666746-27-6|N-Boc-4-iodo-2-methylaniline| Ambeed

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Quality Control of [ 666746-27-6 ] Purity: 97+% SDS Specification

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Product Details of [ 666746-27-6 ]

CAS No. :	666746-27-6
Formula :	C₁₂H₁₆INO₂
M.W :	333.17
SMILES Code :	CC1=CC(I)=CC=C1NC(OC(C)(C)C)=O
MDL No. :	MFCD08703145
Boiling Point :	No data available
InChI Key :	MWSFDHVVTSPHOF-UHFFFAOYSA-N
Pubchem ID :	23074904

Safety of [ 666746-27-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P264-P270-P301+P312-P330

Computational Chemistry of [ 666746-27-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.42
Num. rotatable bonds	4
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	74.37
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	38.33 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.24
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	3.13
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.76
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	3.46
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.15
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.35

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.89
Solubility	0.0428 mg/ml ; 0.000129 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.6
Solubility	0.0829 mg/ml ; 0.000249 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-4.66
Solubility	0.00734 mg/ml ; 0.000022 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	Yes
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	Yes
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.11 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	2.4

Application In Synthesis of [ 666746-27-6 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Downstream synthetic route of [ 666746-27-6 ]

[ 666746-27-6 ] Synthesis Path-Downstream 1~35

1
[ 666746-27-6 ]
[ 78-94-4 ]
[ 666746-53-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;bis-triphenylphosphine-palladium(II) chloride; In 1-methyl-pyrrolidin-2-one; at 130℃; for 3h;	Step 1; Preparation of 4-(3-oxo-1-butenyl)-2-methylcarbanilate-t-butyl. To 20 ml of a N-methylpyrrolidone solution containing 3.0 g of t-butyl 4-iodo-2-methylcarbanilate and 1.26 g of methyl vinyl ketone were added 0.126 g of dichlorobistriphenylphosphine palladium and 1.51 g of sodium hydrogen carbonate, and the mixture was stirred in an autoclave at 130C for 90 minutes. Then, to this reaction mixture were additionally added 1.26 g of methyl vinyl ketone, 0.126 g of palladium dichlorobistriphenylphosphine and 1.51 g of sodium hydrogen carbonate, and stirring was continued at the same temperature for further 90 minutes. After completion of the reaction, the reaction mixture was poured into 100 ml of water and extracted with 100 ml of diethyl ether, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:9 to 2:3) to obtain 2.0 g of the objective material as brown solid. Melting point 116.5 to 119.0C1H NMR (CDCl3, Me4Si, 300MHz) δ 7.99 (d, J=8.4Hz, 1 H), 7.44 (d, J=16.5Hz, 1 H), 7.39 (d, J=8.4Hz, 1 H), 7.34 (s, 1 H), 6.63 (d, J=16.5Hz, 1 H), 6.41 (bs, 1 H), 2.36 (s, 3H), 2.27 (s, 3H), 1.54 (s, 9H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 511.

2
[ 24424-99-5 ]
[ 13194-68-8 ]
[ 666746-27-6 ]

Yield	Reaction Conditions	Operation in experiment
99%	In toluene; at 80℃; for 16h;	To a mixture of 4-iodo-2-methyl-phenylamine (1.29 g, 5.5 mmol) in toluene (40 mL) was added B0C2O (1.81 g, 8.3 mmol). The resulting mixture was then heated at 80C for 16 h. The solvent was removed in vacuum and the residue was purified by silica gel column chromatography (PE to PE/EA = 20/1) to give (4-iodo-2-methyl-phenyl)-carbamic acid tert- butyl ester (1.8 g, 99% yield) as white solid. NMR (300 MHz, CDCh): d = 7.64 (d, J= 9.7 Hz, 1H), 7.55 - 7.41 (m, 2H), 6.24 (brs, 1H), 2.21 (s, 3H), 1.53 (s, 9H). MS: m/z 334.0 (M+H+ ).
	In toluene; for 2h;Heating / reflux;	Step 1; Preparation of t-butyl 4-iodo-2-methylcarbanilate. To 30 ml of a toluene solution containing 10.0 g of 4-iodo-2-methylaniline was added 14.0 g of di-t-butyl dicarbonate, and the mixture was stirred under reflux for 2 hours. After completion of the reaction, 30 ml of water was added to the mixture and the resulting mixture was refluxed for 15 minutes, cooled to room temperature by allowing to stand, and extracted by 100 ml of diethyl ether. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residual solid was washed with hexane to obtain 11.5 g of the objective material as white crystals. Melting point 101.0 to 103.0C1H NMR (CDCl3, Me4Si, 300MHz) δ 7.63 (d, J=8.4Hz, 1 H), 7.45-7.5 (m, 2H), 6.22 (bs, 1 H), 2.19 (s, 3H), 1.52 (s, 9H). Step 2; Preparation of t-butyl 2-methyl-4-(1-trifluoromethylethenyl)carbanilate.

References: [1]Patent: WO2021/50547,2021,A1 .Location in patent: Paragraph 0103-0105; 0142-0144; 0151-0153.
[2]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 499.

3
[ 666746-27-6 ]
[ 666746-34-5 ]

Yield	Reaction Conditions	Operation in experiment
	With trifluoroacetic acid; at 0 - 20℃; for 0.166667h;	Step 1; Preparation of 2-methyl-4-(1-trifluoromethylethenyl)aniline. To 1.5 g of t-butyl 2-methyl-4-(1-trifluoromethylethenyl)carbanilate synthesized in Step 1 to Step 2 of Synthetic example 1 was added dropwise 5 ml of trifluoroacetic acid under ice-cooling and stirring. After stirring was continued at room temperature for 10 minutes, the solvent was removed under reduced pressure to obtain 1.3 g of the crude objective material as brownish oily substance. This product was used in the next step as such without purification.

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 504.

4
[ 666746-27-6 ]
[ 25015-63-8 ]
[ 508223-54-9 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 80℃; for 4h;	Synthesis Example 11 (intermediate); Tert-butyl [2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboran-2-yl)-phenyl]-carbamateA solution of tert-butyl (4-iodo-2-methylpheny)carbamate (1.39 g), pinacolborane (0.8 g), triethyl- amine (1.27 g), l,l'-bis-(diphenylphosphino)ferrocenepalladium (II) chloride (0.09 g) in dioxane (20 ml) was heated and stirred in an argon atmosphere at 80ºC for 4 hours. After cooling, water was added and stirred followed by extraction with ethyl acetate and washing with a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography to obtain tert- butyl [2-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboran-2-yl)-phenyl]-carbamate (0.95 g).1H-NMR (CDC13) δ: 1.33 (13H, s), 1.55 (9H, s), 2.24 (3H, s), 6.38 (1H, br s), 7.58 (1H, s), 7.64 (1H, d), 7.94 (1H, d).

References: [1]Patent: WO2006/133823,2006,A1 .Location in patent: Page/Page column 68.

5
[ 666746-27-6 ]
[ 383-63-1 ]
[ 666746-57-2 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1; Preparation of t-butyl 2-methyl-4-trifluoroacetylcarbanilate. Under nitrogen atmosphere, to 300 ml of a diethyl ether solution containing 10.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 45.0 ml of n-butyllithium (1.5M) at -10C and under stirring, and after completion of the dropwise addition, the mixture was stirred at the same temperature for 15 minutes. Then, this reaction mixture was cooled to -78C, 9.5 g of trifluoroethyl acetate was added dropwise to the mixture, and after completion of the dropwise addition, stirring was continued at the same temperature for further 1 hour. Then, the mixture was warmed up to -10C, 100 ml of 2N hydrochloric acid was added to the mixture and the resulting mixture was vigorously stirred, the organic layer was collected by separation, dehydrated by saturated brine and then dried over anhydrous magnesium sulfate in this order, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with diethyl ether-hexane (1:4) to obtain 3.2 g of the objective material as white crystals. Melting point 85.0 to 87.0C1H NMR (CDCl3, Me4Si, 300MHz) δ 8.25 (d, J=8.8Hz, 1 H), 7.8-8.0 (m, 2H), 6.62 (bs, 1 H), 2.32 (s, 3H), 1.55 (s, 9H).
		Step 1; Preparation of t-butyl 2-methyl-4-trifluoroacetylcarbanilate; Under nitrogen atmosphere, to 300 ml of a diethyl ether solution containing 10.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 45.0 ml of n-butyl lithium (1.5M hexane solution) at -10C under stirring, and after completion of the dropwise addition, the mixture was stirred at the same temperature for 30 minutes. Then, the reaction mixture was cooled to -78C, 9.5 g of trifluoroethyl acetate was added dropwise to the mixture, and after completion of the dropwise addition, stirring was continued at the same temperature for further 1 hour. After completion of the reaction, the temperature of the reaction mixture was raised to -10C, 100 ml of 2N hydrochloric acid was added and the mixture wsa vigorously stirred, then, the organic layer was collected by separation, dehydrated and dried by saturated saline solution and then anhydrous magnesium sulfate in this order, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with diethyl ether-hexane (1:4) to obtain 3.2 g of the objective product as white crystals. Melting point: 85.0 to 87.0C 1H NMR (CDCl3, Me4Si, 300MHz) δ 8.25 (d, J=8.8Hz, 1H), 7.8-8.0 (m, 2H), 6.62 (bs, 1H), 2.32 (s, 3H), 1.55 (s, 9H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 513.
[2]Patent: EP1671941,2006,A1 .Location in patent: Page/Page column 220.

6
[ 666746-27-6 ]
[ 355-17-9 ]
[ 666746-43-6 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1; Preparation of t-butyl 4-(2,2,3,3,4,4,4-heptafluoro-1-hydroxy-1-methylbutyl)-2-methylcarbanilate. Under nitrogen atmosphere, to 100 ml of a diethyl ether solution containing 4.2 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 17 ml of n-butyl lithium (1.57M hexane solution) at -20C under stirring, and after completion of the dropwise addition, the mixture was raised to 0C and stirred for further 15 minutes. Then, this reaction mixture was cooled to -78C, 2.0 g of heptafluoropropyl methyl ketone was added to the mixture, and the temperature of the mixture was gradually raised to at room temperature, and stirring was continued at room temperature for further 2 hours. After completion of the reaction, to the reaction mixture was added 100 ml of a saturated aqueous ammonium chloride solution, the organic layer was collected by separation, dehydrated by saturated brine and then dried over anhydrous magnesium sulfate in this order, and the solvent was removed under reduced pressure. The residual solid was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:9) to obtain 1.3 g of the objective material as pale yellowish oily substance. nD20.3C 1.45571H NMR (CDCl3, Me4Si, 300MHz) δ 7.88 (d, J=9.3Hz, 1 H), 7.34 (m, 2H), 6.31 (bs, 1 H), 2.59 (bs, 1 H), 2.27 (s, 3H), 1.78 (s, 3H), 1.53 (s, 9H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 507.

7
[ 666746-27-6 ]
[ 2868-37-3 ]
[ 666746-40-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1; Preparation of t-butyl 4-cyclopropylcarbonyl-2-methylcarbanilate. Under nitrogen atmosphere, to 48 ml of a t-butyl methyl ether solution containing 3.6 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 15.1 ml of n-butyl lithium (1.6M) at -30C under stirring, and after completion of the dropwise addition, the mixture was raised to 0C and stirred for further 10 minutes. Then, this reaction mixture was cooled to -78C, 2.7 g of methylcyclopropanecarboxylate was added to the mixture, and stirring was continued at the same temperature for 4 hours, and then, at 0C for 2 hours. After completion of the reaction, 100 ml of a saturated aqueous ammonium chloride solution was added to the reaction mixture, the resulting mixture was extracted with diethyl ether (100 mlx2), the organic layer was dehydrated by saturated brine and then dried over anhydrous magnesium sulfate in this order, and the solvent was removed under reduced pressure. The residual solid was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:5) to obtain 0.93 g of the objective material as white crystals.1H NMR (CDCl3, Me4Si, 300MHz) δ 8.10 (d, J=8.7Hz, 1 H), 7.89 (dd, J=8.7, 2.1 Hz, 1H), 7.82 (d, J=1.5Hz, 1 H), 6.50 (s, 1 H), 2.6-2.7 (m, 1 H), 2.30 (s, 3H), 1.54 (s, 9H), 1.15-1.25 (m, 2H), 0.9-1.05 (m, 2H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 506.

8
[ 666746-27-6 ]
[ 866206-04-4 ]
[ 666746-55-0 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3; Preparation of t-butyl 4-[3-(4-chlorophenyl)-3-oxo-1-trifluoromethyl-1-propenyl]-2-methylcarbanilate. Under nitrogen atmosphere, to 100 ml of a diethyl ether solution containing 3.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 13.5 ml of n-butyl lithium (1.5M hexane solution) at -10C and under stirring, and after completion of the dropwise addition, the mixture was stirred at the same temperature for 20 minutes. Then, this reaction mixture was cooled to -78C, 4.6 g of 1-(4-chlorophenyl)-4-trifluoro-2-triphenylphosphoraniliden-1,3-butanedione was added to the mixture, warmed up to 0C over 3 hours, added dropwise 50 ml of 2N hydrochloric acid at 0C to the mixture, and further stirring was continued vigorously at room temperature for 3 hours. After completion of the reaction, insoluble materials were separated by filtration, the organic layer of the filtrate was collected by separation, washed with 50 ml of water and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:4) to obtain 1.3 g of the objective material as pale yellowish crystals. Melting point 72.0 to 74.0C1H NMR (CDCl3, Me4Si, 300MHz) δ 7.86 (d, J=8.0Hz, 1 H), 7.74 (d, J=8.5Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 7.0-7.2 (m, 3H), 6.26 (bs, 1 H), 2.15 (s, 3H), 1.49 (s, 9H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 512.

9
[ 666746-27-6 ]
[ 99-91-2 ]
[ 666746-46-9 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1; Preparation of tertiary butyl 4-[1-(4-chlorophenyl)-1-hydroxyethyl]-2-methylcarbanilate. Under nitrogen atmosphere, 40 ml of a t-butyl methyl ether solution containing 3.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 12 ml of n-butyl lithium (1.57M hexane solution) at -50C under stirring, and after completion of the dropwise addition, the mixture was warmed to 0C, and the mixture was stirred for further 30 minutes. Then, this reaction mixture was cooled to -78C, 1.39 g of 4-chloroacetophenone was added to the mixture, and the resulting mixture was gradually warmed up to 0C, and further stirring was continued at the same temperature for 1 hour. After completion of the reaction, 100 ml of a saturated aqueous ammonium chloride solution was added to the reaction mixture, the organic layer was collected by separation, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with ethyl acetate-hexane (1:9 to 2:3) to obtain 1.7 g of the objective material as yellowish oily substance.1H NMR (CDCl3, Me4Si, 300MHz) δ 7.75 (d, J=8.3Hz, 1 H), 7.1-7.4 (m, 6H), 6.25 (bs, 1 H), 2.21 (s, 3H), 2.16 (bs, 1 H), 1.89 (s, 3H), 1.51 (s, 9H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 508.

10
[ 666746-27-6 ]
[ 1514-82-5 ]
[ 666746-28-7 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2; Preparation of t-butyl 2-methyl-4-(1-trifluoromethylethenyl)carbanilate. Under nitrogen atmosphere, to 9.5 g of zinc powder (Tetrahedron Letters [Tetrahedron Lett.] 1981, vol. 22, p. 649) dispersed in 80 ml of tetrahydrofuran and activated by silver acetate was added 2 ml of chlorotrimethylsilane, and the mixture was stirred at room temperature for 10 minutes, then, 16.2 g of 2-bromo-3,3,3-trifluoropropene and 22 ml of N,N,N',N'-tetramethylethylenediamine were added to the mixture, and the resulting mixture was continued to stirring at 60C for 12 hours. After removing the precipitated insoluble materials by decantation, 10.0 g of t-butyl 4-iodo-2-methylcarbanilate and 1.0 g of tetrakistriphenylphosphine palladium were added to the reaction mixture, and the resulting mixture was stirred at 60C for further 4 hours. After completion of the reaction, the solvent was removed under reduced pressure, 200 ml of water was added to the residue, and the mixture was extracted with diethyl ether (200 mlx2). After the organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography eluted by diethyl ether and alumina column chromatography eluted by diethyl ether to obtain 8.4 g of the objective material as pale yellowish crystals. Melting point 86.0 to 88.0C 1H NMR (CDCl3, Me4Si, 300MHz) δ 7.89 (d, J=8.8Hz, 1 H), 7.29 (d, J=8.8Hz, 1 H), 7.24 (s, 1 H), 6.32 (bs, 1 H), 5.88 (s, 1 H), 5.70 (s, 1 H), 2.30 (s, 3H), 1.53 (s, 9H).

References: [1]Patent: EP1538138,2005,A1 .Location in patent: Page/Page column 499.

11
[ 248274-16-0 ]
[ 666746-27-6 ]
[ 849370-44-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3; Preparation of t-butyl 4-[1-hydroxy-1-(5-trifluoromethylpyridin-2-yl)ethyl]-2-methylcarbanilate; Under nitrogen atmosphere, to 40 ml of a t-butylmethylether solution containing 3.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 12.5 ml of n-butyl lithium (1.57M hexane solution) at -50C under stirring, and after completion of the dropwise addition, the temperature of the mixture was raised to 0C, and the mixture was stirred for further 30 minutes. Then, the reaction mixture was cooled to -78C, 1.7 g of 2-acetyl-5-trifluoromethylpyridine was added thereto, the temperature of the mixture was gradually raised to 0C, and stirring was continued at the same temperature for further 14 hours. After completion of the reaction, to the reaction mixture was added 100 ml of a saturated aqueous ammonium chloride solution, the organic layer was collected by separation, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:9 to 2:3) to obtain 1.3 g of the objective product as brown solid. Melting point: 132.0 to 134.5C 1H NMR (CDCl3, Me4Si, 300MHz) δ 8.79 (bs, 1H), 7.86 (dd, J=8.3, 2.1Hz, 1H), 7.77 (d, J=8.3Hz, 1H), 7.42 (d, J=8.3Hz, 1H), 7.2-7.3 (m, 2H), 6.24 (bs, 1H). 5.23 (s, 1H), 2.22 (s, 3H), 1.92 (s, 3H), 1.51 (s, 9H).

References: [1]Patent: EP1671941,2006,A1 .Location in patent: Page/Page column 217.

12
[ 107713-64-4 ]
[ 666746-27-6 ]
[ 849370-49-6 ]

Yield	Reaction Conditions	Operation in experiment
		Step 3; Preparation of t-butyl 4-[2,2,2-trifluoro-1-hydroxy-1-(4-trifluoromethoxyphenyl)-ethyl]-2-methylcarbanilate; Under nitrogen atmosphere, to 130 ml of a t-butyl methyl ether solution containing 10.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 41.8 ml of n-butyl lithium (1.58M hexane solution) at -60C under stirring, and after completion of the dropwise addition, the temperature of the mixture was raised to 0C, and the mixture was stirred for further 30 minutes. Then, the reaction mixture was cooled to -78C, 7.75 g of 2,2,2-trifluoro-4'-trifluoromethoxyacetophenone was added to the mixture, the temperature of the mixture was gradually raised to 0C, and stirring of the mixture was continued at the same temperature for further 30 minutes. After completion of the reaction, the reaction mixture was poured into 300 ml of a saturated aqueous ammonium chloride solution, the organic layer was collected by separation, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1: 19 to 1: 4) to obtain 9.0 g of the objective product as colorless oily substance. 1H NMR (CDCl3, Me4Si, 300MHz) δ 7.87 (d, J=8.5Hz, 1H), 7.50 (d, J=8.8Hz, 2H), 7.1-7.35 (m, 4H), 6.31 (bs, 1H), 2.95 (bs, 1H), 2.23 (s, 3H), 1.52 (s, 9H).

References: [1]Patent: EP1671941,2006,A1 .Location in patent: Page/Page column 219.

13
[ 666746-27-6 ]
4-(4-chlorophenyl)-1,1,1-trifluorobut-3-en-2-one [ No CAS ]
[ 849370-54-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1; Preparation of t-butyl 4-[3-(4-chlorophenyl)-1-hydroxy-1-trifluoromethyl-2-propenyl]-2-methylcarbanilate; Under nitrogen atmosphere, to 140 ml of a t-butylmethylether solution containing 10.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 41.8 ml of n-butyl lithium (1.58M hexane solution) at -60C under stirring, and after completion of the dropwise addition, the temperature of the mixture was raised to 0C, and the mixture was stirred for further 30 minutes. Then, the reaction mixture was cooled to -78C, 7.0 g of 4-(4-chlorophenyl)-1,1,1-trifluoro-3-buten-2-one was added, and the temperature of the mixture was gradually raised to 0C, and stirring was continued at the same temperature for further 30 minutes. After completion of the reaction, the reaction mixture was poured into 300 ml of a saturated aqueous ammonium chloride solution, the organic layer was collected by separation, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:9 to 2:3) and alumina column chromatography eluting with chloroform to obtain 4.2 g of the objective product as colorless oily substance. 1H NMR (CDCl3, Me4Si, 300MHz) δ 7.90 (d, J=8.1Hz, 1H), 7.25-7.5 (m, 6H), 6.82 (d, J=16.0Hz, 1H), 6.63 (d, J=16.0Hz, 1H), 6.31 (bs, 1H), 2.73 (s, 1H), 2.27 (s, 3H), 1.52 (s, 9H).

References: [1]Patent: EP1671941,2006,A1 .Location in patent: Page/Page column 222.

14
[ 666746-27-6 ]
[ 849370-45-2 ]
[ 849370-46-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 2; Preparation of t-butyl 4-[1-(4-bromodifluoromethoxyphenyl)-2,2,2-trifluoro-1-hydroxyethyl]-2-methylcarbanilate; Under nitrogen atmosphere to 25 ml of t-butyl methyl ether solution containing 1.91 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 8.0 ml of n-butyl lithium (1.58M hexane solution) at -60C under stirring, and after completion of the dropwise addition, the temperature of the mixture was raised to 0C, and the mixture was stirred for further 30 minutes. Then, the reaction mixture was cooled to -78C, 7.0 g of 4'-bromodifluoromethoxy-2,2,2-trifluoroacetophenone was added, and the temperature of the mixture was gradually raised to 0C, and stirring was further continued at the same temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into 100 ml of a saturated aqueous ammonium chloride solution, the organic layer was collected by separation, and the aqueous layer was extracted with 50 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:19 to 1:4) to obtain 1.0 g of the objective product as brownish oily substance. 1H NMR (CDCl3, Me4Si, 300MHz) δ 7.87 (d, J=8.3Hz, 1H), 7.51 (d, J=8.8Hz, 2H), 7.15-7.35 (m, 4H), 6.32 (bs, 1H), 3.00 (bs, 1H), 2.24 (s, 3H), 1.52 (s, 9H).

References: [1]Patent: EP1671941,2006,A1 .Location in patent: Page/Page column 218.

15
[ 666746-27-6 ]
[ 321-37-9 ]
[ 849370-56-5 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1; Preparation of t-butyl 4-[1-(4-chlorophenyl)-2,2,2-trifluoro-1-hydroxyethyl]-2-methylcarbanilate; Under nitrogen atmosphere, to 40 ml of a t-butylmethylether solution containing 3.0 g of t-butyl 4-iodo-2-methylcarbanilate was added dropwise 12.5 ml of n-butyl lithium (1.58M hexane solution) at -50C under stirring, and after completion of the dropwise addition, the temperature of the mixture was raised to 0C, and the mixture was stirred for further 30 minutes. Then, the reaction mixture was cooled to -78C, 1.88 g of 4'-chloro-2,2,2-trifluoroacetophenone was added to the mixture, the temperature of the mixture was gradually raised to 0C, and stirring was continued at the same temperature for further 30 minutes. After completion of the reaction, to the reaction mixture was added 100 ml of a saturated aqueous ammonium chloride solution, the organic layer was collected by separation, and the aqueous layer was extracted with 100 ml of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane (1:9 to 2:3) to obtain 2.96 g of the objective product as colorless transparent oily substance. 1H NMR (CDCl3, Me4Si, 300MHz) δ 7.86 (d, J=8.7Hz, 1H), 7.40 (d, J=8.4Hz, 2H), 7.15-7.35 (m, 4H), 6.30 (bs, 1H), 2.93 (s, 1H), 2.22 (s, 3H), 1.52 (s, 9H).

References: [1]Patent: EP1671941,2006,A1 .Location in patent: Page/Page column 223.

16
[ 666746-27-6 ]
[ 411235-57-9 ]
[ 1263300-08-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate monohydrate; tricyclohexylphosphine;palladium diacetate; In water; toluene; at 100℃; for 15h;	A mixture of <strong>[666746-27-6]tert-butyl (4-iodo-2-methylphenyl)carbamate</strong> (1.04 g), cyclopropylboronic acid monohydrate (422 mg), palladium acetate (35.1 mg), tricyclohexylphosphine (87.5 mg), tripotassium phosphate monohydrate (2.52 g), toluene (8.7 mL) and water (0.87 mL) was stirred at 100 C. for 15 hours. The reaction mixture was allowed to cool to ambient temperature, diluted with ethyl acetate and filtered through celite (registered trademark). The filtrate was washed with water/saturated saline (1/1, 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (668 mg).1H-NMR (CDCl3) δ ppm:0.55-0.70 (2H, m), 0.80-1.00 (2H, m), 1.51 (9H, s), 1.75-1.90 (1H, m), 2.21 (3H, s), 5.85-6.45 (1H, br), 6.75-7.00 (2H, m), 7.45-7.75 (1H, m).
668 mg	With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃; for 15h;	Reference Example 13 tert-Butyl (4-cyclopropyl-2-methylphenyl)carbamate [0234] A mixture of <strong>[666746-27-6]tert-butyl (4-iodo-2-methylphenyl)carbamate</strong> (1.04 g), cyclopropylboronic acid monohydrate (422 mg), palladium(II) acetate (35.1 mg), tricyclohexylphosphine (87.5 mg), tripotassium phosphate monohydrate (2.52 g), toluene (8.7 mL), and water (0.87 mL) was stirred at 100C for 15 hours. The reaction mixture was left to cool and then diluted with ethyl acetate and filtered through Celite (registered trademark). The filtrate was washed with brine and dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (668 mg). [0235] 1H-NMR (CDCl3) δ ppm: 0.55-0.70 (2H, m), 0.80-1.00 (2H, m), 1.51 (9H, s), 1.75-1.90 (1H, m), 2.21 (3H, s), 5.85-6.45 (1H, br), 6.75-7.00 (2H, m), 7.45-7.75 (1H, m).

References: [1]Patent: US2012/129890,2012,A1 .Location in patent: Page/Page column 29.
[2]Patent: EP2669271,2013,A1 .Location in patent: Paragraph 0233-0235.

17
[ 666746-27-6 ]
[ 1263300-09-9 ]

References: [1]Patent: EP2669271,2013,A1 .

18
[ 666746-27-6 ]
[ 1263300-10-2 ]

References: [1]Patent: EP2669271,2013,A1 .

19
[ 666746-27-6 ]
C₁₄H₁₄N₂O₃ [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6342 - 6353.

20
[ 666746-27-6 ]
5-(dimethylamino)-N-(4′-methoxy-3-methyl-2′-nitrobiphenyl-4-yl)naphthalene-1-sulfonamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6342 - 6353.

21
[ 666746-27-6 ]
5-(dimethylamino)-N-(7-methoxy-3-methyl-9H-carbazol-2-yl)-naphthalene-1-sulfonamide [ No CAS ]
5-(dimethylamino)-N-(7-methoxy-1-methyl-9H-carbazol-2-yl)naphthalene-1-sulfonamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6342 - 6353.

22
[ 666746-27-6 ]
[ 860034-09-9 ]
tert-butyl 4′-methoxy-3-methyl-2′-nitrobiphenyl-4-ylcarbamate [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 6342 - 6353.

23
[ 666746-27-6 ]
[ 916975-26-3 ]

References: [1]Patent: WO2006/133823,2006,A1 .

24
[ 666746-27-6 ]
[ 916975-25-2 ]

References: [1]Patent: WO2006/133823,2006,A1 .

25
[ 666746-27-6 ]
[ 431-03-8 ]
tert-butyl(4-acetyl-2-methylphenyl)carbamate [ No CAS ]

References: [1]European Journal of Organic Chemistry,2019,vol. 2019,p. 2721 - 2724.

26
[ 666746-27-6 ]
(2-methyl-4-pentyl-phenyl)-carbamic acid tert-butyl ester [ No CAS ]