Structure of Cinacalcet Impurity 23
CAS No.: 454-89-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
Synonyms: 3-(Trifluoromethyl)benzaldehyde
4.5
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Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening
Shifali Shishodia ; Raymundo Nuñez ; Brayden P. Strohmier ; Karina L. Bursch ; Christopher J. Goetz ; Michael D. Olp , et al.
Abstract: PBRM1 is a subunit of the PBAF chromatin remodeling complex that uniquely contains six bromodomains. PBRM1 can operate as a tumor suppressor or tumor promoter. PBRM1 is a tumor promoter in prostate cancer, contributing to migratory and immunosuppressive phenotypes. Selective chemical probes targeting PBRM1 bromodomains are desired to elucidate the association between aberrant PBRM1 chromatin binding and cancer pathogenesis and the contributions of PBRM1 to immunotherapy. Previous PBRM1 inhibitors unselectively bind SMARCA2 and SMARCA4 bromodomains with nanomolar potency. We used our protein-detected NMR screening pipeline to screen 1968 fragments against the second PBRM1 bromodomain, identifying 17 hits with Kd values from 45 μM to >2 mM. Structure–activity relationship studies on the tightest-binding hit resulted in nanomolar inhibitors with selectivity for PBRM1 over SMARCA2 and SMARCA4. These chemical probes inhibit the association of full-length PBRM1 to acetylated histone peptides and selectively inhibit growth of a PBRM1-dependent prostate cancer cell line.
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Purchased from AmBeed: 77326-36-4 ; 104-87-0 ; 2148-56-3 ; 1591-37-3 ; 387-45-1 ; 936-08-3 ; 1123-56-4 ; 2819989-75-6 ; 703-80-0 ; 1885-29-6 ; 115643-59-9 ; 15764-16-6 ; 487-68-3 ; 145737-61-7 ; 5779-95-3 ; 88-68-6 ; 6575-11-7 ; 77326-62-6 ; 88-65-3 ; 73096-42-1 ; 2835-78-1 ; 4635-59-0 ; 5779-94-2 ; 56043-01-7 ; 5779-93-1 ; 1591-38-4 ; 446-52-6 ; 1108790-90-4 ; 62803-47-8 ; 620-23-5 ; 54166-95-9 ; 22179-72-2 ; 529-20-4 ; 63329-53-3 ; 100-52-7 ; 123-11-5 ; 1711-06-4 ; 454-89-7 ; 170875-01-1 ; 883032-29-9 ; 2819989-61-0 ; 1915012-21-3 ; 2819989-58-5 ; 2819989-60-9 ; 2819989-57-4 ; 2819989-68-7 ; 2819989-67-6 ; 111478-13-8 ; 118-92-3 ; 22458-07-7 ; 80258-99-7 ; 24782-64-7 ; 175204-03-2 ; 97-96-1 ; 1885-31-0 ; 780802-33-7 ; 89-98-5
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| CAS No. : | 454-89-7 |
| Formula : | C8H5F3O |
| M.W : | 174.12 |
| SMILES Code : | C1=C(C=CC=C1C(F)(F)F)C=O |
| Synonyms : |
3-(Trifluoromethyl)benzaldehyde
|
| English Name : | 3-(Trifluoromethyl)benzaldehyde |
| MDL No. : | MFCD00003373 |
| InChI Key : | NMTUHPSKJJYGML-UHFFFAOYSA-N |
| Pubchem ID : | 67990 |
| Num. heavy atoms | 12 |
| Num. arom. heavy atoms | 6 |
| Fraction Csp3 | 0.12 |
| Num. rotatable bonds | 2 |
| Num. H-bond acceptors | 4.0 |
| Num. H-bond donors | 0.0 |
| Molar Refractivity | 36.83 |
| TPSA ? Topological Polar Surface Area: Calculated from |
17.07 Ų |
| Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.58 |
| Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.47 |
| Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.67 |
| Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
2.52 |
| Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.98 |
| Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.64 |
| Log S (ESOL):? ESOL: Topological method implemented from |
-2.71 |
| Solubility | 0.337 mg/ml ; 0.00193 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (Ali)? Ali: Topological method implemented from |
-2.47 |
| Solubility | 0.586 mg/ml ; 0.00337 mol/l |
| Class? Solubility class: Log S scale |
Soluble |
| Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.23 |
| Solubility | 0.103 mg/ml ; 0.000592 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 |
-5.61 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 |
2.0 |
| 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 |
1.0 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) |
1.08 |
* 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 |
|---|---|---|
| (i) Mg, Et2O, (ii) /BRN= 2327537/, (iii) aq. Na2Cr2O7, H2SO4, AcOH, benzene; Multistep reaction; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 100% | With oxygen In toluene at 80℃; for 2h; | |
| 99% | With 1,1,1,3',3',3'-hexafluoro-propanol; oxygen; nitric acid at 20℃; for 23h; | |
| 98% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium carbonate; Cyanuric acid In ethyl acetate at 0 - 10℃; for 5h; | General Procedure for the oxidation of alcohols employing nitroxyl radical / imide / NaOCl in the presence of K2CO3. General procedure: To a mixture of the alcohol (3.839 mmol), K2CO3 (2.0 equiv, 7.678 mmol) and cyanuric acid (0.1 equiv, 0.384 mmol) in 20 mL of ethyl acetate were added TEMPO or AZADO (3 mol%, 0.115 mmol) and 12% NaOCl (1.2 equiv, 4.607 mmol, Wako Pure Chemical Industries, Ltd.) at 0-10°C. The mixture was then stirred to complete. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford the corresponding product. |
| 98% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; potassium carbonate; Cyanuric acid In water; ethyl acetate at 0 - 10℃; for 5h; Inert atmosphere; | Procedure B: Oxidation with NaOCl in the presence of catalytic amountof cyanuric acid and TEMPO To a mixture of 16 (676 mg, 3.84 mmol), cyanuric acid (50 mg, 0.38mmol, 0.1 equiv), and K2CO3 (1.06 g, 7.68 mmol, 2.0 equiv) in EtOAc(10 mL) were added TEMPO (18 mg, 0.12 mmol, 0.03 equiv) and 12%(w/w) aq NaOCl (2.86 g, 4.61 mmol, 1.2 equiv) at 0-10 °C, and themixture was stirred for 5 h at 0-10 °C. The mixture was then extractedwith EtOAc (20 mL). The organic layer was washed with 10% aq.NaCl (10 mL) then concentrated under reduced pressure. The residuewas purified by column chromatography (silica gel, EtOAc-hexane) togive a colorless oil; yield: 398 mg (98%).1H NMR (600 MHz, CDCl3): δ = 7.70 (t, J = 7.7 Hz, 1 H), 7.90 (d, J = 7.9Hz, 1 H), 8.09 (d, J = 7.6 Hz, 1 H), 8.15 (s, 1 H), 10.09 (s, 1 H).13C NMR (151 MHz, CDCl3): δ = 123.6 (q, J = 272.5 Hz), 126.5 (q, J = 3.8Hz), 129.8, 130.8 (q, J = 3.3 Hz), 131.9 (q, J = 33.2 Hz), 132.7, 136.9,190.7. |
| 96% | With sodium thiosulfate; sodium iodide In water; 1,2-dichloro-ethane at 20℃; for 5h; Irradiation; Green chemistry; | |
| 87% | With nitric acid; ytterbium(III) triflate In 1,2-dichloro-ethane for 1h; Heating; | |
| 87% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; C34H51CeN5O8; oxygen In acetonitrile at 85℃; for 28h; Molecular sieve; Schlenk technique; Inert atmosphere; | |
| 85% | With tert.-butylhydroperoxide; copper(II)-salophen; sodium hydroxide In water; acetonitrile at 20℃; | Typical Procedure for the Oxidation of Alcohols General procedure: Alcohol (0.5 mmol), salophen copper (II) complex (2 mol%), NaOH (0.6 equiv), and 70% TBHP in water (1.1 equiv) were dissolved in acetonitrile (5 mL), and the homogeneous solution was stirred at room temperature in air overnight. After completion of the reaction, the solvent was evaporated under reduced pressure. The residue was purified over silica gel by column chromatography (10-25% EtOAc in hexane). |
| 85% | With [RuHCl(CO)(PPh3)3]; oxygen In toluene at 90℃; for 18h; Molecular sieve; Sealed tube; | |
| 73% | With Nitrogen dioxide In acetonitrile at 140℃; for 5h; Sealed tube; | 2.2. General procedure for the aerobic oxidation of various substrates General procedure: To a dried 45 mL tube equipped with a magnetic stirring, 2 mL acetonitrile, 0.5 mmol substrate and 0.046 mmol NO2 were sequentially added (note: the air in the tube was not removed). Then the reaction tube was sealed and stirred magnetically at a constant-temperature to perform the reaction for 5 h. Once the reaction time was reached, GCanalysis of the mixture provided the GC yields of the products. Then the crude product from another parallel experiment was purified by silicagel chromatography to give the desired product. |
| With pyridinium fluorochromate In dimethyl sulfoxide at 24.9℃; ΔH(excit.), ΔS(excit.); | ||
| With pyridinium bromochromate In dimethyl sulfoxide at 24.9℃; for 15h; var. temp.; ΔH(excit.), ΔS(excit.), ΔG(excit.); | ||
| With bis(2,2'-bipyridyl) copper(II) permanganate In acetic acid at 9.9 - 29.9℃; | ||
| With pyridinium chlorochromate In dichloromethane | ||
| With benzyltrimethylammonium dichloroiodate; acetic acid; zinc(II) chloride at 24.85℃; for 15h; ΔH(excit.), ΔS(excit.); | ||
| 52 % Spectr. | With titanium oxide; silver sulfate In acetonitrile for 2h; Ambient temperature; Irradiation; | |
| With benzyltrimethylammonium tribromide; acetic acid In water | ||
| With Mn(N,N'-ethylenebis(salicylaldiminato))O In acetonitrile at 24.85℃; for 12h; | ||
| With benzyltrimethylammonium chlorobromate; acetic acid at 34.85℃; | ||
| With quinolinium fluorochromate In dimethyl sulfoxide at 14.85℃; | ||
| With tetra-N-butylammonium tribromide; potassium bromide In water; acetic acid at 14.85℃; for 12h; | ||
| With quinolinium bromochromate In dimethyl sulfoxide at 34.85℃; | ||
| With perchloric acid; bis-[(trifluoroacetoxy)iodo]benzene In water; acetic acid at 14.85℃; | ||
| With oxygen; sodium acetate In water; dimethyl sulfoxide at 70℃; for 1h; | ||
| With morpholinium chlorochromate In dimethyl sulfoxide at 24.84℃; | ||
| With 2,2'-bipyridiniumchlorochromate In dimethyl sulfoxide at 24.84℃; | ||
| 61 %Chromat. | With acetaldehyde at 30℃; for 24h; aq. phosphate buffer; Microbiological reaction; Combinatorial reaction / High throughput screening (HTS); chemoselective reaction; | |
| With oxygen; titanium oxide In acetonitrile UV-irradiation; | ||
| With 2,2,6,6-tetramethyl-4-(2,2,2-trifluoroacetamido)-1-oxopiperidinium tetrafluoroborate; bobbitt’s salt In acetonitrile | ||
| 89 %Spectr. | With C34H51CeN5O8(1-)*C6H15N*H(1+); oxygen In N,N-dimethyl-formamide at 120℃; for 20h; Molecular sieve; | |
| With 2,2'-azinobis(3-ethylbenzthiazolinesulfonate); horse-radish peroxidase; choline oxidase from Arthrobacter cholorphenolicus, mutant S101A/D250G/F253R/V355T/F357R/M359R In aq. phosphate buffer at 30℃; for 24h; Enzymatic reaction; | ||
| With sulfuryl fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; chemoselective reaction; | ||
| With sulfuryl fluoride; potassium carbonate; dimethyl sulfoxide at 20℃; for 12h; | ||
| Stage #1: 3-(trifluoromethyl)benzyl alcohol With Quinuclidine; 4CzIPN; oxygen; tetrabutylammonium dihydrogen phosphate In 1,2-dichloro-ethane for 0.25h; Molecular sieve; Stage #2: In 1,2-dichloro-ethane for 10h; Molecular sieve; Irradiation; | ||
| With toluene-4-sulfonic acid; benzimidazolium dichromate In dimethyl sulfoxide at 24.84℃; for 12h; Darkness; | Product analysis: General procedure: The product analysis was carried out under kinetic conditions. In a typical experiment, benzyl alcohol(0.1 mol), TsOH (1.0 mol) and BIDC (0.02 mol) were made up to 50 ml in DMSO and kept in the dark for ca. 12 h to ensure completion of the reaction. The solution was then treated with excess (200 ml) of a saturated solution of 2,4-dinitrophenylhydrazine in 2 mol dm3 HCl and kept overnight in a refrigerator. The precipitated 2,4-dinitrophenylhydrazone(DNP) was filtered off, dried, weighed, recrystallized from ethanol, and weighed again. The yields of DNP before and after recrystallization were 7.89 g (92%) and 6.86 g (80%)respectively, indicating the amount of benzaldehyde formed is about 3.0-3.1 g. The DNP was found identical (m.p. andmixed m.p.) with the DNP of benzaldehyde. The identity of the DNP was confirmed by the elemental analysis also. The observed values were C, 54.79%; H, 3.40% and N, 19.39%,the calculated values for C13H10N4O4 are C, 54.55%; H,3.50% and N, 19.58%. In similar experiments, with the other substituted benzyl alcohols the yields of DNP, after recrystallization, were in the range of 75 88%. CrVI is reduced to CrIII. | |
| 71.6 % | With oxygen In neat (no solvent) at 25℃; Irradiation; | |
| 96 % | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; | 2.3 General Procedure for HeterogeneousCopper-Catalyzed Aerobic Oxidation of Primary Alcohols General procedure: Under an air atmosphere, a reaction tube was charged withDpu-SBA-15-CuI (58mg, 0.03mmol), primary alcohol(1mmol), TEMPO (6.3mg, 0.04mmol), and MeCN (3mL).The reaction mixture was stirred at room temperature for 6 or 24h depending on the substrate. After completion of the reaction (monitored by TLC), the copper catalyst was separatedby centrifugation and washed with acetone (2 × 3mL)and dried under vacuum at 90 C for 1h and reused in thenext cycle. The reaction solution was evaporated in vacuo and the residue was then purified by flash column chromatographyon silica gel (petroleum ether/ethyl acetate) toafford the desired aldehyde 2. |
| 96 % | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical In acetonitrile at 20℃; | 2.3 General Procedure for HeterogeneousCopper-Catalyzed Aerobic Oxidation of Primary Alcohols General procedure: Under an air atmosphere, a reaction tube was charged withDpu-SBA-15-CuI (58mg, 0.03mmol), primary alcohol(1mmol), TEMPO (6.3mg, 0.04mmol), and MeCN (3mL).The reaction mixture was stirred at room temperature for 6 or 24h depending on the substrate. After completion of the reaction (monitored by TLC), the copper catalyst was separatedby centrifugation and washed with acetone (2 × 3mL)and dried under vacuum at 90 C for 1h and reused in thenext cycle. The reaction solution was evaporated in vacuo and the residue was then purified by flash column chromatographyon silica gel (petroleum ether/ethyl acetate) toafford the desired aldehyde 2. |
| 99 % | With cesium lead bromide In 1,2-dichloro-ethane at 20℃; Irradiation; | |
| 82 % | With white-rot fungus Bjerkandera adusta lyophilisate In aq. phosphate buffer at 24℃; | 2.6. General procedure for the biotransformation General procedure: BAD lyophilisate (400 mg) was suspended in 15 mL phosphate buffer(0.1 M, pH = 7). The dried cell mass was rehydrated by stirring at 800rpm for 10 min, and 0.5 mmol (final concentration is 20 mM) of thesubstrate was added. The reaction mixture was stirred at 24 C and 800rpm for 24 h. Subsequently, additional lyophilisate (400 mg) andphosphate buffer (10 mL) were added, reaction mixture was stirred forfurther 24 h, 30 mL Et2O was added and the resulting mixture wasstirred for 30 min. The resulting suspension was centrifuged to separatethe phases. Then 30 mL Et2O was added to the aqueous phase, stirred for15 min, centrifuged, and the resulting layers were separated. Thecombined organic phases were dried over Na2SO4 and evaporated todryness. The resulting reaction mixtures were analysed by GC-MS NMR spectroscopy. The isolation of products was performed asdescribed below |
| 84% | Stage #1: 3-(trifluoromethyl)benzyl alcohol With tetrabutyl-ammonium chloride; 5H-5λ3-benzo[4,5][1,2]iodazolo[2,3-d]tetrazol-5-ol In acetonitrile at 60℃; Sealed tube; Stage #2: With dimethylsulfide In acetonitrile Sealed tube; | 4.2 General procedure for oxidation of electron-poor alcohols (GP B) General procedure: Iodane 1a (700 μmol, 201 mg, 1.40 equiv) and alcohol (500 μmol, 1.00 equiv)were dissolved/suspended in MeCN (2.5 mL) in a screw cap vial and TBACl(500 μmol, 139 mg, 1.00 equiv) was added. The reaction was stirred for 2.5 h at60 °C, then Me2S (1.40, 104 μL, 2.80 equiv) was added and stirring wascontinued for 5 min. Then, the solvent was removed under reduced pressureand the reaction was purified on column chromatography with silica to obtainthe pure aldehyde. |
| 84 % | With 1,2-bis(t-butyloxycarbonyl)hydrazine; oxygen; potassium carbonate In toluene at 100℃; | 3.5. General procedure for heterogeneous copper(I)-catalyzed aerobic oxidation of alcohols General procedure: A 25 mL, two-necked flask equipped with a refllux condenser and an oxygen inlet was charged with MCM-41-Phen-CuCl (164 mg, 0.1 mmol,5 mol%), di-tert-butyl hydrazine-1,2-dicarboxylate (DBAD-H2) (24 mg, 0.1 mmol, 5 mol%), K2CO3 (553 mg, 4 mmol), alcohol 1 (2.0 mmol), and toluene (10 mL). The reaction mixture was stirred at 100 C for 2-4 h under a gentle stream of oxygen. After being cooled to room temperature, the supported copper catalyst was filtered and washed with distilled water (2 ×10 mL), acetone (2 ×10 mL), dried at 80 C in vacuo for 2 h and reused in the next cycle. The filtrate was concentrated under a reduced pressure and the residue was further purified by flash column chromatography on silica gel (petroleum ether : EtOAc =20:1-10:1) to provide the desired product 2. |
| 79 %Spectr. | With Fe1 single atoms anchored on NV-rich graphitic carbon nitride; air at 120℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 69% | In ethanol for 1.5h; Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With sodium tetrahydroborate In methanol at 0℃; for 0.5h; Inert atmosphere; | |
| 93% | With [Ir(tpy)(phen)Cl](PF6)2; sodium formate In ethanol; water at 100℃; for 0.5h; Microwave irradiation; chemoselective reaction; | A typical procedure for TH reaction: General procedure: An aldehyde (1 mmol),sodium formate (4.5 eq), and catalyst (0.2 mol%) were taken in70% ethanol in water (4 mL) in a microwave vial and vortexed togenerate a homogenous solution. The mixture was heated in MWat 100 °C using 150W of irradiation. Reaction progress was monitored by TLC. If complete conversion took place, the reaction colorturns to emerald green (color disappears after sometime) from paleyellow, and byproduct Na2CO3 precipitates. The Na2CO3 solid wasremoved by decanting the supernatant. The solid was washed withethyl acetate (20 mL). The combined decanted solution waswashed with water (5.0 mL), followed by brine solution (5.0 mL),dried over Na2SO4, filtered, and evaporated to dryness to affordthe desired alcohol as a pale-yellow liquid or off-white solid. |
| 25% | With lithium diisopropyl amide In tetrahydrofuran at -85℃; for 0.05h; |
| With sodium tetrahydroborate In methanol Ambient temperature; | ||
| With sodium tetrahydroborate In methanol at 20℃; for 1h; | ||
| 98 %Spectr. | With RuCl2(NC6H4NHCC5H3NN2C3H(CH3)2)(P(C6H5)3); potassium isopropoxide; isopropyl alcohol at 82℃; for 0.0166667h; Inert atmosphere; | |
| With potassium <i>tert</i>-butylate In isopropyl alcohol at 90℃; for 0.533333h; Flow reactor; Inert atmosphere; | ||
| With C19H33ClIrN3O; sodium isopropylate In isopropyl alcohol for 0.25h; Inert atmosphere; Reflux; | ||
| Multi-step reaction with 2 steps 1: [(2-diphenylphosphinocyclopentene-1-(2,6-dimethylphenyl)imine)Ni(allyl)]OTf / benzene-d6 / 1.5 h / 20 °C / Inert atmosphere 2: methanol / 0.5 h / 20 °C / Inert atmosphere | ||
| 96 % | With hydrogen In water at 20℃; Green chemistry; | |
| 166 mg | With formic acid; sodium formate; C58H70Cl2N2O2Ru2 In water at 80℃; for 1h; chemoselective reaction; | |
| With sodium tetrahydroborate In methanol at 0 - 25℃; for 3h; Inert atmosphere; Schlenk technique; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 41% | With hydrogen In methanol; water | |
| Stage #1: 3-Trifluoromethylbenzaldehyde; methylamine With magnesium sulfate In ethanol; dichloromethane at 20℃; Stage #2: With methanol; sodium tetrahydroborate at 20℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 81% | With sodium hydroxide In methanol at 0℃; for 2h; Schlenk technique; | |
| 78% | With sodium hydroxide In methanol for 40h; | |
| 69% | With ammonium acetate; glacial acetic acid at 90℃; for 5h; | 5 General procedure for the preparation of substituted 2-nitrovinyl benzene derivatives General procedure: An aromatic aldehyde (5 mmol) was dropped into a solution ofammonium acetate (12 mmol) in dry nitromethane (10 mL) andacetic acid (20 mL) at 90 C with stirring. The mixture was thenrefluxed for 5 h, and the mixture was poured into water andextracted with ethyl acetate (3 50 mL). The extracts werewashed with a saturated NaCl solution, dried over Na2SO4, filteredand evaporated under reduced pressure. The residue was recrystallizedfrom methanol or purified by column chromatography onsilica gel (ethyl acetate/petroleum ether) to afford the target2-nitrovinyl benzene derivative. |
| 69% | With ammonium acetate; glacial acetic acid at 90℃; for 5h; | 4.1.1 General procedure for the preparation of substituted 2-nitrovinyl benzene derivatives General procedure: An aromatic aldehyde (5mmol) was dropped into a solution of ammonium acetate (12mmol) in dry nitromethane (10mL) and acetic acid (20mL) at 90°C with stirring. The mixture was then refluxed for 5h, and the mixture was poured into water and extracted with ethyl acetate (3×50mL). The extracts were washed with saturated saline solution, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was recrystallized from methanol or purified by column chromatography on silica gel (ethyl acetate/petroleum ether) to obtain the target 2-nitrovinyl benzene derivative |
| With sodium hydroxide In methanol; lithium hydroxide monohydrate at 2 - 10℃; for 1.25h; | 5.A Step A: Preparation of 1-[(E)-2-nitroethenyl]-3-(trifluoromethyl)benzene To a stirred solution of 3-(trifluoromethyl)benzaldehyde (12.2 g, 70.1 mmol) in methanol (50 mL) was added nitromethane (4.34 g, 71.1 mmol). The mixture was cooled to 2 °C and sodium hydroxide (5.65 g, 70.6 mmol) was added as a 50% solution in 24.3 mL of water dropwise over 15 min. An exotherm was noted and additional ice was added to maintain the temperature below 10 °C while stirring for an additional 1 h. The reaction mixture was poured into 75 mL (75 mmol) of 1 N hydrochloric acid, rinsing the flask with 10 mL of methanol/water. The quenched reaction mixture was transferred to a separatory funnel and extracted with 150 mL of toluene. The aqueous layer was separated and concentrated under vacuum to yield 15.84 g of a yellow oil. The intermediate thus obtained (15.84 g, 67.3 mmol) was taken up in 160 mL dichloromethane. The solution was cooled to 3 °C and methanesulfonyl chloride (8.03 g, 71.1 mmol) was added via pipette as a solution in 50 mL of dichloromethane. A solution of triethylamine (14.2 g, 140 mmol) in 50 mL of dichloromethane was then added dropwise over 50 min, and the resulting solution was stirred for 2 h. The reaction mixture was poured into 150 mL (150 mmol) of 1 N hydrochloric acid and transferred to a separatory funnel. The layers were separated and the organic layer was washed with 150 mL water and then filtered. The organic layer was concentrated under reduced pressure and the crude solid was tritrated with hexanes to yield 12.09 g of product as a yellow solid. 1H NMR (500 MHz) 7.54-7.66 (m, 2H) 7.69-7.84 (m, 3H) 7.96-8.08 (m, 1H). | |
| 12.09 g | Stage #1: nitromethane; 3-Trifluoromethylbenzaldehyde With sodium hydroxide In methanol at 2 - 10℃; for 1.25h; Stage #2: With methanesulfonyl chloride In dichloromethane at 3℃; for 2.83333h; | 5.A Step A: Preparation of 1 -[(E)-2-nitroethenyl]-3 -(trifluoromethyl)benzene To a stirred solution of 3-(trifluoromethyl)benzaldehyde (12.2 g, 70.1 mmol) in methanol (50 mL) was added nitromethane (4.34 g, 71.1 mmol). The mixture was cooled to 2 °C and sodium hydroxide (5.65 g, 70.6 mmol) was added as a 50% solution in 24.3 mL of water dropwise over 15 mm. An exotherm was noted and additional ice was added tomaintain the temperature below 10 °C while stirring for an additional 1 h. The reaction mixture was poured into 75 mL (75 mmol) of 1 N hydrochloric acid, rinsing the flask with 10 mL of methanol/water. The quenched reaction mixture was transferred to a separatory funnel and extracted with 150 mL of toluene. The aqueous layer was separated and concentrated under vacuum to yield 15.84 g of a yellow oil.The intermediate thus obtained (15.84 g, 67.3 mmol) was taken up in 160 mL dichloromethane. The solution was cooled to 3 °C and methanesulfonyl chloride (8.03 g,71.1 mmol) was added via pipette as a solution in 50 mL of dichloromethane. A solution of triethylamine (14.2 g, 140 mmol) in 50 mL of dichloromethane was then added dropwise over 50 mm, and the resulting solution was stirred for 2 h. The reaction mixture was poured into 150 mL (150 mmol) of 1 N hydrochloric acid and transferred to a separatory funnel.The layers were separated and the organic layer was washed with 150 mL water and then filtered. The organic layer was concentrated under reduced pressure and the crude solid was tritrated with hexanes to yield 12.09 g of product as a yellow solid.1H NMR (500 MHz) ö 7.54-7.66 (m, 2H) 7.69-7.84 (m, 3H) 7.96-8.08 (m, 1H). |
| 12.09 g | Stage #1: nitromethane; 3-Trifluoromethylbenzaldehyde With sodium hydroxide In methanol; lithium hydroxide monohydrate at 2 - 10℃; for 1h; Stage #2: With methanesulfonyl chloride; triethylamine In dichloromethane at 3℃; for 2.83333h; | 5.A Step A: Preparation of 1-[(E)-2-nitroethenyl]-3-(trifluoromethyl)benzene To a stirred solution of 3-(trifluoromethyl)benzaldehyde (12.2 g, 70.1 mmol) in methanol (50 mL) was added nitromethane (4.34 g, 71.1 mmol). The mixture was cooled to 2° C. and sodium hydroxide (5.65 g, 70.6 mmol) was added as a 50% solution in 24.3 mL of water dropwise over 15 min. An exotherm was noted and additional ice was added to maintain the temperature below 10° C. while stirring for an additional 1 h. The reaction mixture was poured into 75 mL (75 mmol) of 1 N hydrochloric acid, rinsing the flask with 10 mL of methanol/water. The quenched reaction mixture was transferred to a separatory funnel and extracted with 150 mL of toluene. The aqueous layer was separated and concentrated under vacuum to yield 15.84 g of a yellow oil. The intermediate thus obtained (15.84 g, 67.3 mmol) was taken up in 160 mL dichloromethane. The solution was cooled to 3° C. and methanesulfonyl chloride (8.03 g, 71.1 mmol) was added via pipette as a solution in 50 mL of dichloromethane. A solution of triethylamine (14.2 g, 140 mmol) in 50 mL of dichloromethane was then added dropwise over 50 min, and the resulting solution was stirred for 2 h. The reaction mixture was poured into 150 mL (150 mmol) of 1 N hydrochloric acid and transferred to a separatory funnel. The layers were separated and the organic layer was washed with 150 mL water and then filtered. The organic layer was concentrated under reduced pressure and the crude solid was tritrated with hexanes to yield 12.09 g of product as a yellow solid. 1H NMR (500 MHz) δ 7.54-7.66 (m, 2H) 7.69-7.84 (m, 3H) 7.96-8.08 (m, 1H). |
| With sodium hydroxide In methanol; lithium hydroxide monohydrate at 10 - 15℃; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 86% | With magnesium In tetrahydrofuran at -78 - 0℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With piperidine In ethanol Heating; | |
| 29% | With piperidine In ethanol for 20h; Reflux; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | In methanol for 24h; Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 3-Trifluoromethylbenzaldehyde; 1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde With potassium cyanide In ethanol; water Stage #2: thiophene-2-carbaldehyde With copper diacetate; ammonium acetate; acetic acid |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 2-(3-Bromophenyl)malononitrile With n-butyllithium In tetrahydrofuran at -70℃; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran at -70℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 64% | With chloro-trimethyl-silane In N,N-dimethyl-formamide for 12h; Heating; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | In toluene at 120℃; Inert atmosphere; | |
| 52% | In dichloromethane | General method for the synthesis of cinnamaldehyde analogues via Wittig reaction General procedure: In a flame-dried flask the aldehyde (1 mmol), dry CH2Cl2 (2.5 mL) and (triphenylphosphoranylidene)acetaldehyde were added (1.2 mmol) and the mixture was stirred overnight. The solvent was removed in vacuo, Et2O was added and the precipitating solid triphenylphosphine oxide was removed by filtration though a pad of Celite. The solvent of the filtrate was removed under reduced pressure and the product was purified by column chromatography eluting with petroleum ether (bp 40- 60 °C)/AcOEt |
| 52% | In dichloromethane | General method for the synthesis of cinnamaldehyde analogues via Wittig reaction General procedure: In a flame-dried flask the aldehyde (1 mmol), dry CH2Cl2 (2.5 mL) and (triphenylphosphoranylidene)acetaldehyde were added (1.2 mmol) and the mixture was stirred overnight. The solvent was removed in vacuo, Et2O was added and the precipitating solid triphenylphosphine oxide was removed by filtration though a pad of Celite. The solvent of the filtrate was removed under reduced pressure and the product was purified by column chromatography eluting with petroleum ether (bp 40- 60 °C)/AcOEt |
| In toluene for 40h; Reflux; | 26a (2E)-3-[3-(trifluoromethyl)phenyl]prop-2-enal (2E)-3-[3-(trifluoromethyl)phenyl]prop-2-enal 3-(Trifluoromethyl)benzaldehyde (0.70 g) was dissolved in toluene (16 mL), and (triphenylphosphoranylidene)acetoaldehyde (1.22 g) was added. The reaction mixture was heated under reflux for 40 hr and concentrated, and the residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.41g) as an oil. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 6.78 (1 H, dd, J=16.1, 7.4 Hz), 7.41 - 7.87 (5 H, m), 9.75 (1 H, d, J=7.5 Hz) | |
| In acetonitrile at 20℃; for 18h; | Preparation of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline: 3-Trifluoromethylbenzaldehyde (20.0 g, 0.115 mol) was taken up in 500 mL of CH3CN along with (triphenylphosphoranylidene)acetaldehyde (35 g, 0.115 mol). The reaction mixture was stirred at room temperature for 18 h. It was then concentrated under reduced pressure. The resulting residue was taken up in 800 mL of 1:1 pentane/EtOAc and filtered. The filtrate was concentrated under reduced pressure to afford crude (E)-3-(3-(trifluoromethyl)phenyl)acrylaldehyde as a dark red oil. This material was taken up in 30 mL of CH2Cl2. The resulting mixture was slowly added to a suspension of 2-nitroaniline (4 g, 0. 029 mol) in concentrated HCl (50 mL) at 90 °C over a period of 30 min. The resulting reaction mixture was stirred at 90 °C for an additional 1 h. The reaction mixture was cooled to room temperature and washed with CH2Cl2 (2 x 100 mL). The aqueous layer was neutralized with 5% aqueous NaOH and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (pentane/EtOAc) to afford 800 mg of 8-nitro-2-(3-(trifluoromethyl)phenyl)quinoline. MS (ESI) calcd for C16H9F3N2O2 (m/z): 318.06, found: 319 [M+1]. | |
| In dichloromethane Reflux; Inert atmosphere; | ||
| In toluene at 100℃; Inert atmosphere; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: trimethylaluminum With 1,4-diaza-bicyclo[2.2.2]octane In toluene at 0℃; Stage #2: 3-Trifluoromethylbenzaldehyde With [(R)-1,1'-binaphthyl-2,2'-diyldioxy]{bis[(S)-(1-phenylethyl)]amino}phosphine In tetrahydrofuran at 5℃; for 1h; Title compound not separated from byproducts; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 57% | With sodium acetate In acetic anhydride at 90℃; for 2h; | 1.A Step A: Step A: 5-Biphenyl-4-yl-3-(3-trifluoromethyl benzylidene)-3H-furan-2-one A suspension of 4-biphenyl-4-yl-4-oxobutyric acid (508.6 mg, 2.0. mmol), 3-trifluoromethyl benzaldehyde (0.27 mL, 2.0 mmol) and sodium acetate (164.0 mg, 2.0 mmol) in acetic anhydride (1.2 mL) was heated at 90° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitate was collected by filtration giving 450 mg of the desired product (57%), which was used without further purification. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In tetrahydrofuran; diethyl ether | 9.C Step C Step C Synthesis of (1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)methanol as an intermediate This compound is prepared in a manner analogous to that of Step B of Example 6, using 22.1 grams (0.09 mole) of the Grignard reagent of 8-bromo-1,4-dioxaspiro[4.5]decane and 17.4 grams (0.10 mole) of 3-trifluoromethylbenzaldehyde in tetrahydrofuran. Upon completion of the reaction, the reaction mixture is poured into a mixture of 100 grams of ice, 100 mL of an aqueous solution saturated with ammonium chloride, and 200 mL of diethyl ether. This mixture is filtered and the organic layer is separated. The organic layer is concentrated under reduced pressure, yielding [(1,4-dioxaspiro[4.5]decan-8-yl) (3-trifluoromethylphenyl)]methanol. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In water | 3 2-Hydroxy-2-(3-trifluoromethylphenyl)ethanoic acid PREPARATION 3 2-Hydroxy-2-(3-trifluoromethylphenyl)ethanoic acid A solution of 3-trifluoromethylbenzaldehyde (69.2 g) in ether (250 ml) was shaken with a solution of sodium metabisulphite (84.5 g) in water (85 ml). The mixture was cooled in the refrigerator overnight, the solid was collected, washed with a little propan-2-ol and dried (120 g). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium acetate In ethanol; water | 14 [4R]-3-(3-Acetylthio-3-benzoyl-2-methylpropionyl)-2-(m-trifluoromethylphenyl)-4-thiazolidinecarboxylic acid EXAMPLE 14 [4R]-3-(3-Acetylthio-3-benzoyl-2-methylpropionyl)-2-(m-trifluoromethylphenyl)-4-thiazolidinecarboxylic acid To a solution of 10.0 g. (0.057 mole) of L-cysteine hydrochloride hydrate and 6.0 g. (0.061 mole) of potassium acetate in 280 ml. of ethanol:water (3:2) is added 13.06 g. (0.075 mole) of m-trifluoromethylbenzaldehyde dropwise over a 10 minute period. The mixture is stirred for 24 hours at room temperature and filtered. The solid (17.0 g.) is recrystallized from methanol to give 13.2 g. of [4R]-2-(m-trifluoromethylphenyl)-4-thiazolidinecarboxylic acid as white crystals, m.p. 152°-154° C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In 5,5-dimethyl-1,3-cyclohexadiene | 1.A A. A. 2-[3-(Dimethylamino)propoxy]-N-[[3-(trifluoromethyl)phenyl]methylene]benzenamine A solution of 19.4g of 2-(3-dimethylaminopropoxy)aniline and 17.4g of m-trifluoromethylbenzaldehyde in 100ml of xylene is refluxed for about 6 hours. The water formed in the reaction is collected in a Dean-Stark tube. The solvent is removed under reduced pressure and the residue fractionated to yield 18.4g of the title compound as an oil, boiling point 155°-160° C. at 0.2-0.3 mm. of Hg. |
[ 454-89-7 ]
[ 120-35-4 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Example 269 4-Methoxy-3-(3-trifluoromethyl-benzylamino)-N-phenyl-benzamide The title compound has been made using the procedure of Example 50, but using 3-amino-4-methoxy-N-phenyl benzamide and 3-trifluoromethylbenzaldehyde as starting materials, which can be purchased from Aldrich; m.p. 167-171 C. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With formic acid In dimethyl sulfoxide |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 80% | With sodium tetrahydroborate In ethanol at 40 - 45℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 73% | Stage #1: (1R,2S)-2-amino-cyclopentanecarboxylic acid methyl ester hydrochloride; 3-Trifluoromethylbenzaldehyde In methanol at 25℃; for 0.25h; Stage #2: With sodium cyanoborohydride In methanol; acetic acid at 25℃; for 16h; | 15.a (lR,25)-2-Amino-cyclopentanecarboxylic acid methyl ester hydrochloride (prepared as described in Example 11a, 130 mg, 0.91 mmol) was dissolved in methanol (5 mL). 3-Trifluoromethyl-benzaldehyde (160 mg, 0.91 mmol) was added, stir at 25 0C for 15 min, acetic acid (0.2 mL) added, followed with sodium cyanoborohydride (150 mg, 2.3 mmol) was added and the mixture was stirred at 25 0C for 16 h. The mixture was poured into a mixture of saturated aqueous sodium bicarbonate solution (100 mL) and ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product (lR,25)-2-(3-trifluoromethyl- benzylamino)-cyclopentanecarboxylic acid methyl ester (200 mg, 0.664 mmol, 73%), as a clear oil. LC-MS (ESI) calcd for C15H18F3NO2 301.13, found 302.2 [M+H+] |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 77% | In tetrahydrofuran at 20℃; Inert atmosphere; | Method C6: General procedure: To a solution of aldehyde (1 mmol) in anhydrous THF at 0°C was added a solutionof 1.8M PhMgBr (1.1 mmol) in THF. This reaction was allowed to warm to room temperatureand stirred until completion by TLC (9:1 heptanes/ethyl acetate). The reaction was quenchedwith 1.0M H2SO4 and separated. The aqueous phase was extracted with diethyl ether three times,washed with brine and dried over MgSO4. The organic phase was concentrated and subjected toflash chromatography. |
| In diethyl ether Reflux; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 92% | Stage #1: 3-Trifluoromethylbenzaldehyde; malononitrile With polyethyleneimine covalently bound on the surface of Fe3O4 magnetic nanoparticle by [3-(2,3-epoxypropoxy)propyl]trimethoxysilane as cross linker In water for 0.0166667h; Sonication; Green chemistry; Stage #2: 3-Dimethylaminophenol In water for 1.33333h; Sonication; Green chemistry; | 2.3 General procedure for catalytic synthesis of compounds 4, 6.9,11 General procedure: A stirring mixture of an active carbonyl compound (aldehyde 1 or isatin 7, 1mmol), malononitrile 2 (1.2mmol), magnetic catalytic system ([PEISi-MNPs], 5mg) and ethylene glycol/water (EG/H2O 20/80, 2mL) were sonicated for one minute. To this stirred mixture, an enolizable compounds (3-(dimethylamino)phenol 3, 4-hydroxycoumarin 5 or dimedone 10, 1mmol) was added. The reaction mixture was heated at appropriate temperature as mentioned in Table 1. The progress of the reaction was monitored by TLC. After completion of the reaction (as shown in Tables 2-4), the reaction mixture was allowed to cool at room temperature and diluted with ethyl acetate and the catalyst was easily separated from the reaction mixture with an external magnet and washed twice with ethyl acetate. The combined organic layers were concentrated in vacuum and the residue was purified by crystallization from ethanol. All compounds gave satisfactory spectral data and they were identical with those reported in the literature [29,31-37]. |
| 70% | With piperidine In ethanol at 35℃; for 12h; | |
| With piperidine In ethanol at 35℃; for 12h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 85% | With ammonium acetate; copper dichloride In N,N-dimethyl-formamide at 100℃; for 15h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 40% | Stage #1: 3-Trifluoromethylbenzaldehyde With n-butyllithium In tetrahydrofuran at 0℃; for 0.5h; Stage #2: Methyltriphenylphosphonium bromide In tetrahydrofuran at 0 - 20℃; for 1h; | |
| 39% | Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.25h; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran at 0 - 20℃; for 17h; Inert atmosphere; | |
| 37% | Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran at 0 - 20℃; for 10h; Inert atmosphere; | General procedure A General procedure: In a 100 mL round-bottom flask equipped with a stir bar, methyltriphenylphosphonium bromide (1.2 equiv.) was dissolved in 50 ml THF under N2 atmosphere. Then, n-BuLi (1.2 equiv) was added dropwise at 0 (ice bath) and the mixture was stirred for 15 minutes. The aldehyde was dissolved in 10 ml of THF and the solution was then syringed through a septum. The mixture was stirred for 1 hour and maintained at 0 . It was then allowed to warm to room temperature and maintained under stirring for 9 hours. It was then quenched with water and extracted with ethyl acetate (3 x 50 ml). The combined organic layers were washed with H2O, brine and dried over by Na2SO4. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel to give the corresponding alkene. |
| With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 16h; | ||
| With potassium carbonate In 1,4-dioxane for 16h; Reflux; | ||
| Stage #1: Methyltriphenylphosphonium bromide With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran; hexane at 0 - 20℃; Inert atmosphere; | ||
| Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran at 0 - 20℃; Inert atmosphere; | ||
| Stage #1: Methyltriphenylphosphonium bromide With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran at 0 - 20℃; Inert atmosphere; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: hydrogenchloride; benzyltrimethylammonium chloride / diethyl ether / 1 h / 10 °C 2: hydrogenchloride; water / 70 °C | ||
| Multi-step reaction with 2 steps 1.1: zinc(II) iodide / 2 h / 0 °C 1.2: 12 h / 0 - 20 °C 2.1: lithium hydroxide; sodium hydride / methanol; tetrahydrofuran / 12 h / 20 °C | ||
| Multi-step reaction with 2 steps 1.1: zinc(II) iodide / 2 h / 0 °C 1.2: 12 h / 0 - 20 °C 2.1: methanol; lithium hydroxide; water / tetrahydrofuran / 12 h / 20 °C |
| Multi-step reaction with 2 steps 1.1: zinc iodide / 2 h / 0 °C 1.2: 12 h / 0 - 20 °C 2.1: methanol; water; lithium hydroxide / tetrahydrofuran / 12 h / 20 °C | ||
| Multi-step reaction with 2 steps 1.1: zinc iodide / 2 h / 0 °C 1.2: 12 h / 0 - 20 °C 2.1: lithium hydroxide; water / tetrahydrofuran; methanol / 12 h / 20 °C | ||
| Multi-step reaction with 3 steps 1: zinc(II) iodide / 0 °C 2: hydrogenchloride / 0 - 20 °C 3: lithium hydroxide monohydrate / tetrahydrofuran; water; methanol / 20 °C |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: chloroform; 3-Trifluoromethylbenzaldehyde With N-benzyl-N,N,N-triethylammonium chloride; sodium hydroxide In water at 60℃; for 2.5h; Stage #2: With hydrogenchloride In water |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With pyridine; diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate at 105℃; for 16h; | 7.a 4-hydroxy-6-iodo-3-(3-(trifluoromethyl)benzyl)quinolin-2(1H)-one A suspension of 6-iodoquinoline-2,4-diol (1.998 g, 6.96 mmol, Intermediate 4: step b), 3-(trifluoromethyl)benzaldehyde (1.0 mL, 7.472 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.776 g, 7.012 mmol) in pyridine (40 mL) was heated at 105° C. for 16 hours. The reaction was then cooled, diluted with EtOAc, washed with 1 N aqueous HCl (2*), and saturated aqueous NaCl (1*). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to afford the title compound, which was used without further purification. | |
| With diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In pyridine at 105℃; for 16h; | 7.a Intermediate 7: step a 4-hydroxy-6-iodo-3-(3-(trifluoromethyl)benzyl)quinolin-2(1H)-one General procedure: Intermediate 7: step a 4-hydroxy-6-iodo-3-(3-(trifluoromethyl)benzyl)quinolin-2(1H)-one A suspension of 6-iodoquinoliiie-2,4-diol (1.998 g, 6.96 mmol. Intermediate 4: step b), 3- (trifluoromethyl)benzaldehyde (1.0 mL, 7.472 mmol), and diethyl 2,6~diniethyl~l,4- dihydropyridine-3,5-dicarboxylate (1.776 g, 7.012 mmol) in pyridine (40 mL) was heated at 105 °C for 16 hours. The reaction was then cooled, diluted with EtOAc, washed with 1 N aqueous F1C1 (2 x), and saturated aqueous NaCl (1 x). The organic layer was dried (MgS04), filtered and concentrated in vacuo to afford the title compound, which was used without further purification. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 99.4% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 1h; Inert atmosphere; | 10.1 (1) Preparation of 5-(2-(3-(trifluoromethyl)phenyl)-1,3-dithian-4-yl)pentanoic acid (Compound M-10) Ar purge was performed and the compound DHLA (0.5 g, 2.4 mmol) was dissolved in DCM, and then 3-(Trifluoromethyl)benzaldehyde (compound a1-10, 0.3 mL, 2.5 mmol) was added dropwise.After 1 hour at room temperature, BF3OEt2(0.32 mL, 2.6 mmol) was added dropwise.After reacting overnight, the reaction wasterminated usingH2O and extracted with DCM.The extracted organic layer was dehydrated with anhydrous MgSO4, filtered under reduced pressure, and the obtained filtrate was concentrated under reduced pressure.The crude residue was separated by column chromatography (DCM→DCM:MeOH=19:1) to give a colorless oily compound M-10 (795 mg, 90.8% yield). |
| Stage #1: dihydrolipoic acid; 3-Trifluoromethylbenzaldehyde In dichloromethane at 20℃; for 1h; Inert atmosphere; Stage #2: With boron trifluoride diethyl etherate In dichloromethane at -25 - 20℃; Inert atmosphere; |
[ 454-89-7 ]
[ 39549-79-6 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | With sodium hydrogensulfite; In N,N-dimethyl acetamide; at 150℃; | General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31.#10;#10; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 82% | With sodium hydrogensulfite In N,N-dimethyl acetamide at 150℃; | General procedure for the synthesis of 2-arylquinazolinones 3-31 General procedure: Sodium hydrogen sulfite (4 mmol) was added to a solution of anthranilamide 1 (2 mmol) and benzaldehyde 2 (2 mmol) in N,N- dimethylacetamide (5 mL). The mixture was heated under continuous stirring at 150 o C for 2-3 h and poured into ice water. The precipitate was then filtered, washed with water followed byethanol, and dried to yield the 2-arylquinazolinones 3-31. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 52% | With piperidine In ethanol at 140℃; for 0.25h; Microwave irradiation; Sealed tube; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 48% | With sodium tris(acetoxy)borohydride; acetic acid In 1,2-dichloro-ethane at 20℃; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 14% | With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; potassium <i>tert</i>-butylate at 20℃; for 3h; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With potassium carbonate In neat (no solvent) at 20℃; Microwave irradiation; Green chemistry; | General procedure for the synthesis of pyrazoline derivatives 4(a-f) under the solvent-free microwave irradiation method General procedure: A mixture of 2-fluorobenzaldehyde (0.45g, 0.0036 mole), 3-acetyl-2,5-dimethylfuran (0.5g, 0.0036 mole) and solid K2CO3 (1.24g, 0.0090 mole) was ground with a mortar and pestle at room temperature. Further, it was subjected to microwave irradiation at 600 W in sealed vessel for 2-3 minutes, monitoring the progress of reaction by TLC. To this was, added thiosemicarbazide (0.40g, 0.0044 mole), stirred with glass rod at room temperature (29°C) and subjected to microwave irradiation at 600 W in sealed vessel for 5-8 minutes, monitoring the progress of reaction by TLC. The reaction mixture was quenched with ice-cold water and filtered at the pump, followed by wash with ice-cold water and crystalized from ethanol to obtain reddish yellow 1-Thiocarbamoyl-3-(2,5-dimethylfuran-3-yl)-5-(2-fluorophenyl)-2-pyrazoline. The above general method was adopted for the synthesis of compounds 4b-f of this series. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | Stage #1: 3-Trifluoromethylbenzaldehyde With hydroxylamine hydrochloride; sodium carbonate In water at 20℃; for 0.5h; Schlenk technique; Stage #2: With [(eta.(5)-pentamethylcyclopentadienyl)Ir(H2O)3](OTf)2 In water at 110℃; for 12h; | 4 4-bromobenzamide 3-Trifluoromethylbenzaldehyde (87.1 mg, 0.5 mmol),Hydroxylamine hydrochloride (34.7 mg, 0.5 mmol)Sodium carbonate (26.5 mg, 0.25 mmol)And water (1 ml) were sequentially added to a 25 ml Schlenk reaction flask,After half an hour of room temperature reaction,[Cp * Ir (H2O) 3] [OTf] 2 (10.2 mg, 0.0150 mmol, 3 mol%) was addedThe reaction mixture was reacted at 110 ° CAfter hours,Cooled to room temperature,Rotary evaporation to remove water,Column to give the title compound,Yield: 75%. |
| 71% | With tert.-butylhydroperoxide; titanium superoxide; saccharin In 1,4-dioxane; hexane at 90℃; for 1h; Green chemistry; | |
| 60% | With C55H45ClN5P2Ru(1+)*Cl(1-); hydroxylamine hydrochloride; sodium carbonate In water at 110℃; for 12h; Sealed tube; |
| 98 %Chromat. | With hydroxylamine hydrochloride; C27H26Cl2NORh; sodium hydrogencarbonate In water at 39.84℃; for 2h; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: Lithium 1,1,1,3,3,3-hexamethyldisilazide / tetrahydrofuran / 0 - 20 °C / Inert atmosphere 2: 10% Pd/C; hydrogen / methanol / 20 °C 3: polyphosphoric acid / 90 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 3 steps 1: sodium acetate; acetic anhydride / 2 h / 140 °C / Inert atmosphere 2: triethylamine / 3 h / 100 °C 3: potassium carbonate / water; toluene / 16 h / 100 °C |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 50.5% | Stage #1: 3,5-dimethoxyphenylacetonitrile; 3-Trifluoromethylbenzaldehyde In methanol at 60℃; for 0.5h; Stage #2: With sodium methylate In methanol at 60℃; | 1.3 General procedure for the synthesis of the derivatives of 2,3-diaryl acrylonitrile (4a-4z and 5a-5d) General procedure: A 50 mL round-bottomed flask was charged with 3 (0.177 g, 1 mmol), aromatic aldehyde or substituted aromatic aldehyde (1 mmol) and 10 mL methanol with stirring, and the mixture was heated to 60 °C. After 30 min, sodium methoxide (0.027 g, 0.5 mmol) was added to the mixture and keep the temperature for 4-6 h. After completion of the reaction as indicated by TLC, the reaction mixture was cooled to RT, and the precipitate was separated by filter and recrystallized from methanol to give 4a-4z and 5a-5d. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | Stage #1: 3-Trifluoromethylbenzaldehyde; (S)-2-amino-4-phenylbutan-1-ol In methanol at 20℃; for 1h; Stage #2: With methanol; sodium tetrahydroborate at 0 - 20℃; for 2h; | A.50.3 Step 3: (2S)-4-phenyl-2-([3-(trifluoromethyl)phenyl]methyl}amino)butan-1 -ol L-Homophenylalaninol (1 .4 g, 8.5 mmol) was dissolved in MeOH (40 ml_). 3-(trifluoromethyl) benzaldehyde (1 .5 g, 8.5 mmol) was added and the reaction was stirred at room temperature for 1 hr. The reaction was then brought to 0 °C and NaBH4 (386 mg, 10.2 mmol) was added at once and the reaction was allowed to warm to room temperature and stir for 2 additional hrs. The reaction was then diluted with EtOAc and washed with saturated aqueous NaHC03 (2X). The organics were dried over Na2S04 and removed to provide the product as a viscous oil (2.6 g, 8.2 mmol, 95% yield). MS- ESI (m/z) calculated for C18H21F3NO [M+H]+ 324.2; found 324.2. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 98% | With potassium hydroxide In ethanol; water at 25℃; for 3h; | 4.2. General method for preparation of 14-61 General procedure: To a stirred solution of hydroxylated indanone (1.0 eq.) and arylaldehyde (R1=b-m) in ethanol (3 mL), 50% aqueous KOH (9.0 eq.,1.0 mL) solution was added dropwise and the reaction was stirredfor 15 min to 3 h till orange precipitation was obtained. The progressof the reactionwas checked by using TLC. Upon completion, icewas added to the reaction mixture and then neutralized by 6 Maqueous HCl solution (pH adjusted to 2) to get white precipitation.The resulted precipitatewas filtered,washed with excess water anddried. The solid residue was further purified by recrystallizationusing ethyl acetate and n-hexane to afford compound 14-61 in48%-99% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With potassium hydroxide In ethanol; water at 25℃; for 3h; | 4.2. General method for preparation of 14-61 General procedure: To a stirred solution of hydroxylated indanone (1.0 eq.) and arylaldehyde (R1=b-m) in ethanol (3 mL), 50% aqueous KOH (9.0 eq.,1.0 mL) solution was added dropwise and the reaction was stirredfor 15 min to 3 h till orange precipitation was obtained. The progressof the reactionwas checked by using TLC. Upon completion, icewas added to the reaction mixture and then neutralized by 6 Maqueous HCl solution (pH adjusted to 2) to get white precipitation.The resulted precipitatewas filtered,washed with excess water anddried. The solid residue was further purified by recrystallizationusing ethyl acetate and n-hexane to afford compound 14-61 in48%-99% yield. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20 - 25℃; for 48h; | 1 The preparation method of m-trifluoromethyl cinnamaldehyde In a four-necked flask, 17.41 g of m-trifluoromethylbenzaldehyde (0.1 mol), 68.0 mL of tetrahydrofuran and 3.04 g of DBU (0.02 mol), freshly distilled 11.01 g of acetaldehyde (0.25 mol) was added with stirring, and the mixture was stirred at room temperature (20 to 25C)Stirring 48h, sampling, HPLC control, to the raw material disappeared, the end of the reaction.Maintain the material temperature below 30 under reduced pressure distillation, remove excess acetaldehyde and solvent, and then add 1mol / L dilutionHydrochloric acid to pH 3 to 5, extracted with dichloromethane, and the organic phase was concentrated under reduced pressure to remove the solvent and distilled under reduced pressure to give a colorless oilWas obtained in a yield of 15.0g, 75.0% and a purity of 98.5% (HPLC). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With ammonium formate In ethanol for 16h; Reflux; | ||
| 255 g | With ammonium formate In ethanol for 12h; Reflux; | 1.1 Step 1: Preparation of 3-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid (0549) (0550) A mixture of malonic acid (298.82 g, 2872 mmol), ammonium formate (362.14 g, 5743 mmol) and 3-(trifluoromethyl)benzaldehyde (500 g, 2873 mmol) in ethanol (1000 mL) was refluxed for 12 h. The reaction mixture was evaporated to remove ethanol and the residue was triturated with acetone (2500 mL). The solid was filtered and dried to afford 3-amino-3-[3-(trifluorome- thyl)phenyl]propanoic acid (255 g) as white solid. (0551) NMR (400 MHz, AcOH-d4) δ 7.87-7.81 (m, 2H), 7.74 (d, 1H, J = 7.6 Hz), 7.66-7.62 (m, 1H), 4.98 (br. S, 1H), 3.36 (dd, 1H, J = 16.0, 8.0 Hz), 3.13 (dd, 1H, J = 17.6, 5.6 Hz); (0552) MS: m z 234 (M+l). |
| 255 g | With ammonium formate In ethanol for 12h; Reflux; | 25.1 Step 1: Preparation of 3-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid A mixture of malonic acid (298.82 g, 2872 mmol), ammonium formate (362.14 g, 5743 mmol) and 3-(trifluoromethyl)benzaldehyde (commercially available) (500 g, 2873 mmol) in ethanol (1000 mL) was refluxed for 12 h. The reaction mixture was evaporated to remove ethanol and the residue was triturated with acetone (2500 mL). The solid was filtered and dried to afford 3-amino-3-[3- (trifluoromethyl)phenyl]propanoic acid (255 g) as a white solid. NMR (400 MHz, AcOH-d4) δ 7.87-7.81 (m, 2H), 7.74 (d, 1H, J = 7.6 Hz), 7.66- 7.62 (m, 1H), 4.98 (br. S, 1H), 3.36 (dd, 1H, J = 16.0, 8.0 Hz), 3.13 (dd, 1H, J = 17.6, 5.6 Hz); MS: m/z 234 (M+l). |
| 255 g | With ammonium formate In ethanol for 12h; Reflux; | 14.1 Step 1: Preparation of 3-amino-3-[3-(trifluoromethyl)phenyl] propanoic acid A mixture of malonic acid (298.82 g, 2872 mmol), ammonium formate (362.14 g, 5743 mmol) and 3-(trifluoromethyl)benzaldehyde (commercially available) (500 g, 2873 mmol) in ethanol (1000 mL) was refluxed for 12 h. The reaction mixture was evaporated to remove ethanol and the residue was triturated with acetone (2500 mL) The solid was filtered and dried to afford 3-amino-3-[3- (trifluoromethyl)phenyl]propanoic acid (255 g) as a white solid. NMR (400 MHz, AcOH-d4) δ 7.87-7.81 (m, 2H), 7.74 (d, 1H, J = 7.6 Hz), 7.66- 7.62 (m, 1H), 4.98 (br. S, 1H), 3.36 (dd, 1H, J = 16.0, 8.0 Hz), 3.13 (dd, 1H, J = 17.6, 5.6 Hz);MS: m/z 234 (M+l). |
| 3.09 g | With ammonium acetate In isopropyl alcohol for 17h; Inert atmosphere; Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 30% | With triethylamine In dichloromethane at 20℃; for 48h; |
[ 13338-63-1 ]
[ 454-89-7 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 43% | With sodium methylate; In methanol; at 60℃; | Using the method of synthesizing an intermediate similar to that of Example 1,Take 0.01 mol of <strong>[13338-63-1]3,4,5-trimethoxyphenylacetonitrile</strong> (5), 0.01 mol of 3-trifluoromethylbenzaldehyde and 20 mL of methanol into a 50 mL three-necked flask.Stirring to 60 C, adding 0.005 mol of sodium methoxide, constant temperature reaction 4-6 h,TLC scanning and detection, after the reaction is completed, it is cooled to room temperature, filtered, washed with water, dried, and recrystallized from methanol to obtain a pale yellow solid. Yield: 43.0%, |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: 5,5-dimethyl-1,3-cyclohexadiene 2: hydrogenchloride; potassium carbonate / 5,5-dimethyl-1,3-cyclohexadiene; dichloromethane; water; isopropyl alcohol; acetonitrile |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 4 steps 1.1: titanium(IV) tetraethanolate / tetrahydrofuran / 70 °C / Large scale 2.1: zinc / tetrahydrofuran / 1 h / 40 - 50 °C 2.2: 20 °C 3.1: lithium hydroxide; water / tetrahydrofuran / 1 h / 5 - 20 °C 4.1: hydrogenchloride / ethyl acetate / 2 h / 5 - 20 °C |
[ 53137-27-2 ]
[ 931-53-3 ]
[ 454-89-7 ]
[ 106-49-0 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 30% | General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds. |
[ 53137-27-2 ]
[ 931-53-3 ]
[ 454-89-7 ]
[ 62-53-3 ]
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 35.5% | General procedure: The aldehyde (0.8 equivalent) and amine (0.7 equivalent) were dissolved in methanol (2.0 mL) and stirred for two to 3 h depending upon the starting material. The acid (100 mg, 1 equivalent) and isocyanide (0.7 equivalent) were added in the reaction mixture and further stirred. The reaction mixture was monitored using TLC analysis.Water (4 mL) was added upon completion of the reaction.The resulted solid was filtered off and dissolved in ethyl acetate(10 mL), washed with water (2 3 mL) and dried over sodium sulphate. The crude product was purified using silica gel column chromatography. The ethyl acetate:hexane (6:4) solvent system was used for the purification of these compounds. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 95% | With 3-(7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methyl-1-(2,4,6-trimethylphenyl)-1H-imidazol-3-ium iodine salt; caesium carbonate In toluene at 60℃; for 3h; | 2.10 10) Preparation of ethyl 3-trifluoromethylbenzoate: Weigh accurately 0.1mol of 3-trifluoromethylbenzaldehyde,Add to 500mL round bottom flask,Then add 0.5mol ethanol,0.005mol 3- (7,7-dimethyl-2-oxobicyclo [2.2.1] hept-1-yl) methyl-1- (2,4,6-trimethyl) phenyl-1H- Imidazole-3-ium iodide,0.05mol cesium carbonate,150mL of toluene, put on an air balloon, and stir at 60 ° C for 3h.After the reaction, the reaction solution was cooled to room temperature, washed with saturated brine to neutrality, concentrated under reduced pressure, and subjected to column chromatography to obtain ethyl 3-trifluoromethylbenzoate. The yield was 95%. |
| 92% | With C22H29N2O(1+)*I(1-); caesium carbonate In toluene at 60℃; for 3h; | 2.4 General Procedure forOxidative Esterication of Aldehydes and Alcohols General procedure: A three-neck flask was charged with aldehyde 7a-7p(1.0mmol), camphor-based imidazolium salts (5mol%),Cs2CO3(163mg, 0.5mmol), alcohol (5mmol) and 10ml oftoluene in an air atmosphere, then the mixture was stirred for3h at 60°C. The reaction mixture was extracted with diethylether (3 × 30ml), concentrated under reduced pressure andthe residue was purified by flash column chromatography onsilica gel (PE (petroleum ether):EA (ethyl acetate) = 20:1)to give the desired product. All products were identified by1H and 13C NMR and in accord with literatures [42-52] (forspectra see Supplementary Data). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium acetate; sodium tris(acetoxy)borohydride In dichloromethane at 0 - 20℃; for 12h; | 4.1.2. General procedure for the synthesis of 3a-3p General procedure: To a solution of (R)-2-aminobutanoate hydrochloride (5 mmol)and different aldehydes or ketones (5.0 mmol) in dichloromethane(40 mL) was added sodium acetate (7.5 mmol) and sodium triacetoxyborohydride(10.0 mmol) at 0 °C. The mixture was stirredunder room temperature for 12 h until the starting materialscompletely transformed. Then saturated sodium bicarbonate solutionwas added to the reaction mixture and the mixture wasstirred for another 30 min. After the organic phase separated byextraction, the aqueous phase was reextracted with dichloromethane.The combined organic phase was washed with brine,dried over MgSO4 and concentrated under reduced pressure. Thecrude product was further purified by column chromatographywith dichloromethane/methanol (V/V = 120/1-60/1) to afford 3a-3p with yields of 50 %-70%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 145 mg | Stage #1: 3-Trifluoromethylbenzaldehyde; tert-butyl 4-(1-amino-2,2,2-trifluoroethyl)piperidine-1-carboxylate In 1,2-dichloro-ethane at 20℃; for 1h; Inert atmosphere; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 0 - 20℃; | a Step a) tert-Butyl 4-(2, 2, 2-trifluoro- 1-((3-(trifluoromethyl)benzyl)amino) ethyl)piperidine- 1- carboxylate A solution of tert-butyl 4-(1-amino-2,2,2-trifluoroethyl)piperidine-1-carboxylate (0.150 g, 531 i.imol) and 3-(trifluoromethyl)benzaldehyde (92.5 mg, 71.1 1.iL, 531 i.imol) in 1,2-DCE (1 mL)was stirred for 1 hour at RT. Sodium triacetoxyborohydride (225 mg, 1.06 mmol) was thenadded at 0°C, and the reaction mixture was stirred at RT overnight. The reaction mixture waspoured onto sat. NaHCO3 and extracted with DCM. The organic layers were combined, washed with brine, dried over Na2504 and concentrated in vacuo. The crude material was purified byflash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane) to yield 145 mg of thedesired compound as a colorless oil. MS (ESI): m/z = 383.1 [M-56+H] |
| 145 mg | Stage #1: 3-Trifluoromethylbenzaldehyde; tert-butyl 4-(1-amino-2,2,2-trifluoroethyl)piperidine-1-carboxylate In 1,2-dichloro-ethane at 20℃; for 1h; Stage #2: With sodium tris(acetoxy)borohydride In 1,2-dichloro-ethane at 0 - 20℃; | a Step a) tert-Butyl 4-(2,2,2-trifluoro-l-((3-(trifluoromethyl)benzyl)amino)ethyl)piperidine-l- carboxylate A solution of tert-butyl 4-(l-amino-2,2,2-trifluoroethyl)piperidine-l-carboxylate (0.150 g, 531 pmol) and 3-(trifluoromethyl)benzaldehyde (92.5 mg, 71.1 pL, 531 pmol) in l,2-DCE (1 mL) was stirred for 1 hour at RT. Sodium triacetoxyborohydride (225 mg, 1.06 mmol) was then added at 0°C, and the reaction mixture was stirred at RT overnight. The reaction mixture was poured onto sat. NaHCCb and extracted with DCM. The organic layers were combined, washed with brine, dried over Na^SCb and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 20 g, 0% to 100% EtOAc in heptane) to yield 145 mg of the desired compound as a colorless oil. MS (ESI): m/z = 383.1 [M-56+H]+ |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 68.4% | With sodium hydroxide In ethanol at 20℃; for 6h; | 4 Add in a round bottom flaskP-diethylaminoacetophenone (765mg, 4mmol),3-(trifluoromethyl)benzaldehyde (696mg, 4mmol),30mL ethanol,Stir and add drop by drop3mL of 10% sodium hydroxide solution.Stir at room temperature for 6 hours,A large amount of yellow solid precipitated.Vacuum filtrationAfter washing with methanol, a yellow solid was obtained,No purification,Used directly in the next reaction.Solid A obtained: 951 mg,Yield: 68.4%. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 75% | With perchloric acid In methanol at 20℃; for 24h; | Synthesis of 1-23; Typical Procedure General procedure: To a solution of 5-amino-4-cyano-1H-imidazole (100 mg, 0.93 mmol, 1.0 equiv) and 4-methoxybenzaldehyde (0.12 mL, 1.02 mmol, 1.1 equiv) in anhydrous methanol (1 mL), perchloric acid (2.74 L, 0.05 equiv) was added. After 5 min stirring, tert-butyl isonitrile (0.16 mL, 1.39 mmol, 1.5 equiv) was added. The reaction was stirred for 24 h at r.t., then the mixture was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (EtOAc/PE, 30:70) to afford the desired product. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 88.4% | Stage #1: 1-(diethoxyphosphorylmethylsulfonyl)-4-methylbenzene With n-butyllithium In tetrahydrofuran at -78℃; for 1h; Schlenk technique; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran at -78 - 20℃; for 1.5h; Schlenk technique; Inert atmosphere; | 4.1.3.6. General synthesis of target compounds (6a ~ o, 7a ~ m, 8a ~ m,9a ~ c, and 10a ~ c). General procedure: The synthetic procedure for the target compounds followed the method described by Park et at. [54]. Briefly, corresponding intermediate 4 (4a 292 mg, 4b 306 mg, 4c 310 mg, 4d 327 mg, 4e322 mg, 1 mmol, 1 eq) was dissolved in an appropriate volume (~20mL) of anhydrous tetrahydrofuran (THF) in schlenk tube, and then it was placed at -78°C. The tube was degassed three times with argon,and then n-BuLi (c = 2 M, 0.6 mL, 1.2 mmol, 1.2 eq) was injected slowly to the reaction at -78°C. After the reaction was stirred at -78°C for 1 h,corresponding aldehyde 5 (5a ~ o) (1.1 mmol, 1.1 eq) diluted in anhydrous THF was injected to the tube at -78°C, at which temperature the reaction was further stirred for 30 min. Later the reaction was stirred at room temperature for ~ 1 h, which was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate. The combined organic layer was then concentrated to obtain a residue, which was purified on column chromatography to give the target compound. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 72% | With pyrrolidine In dichloromethane at 55℃; Molecular sieve; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 70% | With pyrrolidine In dichloromethane at 55℃; Molecular sieve; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sulfuric acid; nitric acid at 0 - 50℃; for 8h; | 12 Example 12: (R)-N -(4-((1-methyl-2-((3-(1-methyl-5-oxopyrrolidin-3-yl)-5-(trifluoromethyl)phenyl)amino)-1H-benzo[d]imidazol-6-yl(oxy(pyridin-2-yl)acetamide and (S)-N-(4-((1 -methyl -2-((3-(1 -methyl -5-oxopyrrolidin-3-yl(-5-(trifluoromethyl(phenyl(ami no(-1H-benzo[d]imidazol-6-yl(oxy(pyridin-2-yl)acetamide [0222] Synthesis of compound 12.2. To a mixture of 3-(trifluoromethyl)benzaldehyde (12.1, 10 g, 57.43 mmol, 1.0 equiv) in concentrated sulfuric acid (98%, 20 mL) at 0 °C was slowly added nitric acid (2.5 mL). The reaction mixture was stirred at 50 °C for 8 h. It was poured over crushed ice, stirred and extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CombiFlash, 10% ethyl acetate in hexane as eluant) to afford 12.2. MS (ES): m/z 220.2 [M+H]+. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: tetrahydrofuran / 2 h / 0 °C / Inert atmosphere 2: Dess-Martin periodane / dichloromethane / 0.25 h / 20 °C / Inert atmosphere |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With piperidine In ethanol at 80℃; | 3.2. General Procedure for the Synthesis of Oxindole Analogues Incorporating α,β-unsaturated Ketones (4a-4x) General procedure: First, compounds1a-1e(3 mmol) and2a-2p(3.3 mmol) were placed in a round-bottom flask, and piperidine (0.6 mmol) was added. After dissolution, anhydrous ethanol (8 mL) was added to the above mixture. The solution was vigorously stirred at 80 °C for 4 h on a magnetic stirrer. Then, after a precipitate was generated, the solid was filtered and washed with ethanol to obtain intermediates3a-3u. Then, acetic anhydride (15 mmol) and NaCO3(15 mmol) were added to a solution of3a-3u(3 mmol) in tetrahydrofuran. After stirring at room temperature for 24 h, the mixture was diluted with H2O and extracted with ethyl acetate (3 × 50 mL). Then, the combined organic layers were washed with a saturated sodium chloride solution (3 × 50 mL) and dried over anhydrous Na2SO4. The filtrate was concentrated under reduced pressure, and the crude residue was purified by silica gel column chromatography (petroleum ether and ethyl acetate) or with a Sephadex LH-20 column (CH3OH) to afford target compounds4a-4w.3q(3 mmol) and di-tert-butyl decarbonate (3 mmol) were added to DCM, and then the reaction was carried out at room temperature for 8 h with DMAP (0.3 mmol) as the catalyst to afford the target compound4x. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With sodium hydroxide In ethanol at 20℃; | General procedure: Thiazolidine-2,4-dione 3 (1 mmol, 117.1 mg, purity: 97%), substitutedbenzaldehyde (1 mmol, purity: 99%) and sodium hydroxide (2 mmol, 80.0 mg, purity:95%) were added into EtOH (35 mL) in steps and stirred at room temperature untilthe reaction completed. Then the mixture was filtered and the crude product waswashed with hexane to produce intermediate 4 [2,3]. | |
| With sodium hydroxide In ethanol at 20℃; | 4.2. Synthesis of indole derivatives containing thiazolidine-2,4-dione (IT1~ 26) General procedure: To 35 mL of EtOH, thiazolidine-2,4-dione S1 (1 mmol), substitutedbenzaldehyde S2 (1 mmol), and sodium hydroxide (2 mmol) were addedand stirred for 6 h at room temperature. Then the suspension wasfiltered and the obtained solid was washed with hexane to yield correspondingintermediate S3. | |
| With sodium hydroxide In ethanol at 20℃; | General procedure: Thiazolidine-2,4-dione3(1 mmol, 117.1 mg, purity: 97%), substitutedbenzaldehyde (1 mmol, purity: 99%) and sodiumhydroxide (2 mmol, 80.0 mg, purity: 95%) wereadded into EtOH (35mL) in steps and stirred at room temperature until the reaction completed. Thenthe mixture was filtered and the crude product was washed with hexane toproduce intermediate 4[2-3]. |
| With sodium hydroxide In ethanol at 20℃; | General procedure: Thiazolidine-2,4-dione3(1 mmol, 117.1 mg, purity: 97%), substitutedbenzaldehyde (1 mmol, purity: 99%) and sodiumhydroxide (2 mmol, 80.0 mg, purity: 95%) wereadded into EtOH (35mL) in steps and stirred at room temperature until the reaction completed. Thenthe mixture was filtered and the crude product was washed with hexane toproduce intermediate 4[2-3]. | |
| 68 % | With sodium acetate; acetic acid Reflux; |

| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 3-Trifluoromethylbenzaldehyde; acetaldehyde With 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride; triethylamine In ethanol at 0 - 80℃; Flow reactor; Stage #2: With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at 0℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 65 % | With nickel dichloride In tetrahydrofuran at 20℃; | Experimental Procedure for Compounds 2a-k, 4-13, and 16 General procedure: To a solution of the appropriate bis(2-oxazoline) (1.0 mmol, 1 equiv.) in THF (0.1 M,10 mL), NiCl2 (10 mol%, 0.1 mmol) and the aldehyde (2.0 mmol, 2 equiv.) were added andthe mixture was stirred at room temperature for 24-48 h.The mixture was concentrated, and the residue was dissolved in ethyl acetate (10 mL)and washed with water (10 mL). The organic phase was dried over Na2SO4 and the solventwas evaporated. Starting from bis(2-oxazoline) and aldehydes, the yields and physical,spectroscopic and analytical data of compounds 2a-k, 4-13, and 16 are as follows.Details of the X-ray structural determination of 2d are reported in SupplementaryMaterials. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 14% | Stage #1: 1-(2-mercaptophenyl)ethan-1-one With lithium diisopropyl amide In tetrahydrofuran; cyclohexane at -15℃; for 1h; Inert atmosphere; Stage #2: 3-Trifluoromethylbenzaldehyde In tetrahydrofuran; cyclohexane at -15 - 20℃; for 2h; Inert atmosphere; | 4.2.3. General procedure 3 - Synthesis of thioflavanones (10-13) General procedure: Lithium diisopropylamide (1.5 M in cyclohexane, 2.0 equiv.) wasadded to a solution of 6 (1.0 equiv.) in anhydrous THF under Ar atmosphereat 15 C and stirred for 1 h at 15 C before addition of a solutionof appropriate benzaldehyde derivative (1.6 equiv.) solubilised inanhydrous THF. After 2 h stirring at 15 C to RT, resulting mixture wasquenched with 1 N HCl and THF and evaporated under reduced pressure.Residue was poured into 1 N HCl aqueous solution, extracted withCH2Cl2 (×3). Combined organic layers were washed with saturatedNaHCO3 solution, dried over anhydrous Na2SO4, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (cyclohexane/EtOAc 95:5) to afford the title thioflavanones10-13. |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Multi-step reaction with 2 steps 1: methanol / 20 °C 2: potassium <i>tert</i>-butylate; methanol / toluene / 6 h / 20 °C / Schlenk technique; Inert atmosphere; Irradiation |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 84% | Stage #1: 1-(4,5-difluoro-2-hydroxyphenyl)ethanone; 3-Trifluoromethylbenzaldehyde With potassium hydroxide In ethanol at 20℃; for 24h; Stage #2: With acetic acid In water |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 94% | Stage #1: 3-Trifluoromethylbenzaldehyde; 1-(3,5-difluoro-2-hydroxyphenyl)ethan-1-one With potassium hydroxide In ethanol at 20℃; for 24h; Stage #2: With acetic acid In water |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| With hydrogenchloride In ethanol at 65℃; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| Stage #1: 3-Trifluoromethylbenzaldehyde; (trifluoromethyl)trimethylsilane In N,N-dimethyl-formamide for 0.166667h; Inert atmosphere; Stage #2: With tetrabutyl ammonium fluoride In N,N-dimethyl-formamide at 20℃; for 6.16667h; Inert atmosphere; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| In ethanol for 6h; Reflux; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 91% | With (5aR,10bS)-2-mesityl-5a,10b-dihydro-4H,6H-indeno[2,1-b][1,2,4]triazolo[4,3-d][1,4]oxazin-2-ium salt; 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone; sodium acetate In tetrahydrofuran at 20℃; for 12h; Sealed tube; Inert atmosphere; enantioselective reaction; |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 0.2 g | With methanol; decaborane at 20℃; for 0.5h; | Reference Example G-8:(R)-3-Amino-2-oxo-1-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroquinoline-7-carbonitrile. Decaborane (0.019 g) was added to a mixture of 3-amino-4-bromobenzonitrile (0.100 g), 3-(trifluoromethyl)benzaldehyde (0.088 g), and methanol (2.0 mL) at room temperature, followed by stirring at the same temperature for 30 minutes. APS was added to the reaction mixture, followed by stirring at room temperature for 10 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate = 98/2 to 85/15) to give 4-bromo-3-((3-(trifluoromethyl)benzyl)amino)benzonitrile (0.200 g). |
| Yield | Reaction Conditions | Operation in experiment |
|---|---|---|
| 0.212 g | Stage #1: 3-Trifluoromethylbenzaldehyde; tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20 - 50℃; for 2h; Stage #2: N-carbamoylglycine With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 20 - 50℃; for 1h; Stage #3: With hydrogenchloride In ethyl acetate at 20℃; for 1h; | D-8 N-(3-aminobicyclo[1.1.1]pentan-1-yl)-N-(3-(trifluoromethyl)benzyl)-2-ureidoacetamide hydrochloride To a mixture of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (0.300 g), 3-(trifluoromethyl)benzaldehyde (0.316 g), and THF (6 mL) was added sodium triacetoxyborohydride (0.481 g) at room temperature. The reaction mixture was stirred at the same temperature overnight and then at 50 °C for 2 hours, then allowed to cool to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.To a mixture of the residue, N-carbamoylglycine (0.268 g), HOBt hydrate (0.348 g), and MeCN (6 mL) was added EDC-HCl (0.435 g) at room temperature. The reaction mixture was stirred at the same temperature for 30 minutes, then at 50 °C for 30 minutes, and then allowed to cool to room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/methanol = 100/0 - 46/54) to obtain the amide.To a mixture of the obtained amide and ethyl acetate (2 mL), hydrogen chloride (4 mol/L in ethyl acetate) (1.28 mL) was added at room temperature. The reaction mixture was stirred at the same temperature for 1 hour, and then concentrated under reduced pressure to obtain the title compound (0.212 g). |

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