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Chemical Structure| 663193-80-4 Chemical Structure| 663193-80-4

Structure of 663193-80-4

Chemical Structure| 663193-80-4

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Product Details of [ 663193-80-4 ]

CAS No. :663193-80-4
Formula : C4H3BrClN3
M.W : 208.44
SMILES Code : NC1=NC=NC(=C1Br)Cl
MDL No. :MFCD09999224
InChI Key :DQSBRYJETNYGCI-UHFFFAOYSA-N
Pubchem ID :45789713

Safety of [ 663193-80-4 ]

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

Computational Chemistry of [ 663193-80-4 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 39.15
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

51.8 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.45
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

1.51
Log Po/w (WLOGP)?

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

1.48
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.

0.78
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

1.67
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.

-2.58
Solubility 0.552 mg/ml ; 0.00265 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.

-2.21
Solubility 1.3 mg/ml ; 0.00622 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

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

-2.77
Solubility 0.356 mg/ml ; 0.00171 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

No
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.

-6.5 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

1.76

Application In Synthesis of [ 663193-80-4 ]

* 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 [ 663193-80-4 ]

[ 663193-80-4 ] Synthesis Path-Downstream   1~13

  • 1
  • [ 53220-41-0 ]
  • [ 663193-80-4 ]
  • [ 1427595-75-2 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In N,N-dimethyl-formamide; at 50.0℃; Intermediate (138.1 ): [1-(6-Amino-5-bromo^yrimidin-4-yl)-piperidin-4-yl]-(4-chloro- phenyl)-methanoneThe mixture of 5-bromo-6-chloro-pyrimidine-4-ylamine (2.0 g, 9.59 mmol, 1 .0 eq), 4- chlorophenyl-piperidin-4-yl-methanone (2.36 g, 10.55 mmol, 1 .10 eq) and potassium carbonate (6.63 g, 47.97 mmol, 5.0 eq) in DMF (5 ml_) was stirred at 50 C overnight. After pouring the reaction mixture to water, the precipitate was collected to give Intermediate (138.1 ). LC-MS (M+1 : 396, obsd: 396).
  • 2
  • N-[(3-aminopyrrolidin-3-yl)methyl]-2,4-difluorobenzamide dihydrochloride [ No CAS ]
  • [ 663193-80-4 ]
  • [ 1427596-35-7 ]
YieldReaction ConditionsOperation in experiment
76% With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; N-[3-Amino-1 -(6-amino-5-bromo-pyrimidin-4-yl)-pyrrolidin-3-ylmethyl1-2,4-difluoro- benzamide ("195")A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (272.7 mg; 1 .24 mmol; 1 .02 eq.), N- [(3-aminopyrrolidin-3-yl)-methyl]-2,4-difluorobenzamide dihydrochloride (400.0 mg; 1 .22 mmol; 1 .0 eq.), potassium carbonate (336.8 mg; 2.44 mmol; 2.0 eq.) in DMSO (5.00 ml) was stirred at 60 C overnight. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, basic condition) to afford the title compound in 76% yield. LC-MS: (M+1 =427, obsd. = 427).
  • 3
  • 2-piperazin-1-yl-2-(4-trifluoromethylphenyl)ethylamine hydrochloride [ No CAS ]
  • [ 663193-80-4 ]
  • [ 1427594-18-0 ]
YieldReaction ConditionsOperation in experiment
70% With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; for 8.0h; A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (51 .6 mg; 0.24 mmol, 1 .0 eq.), intermediate (1 .1 ) (1 00.0 mg; 0.24 mmol, 1 .0 eq.) and potassium carbonate (97.5 mg; 0.7 mmol; 3.0 eq.) in DMSO (2.00 ml) was heated at 60 C for 8h. The reaction mixture was purified by pre-HPLC (Waters, basic condition) to afford the title compound as white solid in 70% yield. LC-MS: (M+1 =445, obsd. = 445).
  • 4
  • [ 1427594-83-9 ]
  • [ 663193-80-4 ]
  • [ 1427594-81-7 ]
YieldReaction ConditionsOperation in experiment
With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; for 14.0h; A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (317.78 mg; 1 .45 mmol; 1 .00 eq.), Intermediate (51 .2) (500.00 mg; 1 .45 mmol; 1 .00 eq.) and potassium carbonate (600.48 mg; 4.34 mmol; 3.00 eq.) in DMSO (5.00 m) was heated at 60 C for 14h. The reaction mixture was purified by pre-HPLC (Waters, basic condition) to afford the title compound. LC-MS: (M+1 =444, obsd. = 444).
  • 5
  • [ 663193-80-4 ]
  • 4-[1-(2-azetidin-1-ylethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethylpyridine hydrochloride [ No CAS ]
  • [ 1428249-94-8 ]
YieldReaction ConditionsOperation in experiment
21% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 80.0℃; 6-(4-(1 -(2-(azetidin-1 -vnethvn-4-(2-(trifluoromethyl)Dyridin-4-yl)-1 H-imidazol-2- yl)piperidin-1 -yl)-5-bromopyrimidin-4-amine ("126")A reaction mixture of 5-Bromo-6-chloro-pyrimidin-4-ylamine (53.00 mg; 0.25 mmol; 1 .00 eq.), 4-[1 -(2-azetidin-1 -yl-ethyl)-2-piperidin-4-yl-1 H-imidazol-4-yl]-2- trifluoromethyl-pyridine hydrochloride (4) (133.56 mg; 0.25 mmol; 1 .00 eq.), and ethyl-diisopropyl-amine (0.23 ml; 1 .27 mmol; 5.00 eq.) in ACN 3ml was stirred at 80C for overnight. Purified by HPLC(basic), collected title compound, 30mg, yield, 21 %. LC-MS: (M+1 = 551 , obsd. = 551 ).
  • 6
  • [ 663193-80-4 ]
  • 2-[4-(4-fluoro-3-methylphenyl)-2-piperidin-4-ylimidazol-1-yl]ethanol hydrochloride [ No CAS ]
  • [ 1446104-05-7 ]
YieldReaction ConditionsOperation in experiment
88.9% With caesium carbonate; In dimethyl sulfoxide; at 100.0℃; Step 3: 2-(2-(1-(6-amino-5-bromopyrimidin-4-yl)piperidin-4-yl)-4-(4-fluoro-3- methylphenyl)- 1 H-imidazol- 1 -yl)ethanolA reaction mixture of 5-bromo-6-chloro-pyrimidin-4-ylamine (370.00 mg; 1 .78 mmol; 1 .00 eq.), 2-[4-(4-fluoro-3-methyl-phenyl)-2-piperidin-4-yl-imidazol-1 -yl]-ethanol hydrochloride (3) (732.67 mg; 1 .78 mmol; 1 .00 eq.), and Cs2C03 (2313.40 mg; 7.1 0 mmol; 4.00 eq.) in DMSO 10ml, stirred at 1 00C for overnight, cooled, poured into water 60ml, stirred for 15mins, filtered, collected light yellow solid, which was washed with water, dried, got title compound , 750mg, 88.9%.
  • 7
  • [ 1083051-56-2 ]
  • [ 663193-80-4 ]
  • [ 1428248-69-4 ]
YieldReaction ConditionsOperation in experiment
86% With potassium carbonate; In dimethyl sulfoxide; at 60.0℃; 5-Bromo-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1 -methyl-1 H-imidazol-2-yll-piperidin- 1 -yl)-pyrimidin-4-ylamine ("1 ")A mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (357.2 mg; 1 .71 mmol; 1 .02 eq.), 4-[4- (4-fluoro-3-trifluoromethyl-phenyl)-1 -methyl-1 h-imidazol-2-yl]-piperidine (550.00 mg; 1 .68 mmol; 1.0 eq.), potassium carbonate (464.4 mg; 3.36 mmol; 2.0 eq.) in DMSO (6.0 ml) was stirred at 60 C overnight. The reaction mixture was poured into water. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound in 86% yield. LC-MS: (M+1 =499, obsd. = 499).
  • 8
  • [ 1403943-08-7 ]
  • [ 663193-80-4 ]
  • [ 1605328-72-0 ]
YieldReaction ConditionsOperation in experiment
60% With N-ethyl-N,N-diisopropylamine; cesium fluoride; In tert-butyl alcohol; at 140.0℃; for 40.0h;Sealed tube; (S)-2-(1 -Aminoethyl)-5-methyl-3-phenylpyrrolo[2, 1 -f{ ,2,4]triazin-4(3H)-one(300 mg, 1.12 mmol) was treated <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (373 mg, 1.79 mmol), cesium fluoride (340 mg, 2.24 mmol), Lambda/,/V-diisopropylethylamine (0.974 ml_, 5.59 mol) according to Preparation 13. The residue was purified using SP1Purification System (0% to 10%, dichloromethane-methanol) to give 0.26 g (60% yield) of the title compound as a solid. Purity 98%.LRMS (m/z): 440, 442 (M+1 )+.
  • 9
  • [ 663193-80-4 ]
  • [ 1605328-78-6 ]
  • [ 1605328-79-7 ]
YieldReaction ConditionsOperation in experiment
75% With N-ethyl-N,N-diisopropylamine; cesium fluoride; In tert-butyl alcohol; at 140.0℃; for 40.0h;Sealed tube; (S)-2-(1 -Aminoethyl)-3-phenyl-5-(phenylthio)pyrrolo[2 -/][1 2 4]triazin-4(3H)-one (142 mg, 0.39 mmol) was treated with treated <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (245 mg, 1 .18 mmol), cesium fluoride (178 mg, 1 .17 mmol), /V,/V-diisopropylethylamine (341 muIota, 1 .96 mol) according to Preparation 13 to give 0.23 g (75% yield) of the title compound as a solid.LRMS (m/z): 534, 536 (M+1 )+
  • 10
  • [ 663193-80-4 ]
  • 4-[1-(2-azetidin-1-ylethyl)-4-(4-fluoro-3-methylphenyl)-1H-imidazol-2-yl]piperidine tetrahydrochloride [ No CAS ]
  • [ 1428250-64-9 ]
YieldReaction ConditionsOperation in experiment
With caesium carbonate; In dimethyl sulfoxide; at 120.0℃; The reaction mixture of 5-bromo-6-chloro-pyrimidin-4-ylamine (215.00 mg; 1.03 mmol; 1.0 eq.), 4-[1-(2-azetidin-1-yl-ethyl)-4-(4-fluoro-3-methyl-phenyl)-1H-imidazol-2-yl]-piperidine tetrahydrochloride (503.6 mg; 1.03 mmol; 1 eq.), and Cs2CO3 (1344.27 mg; 4.13 mmol; 4 eq.) in DMSO (1.5 ml) was stirred at 120 C. overnight. After cooling, the reaction mixture was poured into water. The precipitate was collected by filtration to yield the title compound as a yellow solid.
  • 11
  • [ 663193-80-4 ]
  • C34H34N4O6S2 [ No CAS ]
  • C21H20BrN5O3S [ No CAS ]
YieldReaction ConditionsOperation in experiment
31 mg With tris-(2-carboxyethyl)-phosphine hydrochloride; sodium hydroxide; In N,N-dimethyl-formamide; at 20.0℃;Inert atmosphere; (0190) Compound 15. The disulfide, Intermediate 4, from above (111 mg, 0.169 mmol) was mixed with tris-2-carboxyethylphosphine hydrochloride (53 mg, 0.185 mmol) and DMF (2 mL), 1 M NaOH (0.88 mL, 0.88 mmol), and <strong>[663193-80-4]4-amino-5-bromo-6-chloro-pyrimidine</strong> (70 mg, 0.336 mmol) were added. The reaction was allowed to stir at RT overnight, whereupon it was flooded with 50 mL EtOAc, rinsed with 2x25 mL water, 25 mL brine, dried over sodium sulfate, filtered, evaporated to dryness, and purified by reverse phase HPLC to yield Compound 15 (31 mg) as a white solid. ES (+) MS m/e = 504 (M+1).
  • 12
  • [ 663193-80-4 ]
  • 1-[3-(pyridin-2-yl)indolizin-2-yl]ethan-1-amine [ No CAS ]
  • 5-bromo-4-N-{1-[3-(pyridin-2-yl)indolizin-2-yl]ethyl}pyrimidine-4,6-diamine [ No CAS ]
YieldReaction ConditionsOperation in experiment
0.144 g With N-ethyl-N,N-diisopropylamine; In tert-butyl alcohol; for 144.0h;Reflux; Example 48 5-bromo-4-N-{1-[3-(pyridin-2-yl)indolizin-2-yl]ethyl}pyrimidine-4,6-diamine Prepared similarly to Example 47, starting from 1-[3-(pyridin-2-yl)indolizin-2-yl]ethan-1-amine Q2 (0.171 g, 0.72 mmol) and <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (0.150 g, 0.72 mmol), heating to reflux for 6 days, and purified by flash chromatography on 28 g Biotage silica-NH SNAP cartridge (DCM to DCM:MeOH=99.5:0.5) followed by flash chromatography on Biotage silica-NH SNAP cartridge (cyclohexane:EtOAc=90:10 to 80:20) to afford title compound as a white solid (0.144 g). MS/ESI+ 408.9-410.9 [MH]+, Rt 0.63 min (Method A). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.73-7.77 (m, 1H), 8.67 (d, 1H), 7.92 (td, 1H), 7.82 (s, 1H), 7.74 (d, 1H), 7.49 (d, 1H), 7.32-7.37 (m, 1H), 6.77-6.86 (m, 2H), 6.68 (s, 1H), 6.57-6.64 (m, 1H), 6.43 (br. s., 2H), 5.58-5.68 (m, 1H), 1.40 (d, 3H).
  • 13
  • [ 663193-80-4 ]
  • tributyl[(tributylstannyl)methoxy]methyl}stannane [ No CAS ]
  • 4-amino-5,7-dihydrofuro[3,4-d]pyrimidine [ No CAS ]
YieldReaction ConditionsOperation in experiment
25% With tris-(dibenzylideneacetone)dipalladium(0); XPhos; In 1,4-dioxane; at 135.0℃; for 2.0h;Microwave irradiation; Example 14 4-Amino-5,7-dihydrofuro[3,4-d]pyrimidine To a mixture of <strong>[663193-80-4]5-bromo-6-chloropyrimidin-4-amine</strong> (15 mg, 0.070 mmol), tributyl[tributylstannyl)methoxy]methyl}stannane according to Production Example 1-1 (53 mg, 0.084 mmol), tris(dibenzylideneacetone)dipalladium (6.4 mg, 0.0070 mmol), and X-Phos (13 mg, 0.028 mmol), 1,4-dioxane (0.7 mL) was added, and the resulting mixture was stirred at 135 C. for 2 hours under microwave irradiation. The resulting mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate:methanol=20:1) to obtain the title compound (2.4 mg, 25% yield). MS(ESI)m/z 138(MH)+
 

Historical Records

Technical Information

Categories

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[ 663193-80-4 ]

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