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Structure of 31181-90-5

Chemical Structure| 31181-90-5

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Product Citations

Product Citations

Nicholas O. Schneider ; Kendra Gilreath ; Daniel J. Burkett ; Martin St. Maurice ; William A. Donaldson ;

Abstract: Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase which plays a center role in the phosphorylation of a wide variety of proteins, generally leading to their inactivation. As such, GSK-3 is viewed as a therapeutic target. An ever-increasing number of small organic molecule inhibitors of GSK-3 have been reported. Phenylmethylene hydantoins are known to exhibit a wide range of inhibitory activities including for GSK-3β. A family of fourteen 2-heterocycle substituted methylene hydantoins (14, 17–29) were prepared and evaluated for the inhibition of GSK-3β at 25 μM. The IC50 values of five of these compounds was determined; the two best inhibitors are 5-[(4′-chloro-2-pyridinyl)methylene]hydantoin (IC50 = 2.14 ± 0.18 μM) and 5-[(6′-bromo-2-pyridinyl)methylene]hydantoin (IC50 = 3.39 ± 0.16 μM). The computational docking of the compounds with GSK-3β (pdb 1q41) revealed poses with hydrogen bonding to the backbone at Val135. The 5-[(heteroaryl)methylene]hydantoins did not strongly inhibit other metalloenzymes, demonstrating poor inhibitory activity against matrix metalloproteinase-12 at 25 μM and against human carbonic anhydrase at 200 μM, and were not inhibitors for Staphylococcus aureus pyruvate carboxylase at concentrations >1000 μM.

Keywords: nitrogen heterocycles ; glycogen synthase kinase 3β ; computational docking

Alternative Products

Product Details of [ 31181-90-5 ]

CAS No. :31181-90-5
Formula : C6H4BrNO
M.W : 186.01
SMILES Code : O=CC1=NC=C(Br)C=C1
MDL No. :MFCD04112535
InChI Key :ZQVLPMNLLKGGIU-UHFFFAOYSA-N
Pubchem ID :9877562

Safety of [ 31181-90-5 ]

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

Computational Chemistry of [ 31181-90-5 ] 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 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

1.13
Log Po/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 Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.66
Log Po/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 Po/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 Po/w?

Consensus Log Po/w: Average of all five predictions

1.38

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)

1.2

Application In Synthesis of [ 31181-90-5 ]

* 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 [ 31181-90-5 ]

[ 31181-90-5 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 31181-90-5 ]
  • [ 845827-13-6 ]
YieldReaction ConditionsOperation in experiment
74% With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In dichloromethane; at 45℃; for 16h; Dissolve 5-bromopyridine-2-carboxaldehyde (10.0 g, 53.76 mmol) in DCM (200 mL). Add bis(2-methoxyethyl)aminosulfur trifluoride (39 g, 134.4 mmol) slowly. Heat the resulting solution to 45 C. and stir for 16 hours. Pour the reaction slowly into ice water (50 mL). Adjust the pH of the solution to 7 with a saturated NaHCO3 aqueous solution. Extract the aqueous solution with DCM (3*20 mL). Dry the combined organic extracts over sodium sulfate; filter; collect the filtrate; and concentrate the filtrate under reduced pressure. Purify the residue by flash chromatography eluting with a 4:1 ratio of petroleum ether to EtOAc to give the title compound (8.5 g, 74% yield) as a yellow liquid. 1H NMR (300 MHz, CDCl3) delta 8.73 (d, J=2.4 Hz, 1H), 8.00 (dd, J=2.4, 8.1 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 6.44-6.80 (t, J=54.9 Hz, 1 Hz).
67% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 6h; To a cooled solution of 5-bromopyridine-2-carbaldehyde (A) (7.0 g, 38 mmol) in CH2Cl2 (300 mL) at -78 C. was added diethylaminosulfur trifluoride (DAST, 10.8 mL, 83 mmol). The reaction was allowed to warm to room temperature over the course of 6 h, then it was quenched slowly with H2O, washed with saturated aqueous NaHCO3 and dried over Na2SO4. Concentration and purification by silica gel plug (CH2Cl2 eluent) furnished 5-bromo-2-difluoromethylpyridine (B) as brown crystals (5.3g, 67%). 1H NMR (300 MHz, CDCl3) delta 8.8 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 6.6 (t, 1H).
67% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 6h; To a cooled solution of 5-bromopyridine-2-carbaldehyde (A) (7.0 g, 38 mmol) in CH2Cl2 (300 mL) at -78 C. was added diethylaminosulfur trifluoride (DAST, 10.8 mL, 83 mmol). The reaction was allowed to warm to room temperature over the course of 6 h, then it was quenched slowly with H2O, washed with saturated aqueous NaHCO3 and dried over Na2SO4. Concentration and purification by silica gel plug (CH2Cl2 eluent) furnished 5-bromo-2-difluoromethylpyridine (B) as brown crystals (5.3 g, 67 percent). 1H NMR (300 MHz, CDCl3) delta 8.8 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 6.6 (t, 1H).
67% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 6h; To a cooled solution of 5-bromopyridine-2-carbaldehyde (A) (7.0 g, 38 mmol) in CH2Cl2 (300 mL) at -78 C. was added diethylaminosulfur trifluoride (DAST, 10.8 mL, 83 mmol). The reaction was allowed to warm to room temperature over the course of 6 h, then it was quenched slowly with H2O, washed with saturated aqueous NaHCO3 and dried over Na2SO4. Concentration and purification by silica gel plug (CH2Cl2 eluent) furnished 5-bromo-2-difluoromethylpyridine (B) as brown crystals (5.3 g, 67 percent). 1H NMR (300 MHz, CDCl3) delta 8.8 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 6.6 (t, 1H).
67% To a cooled solution of 5-bromopyridine-2-carbaldehyde (A) (7.0 g, 38 mmol) in CH2Cl2 (300 mL) at -78 C. was added diethylaminosulfur trifluoride (DAST, 10.8 mL, 83 mmol). The reaction was allowed to warm to room temperature over the course of 6 h, then it was quenched slowly with H2O, washed with saturated aqueous NaHCO3 and dried over Na2SO4. Concentration and purification by silica gel plug (CH2Cl2 eluent) furnished 5-bromo-2-difluoromethylpyridine (B) as brown crystals (5.3 g, 67%). 1H NMR (300 MHz, CDCl3) delta 8.8 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 6.6 (t, 1H).
63% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 6h; To a cooled solution of 5-bromopyridine-2-carbaldehyde (A) (7.0 g, 38 mmol) in CH2Cl2 (300 mL) at -78 C. was added diethylaminosulfur trifluoride (DAST, 10.8 mL, 83 mmol). The reaction was allowed to warm to room temperature over the course of 6 h, then it was quenched slowly with H2O, washed with saturated aqueous NaHCO3 and dried over Na2SO4. Concentration and purification by silica gel plug (CH2Cl2 eluent) furnished 5-bromo-2-difluoromethylpyridine (B) as brown crystals (5.3 g, 67%). 1H NMR (300 MHz, CDCl3) delta 8.8 (s, 1H), 8.0 (d, 1H), 7.6 (d, 1H), 6.6 (t, 1H).
54% With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 12h; Into a 2000-mL 4-necked round-bottom flask, was placed a solution of 5-bromopyridine-2- carbaldehyde (30 g, 161 .29 mmol, 1.00 equiv) in dichloromethane (800 mL). This was followed by the addition of DAST (diethylaminosulfur trifluoride) (40 g, 1 .08 mol, 6.69 equiv) dropwise with stirring at 0C. The resulting solution was stirred for 12 hours at room temperature. The reaction was then quenched by the addition of water. The pH value of the solution wasadjusted to 8 with sodium carbonate (2 mol/L). The resulting solution was extracted with 3x500 mL of dichloromethane and the organic layers were combined. The resulting mixture was washed with 1x300 mL of H20. The resulting mixture was washed with 1x300 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Thisresulted in 18 g (54%) of 5-bromo-2-(difluoromethyl)pyridine as yellow oil.
54% With diethylamino-sulfur trifluoride; In dichloromethane; at -78 - 20℃; for 5h; A stirred solution of 5-bromo-2-picolinaldehyde (10 g, 54 mmol) (Org. Lett. 2004, 6,4905) in dry CH2Cl2 (100 mL) at -78 0C was treated with DAST (9.2 g, 70 mmol) and the resulting reaction mixture was allowed to warm to room temperature over a period 5h. After completion of the reaction, the reaction mixture was quenched by ice-cold water and extracted with CH2Cl2. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo. The residue was purified by column chromatography (SiO2, 5% Et2O/pet. ether) to afford the title compound (6 g, 54% yield). MS: 210 [M+l]+; 1H-NMR (300 MHz, CDCl3): delta 8.72 (s, IH), 7.93 (d, IH, J= 8.3Hz), 7.54 (d, IH, J= 8.3Hz), 6.60 (t, IH, J= 55.1Hz).
54% With diethylamino-sulfur trifluoride; In dichloromethane; at 0 - 20℃; for 12h; Into a 2000-mL 4-necked round-bottom flask, was placed a solution of 5-bromopyridine-2- carbaldehyde (30 g, 161.29 mmol, 1.00 equiv) in dichloromethane (800 mL). This was followed by the addition of DAST (diethylaminosulfur trifluoride) (40 g, 1.08 mol, 6.69 equiv) dropwise with stirring at 0C. The resulting solution was stirred for 12 hours at room temperature. The reaction was then quenched by the addition of water. The pH value of the solution was adjusted to 8 with sodium carbonate (2 mol/L). The resulting solution was extracted with 3x500 ml. of dichloromethane and the organic layers were combined. The resulting mixture was washed with 1x300 ml. of water. The resulting mixture was washed with 1x300 ml. of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1 :10). This resulted in 18 g (54%) of 5-bromo-2-(difluoromethyl)pyridine as yellow oil.
36% With (bis-(2-methoxyethyl)amino)sulfur trufluoride; In ethanol; dichloromethane; at 0 - 23℃; for 18h; Example 32 Preparation of 5-bromo-2-(difluoromethyl)pyridine Deoxofluor (1.7 mL, 9.1 mmol, 1.7 equiv) and ethanol (63 muL, 1.1 mmol, 0.20 equiv) were sequentially added to a stirred solution of 5-bromopicolinaldehyde (1.0 g, 5.4 mmol, 1.0 equiv) in dichloromethane (5.4 mL) at 0 C. The resulting orange solution was allowed to slowly warm to 23 C. and stirred for 18 h. The dark brown reaction mixture was quenched with saturated sodium bicarbonate solution (6 mL) and stirred at 23 C. for 1 h. The reaction mixture was diluted with water (100 mL) and extracted with dichloromethane (3*50 mL). The combined organic layers were washed with 0.1M HCl (1*150 mL), dried (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the title compound as a brown semisolid (400 mg, 36%): IR (thin film) 3051 (m), 2925 (s), 2853 (m), 1641 (w) cm-1; 1H NMR (300 MHz, CDCl3) delta 8.72 (d, J=2 Hz, 1H), 7.98 (dd, J=8, 2 Hz, 1H), 7.55 (d, J=8 Hz, 1H), 6.61 (t, J=55 Hz, 1H).
With diethylamino-sulfur trifluoride; In chloroform; at 0 - 20℃; A solution of 5-bromo-pyridine-2-carbaldehyde (1.0 mmol) in dry chloroform (5 mL) is cooled to 00C and N,Lambda/-diethylaminosulfur trifluoride (2.0 mmol) is slowly added under vigorous stirring. The reaction mixture is reacted 5 minutes at 00C and is then allowed to reach room temperature and is further stirred at this temperature overnight. The reaction is diluted by the addition of chloroform (15 mL), an aqueous saturated sodium carbonate solution (10 mL) is added drop wise and the resulting mixture is stirred for 10 minutes. The organic phase is collected and washed with water (10 mL), brine (10 mL), is dried over magnesium sulphate, filtered and concentrated under reduced pressure to afford the desired product which is used in the next step without further purification.
1.06 g 1 g 5-Bromo-pyridine-2-carboxaldehyde was dissolved in 50 mL DCM. The solution was cooled to -70C, then 1.55 mL diethylaminosulfurtrifluoride was added dropwise over 20 minutes. The suspension was stirred for 30 minutes at room temperature, then 10 mL water was added at 0C followed by slow addition of 20 mL saturated NaHC03 (gas formation). The phases were separated and 2 mL of 4N HC1 in dioxane is added to the organic phase which was concentrated in vacuo to provide 1.06 g product as yellow solid. HPLC-MS: Rt = 0.72 min (method X001 004), M+H =208 / 210.
1.06 g With hydrogenchloride; diethylamino-sulfur trifluoride; In dichloromethane; at -70 - 20℃; for 0.833333h; 5-Bromo-2-(difluoromethyl)pyridine for Example 120 1 g 5-Bromo-pyridine-2-carboxaldehyde was dissolved in 50 mL DCM. The solution was cooled to -70 C., then 1.55 mL diethylaminosulfurtrifluoride was added dropwise over 20 minutes. The suspension was stirred for 30 minutes at room temperature, then 10 mL water was added at 0 C. followed by slow addition of 20 mL saturated NaHCO3 (gas formation). The phases were separated and 2 mL of 4N HCl in dioxane is added to the organic phase which was concentrated in vacuo to provide 1.06 g product as yellow solid. HPLC-MS: Rt=0.72 min (method X001-004), M+H=208/210.
1.06 g With diethylamino-sulfur trifluoride; In dichloromethane; at -70 - 20℃; for 0.833333h; Synthesis of 5-Bromo-2-(difluoromethyl)pyridine 3.3A solution of 1 g of 5-bromopyridine-2-carbaldehyde in 50 mL DCM was cooled to -70C, then 1 .55 mL diethylaminosulfurtrifluoride were added dropwise over 20 minutes. The suspension was stirred for 30 minutes at room temperature, then 10 mL water were added at 0C followed by slow addition of 20 mL saturated NaHC03 (gas formation). The phases were separated and 2 mL of 4M HCI in dioxane were added to the organic phase which was concentrated in vacuo to provide 1.06 g product as yellow solid. Analysis: HPLC-MS: Rt = 0.72 min (method D), M+H =208 / 210.

  • 2
  • [ 31181-90-5 ]
  • [ 163520-14-7 ]
  • [ 956316-47-5 ]
  • 3
  • [ 7504-94-1 ]
  • [ 31181-90-5 ]
  • [ 1333991-73-3 ]
  • 4
  • [ 31181-90-5 ]
  • [ 103291-07-2 ]
  • [ 1357563-99-5 ]
YieldReaction ConditionsOperation in experiment
To a solution of <strong>[103291-07-2]5-bromo-2-fluoroanisole</strong> (1.00 g, 4.88 mmol, 1 equiv) in anhydrous THF was added granules of magnesium (125 mg, 5.12 mmol, 1.05 equiv) under nitrogen. The mixture was heated to 60 C for 2 h. After cooling to room temperature, 5-bromo-2-formylpyridine (1.09 g, 5.86 mmol, 1.2 equiv) was added and the reaction mixture was stirred at 80 C overnight. The reaction was cooled to room temperature, quenched with brine and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The product was used in the next step without further purification. C13H11BrFNO2; MW 312.
 

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 31181-90-5 ]

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