Structure of 38980-96-0
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CAS No. : | 38980-96-0 |
Formula : | C8H8ClF3N2 |
M.W : | 224.61 |
SMILES Code : | N=C(N)C1=CC=C(C(F)(F)F)C=C1.[H]Cl |
MDL No. : | MFCD04114431 |
Boiling Point : | No data available |
InChI Key : | DKIFMADLURULQV-UHFFFAOYSA-N |
Pubchem ID : | 12535791 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.12 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 49.67 |
TPSA ? Topological Polar Surface Area: Calculated from |
49.87 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.6 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.94 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.97 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.13 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.33 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.06 |
Solubility | 0.198 mg/ml ; 0.00088 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.3 |
Solubility | 0.113 mg/ml ; 0.000505 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.02 |
Solubility | 0.215 mg/ml ; 0.000955 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.82 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
2.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.34 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With ammonium chloride; sodium methylate; In methanol; diethyl ether; | 4-(Trifluoromethyl)benzamidine Hydrochloride A solution of 4-(trifluoromethyl)benzonitrile (Avocado 14514, 15 g) in anhydrous methanol (90 ml) was treated with sodium methoxide (0.50 g) and the resulting solution stirred for 4 d at ambient temperature. After this time, ammonium chloride (4.7 g) was added and the mixture stirred for a further day. The mixture was subsequently evaporated and the residual white solid triturated in diethyl ether, filtered and dried to afford of 4-(trifluoromethyl)benzamidine hydrochloride as a white solid (14.2 g, 72%). Mass spectrum 188 [M]+. |
With hydrogenchloride; NaNH2; In ethanol; ethyl acetate; toluene; | EXAMPLE 1 Preparation of p-(Trifluoromethyl)benzamidine Hydrochloride STR13 A stirred solution of p-(trifluoromethyl)-benzonitrile (100 g, 0.585 mol)in toluene is treated with NaNH2 (38 g, 0.878 mol. 90% pure) and dibenzo-18-crown-6 (1.5 g), heated at reflux temperatures for 4 hours, cooled to 10 C. and treated slowly with 175 ml of concentrated HCl over a 30 minute period. The resultant reaction mixture is filtered and the filtercake is washed with toluene and dried to give a powdery yellowish solid. The solid is dissolved in ethanol and filtered. The filtrate is concentrated in vacuo to give a yellow solid residue. The residue is slurried in ethyl acetate and filtered. The filtercake is washed with ether and dried to give the title product as a yellow solid, 132.3 g (quantitative yield), identified by 1 H-NMR, 13 C-NMR and 19 FNMR analyses. | |
4-(trifluoromethyl)benzimidamide hydrochloride To a 3-neck flask equipped with a reflux condenser was added 4-(trifluoromethyl)benzonitrile (80 g, 0.468 mol), NaNH2 (27.4 g, 0.701 mol), 18-Crown-6 (1.2 g) and toluene (350 mL). The solution was heated to reflux for 4 h. The mixture was cooled to 0 C. and concentrated aqueous HCl (140 mL) was added slowly. The precipitated solid was collected by filtration and washed with 1:2 methanol:dichloromethane (1:2, 250 mL) to provide 4-(trifluoromethyl)benzimidamide hydrochloride (53 g) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) delta 9.83 (s, 2H), 9.62 (s, 2H), 8.09 (d, J=8.0 Hz, 2H), 7.90 (d, J=8.0 Hz, 2H). |
General procedure: A 100 mL flask was charged with 30 mL of anhydrous MeOH, 10 mmol of the arylnitrile, and 1.0 mmol of sodium methoxide. The complex was protected from moisture and stirred for 48 h. Then, 10 mmol of NH4Cl was added and stirring was continued for 24 h. Unreacted NH4Cl was filtered, and methanol was stripped from the filtrate to afford the product aryl amidine hydrochlorides, which was dissolved in 2.5 mL 8M sodium hydroxide aqueous solution and stirred for 1 h. Then chloroform (20 ml x 3) and H2O (20 ml x 3) were added successively to extract the product, and the combined organic layer was dried with anhydrous MgSO4 and then evaporated under vacuum to remove the organic solvent to give the desired arylamidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In ethanol; at 20℃;Heating / reflux; | To a solution of 2 g (7.67 mmol) 4-trifluoromethyl-benzamidine HCl in 30 ml ethanol was added 0.76 g (7.67 mmol) sodium tert-butoxide and 1.43 g (7.67 mmol) 2-[1-ethoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester. The reaction was stirred at RT over night and for 1 h under reflux. After the solvent was removed under reduced pressure, the residue was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3 to provide 1.7 g pure 4-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester. MS: 311.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 150℃; for 0.333333h;Irradiation; | To a microwave reaction vial was added methyl 2-chloro-3-hydroxypropenoate (64a, 182.5 mg, 1.3 mmol), 4-trifluoromethylphenyl AMIDINE hydrochloride dihydrate (360.0 mg, 1.4 mmol), diisopropylethylamine (0.3 mL, 1.7 mmol), dry acetonitrile (3 mL) and a stir bar. The vial was sealed and irradiated under focused microwave energy for 20 minutes holding at 150 C. The solution was concentrated under a stream of nitrogen, diluted with methanol, filtered and purified by PREP LCMS. The above REACTION/PURIFICATION sequence was repeated to obtain a combined 121.2 mg (11 %) of the TFS SALT OF 6DB. LC-MS 271. 0 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In ethanol; at 20℃; | D] 4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester To a solution of 4.74 g (18.19 mmol) 4-trifluoromethyl-benzamidine HCl in 50 ml of ethanol was added 1.818 g (18.186 mmol) of sodium tert-butoxide. After 2 min, 3.605 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester was added and the reaction mixture was then stirred over night at RT. The ethanol was removed under reduced pressure, the residue taken up in ether and washed with 1N HCl and water. The ether solution was concentrated under reduced pressure and the crude product purified by chromatography over silica gel with AcOEt/heptane 1:3 to give 4.25 g of pure 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester. MS: 337.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In ethanol; at 20℃; | To a solution of 4.74 g (18.19 mmol) 4-trifluoromethyl-benzamidine HCl in 50 ml of ethanol was added 1.82 g (18.19 mmol) of sodium tert-butoxide. After 2 min, 3.61 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester was added and the reaction mixture was stirred over night at RT. The ethanol was removed under reduced pressure, the residue taken up in ether and washed with 1N HCl and water. The ether solution was concentrated under reduced pressure and the crude product purified by chromatography over silica gel with AcOEt/heptane 1:3 to give 4.25 g of pure 4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester. MS: 337.1 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium t-butanolate; In ethanol; at 20℃;Heating / reflux; | To a solution of 6.02 g (23.1 mmol) 4-trifluoromethyl-benzamidine HCl in 50 ml ethanol was added 2.29 g (23.1 mmol) sodium tert-butoxide and 5 g (23.1 mmol) 2-[1-ethoxy-meth-(E,Z)-ylidene]-5-methoxy-3-oxo-pentanoic acid ethyl ester. The reaction mixture was stirred at RT over night and for 1 h at reflux temperature. After the solvent was removed under reduced pressure, the residue was taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3 to provide 5.9 g pure 4-(2-methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester. MS: 355.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium t-butanolate; In ethanol; at 20℃; | A solution of 4-trifluoromethyl-benzamidine HCl (7.23 g, 27.5 mmol) in ethanol (30 ml) was treated with sodium tert-butoxide (2.67 g, 27.5 mmol). After 4 min a solution of 5-methoxy-2-[1-methoxy-eth-(E,Z)-ylidene]-3-oxo-pentanoic acid methyl ester (6 g, 27.7 mmol) in ethanol (30 ml) was added. The reaction mixture was stirred over night at ambient temperature, taken up in ether and washed with 1 N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3, providing 4.9 g (13.8 mmol, 50%) of pure 4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester. MS: 355.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | In diethyl ether; ammonia; | Reaction Scheme 6, Step 1 [2-(4-Trifluoromethyl-phenyl)-1H-imidazol-4-yl]-methanol A mixture of <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (2.5 g) and 1,3-dihydroxyacetone dimer (Avocado 14189, 2 g) was heated at 80 C. in concentrated ammonia solution (20 ml) for 1 h. The mixture was allowed to cool and the product extracted with ethyl acetate (150 ml). The organic phase was dried (anhydrous magnesium sulphate), filtered and evaporated. The residue was triturated in diethyl ether to give the title compound as a white solid (1.2 g, 44%). Mass spectrum 243 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
ii) Preparation of (23) Ethanol (300 ml) was saturated with ammonia, and cooled below 10 C. 4-Trifluoromethylbenziminoethyl ether (33.4 g) was added in portions to the stirred solution, and the mixture allowed to stand at room temperature for 24 hours. The solvent was evaporated off under reduced pressure, 200 ml of isopropyl acetate added, the mixture cooled to 0 C., and the solid filtered off and washed several times with isopropyl acetate, giving 27.3 g of 4-trifluoromethylbenzamidine hydrochloride, m.p. 184 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With potassium methanolate; In methanol; water; | EXAMPLE 52 6-Hydroxy-2-(4'-trifluoromethylphenyl)-4-pyrimidinone 4-Trifluormethylbenzamidine hydrochloride (22.4 g, 0.1 mol, from example 41) is added to a solution of potassium methylate (0.22 mol) in anhydrous methyl alcohol (65 mL) and stirred for 15 minutes at ambient temperature. Dimethyl malonate (12.6 mL, 0.11 mol) is added and the mixture is heated to reflux for 4 hours. After cooling, the resulting suspension is diluted with methyl alcohol (50 mL). The solvent is removed in vacuo and the residue is dissolved in water (50 mL). Then the mixture is brought to pH 1 with concentrated hydrochloric acid. The precipitate is filtered off and washed with water. After drying, pale yellow crystals (15.1 g, 59%) of melting point >200 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | In ethanol; water; | Now the sodium salt (0.075 mol) is added to <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (16.8 g, 0.075 mol, from example 41) in dry ethyl alcohol (150 mL) and the mixture is stirred for 48 hours at ambient temperature. After heating to reflux for 1 hour water (100 mL) is added to the mixture and the solution is filtered. The filtrate is brought to pH 5 with acetic acid and the ethyl alcohol is removed in vacuo. The precipitate is filtered off and washed with ethyl alcohol. After drying crystals (13.7 g, 68%) of melting point >200 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium methylate; In methanol; toluene; | EXAMPLE 1 5-Propyl-2-(4-trifluoromethylphenyl)pyrimidine 4-Trifluoromethylbenzamidine hydrochloride (5 g, 0.02 mol) and alpha-propyl-beta-dimethylaminoacrolein (3 g, 0.02 mol) were added to a sodium methylate solution having metallic sodium (1 g) dissolved in anhydrous methanol (50 ml), followed by boiling the mixture for 4 hours with stirring, distilling off methanol, adding toluene (50 ml) to the reaction residue to extract the product, washing the resulting extract with water, drying the toluene layer with anhydrous sodium sulfate, distilling off toulene and three times recrystallizing the residue from methanol to obtain 5-propyl-2-(4-trifluoromethylphenyl)pyrimidine (3 g, 0.01 mol). The values of the elemental analysis of this compound accorded well with the theoretical values as follows: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3,07 g (80%) | With potassium carbonate; In 1,2-dimethoxyethane; water; | EXAMPLE 11 Enhanced preparation of 4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine Water (20 mmoles) is added to a solution of 1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25 ml). The reaction mixture is stirred for 2 h under reflux. The resulting mixture is slowly added to a mixture consisting of a <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein solution is completed additional <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (1 mmoles) is added. The reaction mixture is stirred for 2 hours under reflux and subsequently cooled down to ambient temperature, filtered through silica, and the organic phase is concentrated in vacuo. The residue is purified by chromatography on SiO2 (petrol ethers/diisopropylether: 6/1) to yield 3,07 g (80%) of the product having a melting point of 66-67 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Example 11 Enhanced preparation of 4-(3-trifluoromethylphenoxy)-2-(4-trifluoromethylphenyl)-pyrimidine Water (20 mmoles) is added to a solution of 1,1,1,3-tetrachloro-3-ethoxypropane (10 mmoles) in dimethoxyethane (25 ml). The reaction mixture is stirred for 2 h under reflux. The resulting mixture is slowly added to a mixture consisting of a <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (10 mmoles), 3-trifluoromethylphenol (11 mmoles), potassium carbonate (60 mmoles) and dimethoxyethane (50 ml), which is stirred under reflux. When the addition of 3,3-dichloroacrolein solution is completed additional <strong>[38980-96-0]4-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> (1 mmoles) is added. The reaction mixture is stirred for 2 hours under reflux and subsequently cooled down to ambient temperature, filtered through silica, and the organic phase is concentrated in vacuo. The residue is purified by chromatography on SiO2 (petrol ethers / diisopropylether: 6 / 1) to yield 3,07 g (80 %) of the product having a melting point of 66-67 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
F] 4-Cyclopropyl-6-methoxeththyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid A solution of 7.4 g (28.28 mmol) 4-trifluoromethyl-benzamidine HCl in 40 ml ethanol was treated with 2.81 g (28.28 mmol) sodium tert.-butoxide. After 4 min, 6.48 g (28.28 mmol) of the crude (E,Z)-2-cyclopropanecarbonyl-3,4-dimethoxy-but-2-enoic acid methyl ester, in 30 ml ethanol, was added. The reaction mixture was stirred over night, taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3, providing 2.86 g pure 4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester (example E]) MS: 367.1 (M+H)+. And 1.2 g of pure 4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (example F]). MS: 351.4 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
E] 4-(2-Methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester A solution of 7.23 g (27.47 mmol) 4-trifluoromethyl-benzamidine HCl in 30 ml Ethanol was treated with 2.67 g (27.47 mmol) Sodium tert.Butoxide. After 4 min, 6 g (27.74 mmol) of the crude 5-methoxy-2-[1-methoxy-eth-(E,Z)-ylidene]-3-oxo-pentanoic acid methyl ester, in 30 ml Ethanol, was added. The reaction mixture was stirred over night, then taken up in ether and washed with 1N HCl and water. The crude product was purified by chromatography over silica gel with AcOEt/heptane 1:3, providing 4.9 g of pure 4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid methyl ester. MS: 355.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium ethanolate; In ethanol; at 20℃; for 18h; | A suspension of sodium ethoxide (940 mg, 13.8 mmol) in ethanol (4.5 ml) was added to a solution of <strong>[38980-96-0]4-(trifluoromethyl)benzamidine hydrochloride</strong> dihydrate (2.79 g, 12.4 mmol) and diethyl oxalpropiolate (2.6 ml, 13.8 mmol) in ethanol (30ml) and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, then dichloromethane was added and the solution dried over magnesium sulphate, filtered and evaporated under redcued pressure. The crude product was purified by chromatography on silica using hexane/ethyl acetate (3:2) as eluent to provide a mixture of 6-ethoxycarbonyl-4-hydroxy- 5-methyl-2-(4-trifluoromethylphenyl)-pyrimidine and 4,6-dihydroxy-6-ethoxycarbonyl-5- methyl-2-(4-trifluoromethylphenyl)-3,4-dihydropyrimidine as a pale brown solid (2.21 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydrogencarbonate; In tetrahydrofuran; water; at 60℃; for 16h; | Example 1 Production of 4-[4-(4-bromo-2-fluorobenzyloxy)-3-methoxyphenyl]-2-[4-(trifluoromethyl)phenyl]-1H-imidazole hydrochloride Potassium hydrogen carbonate (2.8 g, 28.0 mmol), the compound (3.0 g, 6.9 mmol) of Reference Example 1, and <strong>[38980-96-0]p-<strong>[38980-96-0]trifluoromethylbenzamidine hydrochloride</strong></strong> dihydrate (1.6 g, 6.9 mmol) were added to a mixture solution of water (4 ml) and THF (12 ml), and the mixture solution was stirred at 60 C. for 16 hours. The reaction solution was cooled to room temperature, ethyl acetate (70 ml) was added to the solution, and the solution was stirred for 30 minutes. This solution was sequentially washed with water and saturated saline, and dried with anhydrous magnesium sulfate. After the solvent was distilled away under reduced pressure, diethyl ether was added, and the precipitated crystals were filtered. The crystals were vacuum-dried at 70 C. for 1 hour, yielding the desired compound (3.0 g). Table 4 shows the structure and properties of the obtained compound. |
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Similarity: 0.80