348-37-8|Ethyl 6-fluoro-1H-indole-2-carboxylate| Ambeed

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Quality Control of [ 348-37-8 ] Purity: 97% SDS Specification

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Product Details of [ 348-37-8 ]

CAS No. :	348-37-8
Formula :	C₁₁H₁₀FNO₂
M.W :	207.20
SMILES Code :	O=C(C(N1)=CC2=C1C=C(F)C=C2)OCC
MDL No. :	MFCD03095203
InChI Key :	KOLXHQLPMICACW-UHFFFAOYSA-N
Pubchem ID :	15370496

Safety of [ 348-37-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H317
Precautionary Statements:	P280

Computational Chemistry of [ 348-37-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	9
Fraction Csp3	0.18
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	54.34
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	42.09 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.3
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	2.7
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.9
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.	2.08
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	3.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.62

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.07
Solubility	0.176 mg/ml ; 0.000848 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.	-3.24
Solubility	0.12 mg/ml ; 0.00058 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	-4.05
Solubility	0.0185 mg/ml ; 0.0000891 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	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.65 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	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.97

Application In Synthesis of [ 348-37-8 ]

* 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 [ 348-37-8 ]

[ 348-37-8 ] Synthesis Path-Downstream 1~35

1
[ 348-37-8 ]
[ 3093-97-8 ]

Yield	Reaction Conditions	Operation in experiment
89%		General procedure: A mixture of compound 3a (33.5 g, 0.15 mol), 4% NaOH solution (335 mL) and ethanol (335 mL) was heated to reflux for 3 h. Upon cooling to room temperature, the mixture was poured into ice-water, adjusted to pH 5 with glacial acetic acid, and then the precipitate was collected by filtration. 4a was obtained as a white solid (26.4 g, 90%).

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.
[2]Journal of the Chemical Society,1955,p. 1283,1284.
[3]European Journal of Medicinal Chemistry,2019,vol. 173,p. 15 - 31.

2
[ 404-69-3 ]
[ 348-37-8 ]
[ 348-32-3 ]

References: [1]Journal of the Chemical Society,1955,p. 1283,1284.

3
6-fluoro-2-hydroxy-2,3-dihydro-1<i>H</i>-indole-2-carboxylic acid ethyl ester [ No CAS ]
[ 348-37-8 ]

References: [1]Synthetic Communications,1999,vol. 29,p. 447 - 455.

5
potassium-compound of <4-fluoro-2-nitro-phenyl>-pyruvic acid ethyl ester [ No CAS ]
[ 3093-97-8 ]
[ 348-37-8 ]

References: [1]Journal of the Chemical Society,1955,p. 1283,1284.

6
[ 348-37-8 ]
[ 102-47-6 ]
Ethyl N-(3,4-dichlorobenzyl)-6-fluoroindole-2-carboxylate [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 405 - 408.

7
[ 348-37-8 ]
N-(3,4-Dichlorobenzyl)-6-fluoroindole-2-carboxylic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 405 - 408.

8
(5-fluoro-2-methyl-phenyl)-carbamic acid <i>tert</i>-butyl ester [ No CAS ]
[ 348-37-8 ]

References: [1]Synthetic Communications,1999,vol. 29,p. 447 - 455.

9
[ 348-37-8 ]
[ 399-51-9 ]

References: [1]Journal of the Chemical Society,1955,p. 1283,1284.
[2]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.
[3]Bioorganic and Medicinal Chemistry Letters,2016,vol. 26,p. 4403 - 4407.

10
[ 348-37-8 ]
[ 74-88-4 ]
[ 550349-31-0 ]
[ 550349-32-1 ]

Yield	Reaction Conditions	Operation in experiment
		A suspension of 7.9 g(197 mmol) of 60% sodium hydride and of 36.1 g (176 mmol) of m<strong>[348-37-8]ethyl 6-fluoro-1H-indole-2-carboxylate</strong> (obtained in stage 1.2.) in 250 ml of N,N-dimethylformamide is stirred for 2 h at ambient temperature. 12 ml (193 mmol) of iodomethane in 50 ml of N,N-dimethylformamide are subsequently added. The mixture is stirred at ambient temperature for 12 h. The above reaction medium is poured into a mixture of water and ice. Dichloromethane is added and the aqueous phase is neutralized with hydrochloric acid (1M). The organic phase is separated by settling, washed with water, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel with a mixture of solvents (cyclohexane/dichlormethane: 50/50; then dichloromethane/ethyl acetate: 100/0 to 70/30). 37.2 g (170 mmol) of a white compound formed of methyl 6-fluoro-1-methyl-1H-indole-2-carboxylate are isolated, comprising 10 to 20% of ethyl 6-fluoro-1-methyl-1H-indole-2-carboxylate.

References: [1]Patent: US2005/96321,2005,A1 .Location in patent: Page/Page column 5.

11
potassium 2-(4-fluoro-2-nitrophenyl)-1-methoxy-carbonylethenolate [ No CAS ]
potassium 2-(4-fluoro-2-nitrophenyl)-1-ethoxycarbonylethenolate [ No CAS ]
[ 348-37-8 ]
[ 136818-43-4 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; iron; In ethanol; water; at 0℃; for 5h;Heating / reflux;	1.2. Methyl 6-fluoro-1H-indole-2-carboxylate A mixture of 35 g of potassium salt obtained in stage 1.1. in 500 ml of ethanol is cooled to approximately 0 C. 80 ml of concentrated hydrochloric acid are added in small portions. 35 g (627 mmol) of iron powder are also added portionwise. The mixture is heated at reflux for 5 h and then cooled and filtered. The solid obtained is rinsed with dichloromethane. The filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel with a mixture of solvents (dichloromethane/ethyl acetate: 100/0 to 70/30). The chromatography fractions are partially concentrated. The solid which precipitates is collected by filtration, washed with cyclohexane and dried under reduced pressure. 18 g of a white solid formed of methyl 6-fluoro-1H-indole-2-carboxylate are obtained, comprising 10 to 20% of ethyl 6-fluoro-1H-indole-2-carboxylate.

References: [1]Patent: US2005/96321,2005,A1 .Location in patent: Page/Page column 5.

12
[ 348-37-8 ]
[ 24424-99-5 ]
[ 870536-83-7 ]

Yield	Reaction Conditions	Operation in experiment
95%	With dmap; triethylamine; In dichloromethane; at 20℃;	(3-3) Ethyl 6-fluoro-1H-indole-2-carboxylate (1.70 g, 8.19 mmol) obtained in Reference Example (3-2) was dissolved in methylene chloride (82 ml) and triethylamine (4.55 ml, 32.8 mmol), di-tert-butyl dicarboxylate (3.57 g, 16.4 mmol) and N,N-dimethylaminopyridine (100 mg, 0.819 mmol) were added thereto at room temperature, followed by stirring overnight. Water and saturated aqueous NaCl solution were added to the reaction mixture and, after the mixture was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=9/1) to obtain 1-tert-butyl 2-ethyl 6-fluoro-1H-indole-1,2-dicarboxylate as a yellow oil (1.94 g, yield: 95%). 1H-NMR (400MHz, CDCl3) : delta 7.77 (1H, dd, J = 10.2, 2.4 Hz) , 7.51(1H, dd, J = 8.6, 5.8 Hz), 7.05 (1H, s), 7.00 (1H, app. td, J = 9.0, 2.4 Hz), 4.36 (2H, q, J = 7.0 Hz), 1.63 (9H, s), 1.30 (3H, t, J = 7.0 Hz).; (9-7) Triethylamine (4.55 ml, 32.8 mmol), di-tert-butyl dicarbonate (3.57 g, 16.4 mmol) and N,N-dimethylaminopyridine (100 mg, 0.819 mmol) were added to a solution of <strong>[348-37-8]ethyl 6-fluoro-1H-indole-2-carboxylate</strong> (1.70 g, 8.19 mmol) obtained in Reference Example (9-6) in methylene chloride (82 ml) at room temperature, and the mixture was stirred overnight. Water and saturated aqueous NaCl solution were added to the reaction mixture and, after the mixture was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate=9/1) to obtain 1-tert-butyl 2-ethyl 6-fluoro-1H-indole-1,2-dicarboxylate as a yellow oil (1.94 g, yield: 95%). 1H-NMR (400MHz, CDCl3): delta 7.77 (1H, dd, J = 10.2, 2.4 Hz) , 7.51 (1H, dd, J = 8.6, 5.8 Hz), 7.05 (1H, s), 7.00 (1H, app td, J = 9.0, 2.4 Hz), 4.36 (2H, q, J = 7.0 Hz), 1.63 (9H, s), 1.30 (3H, t, J = 7.0 Hz).

References: [1]Patent: EP1764075,2007,A1 .Location in patent: Page/Page column 82; 91.
[2]Patent: WO2006/109633,2006,A1 .Location in patent: Page/Page column 139.

13
[ 346-43-0 ]
[ 348-37-8 ]

Yield	Reaction Conditions	Operation in experiment
81%	With iron; In ethanol; acetic acid; for 3.5h;Heating / reflux;	(3-2) Ethyl 3-(4-fluoro-2-nitrophenyl)-2-oxopropanoate (5.51 g, 21.6 mmol) obtained in Reference Example (3-1) was dissolved in a mixed solvent of ethanol-acetic acid (1:1, 84 ml), and iron powder (10.9 g, 144 mmol) was added thereto, followed by heating under reflux for 3.5 hours. After the reaction mixture was diluted with tetrahydrofuran, the insolubles were filtered through Celite, and the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (elution solvent: methylene chloride/acetone=15/1) to obtain ethyl 6-fluoro-1H-indole-2-carboxylate (3.62 g, yield: 81%). 1H-NMR (400MHz, CDCl3): delta 8.89 (1H, br. s), 7.61 (1H, dd, J = 8.8, 5.5 Hz), 7.20 (1H, m), 7.09 (1H, dd, J = 9.4, 2.0 Hz), 6.94 (1H, ddd, J = 9.4, 8.8, 2.0 Hz), 4.41 (2H, q, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz).; (9-6) Ethyl 3-(4-fluoro-2-nitrophenyl)-2-oxopropanoate (5.51 g, 21.6 mmol) obtained in Reference Example (9-5) was dissolved in a mixed solvent of ethanol-acetic acid (1:1, 84 ml), and iron powder (10.9 g, 144 mmol) was added thereto, followed by heating under reflux of the mixture for 3.5 hours. The temperature of the reaction mixture was returned to room temperature, and the mixture was diluted with tetrahydrofuran. The insolubles were removed by filtration using Celite, and the filtrate was concentrated under reduced pressure. The thus obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride/acetone=15/1) to obtain ethyl 6-fluoro-1H-indole-2-carboxylate as yellow crystals (3.62 g, yield: 81%). 1H-NMR (400MHz, CDCl3) : delta 8.89 (1H, br. s), 7.61 (1H, dd, J = 8.8, 5.5 Hz), 7.20 (1H, m), 7.09 (1H, dd, J = 9.4, 2.0 Hz), 6.94 (1H, ddd, J = 9.4, 8.8, 2.0 Hz), 4.41 (2H, q, J = 7.0 Hz), 1.42 (3H, t, J = 7.0 Hz).

References: [1]Patent: EP1764075,2007,A1 .Location in patent: Page/Page column 81-82; 91.
[2]Patent: WO2006/109633,2006,A1 .Location in patent: Page/Page column 138-139.

14
[ 348-37-8 ]
[ 136818-43-4 ]
[ 74-88-4 ]
[ 550349-31-0 ]
[ 550349-32-1 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 1 Compound 1 7-fluoro-N,N,5-trimethyl-4-oxo-3-(pyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide 1.1. Methyl 6-fluoro-1-methyl-1H-indole-2-carboxylate A 60% suspension of 7.9 g (197 mmol) of sodium hydride (washed with petroleum ether beforehand) and 36.1 g (176 mmol) of m<strong>[348-37-8]ethyl 6-fluoro-1H-indole-2-carboxylate</strong> (containing 10 to 20% of <strong>[348-37-8]ethyl 6-fluoro-1H-indole-2-carboxylate</strong>) in 250 ml of N,N-dimethylformamide is stirred at ambient temperature for 2 h. Then 12 ml (193 mmol) of iodomethane in 50 ml of N,N-dimethylformamide are added and the mixture is stirred at ambient temperature for 12 h. The contents are poured into an ice/water mixture. Dichloromethane is added and the aqueous phase is neutralized with hydrochloric acid (1N). The organic phase is separated off, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column in a mixture of solvents (cyclohexane/dichloromethane: 50/50 to 0/100 then dichloromethane/ethyl acetate: 100/0 to 70/30). 32.7 g (170 mmol) are isolated of a white compound of methyl 6-fluoro-1-methyl-1H-indole-2-carboxylate containing 10 to 20% of ethyl 6-fluoro-1-methyl-1H-indole-2-carboxylate.

References: [1]Patent: US2005/124615,2005,A1 .Location in patent: Page/Page column 4.

15
[ 348-37-8 ]
[ 108-23-6 ]
[ 912959-93-4 ]

References: [1]Patent: WO2006/109633,2006,A1 .Location in patent: Page/Page column 151-152.

16
[ 911301-34-3 ]
[ 348-37-8 ]

Yield	Reaction Conditions	Operation in experiment
	In hexane; at 200℃; under 9000.9 - 9750.98 Torr; for 0.0833333h;Microwave irradiation; Inert atmosphere;	General procedure: Sodium (4.0 equiv) was dissolved in absolute ethanol (0.5 mL/mmol) and the solution was cooled to -10 C in an ice/acetone bath. A corresponding benzaldehyde (1.0 equiv) was dissolved in a commercial 25% solution of ethyl azidoacetate in ethanol (2.1 g per mmol of starting benzaldehyde, 4.0 equiv) and this solution was added dropwise to the sodium ethoxide solution during 30 min while the bath temperature was kept at -10 C. The reaction mixtures typically turned into bright yellow suspensions. The stirring was continued until TLC (developing with 15% EtOAc in cyclohexane) indicated completion or the reaction (1.5-2.5 h). If the reaction required more than 1.5 h, the temperature was allowed to rise to 0 C. In one case (5r), the reaction had to be run overnight. The mixtures were partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate and the organic layers were pooled, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide crude azidoacrylic esters (5) as yellow to orange oils or liquids in a 46-100% yield. These products were suspended in n-hexane (6-9 mL/mmol of crude azidoacrylic ester) and subjected to microwave heating at 200 C for 5 min (P = 100-140 W, p = 12-13 bar). The resulting residues were taken into ethyl acetate and evaporated with silica gel. The corresponding indolic esters 3 (yields 19-93%) were purified by chromatography. In one case, a mixture of isomers was obtained. 2-Azido-3-(3-methoxyphenyl)-acrylic acid ethyl ester gave 5-methoxy-1H-indole-2-carboxylic acid ethyl ester (3j) and 7-methoxy-1H-indole-2-carboxylic acid ethyl ester (3q) in a 1:1 ratio (each in a 47% yield).

References: [1]RSC Advances,2014,vol. 4,p. 20048 - 20052.
[2]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1550 - 1561.

17
[ 108-99-6 ]
[ 348-37-8 ]
[ 1278517-91-1 ]

Yield	Reaction Conditions	Operation in experiment
60%		General procedure: An oven-dried flask was purged with argon while hot, then allowed to cool down to room temperature under argon and charged with dry THF (2 mL/mmol of starting indole 3/6) and diisopropylamine (4.0 equiv). The solution was cooled to -78 C in a dry ice/isopropanol bath and n-butyl lithium, 1.6 M solution in hexanes (4.0 equiv), was added to give a bright yellow solution. The mixture was stirred for 30 min below -60 C whereupon a solution of picoline or another appropriate reagent with an ionizable methyl(ene) group (4.0 equiv) in THF (2 mL/mmol of starting indole 3 or 6) was added to give a yellow to red colored mixture. During a further 30 min, the bath temperature was allowed to rise to approx. 0 C during which time the reaction mixture became a yellow to red suspension. The temperature was then kept at 0 C (using an ice/water bath) for an additional 30 min. At this point, a solution of the indole-2-carbonyl compound 3/6 (1.0 equiv) in THF (4 mL/mmol) was added dropwise over the flask wall. The reaction mixture darkened (dark purple to dark brown color in most cases) and was then allowed to attain room temperature overnight. At 18 h (unless otherwise stated) after the addition of the indole component, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL/mmol of starting compound 3/6) and stirred for several minutes. Upon partition between ethyl acetate and water, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were dried over MgSO4. The title products were purified by chromatography (the products typically eluted with 70-80% of ethyl acetate). The products were then precipitated by concentration of the pooled column fractions combined with the addition of cyclohexane. The precipitates formed were filtered off, washed twice with cyclohexane and dried at 40 C in vacuo to yield analytically pure samples. The following compounds were prepared in this way:

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1550 - 1561.

18
[ 459-57-4 ]
[ 348-37-8 ]

References: [1]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1550 - 1561.

19
[ 348-37-8 ]
1-(6-fluoro-1-methyl-1H-indol-3-yl)ethanone [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.

20
[ 348-37-8 ]
[ 949035-26-1 ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.

21
[ 348-37-8 ]
2-amino-6-(6-fluoro-1H-indol-3-yl)-4-(3,4,5-trimethoxyphenyl)nicotinonitrile [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.

22
[ 348-37-8 ]
2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-6-(6-fluoro-1H-indol-3-yl)nicotinonitrile [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.

23
[ 348-37-8 ]
2-amino-6-(6-fluoro-1H-indol-3-yl)-4-(2,3,4-trimethoxyphenyl)nicotinonitrile [ No CAS ]

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.

24
(Z)-ethyl 2-azido-3-(4-fluorophenyl)acrylate [ No CAS ]
[ 348-37-8 ]

Yield	Reaction Conditions	Operation in experiment
52%	In 5,5-dimethyl-1,3-cyclohexadiene;Reflux;	A solution of compound 8c (35.3 g, 0.15 mol) in xylene (350 mL) was heated to reflux for 3-5 h and then the solvent was removed under reduced pressure to form a light yellow solid. The crude product was purified by recrystallization from toluene and 3c was obtained as a yellow solid (16.1 g, 52%). m.p. 147-148 C. ESI-MS m/z: 206.1 [M - H]-. 1H NMR (300 MHz, DMSO-d6) delta: 1.33 (t, J = 6.9 Hz, 3H), 4.37-4.30 (q, J1 = 6.9 Hz, J2 = 14.1 Hz, 2H), 6.99-6.92 (m, 1H), 7.17-7.14 (m, 2H), 7.71-7.66 (m, 1H), 11.95 (s, 1H).

References: [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157.

25
[ 348-37-8 ]
[ 1334123-75-9 ]

Yield	Reaction Conditions	Operation in experiment
21%	With magnesium oxide; Selectfluor; In acetonitrile; at 20℃;	Intermediate 673,6-Difluoro-lH-indole-2-carboxylic acid[0355][Chemical Formula 98]Ethyl 6-Fluoroindole-2-carboxylate (0.48 mmol, 0.10 g) was dissolved in acetonitrile (5 mL). To the solution was added magnesium oxide (0.96 mmol, 0.039 g) at room temperature. To the mixture was added Selectfluor (0.58 mmol, 0.21 g) gradually at room temperature, and stirred overnight at room temperature. The mixture was dried under reduced pressure, and purified with silica gel column chromatography (amine silica gel) (hexane/ethyl acetate = 100/0- >5/l) to give a 22.5 mg of white solid (yield 21%). The solid was dissolved in ethanol (1 mL). To the solution was added aqueous lithium hydroxide solution (2 M, 0.3 mmol, 0.15 mL) at room temperature, and stirred overnight at room temperature. The mixture was dried under reduced pressure, and the residuum was dissolved in water. To the solution was added aqueous hydrochloric acid solution (1 M), and the precipitated solid was collected by filtration to give the title compound (14.7 mg, yield 75%). MS (ESI+) 198 (M++1, 14%) [0356]

References: [1]Patent: WO2011/111875,2011,A1 .Location in patent: Page/Page column 91-92.

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References: [1]Patent: WO2011/111875,2011,A1 .

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References: [1]European Journal of Organic Chemistry,2014,vol. 2014,p. 511 - 514.

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