CAS No. 3430-23-7 ] {[proInfo.proName]}

Name: 3430-23-7|3,5-Dibromo-4-methylpyridine|98%
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SKU: A132983
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Quality Control of [ 3430-23-7 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 3430-23-7 ]

Product Details of [ 3430-23-7 ]

CAS No. :	3430-23-7	MDL No. :	MFCD00128859
Formula :	C₆H₅Br₂N	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BNCGUATWCKZLLN-UHFFFAOYSA-N
M.W :	250.92	Pubchem ID :	819338
Synonyms :

Calculated chemistry of [ 3430-23-7 ]

Physicochemical Properties

Num. heavy atoms :	9
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.17
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	0.0
Molar Refractivity :	44.6
TPSA :	12.89 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.16
Log Po/w (XLOGP3) :	2.6
Log Po/w (WLOGP) :	2.92
Log Po/w (MLOGP) :	2.33
Log Po/w (SILICOS-IT) :	3.18
Consensus Log Po/w :	2.64

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.53
Solubility :	0.0746 mg/ml ; 0.000297 mol/l
Class :	Soluble
Log S (Ali) :	-2.52
Solubility :	0.758 mg/ml ; 0.00302 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-4.12
Solubility :	0.019 mg/ml ; 0.0000757 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.39

Safety of [ 3430-23-7 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362+P364-P403+P233-P501	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 3430-23-7 ]

* 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.

Upstream synthesis route of [ 3430-23-7 ]
Downstream synthetic route of [ 3430-23-7 ]

[ 3430-23-7 ] Synthesis Path-Upstream 1~8

1
[ 625-92-3 ]
[ 74-88-4 ]
[ 3430-23-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 3009 - 3013
[2] Patent: US2007/185187, 2007, A1, . Location in patent: Page/Page column 9

2
[ 74-88-4 ]
[ 3430-23-7 ]

Reference： [1] Patent: US2006/4000, 2006, A1, . Location in patent: Page/Page column 13

3
[ 625-92-3 ]
[ 74-88-4 ]
[ 3430-23-7 ]
[ 125419-80-9 ]

Reference： [1] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2565 - 2568

4
[ 625-92-3 ]
[ 74-88-4 ]
[ 3430-23-7 ]

Reference： [1] Tetrahedron Letters, 1996, vol. 37, # 15, p. 2565 - 2568

5
[ 3430-23-7 ]
[ 68-12-2 ]
[ 351457-86-8 ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -100℃; for 0.0833333 h; Stage #2: at -100 - -78℃; for 1.33333 h; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; waterSaturated solution	(a) Intermediate 1a: δ-Bromo^-methyl-pyridine-S-carbaldehyde:; 3,5-Dibromo-4-methyl-pyridine (3.8 g, 15.1 mmol) C1 was stirred in dry THF (150 mL) at -100⁰C(N₂/ether) under argon. n-Butyllithium (2.5 M in hexanes, 6.2 mL, 15.4 mmol) was added dropwise, and the reaction stirred for 5 minutes DMF (1.8 mL, 23.2 mmol) was added, and the reaction was stirred for 20 minutes at -100 ⁰C and then for 1 hour at -78 ⁰C. The reaction was quenched with sat. NH₄CI and extracted with ether. Organics were washed with brine, dried over Na₂SO₄, and concentrated in vacuo. Purification by silica gel chromatography (20percent ethyl acetate/hexanes) gave 2.18 g (72percent) of intermediate 1a as a clear oil which slowly solidified. ¹H NMR (300 MHz, CDCI₃) δ 10.25 (s, 1 H), 8.84 (s, 1H), 8.83 (s, 1H), 2.76 (s, 3H). Anal. (C₇H₆BrNO) C, H, N.

Reference： [1] Patent: WO2006/54151, 2006, A1, . Location in patent: Page/Page column 8
[2] Bioorganic and Medicinal Chemistry Letters, 2007, vol. 17, # 15, p. 4297 - 4302

6
[ 109-72-8 ]
[ 3430-23-7 ]
[ 351457-86-8 ]

Reference： [1] Patent: US2011/34441, 2011, A1,

7
[ 3430-23-7 ]
[ 105-56-6 ]
[ 890092-52-1 ]

Reference： [1] Organic Letters, 2012, vol. 14, # 14, p. 3644 - 3647

8
[ 3430-23-7 ]
[ 890092-52-1 ]

Reference： [1] Patent: WO2012/148808, 2012, A1, . Location in patent: Page/Page column 56

[ 3430-23-7 ] Synthesis Path-Downstream 1~66

1
[ 625-92-3 ]
[ 74-88-4 ]
[ 3430-23-7 ]
[ 125419-80-9 ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 2565 - 2568

2
[ 625-92-3 ]
[ 74-88-4 ]
[ 3430-23-7 ]
3,5,3',5'-Tetrabromo-1,4-dihydro-[4,4']bipyridinyl [ No CAS ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 2565 - 2568

3
[ 3430-23-7 ]
[ 123-72-8 ]
1-(5-Bromo-4-methyl-pyridin-3-yl)-butan-1-ol [ No CAS ]

Reference： [1]Tetrahedron Letters,1996,vol. 37,p. 2565 - 2568

5
[ 625-92-3 ]
[ 74-88-4 ]
[ 3430-23-7 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of n-butyllithium in hexane (1.6 N, 16 ml) is added dropwise, under argon, to a solution of diisopropylamine (3.6 ml, 1.02 equiv.) in anhydrous THF (145 ml) maintained at -10 C. The reaction mixture is cooled to -78 C. and then a solution of 3,5-dibromopyridine (5.92 g, 25 mmol) in THF (200 ml), cooled to -78 C., is added dropwise. The reaction mixture is stirred for 30 min and then methyl iodide (2.17 ml, 1.4 equiv.) is added dropwise. The stirring is maintained for 2 h at -78 C. A saturated aqueous NH4Cl solution (120 ml) is added. After evaporation of the solvents, the reaction mixture is extracted with EtOAc. The organic phase is washed with brine, dried over MgSO4 and evaporated. The yellow solid obtained is taken up with EtOAc. The suspension is filtered. The filtrate is evaporated and the residue is chromatographed on silica gel, elution being carried out with a petroleum ether/EtOAc (97.5/2.5) mixture. 1.67 g of product are obtained in the form of a white solid.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3009 - 3013
[2]Patent: US2007/185187,2007,A1 .Location in patent: Page/Page column 9

6
[ 3430-23-7 ]
[ 594-27-4 ]
[ 20579-43-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3009 - 3013

7
[ 3430-23-7 ]
[ 68-12-2 ]
[ 351457-86-8 ]

Yield	Reaction Conditions	Operation in experiment
72%		(a) Intermediate 1a: delta-Bromo^-methyl-pyridine-S-carbaldehyde:; 3,5-Dibromo-4-methyl-pyridine (3.8 g, 15.1 mmol) C1 was stirred in dry THF (150 mL) at -1000C(N2/ether) under argon. n-Butyllithium (2.5 M in hexanes, 6.2 mL, 15.4 mmol) was added dropwise, and the reaction stirred for 5 minutes DMF (1.8 mL, 23.2 mmol) was added, and the reaction was stirred for 20 minutes at -100 0C and then for 1 hour at -78 0C. The reaction was quenched with sat. NH4CI and extracted with ether. Organics were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification by silica gel chromatography (20% ethyl acetate/hexanes) gave 2.18 g (72%) of intermediate 1a as a clear oil which slowly solidified. 1H NMR (300 MHz, CDCI3) delta 10.25 (s, 1 H), 8.84 (s, 1H), 8.83 (s, 1H), 2.76 (s, 3H). Anal. (C7H6BrNO) C, H, N.

Reference： [1]Patent: WO2006/54151,2006,A1 .Location in patent: Page/Page column 8
[2]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4297 - 4302

8
[ 3430-23-7 ]
[ 916326-88-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4297 - 4302

9
[ 3430-23-7 ]
C₃₆H₅₃N₇O₃Si₂ [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4297 - 4302

10
[ 3430-23-7 ]
ethyl-{5-[3-(4-methoxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-4-methyl-pyridin-3-ylmethyl}-amine [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 4297 - 4302

11
[ 3430-23-7 ]
2-{4-[1-(3,4-bis-difluoromethoxy-phenyl)-2-(3,5-dimethyl-pyridin-4-yl)-ethyl]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3009 - 3013

12
[ 3430-23-7 ]
2-{4-[1-(3,4-bis-difluoromethoxy-phenyl)-2-(3,5-dimethyl-1-oxy-pyridin-4-yl)-ethyl]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3009 - 3013

13
[ 3430-23-7 ]
[ 524775-16-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 3009 - 3013

14
[ 74-88-4 ]
[ 3430-23-7 ]

Yield	Reaction Conditions	Operation in experiment
		Under argon, an n-butyllithium solution in hexane (1.6N, 16 ml) is added dropwise to a diisopropylamine solution (3.6 ml, 1.02 equiv.) in anhydrous THF (145 ml) kept at -10 C. The reaction mixture is cooled to -78 C. and then a 3,5-dibromopyridine solution (5.92 g, 25 mmol) in THF (200 ml) cooled to -78 C. is added dropwise. The reaction mixture is stirred for 30 min and then methyl iodide (2.17 ml, 1.4 equiv.) is added dropwise. The stirring is maintained for 2 h at -78 C. A saturated aqueous NH4Cl solution (120 ml) is added. After evaporation of the solvents, the reaction mixture is extracted with AcOEt. The organic phase is washed with brine, dried over MgSO4 and evaporated. The yellow solid obtained is taken up in AcOEt. The suspension is filtered. The filtrate is evaporated and then the residue is chromatographed on silica gel, eluding with a petroleum ether/AcOEt (97.5/2.5) mixture. 1.67 g of product are obtained in the form of a white solid.

Reference： [1]Patent: US2006/4000,2006,A1 .Location in patent: Page/Page column 13

15
[ 3430-23-7 ]
[ 5720-07-0 ]
[ 885681-79-8 ]

Reference： [1]Patent: WO2006/46593,2006,A1 .Location in patent: Page/Page column 257-258

16
[ 3430-23-7 ]
[ 181219-01-2 ]
[ 351457-72-2 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 48h;	Under argon, pinacolyl ester of pyridine-4-boronic acid (910 mg, 4.45 mmol), an aqueous Na2CO3 solution (2.35 g/9 ml H2O) and finally tetrakis(triphenylphosphine)palladium (153 mg) are added to a solution of intermediate 10.1 (1.3 g, 5.18 mmol) in DME (18 ml). The mixture is heated at 85 C. for 2 days. The solvent is evaporated and then the residue is extracted with AcOEt/H2O. The compound obtained after washing the organic solution with brine, drying over MgSO4 and evaporation is chromatographed on silica gel (200 g), eluting with an AcOEt/petroleum ether (1/1) mixture. 440 mg of product are obtained in the form of an oil.
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 85℃; for 48h;	Pyridine-4-boronic acid pinacolic ester (910 mg, 4.45 mmol), an aqueous Na2CO3 solution (2.35 g/9 ml H2O) and, finally, tetrakis(triphenylphosphine)palladium (153 mg) are added, under argon, to a solution of intermediate 2.1 (1.3 g, 5.18 mmol) in DME (18 ml). The mixture is heated at 85 C. for 2 days. The solvent is evaporated off and the residue is then extracted with EtOAc/H2O. The compound obtained after washing the organic solution with brine, drying over MgSO4 and evaporation is chromatographed on silica gel (200 g), elution being carried out with an EtOAc/petroleum ether (1/1) mixture. 440 mg of product were obtained in the form of an oil.

Reference： [1]Patent: US2006/4000,2006,A1 .Location in patent: Page/Page column 14
[2]Patent: US2007/185187,2007,A1 .Location in patent: Page/Page column 9

Yield	Reaction Conditions	Operation in experiment
74%		(a) Intermediate 61a-3,5-Dibromo-4-ethyl-pyridine: The title compound was prepared in 74% yield by the substitution of iodoethane for iodomethane in the procedure for the preparation of 3,5-dibromo-4-methyl-pyridine (see Gu, et al., Tet Leff., 37,15,1996, 2565-2568). 1H NMR (300 MHz, CDCl3) delta 8.49 (s, 2H), 2.92 (q, 2H, J=7.5 Hz), 1.12 (t, 3H, J=7.5 Hz).

18
[ 3430-23-7 ]
[ 87199-15-3 ]
[ 351458-12-3 ]

Yield	Reaction Conditions	Operation in experiment
79%		(a) Intermediate 69a-[3-(5-Bromo-4-methyl-pyridin-3-yl)-phenyl]-methanol: The title compound was prepared in 79% yield from <strong>[3430-23-7]3,5-dibromo-4-methyl-pyridine</strong> and 3-(hydroxymethyl)-phenyl-boronic acid similar to the procedure for intermediate 53a. 1H NMR (300 MHz, CDCl3) delta 8.62 (s, 1H), 8.22 (s, 1H), 7.42-7.46 (m, 2H), 7.29 (s, 1H), 7.16-7.20 (m, 1H), 4.76 (d, 2H, J=5.7 Hz), 2.48 (t, 1H, J=5.7 Hz), 2.32 (s, 3H). Anal. (C13H12BrNO.0.2 H2O) C, H, N.

Reference： [1]Patent: US2002/161022,2002,A1

Yield	Reaction Conditions	Operation in experiment
		(76-1) Tetrakis(triphenylphosphine)palladium (0) (1.03 g, 0.89 mmol) and potassium carbonate (8.22 g, 59.5 mmol) were added to a solution of 3,5-dibromo-4-methylpyridine (7.46 g, 29.73 mmol) which was synthesised according to the method described in literature () and 4-methoxyphenylboronic acid (4.52 g, 29.73 mmol) in a mixture of N,N-dimethylacetamide-water (20:1, 100 ml), and the mixture was stirred at 80C for 4 hours. After the temperature of the reaction mixture was set to room temperature and ethyl acetate was added thereto, the insolubles were removed by filtration. The obtained filtrate was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluding solvent: n-hexane/ethyl acetate=4/1) to give 3-bromo-5-(4-methoxyphenyl)-4-methylpyridine (3.83 g, yield: 46%). 1H-NMR (400MHz, CDCl3): delta 8.63 (1H, s), 8.32 (1H, s), 7.22 (2H, d, J = 8.6 Hz), 6.99 (2H, d, J = 8.6 Hz), 3.87 (3H, s), 2.35 (3H, s).

20
[ 3430-23-7 ]
[ 65399-03-3 ]
[ 1231891-05-6 ]

Yield	Reaction Conditions	Operation in experiment
30%	With copper(l) iodide; potassium carbonate; N,N-dimethylethylenediamine; In 1,4-dioxane; at 100℃; for 15h;	Step 2 A mixture of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (2.00 g, 7.97 mmol), 6-methylisoindolin-1-one (1.173 g, 7.97 mmol), copper (I) iodide (0.076 g, 0.399 mmol), potassium carbonate (2.203 g, 15.94 mmol) and N1,N2-dimethylethane-1,2-diamine (0.070 g, 0.797 mmol) in 1,4-dioxane (20 mL) was heated at 100 C. for 15 h. The mixture was cooled to rt, filtered through Celite and washed with DCM. The filtrate was diluted with DCM (100 mL) and washed with water (10 mL) and brine (10 mL), then was dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 80:20 hexane-EtOAc to EtOAc) to give 2-(5-bromo-4-methylpyridin-3-yl)-5-methylisoindolin-1-one (760 mg, 30%). 1H NMR (400 MHz, chloroform-d) delta 8.68 (1H, s), 8.42 (1H, s), 7.84 (1H, d, J=7.77 Hz), 7.37 (1H, d, J=7.77 Hz), 7.34 (1H, s), 4.73 (2H, s), 2.50 (3H, s), 2.35 (3H, s). Mass spectrum m/z 317, 319 (M+H)+.

Reference： [1]Patent: US2010/160303,2010,A1 .Location in patent: Page/Page column 30

21
[ 109-72-8 ]
[ 3430-23-7 ]
[ 351457-86-8 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium chloride; In tetrahydrofuran; N,N-dimethyl-formamide;	Step a n-Butyllithium (2.5 M in hexanes, 6.2 mL, 15.4 mmol) was added dropwise to a solution of <strong>[3430-23-7]3,5-dibromo-4-methyl-pyridine</strong> (XVII) (3.8 g, 15.1 mmol) in dry THF stirred at -100 C. under argon. The reaction was further stirred for 5 minutes at the same temperature before adding dry DMF (1.8 mL, 23.2 mmol). The solution was further stirred at -100 C. for 20 minutes and then at -78 C. for 1 hour. The reaction was quenched with saturated NH4Cl solution and extracted with ether. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated in vacuo. Purification of crude product by flash chromatography gave 5-bromo-4-methylnicotinaldehyde (XVIII). 1H NMR (CDCl3, 400 MHz) delta ppm 2.80 (s, 3H), 8.84 (m, 2H), 10.20 (s, 1H).

Reference： [1]Patent: US2011/34441,2011,A1

22
[ 6224-91-5 ]
[ 3430-23-7 ]
[ 1383985-19-0 ]

Yield	Reaction Conditions	Operation in experiment
16%	copper(l) iodide; tetrakis(triphenylphosphine) palladium(0); tetrabutyl ammonium fluoride; In tetrahydrofuran; toluene; at 70℃;Inert atmosphere;	Intermediate 453-Bromo-4-methyl-5-(prop-1-ynyl)pyridine; 3,5-Dibromo-4-methylpyridine (0.50 g, 2.0 mmol), 1-(trimethylsilyl)-1-propyne (0.35 mL, 2.4 mmol), copper(I) iodide (0.11 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02 mmol) were mixed in toluene (2 mL). The mixture was degassed by a stream of argon for a couple of min. Tetra-n-butylammonium fluoride (1 M in THF) (2.4 mL, 2.4 mmol) was added, and the reaction was heated under N2 at 70 C. overnight. The mixture was partitioned between water containing sat aq. NaHCO3 and EtOAc. The organic phase was dried (MgSO4) and evaporated to give a crude product which was purified by flash chromatography (40 g SiO2, heptane/EtOAc gradient) affording the title compound (0.067 g, 16% yield): 1H NMR (500 MHz, DMSO-d6) delta ppm 2.15 (s, 3H), 2.46 (s, 3H), 8.48 (s, 1H), 8.61 (s, 1H); MS (ES+) m/z 210 [M+H]+.

Reference： [1]Patent: US2012/165347,2012,A1 .Location in patent: Page/Page column 33

23
[ 3430-23-7 ]
[ 1383983-47-8 ]

Reference： [1]Patent: US2012/165347,2012,A1

24
[ 3430-23-7 ]
[ 1383986-37-5 ]

Reference： [1]Patent: US2012/165347,2012,A1

25
[ 3430-23-7 ]
[ 105-56-6 ]
[ 890092-52-1 ]

Reference： [1]Organic Letters,2012,vol. 14,p. 3644 - 3647

26
[ 3430-23-7 ]
[ 124-41-4 ]
[ 70201-49-9 ]

Yield	Reaction Conditions	Operation in experiment
	In methanol; N,N-dimethyl-formamide; at 80℃;	To a freshly prepared sodium methoxide from sodium metal (0.165 g, 0.0072 mol) and methanol (2.5 mL), <strong>[3430-23-7]3,5-dibromo-4-methyl-pyridine</strong> (1.0 g, 0.0040 mol) dissolved in N,N-dimethylformamide (10 mL) was added and heated at 80 C overnight Reaction was diluted with ethyl acetate and quenched with ice water, and layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated to provide the title compound. 1H NMR (400 MHz, CDC13) delta 8.33 (s, 1 H), 8.09 (s, 1 H), 3.05 (s, 3 H), 2.32 (s, 3 H).

Reference： [1]Patent: WO2012/148808,2012,A1 .Location in patent: Page/Page column 47; 48

27
[ 3430-23-7 ]
copper(l) cyanide [ No CAS ]
[ 890092-52-1 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 150.0℃; for 6.0h;	To a stirred solution of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (2.0 g, 7.97 mmol) in dry N,N-dimethylformamide (10 mL) was added copper cyanide (1.07 g,l 1.95 mmol) at room temperature . The reaction mixture was heated at 150 C for 6 h, cooled it, quenched with water (5 mL) and extracted with 50% ethyl acetate/hexane (2 x 100 mL). The combined organic layer was washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under vacuum to obtain the title compound. MS (M+l): 199.1.

Reference： [1]Patent: WO2012/148808,2012,A1 .Location in patent: Page/Page column 56

28
[ 3430-23-7 ]
[ 411235-57-9 ]
[ 1404367-13-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;	To a stirred solution of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (1.0 g, 0.0039 mol) and cyclopropylboronic acid (0.34 g, 0.0039 mol) in the mixture of 1,4-dioxan (35 mL) and water (15 mL) was added cesium carbonate (2.59 g, 0.00797 mol). Reaction mass was purging with argon for the 20 min. After 20 min, Pd(dppf)2Cl2 (0.14 g, 0.000199 mol) was added. The reaction mixture was heated to 100 C and stirred for 6 h. The reaction mixture was cooled to room temperature, filtered the reaction mixture through CELITE bed and the CELITE bed was thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. The residue was dissolved with dichloromethane and washed with water, saturated aqueous sodium chloride solution, dried over sodium sulphate, concentrated under vacuum, which was purified with silica gel (60-120) column chromatography by 0-2.5% ethyl acetate in hexane to afford the title compound (IN-14). 1H NMR (400 MHz, CdCl3) delta 8.51 (s, 1 H), 8.17 (s, 1 H), 2.52 (s, 3 H), 1.87-1.82 (m, 1H), 1.03-0.99 (m 2 H), 0.71-0.68 (m, 2 H). MS (M+l): 211.8.
	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In 1,4-dioxane; water; at 100℃; for 6h;Inert atmosphere;	Cesium carbonate (2.59 g, 0.00797 mol) was added to a stirred solution of 3,5- dibromo-4-methylpyridine (1.0 g, 0.0039 mol) and cyclopropylboronic acid (0.34 g, 0.0039 mol) in the mixture of 1,4-dioxan (35 mL) and water (15 mL). The reaction mixture was purged with argon for 20 min. Next, Pd(dppf)2Cl2 (0.14 g, 0.000199 mol) was added. The reaction mixture was heated at 100 C and for 6 h. It was cooled to room temperature, filtered through a bed of CELITE and the bed was thoroughly washed with ethyl acetate. The filtrate was concentrated under vacuum. The residue was dissolved with dichloromethane, washed with water and saturated sodium chloride solution, dried over sodium sulphate, concentrated under vacuum and purified by silica gel (60-120) column chromatography with 0-2.5% ethyl acetate in hexane to afford the title compound. 1H NMR (400 MHz, CdCl3) delta 8.51 (s, 1 H), 8.17 (s, 1 H), 2.52 (s, 3 H), 1.87- 1.82 (m, 1 H), 1.03-0.99 (m, 2 H), 0.71-0.68 (m, 2 H). MS (M+l): 211.8.

Reference： [1]Patent: WO2012/148808,2012,A1 .Location in patent: Page/Page column 52; 53
[2]Patent: WO2013/43521,2013,A1 .Location in patent: Page/Page column 41

29
[ 3430-23-7 ]
[ 1428432-84-1 ]

Reference： [1]Patent: WO2013/43521,2013,A1

30
[ 3430-23-7 ]
[ 1428651-90-4 ]

Reference： [1]Patent: WO2013/79452,2013,A1
[2]Patent: WO2013/156423,2013,A1
[3]Patent: US2013/274287,2013,A1
[4]Patent: WO2018/172852,2018,A1

31
[ 3430-23-7 ]
[ 1428651-91-5 ]

Reference： [1]Patent: WO2013/79452,2013,A1

32
[ 3430-23-7 ]
[ 1428651-88-0 ]

Reference： [1]Patent: WO2013/79452,2013,A1
[2]Patent: WO2013/156423,2013,A1
[3]Patent: US2013/274287,2013,A1

33
[ 3430-23-7 ]
[ 105-36-2 ]
[ 1440520-08-0 ]

Yield	Reaction Conditions	Operation in experiment
33.5%		A solution of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (20 g, 0.08 mol) in THF (50 mL) was added over a period of 1 hour to a solution of LDA (0.088 mol) [generated from N,N- diisopropylamine (8.9 g, 0.088 mol) and n-butyllithium (35 mL, 0.088 mol, 2.5 M in hexane) in 400 mL THF] at -78C. The resulting dark red solution was stirred at -78 C for 30 min before ethylbromo acetate (33.4 g, 0.2 mol) in THF (50 mL) was added over a period of 30 min. The reaction mixture was stirred for an additional 2.5 hour at -78 C before 10% AcOH was added (resulting in a pH = 4-5). The reaction mixture was then allowed to warm up to room temperature. After evaporation of the solvents, the residue was poured into satd. aq. NaHC03 solution and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhy. Na2S04, filtered, and concentrated in vacuo. The residue was purified by column chromatography to afford the title compound (9 g, 33.5 %) as a yellow solid. MS: 337.7(M+H+, 2Br).
33%		To a solution 10.0 g (40.3 mmol, 1.0 eq.) of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (LXXIII) in 100 mL of anhydrous THF at -78 C under an argon atmosphere was added 22 mL (44.3 mmol, 1.1 eq.) of a 2 M solution of LDA in THF. The resulting mixture was stirred at -78 C for 30 mm and 16.8 g (100.7 mmol, 2.5 eq.) of ethyl 2-bromoacetate was added. The mixture was stirred at -78 C for a further 2.5 h and the mixture was then quenched by the slow addition of10 mL of saturated aqueous ammonium chloride solution. The mixture was diluted with 200 mL of water and extracted with 3 x 150 mL of ethyl acetate. The combined organic extracts were washed with 200 mL of brine, dried (Na2SO4), filtered and the solvent was removed in vacuo. The residue was purified by flash chromatography (Si02, eluting with 0-10% ethyl acetate/petroleum ether) to provide 4.5 g (33%, 13.4 mmol) of ethyl 3-(3,5-dibromopyridin-4-yl) propanoate (LXXIV). LCMS: m/z found 336.03 [M+H], RT = 2.28 mm (Method H); ?HNMR (400 IVIFIz, CDC13): 8.59 (s, 2H), 4.19 (q, 2H), 3.3 1-3.27 (m, 2H), 2.59-2.55 (m, 2H), 1.28 (t, 3H).
32%		To a solution of LDA (0.308 mol) [generated from N,N-diisopropylamine (31.2 g, 0.308 mol) and n-BuLi (123 mL, 0.308 mol, 2.5M in hexane) in 800 mL THF] was added slowly a solution of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (70 g, 0.28 mol) in THF (300 mL) while the inner temperature was maintained below -70 C. After the addition, the resulting mixture was stirred for another 30 min at -78 C before ethyl bromoacetate (116.9 g, 0.7 mol) was slowly added and the reaction mixture was stirred at -78C for another 1.5 h. 10% aq. AcOH was added (resulting pH = 4-5), and the reaction was allowed to warm up to room temperature. After evaporation of solvent, the residue was poured into sat. aq. NaHCC"3 solution, and was extracted with EtOAc (1 L x 3). The combined organic layers were washed with brine and dried over Na2S04, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (n- pentane:EtOAc = 15: 1 ~ 5: 1) to afford the title compound (30 g, 32%) as a gray solid. MS: 337.7 (M+H+, 2 Br).

32%

[A] Ethyl 3-(3,5-dibromopyridin-4-yl)propanoate To a solution of LDA (0.308 mol) [generated from N,N-diisopropylamine (31.2 g, 0.308 mol) and n-BuLi (123 mL, 0.308 mol, 2.5M in hexane) in 800 mL THF] was added slowly a solution of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (70 g, 0.28 mol) in THF (300 mL) while the inner temperature was maintained below -70 C. After the addition, the resulting mixture was stirred for another 30 min at -78 C. before ethyl bromoacetate (116.9 g, 0.7 mol) was slowly added and the reaction mixture was stirred at -78 C. for another 1.5 h. 10% aq. AcOH was added (resulting pH=4-5), and the reaction was allowed to warm up to room temperature. After evaporation of solvent, the residue was poured into sat. aq. NaHCO3 solution, and was extracted with EtOAc (1 L*3). The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by column chromatography (n-pentane:EtOAc=15:1?5:1) to afford the title compound (30 g, 32%) as a gray solid. MS: 337.7 (M+H+, 2 Br).

Reference： [1]Patent: WO2013/79452,2013,A1 .Location in patent: Page/Page column 184
[2]Patent: WO2018/172852,2018,A1 .Location in patent: Page/Page column 269; 270
[3]Patent: WO2013/156423,2013,A1 .Location in patent: Page/Page column 57; 58
[4]Patent: US2013/274287,2013,A1 .Location in patent: Paragraph 0415; 0416

34
[ 3430-23-7 ]
[ 1469979-92-7 ]

Reference： [1]Patent: WO2013/156423,2013,A1
[2]Patent: US2013/274287,2013,A1

35
[ 3430-23-7 ]
[ 1428651-91-5 ]
[ 1469979-87-0 ]

Reference： [1]Patent: WO2013/156423,2013,A1
[2]Patent: US2013/274287,2013,A1

36
[ 3430-23-7 ]
[ 98139-01-6 ]

Yield	Reaction Conditions	Operation in experiment
65%	With copper(l) iodide; potassium iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 130℃; for 16h;	GammaAlpha1 3,5-Diiodo-4-methyl-pyridine A solution of <strong>[3430-23-7]3,5-dibromo-4-methyl-pyridine</strong> (10.0 g, 39.8 mmol), KI (70.0 g, 422 mmol), N,A^-dimethylethane-l,2-diamine (4.0 g, 45.4 mmol), Cul (4.0 g, 21.0 mmol) in dioxane (150 mL) was heated at 130 C for 16 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (8.9 g, 65%) as a yellow solid. MS: 346.1 (M+H+).
	With copper(l) iodide; potassium iodide; N,N`-dimethylethylenediamine; In 1,4-dioxane; at 110℃; for 16h;Inert atmosphere;	A mixture of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (20 g, 80 mmol), KI (79.7 g, 480 mmol), CuT (4.57 g, 24 mmol) and N?, N2-dimethylethane- 1 ,2-diamine (4.23 g, 48 mmol) in dioxane (400 mL) was heated at 110C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a crude solid, which was washed with DCM and EtOAc to afford the crude product (18 g, 65%) as a white solid. MS: 345.5 [M+H41. It was used in the next step without further purification.

Reference： [1]Patent: WO2016/55394,2016,A1 .Location in patent: Page/Page column 60
[2]Patent: WO2014/191338,2014,A1 .Location in patent: Page/Page column 43; 44

37
[ 3430-23-7 ]
5-chloro-2-(5-iodo-4-methyl-3-pyridyl)-3-methyl-isoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2016/55394,2016,A1

38
[ 3430-23-7 ]
tert-butyl 6-[5-(5-chloro-3-methyl-1-oxo-isoindolin-2-yl)-4-methyl-3-pyridyl]-2,6-diazaspiro[3.3]heptane-2-carboxylate [ No CAS ]

Reference： [1]Patent: WO2016/55394,2016,A1

39
[ 3430-23-7 ]
5-chloro-2-[5-(2,6-diazaspiro[3.3]heptan-2-yl)-4-methyl-3-pyridyl]-3-methyl-isoindolin-1-one [ No CAS ]

Reference： [1]Patent: WO2016/55394,2016,A1

40
[ 3430-23-7 ]
[ 75-07-0 ]
1-(5-bromo-4-methyl-pyridin-3-yl)-ethanol [ No CAS ]
1-(5-bromo-4-methyl-pyridin-3-yl)-ethanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[3430-23-7]3,5-dibromo-4-methyl-pyridine</strong> (2.0 g, 8.0 mmol) in 100 mL of THF cooled in a liquid N2/ethanol bath below -100C is added 2.5 M n-butyllithim in hexanes solution (3.2 mL, 8.0 mmol). This is stirred for 5 minutes, then neat acetaldehyde (4.5 mL, 8.0 mmol) is added all at once. The reaction is allowed to warm to -78C over 30 minutes. The temperature is held at - 78C by adding dry ice to the bath. The reaction is kept at -78C for 1 hour. The reaction is quenched with sat NH4C1 at -78C. The reaction is allowed to warm to room temperature. The reaction is diluted with EtOAc and water. The organic layer is concentrated to dryness. The residue is purified by silica gel flash column chromatography eluting with 20-100% EtOAc in heptanes to give 0.88 g of the title compound.Chiral SFC (LUX Cellulose-4, 12%(1:1:1 MeOH:EtOH:IPA):C02, 70 mL/min, 120 bar, 40C) of 2.5g of 1-(5-bromo-4-methyl-pyridin-3- yl)-ethanol gives 0.98 g of enantiomer A and 0.98 g of enantiomer B.

Reference： [1]Patent: WO2016/61161,2016,A1 .Location in patent: Page/Page column 43

41
[ 3430-23-7 ]
N-(3-chloro-4-fluorophenyl)-7-(cyclopropanesulfonamido)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/172852,2018,A1

42
[ 3430-23-7 ]
O-(pyridin-2-ylmethyl) N-[(4-((3-chloro-4-fluorophenyl)carbamoyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)] carbamate [ No CAS ]
O-(pyridin-2-ylmethyl) N-[(4-((3-chloro-4-fluorophenyl)carbamoyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)]carbamate [ No CAS ]

Reference： [1]Patent: WO2018/172852,2018,A1

43
[ 3430-23-7 ]
N-(3-chloro-4-fluorophenyl)-7-oxo-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/172852,2018,A1

44
[ 3430-23-7 ]
7-amino-N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[c]pyridine-4-carboxamide [ No CAS ]

Reference： [1]Patent: WO2018/172852,2018,A1

45
[ 3430-23-7 ]
[ 124-38-9 ]
[ 677702-58-8 ]

Yield	Reaction Conditions	Operation in experiment
53%		n-BuLi (0.72 mL, 7.64 mmol, 11M in hexanes) was added dropwise to a solution of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (500 mg, 1.99 mmol) in tetrahydrofuran (10 mL) at -78 C. under nitrogen. After 1 h, CO2 (g) was introduced in the solution at -78 C., and the resulting solution was warmed to room temperature. After 1 h, the reaction was diluted with 1M aqueous HCl. The resulting solution was extracted with ethyl acetate. The combined organic extract was dried over Na2SO4, filtered, and concentrated under vacuum to provide 5-bromo-4-methylpyridine-3-carboxylic acid (0.23 g, 53%) as a white solid.

Reference： [1]Patent: US2018/282328,2018,A1 .Location in patent: Paragraph 1835; 1836

46
[ 3430-23-7 ]
[4-methyl-5-(methylamino)pyridin-3-yl]boronic acid [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

47
[ 3430-23-7 ]
cis-N-[8-amino-6-[4-methyl-5-(methylamino)pyridin-3-yl]-2,7-naphthyridin-3-yl]-2-fluorocyclopropane-1-carboxamide [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

48
[ 3430-23-7 ]
5-bromo-N,4-dimethylpyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

49
[ 3430-23-7 ]
[4-methyl-5-(methylcarbamoyl)pyridin-3-yl]boronic acid [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

50
[ 3430-23-7 ]
cis-5-(1-amino-6-[[-2-fluorocyclopropane]amido]-2,7-naphthyridin-3-yl)-N,4-dimethylpyridine-3-carboxamide [ No CAS ]

Reference： [1]Patent: US2018/282328,2018,A1

51
[ 3430-23-7 ]
[ 74-89-5 ]
5-bromo-N,4-dimethylpyridin-3-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With copper; In 1,4-dioxane; at 100℃; for 5h;	A mixture of <strong>[3430-23-7]3,5-dibromo-4-methylpyridine</strong> (1 g, 3.98 mmol), Cu (52 mg, 0.81 mmol) and CH3NH2 (8 mL) in dioxane (5 mL) was heated at 100 C. After 5 h, the mixture was concentrated under vacuum, and the resulting residue was purified by silica gel chromatography (10:1 dichloromethane/methanol) to afford 5-bromo-N,4-dimethylpyridin-3-amine (400 mg, 50%) as a light yellow solid. LCMS (ESI): M+H+=201.0.

Reference： [1]Patent: US2018/282328,2018,A1 .Location in patent: Paragraph 1762; 1763

52
[ 3430-23-7 ]
(S,E)-2-(2,6-dimethoxy-4-(2-(4-methyl-5-phenylpyridin-3-yl)vinyl)benzylamino)-3-hydroxypropanoic acid [ No CAS ]