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Structure of 157837-31-5

Chemical Structure| 157837-31-5

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Product Details of [ 157837-31-5 ]

CAS No. :157837-31-5
Formula : C9H8N2O
M.W : 160.17
SMILES Code : NC1=CC(=CC=C1)C1=CN=CO1
MDL No. :MFCD00052191
InChI Key :AIELNJDAOGTASK-UHFFFAOYSA-N
Pubchem ID :2739289

Safety of [ 157837-31-5 ]

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

Computational Chemistry of [ 157837-31-5 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 11
Fraction Csp3 0.0
Num. rotatable bonds 1
Num. H-bond acceptors 2.0
Num. H-bond donors 1.0
Molar Refractivity 46.34
TPSA ?

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

52.05 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.55
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

1.32
Log Po/w (WLOGP)?

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

1.93
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.

0.44
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

1.73
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.4

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-2.28
Solubility 0.846 mg/ml ; 0.00528 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.

-2.01
Solubility 1.55 mg/ml ; 0.00968 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

-3.38
Solubility 0.066 mg/ml ; 0.000412 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.

-6.34 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)

2.24

Application In Synthesis of [ 157837-31-5 ]

* 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 [ 157837-31-5 ]

[ 157837-31-5 ] Synthesis Path-Downstream   1~35

  • 1
  • [ 268725-61-7 ]
  • [ 157837-31-5 ]
  • 2-benzyl-5-(3-dimethylamino-propoxy)-2<i>H</i>-pyrazole-3-carboxylic acid (3-oxazol-5-yl-phenyl)-amide [ No CAS ]
  • 2
  • [ 157837-31-5 ]
  • ((1R,2R,5S)-2-Benzyloxy-5-benzyloxycarbonylamino-4-chlorocarbonyl-cyclohex-3-enyl)-carbamic acid benzyl ester [ No CAS ]
  • [(1R,2R,5S)-2-Benzyloxy-5-benzyloxycarbonylamino-4-(3-oxazol-5-yl-phenylcarbamoyl)-cyclohex-3-enyl]-carbamic acid benzyl ester [ No CAS ]
  • 3
  • [ 1885-14-9 ]
  • [ 157837-31-5 ]
  • phenyl (3-(oxazol-5-yl)phenyl)carbamate [ No CAS ]
  • 4
  • [ 874143-25-6 ]
  • [ 157837-31-5 ]
  • N-(3-(6-(3-(oxazol-5-yl)phenylamino)pyrazin-2-yl)phenyl)acetamide [ No CAS ]
  • 5
  • [ 895635-25-3 ]
  • [ 157837-31-5 ]
  • 2,6-Difluoro-N-{3-[3-(2-[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
59% Example 35 2,6-Difluoro-N-{3-[3-(2-[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}benzamide To a slurry of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (100 mg, 0.216 mmol.) in 1 mL of EtOH/0.25 mL of DMF, added [3-(1,3-oxazol-5-yl)phenyl]amine (41 mg, 0.26 mmol.) and 5 uL of conc. HCl, the reaction contents were heated to 70 C. After heating for 18 h, the reaction was cooled to RT, partitioned the reaction with EtOAc and sat. aq. NaHCO3. The layers were separated, extracted the aqueous layer with EtOAc (2×10 mL), the organic layers were pooled, dried over MgSO4, filtered, reduced in vacuo onto silica. Purification via ISCO (hexanes:EtOAc) afforded 73 mg (59% yield) of the title compound as a yellow solid. 1H NMR (400 MHz, d6-DMSO): δ 10.91 (s, 1H); 9.71 (s, 1H); 8.83 (d, J=6 Hz, 1H); 8.51 (d, J=9 Hz, 1H); 8.37 (s, 1H); 8.28 (d, J=5 Hz, 1H); 8.17 (s, 1H); 7.99 (s, 1H); 7.79 (d, J=9 Hz, 1H); 7.68 (d, J=7 Hz, 1H); 7.60-7.53 (m, 2H); 7.46 (t, J=15 Hz, 1H); 7.39-7.28 (m, 5H); 7.23 (t, J=15 Hz, 2H); 7.20 (t, J=6 Hz, 1H). HRMS calculated C33H22F2N7O2 [M+H]+ 586.1803, found 586.1802.
  • 6
  • [ 157837-31-5 ]
  • N-{3-[(3S)-3-(4-fluorobenzyl)piperidinyl]propyl}-N'-[3-(1,3-oxazol-5-yl)phenyl]-urea [ No CAS ]
  • 7
  • [ 157837-31-5 ]
  • [ 49845-33-2 ]
  • [ 840537-54-4 ]
YieldReaction ConditionsOperation in experiment
With N,N-diethylaniline; In dichloromethane; at -40 - 20℃; A mixture of 2, 4-DICHLORO-5-NITROPYRIMIDINE (5 mmol) in CH2C12 (20 ml) was stirred at -30 C/-40 C. ALTERNATELY, a solution of 3- (5-OXAZOLYL)-BENZENAMINE (5 mmol) in CH2C12 (10 ml) and a solution OF N, N-DIETHYLBENZENAMINE (5 mmol) in CH2C . 2 (10 ML) were added dropwise over a period of 1 hour, followed by stirring for 2 hours at-20 C/-30 C. The mixture was allowed to come to room temperature while stirring. The mixture was diluted with 50 ml of CH2CL2 and 50 ml of ice water was added. The precipitate was filtered and dried. Yield : 490 mg of intermediate 51. Of the filtrate, the layers were separated and the organic layer was dried, filtered and evaporated. The residue was stirred in CH3CN. The precipitate was filtered off and dried. Yield : 305 mg of intermediate 51.
With N,N-diethylaniline; In dichloromethane; at -40 - -20℃; for 3h; A mixture of 2,4-dichloro-5-nitropyrimidine (5 mmol) in CH2Cl2 (20 ml) was stirred at - 30C/-40C. Alternately, a solution of <strong>[157837-31-5]3-(5-oxazolyl)-benzenamine</strong> (5 mmol) in CH2Cl2 (10 ml) and a solution of N,N-diethylbenzenamine (5 mmol) in CH2Cl2 (10 ml) were added dropwise over a period of 1 hour, followed by stirring for 2 hours at- 20C/-30C. The mixture was allowed to come to room temperature while stirring. The mixture was diluted with 50 ml of CH2Cl2 and 50 ml of ice water was added. The precipitate was filtered and dried. Yield: 490 mg of intermediate 41. Of the filtrate, the layers were separated and the organic layer was dried, filtered and evaporated. The residue was stirred in CH3CN. The precipitate was filtered off and dried. Yield: 305 mg of intermediate 41.
  • 8
  • intermediate 25 [ No CAS ]
  • [ 157837-31-5 ]
  • [ 842127-57-5 ]
YieldReaction ConditionsOperation in experiment
48% In 2-methoxy-ethanol; at 100℃; for 4h; A mixture of intermediate 25 (prepared according to A2. c-3) (0.0005 mol) and 3-(5-oxazolyl)benzenamine (0.0005 mol) in 2-methoxyethanol (2.5 ml) was stirred for 4 hours at 100C and the solvent was evaporated. The residue was crystallised from CH3CN/CH3OH (4ml/Lml), then the precipitate was filtered off and dried. Yield: 0.171 g of fraction 1. This fraction was further crystallised from 2-methoxyethanol (92 ml) and CH3CN (4 ml) and the resulting mixture was stirred overnight. The precipitate was filtered off and dried. Yield: 0.103 g of final compound 115 (48 %, m. p.: 156-160C).
  • 9
  • [ 840537-49-7 ]
  • [ 157837-31-5 ]
  • [ 842127-58-6 ]
YieldReaction ConditionsOperation in experiment
37% In 2-methoxy-ethanol; at 100℃; for 48h; A mixture of intermediate 28 (prepared according to A2. c-4b) (0.0001 mol) and 3-(5-oxazolyl)benzenamine (0.0001 mol) in 2-methoxyethanol (1 ml) was stirred for 48 hours at 100C and then the solvent was evaporated. The residue was purified on RediSep (eluent: CH2Cl2/CH3OH 100/0-> 98/2). The product fractions were collected and the solvent was evaporated. The residue was crystallised from CH3OH with 1 drop of H2O, then the resulting precipitate was filtered off and dried. Yield: 0.017 g final compound 122 (37 %, m. p. (KOFFLER): 210-214C)
  • 10
  • [ 610277-86-6 ]
  • [ 157837-31-5 ]
  • [1-(2,4-dimethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(3-oxazol-5-yl-phenyl)-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 50: [1- (2, 4-Dimethyl-phenyl)-lH-pyrazolo [3,4-d] pyrimidin-4-yl]- (3-oxazol-5- yl-phenyl)-amine; Reaction of Intermediate 1 (75mg) with <strong>[157837-31-5]3-oxazol-5-yl-phenylamine</strong> (95mg) gave the title compound after purification by Method B LCMS rt 5.16 (M-H)-381 1H NMR 6 10.35 (1H, s), 8.55 (1H, s), 8.51 (1H, s), 8.46 (1H, s), 8.26 (1H, s), 7.95 (1H, m), 7.73 (1H, s), 7.54 (2H, d), 7.18-7. 30 (3H, m), 2.39 (3H, s), 2.04 (3H, s)
  • 11
  • [ 157837-31-5 ]
  • C9H9N3O [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 9 4-Pyridinecarboxyaldehyde 3-(oxazol-5-yl)phenylhydrazone; [Show Image] 3-(Oxazol-5-yl)phenylamine (421 mg) was dissolved in water (8 ml) and concentrated hydrochloric acid (8 ml), and an aqueous solution (2 ml) of sodium nitrite (218 mg) was added dropwise to the solution at 0C over 30 minutes. After stirring at the same temperature for 30 minutes, a concentrated hydrochloric acid (3 ml) solution of tin chloride dihydrate (1.19 g) was added dropwise to the mixture, followed by stirring at room temperature for 30 minutes. The reaction mixture was alkalified by adding an aqueous solution of 20% potassium hydroxide and extracted with methanol:chloroform = 1:9 (200 ml) twice. After drying over anhydrous sodium sulfate, the solvent was evaporated to obtain a yellow solid as the residue. The residue and 4-pyridinecarboxyaldehyde (227 µl) were dissolved in ethanol (8 ml) and heated under reflux for 15 hours. The solvent was evaporated, and the thus obtained solid was washed with ether to obtain the title compound (472 mg) as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ: 7.11 (1H, d, J=7.9 Hz), 7.23 (1H, d, J=7.6 Hz), 7.36 (1H, t, J=7.8 Hz), 7.39 (1H, s), 7.46 (1H, s), 7.54 (2H, d, J=5.9 Hz), 7.65 (1H, s), 7.94 (1H, s), 8.04 (1H, s), 8.62 (2H, d, J=5.9 Hz). ESI-MS m/z: 265 (M+H)+.
  • 12
  • [ 89808-77-5 ]
  • [ 157837-31-5 ]
YieldReaction ConditionsOperation in experiment
93% With hydrogenchloride; tin(II) chloride dihdyrate; water; In ethanol; at 20℃; A solution of intermediate la (3.52g, 18.5mmol) in absolute ethanol (210ml) was treated with water (21ml) then SnCI2.2H20 (20.9g, 92.6mmol) and cone. HCI (15ml, 180mmol). After stirring at room temperature overnight, the solution was taken to pH 7 with 10% aqueous NaOH solution and extracted repeatedly with EtOAc. The organics were dried (MgS04), filtered and evaporated to afford the title compound as a pale orange powder (2.74g, 93%). *H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.49 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.90 (t, J = 1.8 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.59 - 6.54 (m, 1H), 5.25 (s, 2H).
93% With hydrogenchloride; tin(II) chloride dihdyrate; In ethanol; water; at 20℃; [0087] A solution of intermediate Ia (3.52g, 18.5mmol) in absolute ethanol (210ml) was treated with water (21ml) thenSnCl2.2H2O (20.9g, 92.6mmol) and conc. HCl (15ml, 180mmol). After stirring at room temperature overnight, the solutionwas taken to pH 8 with 10% aqueous NaOH solution and extracted repeatedly with EtOAc. The organics were dried(MgSO4), filtered and evaporated to afford the title compound as a pale orange powder (2.74g, 93%). 1H NMR (400MHz, DMSO-d6) δ 8.37 (s, 1H), 7.49 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.90 (t, J = 1.8 Hz, 1H), 6.86 (d, J = 7.6 Hz, 1H),6.59 - 6.54 (m, 1H), 5.25 (s, 2H).
83% 1 g (5.26 mmol, 1 eq.) of 5-(3-nitrophenyl)oxazole and 10 mL of TFA are introduced into a 1 L flask. 1 g of zinc is carefully added in a plurality of batches. The mixture is stirred for 2 hours at room temperature then is poured over ice. Sodium hydroxide is slowly added <n="56"/>until the medium becomes basic, and the medium is extracted with diethyl ether. The organic phase is washed with a 1 M solution of HCl and the impurities are extracted with diethyl ether. The aqueous phase is again basified with sodium hydroxide and the product is extracted with diethyl ether. The organic phases are combined, dried over MgSO4 and filtered. After concentration to dryness, 700 mg (yield = 83 %) of aniline 3-oxazol-5-yl- phenylamine are obtained, in the form of a beige solid. The product is used without subsequent purification.1H NMR(400 MHz, CD3OD): ppm 6.74 (d, IH, aromatic H), 7.05 (d, IH, aromatic H), 7.09 (s, IH, aromatic H), 7.18 (t, IH, aromatic H), 7.41 (s, IH, Hoxazoie), 8.22 (s, IH, Hoxazoie). MS: 16I+ (M+H)+
With hydrogen;5% palladium over charcoal; In ethanol; ethyl acetate; at 20℃; for 15h; Reference Example 9 3-(Oxazol-5-yl)phenylamine 3-(Oxazol-5-yl)nitrobenzene (3.56 g) was dissolved in ethanol (80 ml) and ethyl acetate (80 ml), 5% palladium-carbon (1.9 g) was added to the mixture and stirred at room temperature for 15 hours in an atmosphere of hydrogen. After filtration of the catalyst, the solvent was evaporated, and the thus obtained crystals were washed with hexane to obtain the title compound (2.80 g) as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 3.77 (2H, br s), 6.66 (1H, d, J=7.8 Hz), 6.98 (1H, br s), 7.05 (1H, br d, J=7.9 Hz), 7.20 (1H, t, J=8.1 Hz), 7.30 (1H, s), 7.88 (1H, s). FAB-MS m/z: 161 (M+H)+.

  • 13
  • [ 98-74-8 ]
  • [ 157837-31-5 ]
  • [ 940868-55-3 ]
YieldReaction ConditionsOperation in experiment
In pyridine; at 20℃; A solution of <strong>[157837-31-5]3-oxazol-5-yl-phenylamine</strong> (0.5 g, 3.1 mmol) and 4-nitro-benzenesulfonyl chloride (0.91 g, 4.1 mmol) in pyridine (20 ml) was stirred over weekend at room temperature. The residue was partitioned between EtOAc and H2O. The organic layer was separated, washed twice with H2O and once with saturated aqueous sodium chloride solution, dried and concentrated by evaporation. The residue was purified by column chromatography on silica-gel (5%-15% EtOAc-hexane) to afford 0.63 g of product. 1H-NMR (DMSO), δ8.47(s, 1H), 8.39(d, 2H), 8.04(d, 2H), 7.67(s, 1H), 7.48(m, 2H), 7.38(t, 1H), 7.1(d, 1H) MS (ei): M(+)+H=346
  • 14
  • [ 894416-97-8 ]
  • [ 157837-31-5 ]
  • [ 894418-08-7 ]
  • 15
  • [ 894416-98-9 ]
  • [ 157837-31-5 ]
  • [ 894418-12-3 ]
  • 16
  • [ 1153950-20-9 ]
  • [ 157837-31-5 ]
  • [ 1153945-31-3 ]
YieldReaction ConditionsOperation in experiment
With toluene-4-sulfonic acid; In 1,4-dioxane;Heating / reflux; A mixture of 3-[4-(2-chloro-5-methoxypyrimidin-4-yl)-lH-pyrazol-l-yl]-3- cyclopropylpropanenitrile (20 mg, 0.00008 mol), 3-(l,3-oxazol-5-yl)aniline (18.1 mg, 0.000113 mol), and p-toluenesulfonic acid (11 mg, 0.000064 mol) in dry 1,4-dioxane (0.5 mL, 0.006 mol) was refluxed overnight. The mixture was diluted with acetonitrile and water, purified on RP-HPLC at pH 10 to give the desired product as a racemic mixture (free base). LCMS (M+H) 428.1.
  • 17
  • [ 895635-03-7 ]
  • [ 157837-31-5 ]
  • [ 941318-65-6 ]
YieldReaction ConditionsOperation in experiment
69% Step A. 2,2,2-Trifluoro-N-{3-[3-(2-[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}acetamide To a solution of N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,2,2-trifluoroacetamide (1.0 g, 0.002 mol) (see Example 1, Step C) in 1,4-dioxane (25 mL) and i-PrOH (5 mL) was added <strong>[157837-31-5]3-(1,3-oxazol-5-yl)aniline</strong> (1.15 g, 0.007 mols) followed by catalytic 12M HCl. After heating overnight at 90 C., the reaction was quenched with saturated NaHCO3 (25 mL), the solvent was removed by rotary evaporation, the aqueous layer extracted with DCM (25 mL), the organic layer concentrated, and purified by column chromatography (5-50% EtOAc in hexanes then 100% EtOAc) to provide the product (0.89 g, 69%) as an off-white solid. ES-LC/MS m/z=542 [M+H]+.
  • 18
  • [ 1160624-46-3 ]
  • [ 157837-31-5 ]
  • [ 1160624-44-1 ]
YieldReaction ConditionsOperation in experiment
76% Step D: 4-(2-Amino-4-{3-[(phenylmethyl)oxy]phenyl}-1 ,3-thiazol-5-yl)-λ/-[3-(1 ,3- oxazol-5-yl)phenyl]-2-pyrimidinamine; To a solution containing 95 mg (0.17 mmol) of 5-(2-chloro-4-pyrimidinyl)-4-{3- [(phenylmethyl)oxy]phenyl}-1 ,3-thiazol-2-amine, 1 mL of i-PrOH, and 0.5 mL of DMA, was added 27 mg (0.17 mmol) of 3-(1 ,3-oxazol-5-yl) phenyl amine and 1 drop of cone HCI. The reaction mixture was heated at 70 0C for 48 h, neutralized by the addition of aqueous NaHCO3, and extracted with DCM. The combined organic layers were dried over MgSO4 and filtered, and the solvent was removed under reduced pressure. The residue was subjected to silica gel chromatography, eluting with an EtOAc/hexane mixture, and the DMA was removed by triturating from DCM to give 66 mg (76 %) of the title compound of Example 69 as a yellow solid: 1H-NMR (d6- DMSO, 400MHz) δ 9.65 (s, 1 H), 8.46 (s, 1 H), 8.20 (s, 1 H), 8.08 (d, I H1 J = 5.5 Hz), 7.72 (d, 1 H, J = 7.8 Hz), 7.61 (s, 2 H), 7.30 - 7.43 (m, 8 H), 7.12 (s, 1 H), 7.06 - <n="194"/>7.09 (m, 2 H), 6.29 (d, 1 H, J = 5.5 Hz), and 5.10 (s, 2 H); HRMS Calcd for C29H22N6O2S: 518.1525. Found: 519.1603 (M+H+).
  • 19
  • [ 1160624-15-6 ]
  • [ 157837-31-5 ]
  • C28H27N5O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In water; isopropyl alcohol; at 80℃; Example 62: λ/-{3-F2-Amino-5-(2-fr3-(1 ,3-oxazol-5-yl)phenvϖamino)-4-pyrimidinyl)- i ^-thiazoM-yliphenyPcyclohexanecarboxamide; To obtain the title compound of Example 62, λ/-{3-[(E)-2-(2-chloro-4-pyrimidinyl)-1- hydroxyethenyljphenyljcyclohexanecarboxamide (0.1 g, 0.28 mmol), prepared by a procedure analogous to Example 60, Step A, 3-(1 ,3-oxazol-5-yl)phenyl amine (0.065 g, 0.41 mmol), iPrOH (2 ml_) and concentrated HCI (0.05 ml_) were combined and heated at 80 0C overnight. NBS (0.03 g, 0.17 mmol) was added and the resulting mixture was allowed to stir at rt for 15 min. Thiourea (0.03 g, 0.47 mmol) and MgCO3 λ/-hydrate (0.03 g) were added and the reaction was then heated 90 0C for 1 hr. The crude reaction was then diluted with EtOAc and H2O. The desired compound was extracted into the organic layer which after concentrating yielded brown oil which was then purified using basic RP HPLC conditions. 50 mg (33%) of the title compound of Example 62 was obtained. 1H-NMR (300 MHz, DMSO-d6) δ 9.88 (s, 1 H), 9.65 (s, 1 H), 8.46 (s, 1 H), 8.21 (s, 1 H), 8.11 (d, J= 5.4 Hz, 1 H), 7.78 (s, 1 H), 7.75-7.62 (m, 4 H), 7.61 (s, 1 H), 7.40-7.29 (m, 3 H), 7.14 (d, J= 7.8 Hz, 1 H), 6.34 (d, J= 5.2 Hz, 1 H), 2.30 (m, 1 H), 1.84-1.58 (m, 5 H), and 1.47-1.12 (m, 5 H); MS (ESI) m/z 538 (M+H)+.
  • 20
  • [ 1160623-85-7 ]
  • [ 157837-31-5 ]
  • [ 1160626-51-6 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In N,N-dimethyl acetamide; isopropyl alcohol; at 70℃; for 12h; Step A: 2,5-Difluoro-λ/-methyl-λ/-{3-[(2-[3-(1 ,3-oxazol-5-yl)phenyl]amino}-4- pyrimidinyl)acetyl]phenyl}benzamide; <n="168"/>To a solution containing 250 mg (0.64 mmol) of /V-{3-[(2-chloro-4- pyrimidinyl)acetyI]phenyl}-2,5-difluorobenzamide, prepared by a procedure analogous to Example 50, Step B, 1.5 mL of i-PrOH, and 0.5 ml_ of DMA was added 103 mg (0.64 mmol) 3-(1 ,3-oxazol-5-yl) phenyl amine and 1 drop of cone HCI. The reaction mixture was heated at 70 0C for 12 h, diluted with H2O1 and filtered to give the title compound of Step A as a yellow solid, which was used without further purification: ESIMS: 512.20 (M+H+).
  • 21
  • tert-butyl 4-(chlorocarbonyl)-4-methylpiperidine-1-carboxylate [ No CAS ]
  • [ 157837-31-5 ]
  • [ 1192189-37-9 ]
YieldReaction ConditionsOperation in experiment
With pyridine; In 1,2-dichloro-ethane; for 1.5h; A. Preparation of tert-butyl 4-methyl-4-(3-(oxazol-5-yl)phenylcarbamoyl)-piperidine-1-carboxylate. To a solution of 1-(tert-butoxycarbonyl)-4-methylpiperidine-4-carboxylic acid (61.3 mg, 0.252 mmol) and pyridine (79.7 mg, 0.08 mL, 1.01 mmol) in 1,2-dichloroethane (2 mL) at 0 C. was added DMF (1-2 drops) followed by oxalyl chloride (31.9 mg, 0.022 mL, 0.252 mmol). The reaction was stirred for 0.5 hour, and <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (40.4 mg, 0.252 mmol) was added. The reaction was allowed to stir for another 1.5 hours. The mixture was diluted with ethyl acetate (10 mL), and the organics were washed with 0.1 N HCl (2*10 mL), brine (4 mL), dried over MgSO4, filtered, and concentrated to give the title compound, which was used in the next step without further purification. MS (ES+) [M+H]+=386.2.
  • 22
  • 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride [ No CAS ]
  • [ 157837-31-5 ]
  • [ 1365718-69-9 ]
YieldReaction ConditionsOperation in experiment
63% In 1,4-dioxane; water; at 20℃; for 672h; A solution containing 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (20 mg, 0.071 mmol) and 3-(l,3-oxazol-5-yl)-aniline (17 mg, 0.11 mmol) in aqueous dioxane (1 mL, 95:5 dioxane/wter) was stirred at room temperature for 4 weeks. The reaction mixture was diluted with MeOH/water and the crude product was purified by reversed phase chromatography(ACE C8, 5μιη, 21x50mm, flow 25 ml/min, gradient: 0.1% TFA in water/MeCN over 6 minutes). The title compound was obtained in 63% yield (18 mg). 1H MR (500 MHz, DMSO- d6) δ ppm 2.54 (s, 3 H) 7.09 - 7.16 (m, 1 H) 7.35 (t, J=7.93 Hz, 1 H) 7.45 (d, J=8.06 Hz, 1 H) 7.52 (t, J=1.83 Hz, 1 H) 7.56 (dd, J=8.79, 2.20 Hz, 1 H) 7.61 (s, 1 H) 8.00 (d, J=1.71 Hz, 1 H) 8.06 (d, J=8.30 Hz, 1 H) 8.43 (s, 1 H) 10.96 (s, 1 H). MS (ESI+) m/z 405 [M+H]+.
  • 23
  • [ 157837-31-5 ]
  • [ 1416334-09-2 ]
  • 24
  • [ 157837-31-5 ]
  • [ 1416337-42-2 ]
  • 25
  • [ 157837-31-5 ]
  • [ 1416337-43-3 ]
  • 26
  • [ 157837-31-5 ]
  • [ 1416335-46-0 ]
  • 27
  • [ 321-23-3 ]
  • [ 157837-31-5 ]
  • [ 1416337-41-1 ]
YieldReaction ConditionsOperation in experiment
53% With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 26h; Step A5-bromo-2-ni henyl]aniline[00447] An orange mixture of 4-bromo-2-fluoro-1 -nitrobenzene (1.353 g, 6.15 mmol), 3-(1 ,3-oxazol-5-yl)aniline (0.985g, 6.15 mmol) and K2C03 (1.7 g, 12.3 mmol) in DMF (13.5 mL) was heated at 90 C for 26 h. The resulting mixture was diluted with EtOAc (100 mL) and washed with a 5% LiCI solution (3x100 mL). The organic layer was concentrated and the residue was purified by silica gel chromatography (0-40% EtOAc/hexane) to obtain 5-bromo-2- nitro-N-[3-(1 ,3-oxazol-5-yl)phenyl]aniline as bright red - orange solid (1.18g, 53%). 1H NMR (400 MHz, DMSO-c/s) δ ppm 9.54 (s, 1 H) 8.48 (s, 1 H) 8.07 (d, .7=9.2 Hz, 1 H) 7.75 (s, 1 H) 7.71 (s, 1 H) 7.59 - 7.64 (m, 1 H) 7.53 - 7.58 (m, 1 H) 7.36 (d, J=8.0 Hz, 1 H) 7.23 (d, J=2.0 Hz, 1 H) 7.07 (dd, J=9.0, 2.0 Hz, 1 H). ES-LCMS: 360.0 (M+1 ).
  • 28
  • [ 42883-45-4 ]
  • [ 157837-31-5 ]
  • [ 1428968-42-6 ]
YieldReaction ConditionsOperation in experiment
5% With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 200℃; for 0.5h;Microwave irradiation; General procedure: A mixture of an a-halogenoketone, an amine and a base (DIPEA or triethylamine) in a solvent (e.g. DMF, ethanol, acetonitrile, dioxane or THF) was irradiated in a microwave oven at 100C to 200C (more in particular at 120 to 200 C) for 5 to 180 min. (more in particular for 15 to 120 min). The reaction mixture was concentrated under reduced pressure and the residue was purified by flash chromatography on silica gel.
  • 29
  • [ 1054120-17-0 ]
  • [ 157837-31-5 ]
  • [ 1443437-99-7 ]
  • 30
  • [ 32315-10-9 ]
  • (4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methanobenzo[b][1,4]diazepine [ No CAS ]
  • [ 157837-31-5 ]
  • (4S)-N-(3-(oxazol-5-yl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methanobenzo[b][1,4]diazepine-5(2H)-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% The mixture of (4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-l,4- methanobenzo[b][l,4]diazepine (50 mg, 0.16 mmol), TEA (0.1 mL) and triphosgene (40 mg, 0.13 mmol) in THF (5mL) was stirred at 60 C for 2 h. <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (38 mg, 0.24 mmol) was added. The mixture was stirred at 60 C overnight. After cooling down, the resulting mixture was concentrated, the residue was purified by prep-TLC (DCM/MeOH = 20/1) to give (4S)-N-(3-(oxazol-5-yl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro- l,4-methanobenzo[b][l ,4]diazepine-5(2H)-carboxamide (26.1 mg, yield 33%)
33% The mixture of (4S)-7-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydro-1,4-methanobenzo[b][1,4]diazepine (50 mg, 0.16 mmol), TEA (0.1 mL) and triphosgene (40 mg, 0.13 mmol) in THF (5 mL) was stirred at 60 C. for 2 h. <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (38 mg, 0.24 mmol) was added. The mixture was stirred at 60 C. overnight. After cooling down, the resulting mixture was concentrated, the residue was purified by prep-TLC (DCM/MeOH=20/1) to give (4S)-N-(3-(oxazol-5-yl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methanobenzo[b][1,4]diazepine-5(2H)-carboxamide (26.1 mg, yield 33%).
  • 31
  • [ 157837-31-5 ]
  • (4S)-N-(3-(oxazol-5-yl)phenyl)-7-(3-(trifluoromethyl)phenyl)-3,4-dihydro-1,4-methanopyrido[2,3-b][1,4]diazepine-5(2H)-carbothioamide [ No CAS ]
  • 32
  • [ 463-71-8 ]
  • [ 157837-31-5 ]
  • 5-(3-isothiocyanatophenyl)oxazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
With triethylamine; In tetrahydrofuran; at 0 - 20℃; for 0.666667h;Inert atmosphere; To a solution of <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (160 mg, 1.0 mmol) and TEA (0.4 mL, 3.0 mmol) in dry THF (6 mL) was added a solution of thiophosgene (0.152 mL, 2.0 mmol) in dry o THF (1.5 mL) dropwise over 10 min at 0 C under Argon atmosphere. The reaction mixture was stirred at ambient temperature for 30 min, TLC showed <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> was fully consumed. The solvent was removed by evaporator under reduced pressure, the residue was diluted with water (10 mL) and ethyl acetate (25 mL), the organic layer was separated. The aqueous phase was extracted with ethyl acetate (3x30 mL), the combined organic layers were washed with saturated aqueous NaHCC"3 followed by water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 5-(3- isothiocyanatophenyl)oxazole which was used for the next reaction without any further purification
  • 33
  • [ 118-48-9 ]
  • [ 2058-72-2 ]
  • [ 157837-31-5 ]
  • 5-bromo-1-methyl-3'-(3-(oxazol-5-yl)phenyl)-1'H-spiro[indoline-3,2'-quinazoline]-2,4'(3'H)dione [ No CAS ]
  • 34
  • N-((7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-N,N-diethylethanaminium bromide [ No CAS ]
  • [ 73874-95-0 ]
  • [ 157837-31-5 ]
  • tert-butyl (1-((7-bromo-4-((3-(oxazol-5-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-4-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
49% Part F: tert-butyl (l-((7-bromo-4-((3-(oxazol-5-yl)phenyl)amino)pyrrolo[2, 1- fjf 1, 2, 4]triazin-5-yl)methyl)piperidin-4-yl)carbamate To a solution of N-((7-bromo-4-chloropyrrolo[l,2- J[l,2,4]triazin-5- yl)methyl)-N,N-diethylethanaminium (0.5 g, 1.442 mmol) in dry acetonitrile (10 mL) in a microwave tube flushed with nitrogen was added <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (0.231 g, 1.442 mmol). The reaction tube was capped and heated in the microwave at 75C for 30 min. To the reaction mixture was added tert-butyl piperidin-4-ylcarbamate (0.289 g, 1.442 mmol) and DIEA (0.252 mL, 1.442 mmol). The reaction tube was capped again and heated in a microwave at 75C for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel chromatography (dichloromethane/ethyl acetate/0.5% TEA) to obtain tert-butyl l-((7-bromo-4-(3- (oxazol-5 -yl)phenylamino)pyrrolo [ 1 ,2-f [ 1 ,2,4]triazin-5 -yl)methyl)piperidin-4- ylcarbamate (0.398 g, 0.700 mmol, 49 % yield). LCMS (ESI) m/e 568.2, 570.2 Br pattern [(M+H)+, calcd for C26H3iBrN703 568.2].
  • 35
  • N-((4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-N,N-diethylethanaminium bromide [ No CAS ]
  • [ 73874-95-0 ]
  • [ 157837-31-5 ]
  • tert-butyl (1-((4-((3-(oxazol-5-yl)phenyl)amino)pyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)piperidin-4-yl)carbamate [ No CAS ]
YieldReaction ConditionsOperation in experiment
70% Part B. tert-butyl (l-((4-((3-(oxazol-5-yl)phenyl)amino)pyrrolo[2,l-fj [1,2,4] triazin- 5-yl)methyl)piperidin-4-yl)carbamate To a solution of N-((4-chloropyrrolo[l,2: ][l,2,4]triazin-5-yl)methyl)-N,N- diethylethanaminium, bromide salt (0.1 g, 0.288 mmol) in dry acetonitrile (4 mL) in a microwave tube flushed with nitrogen was added <strong>[157837-31-5]3-(oxazol-5-yl)aniline</strong> (0.046 g, 0.288 mmol). The reaction tube was capped and heated in a microwave at 75C for 30 min. To the reaction mixture was added 4-(N-BOC amino)-piperidine (0.058 g, 0.288 mmol) and DIEA (0.126 mL, 0.719 mmol). The reaction tube was capped again and heated in a microwave at 75C for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane: ethyl acetate containing 0.5% TEA). Obtained tert-butyl 1 -((4-(3-(oxazol-5-yl)phenylamino)pyrrolo[ 1 ,2- J [1 ,2,4]triazin-5- yl)methyl)piperidin-4-ylcarbamate (0.099 g, 0.202 mmol, 70 % yield) as a yellow solid. LCMS (ESI) m/e 490.2 [(M+H)+, calcd for C26H32N7O3 490.3].
 

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