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Quality Control of [ 216393-67-8 ] Purity: 98% SDS Specification

COA

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Product Details of [ 216393-67-8 ]

CAS No. :	216393-67-8
Formula :	C₆H₄ClFIN
M.W :	271.46
SMILES Code :	ClC1=CC(=C(N)C(=C1)I)F
MDL No. :	MFCD01318122
Boiling Point :	No data available
InChI Key :	SSNQXCONXNVTJN-UHFFFAOYSA-N
Pubchem ID :	2773650

Safety of [ 216393-67-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H317-H319
Precautionary Statements:	P280-P305+P351+P338

Calculated chemistry of [ 216393-67-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	48.53
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	26.02 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.98
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	2.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.09
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.	3.41
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	3.17
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.86

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.62
Solubility	0.0655 mg/ml ; 0.000241 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.82
Solubility	0.414 mg/ml ; 0.00153 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.88
Solubility	0.0355 mg/ml ; 0.000131 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	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.	-6.1 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	2.0 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)	2.17

Application In Synthesis of [ 216393-67-8 ]

* 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 [ 216393-67-8 ]

[ 216393-67-8 ] Synthesis Path-Downstream 1~29

1
[ 216393-67-8 ]
[ 536-74-3 ]
5-chloro-7-fluoro-2-phenyl-1H-indole [ No CAS ]

References: [1]Synthesis,2005,p. 1706 - 1712.

2
[ 57946-56-2 ]
[ 216393-67-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With silver(II) sulfate; iodine; In ethanol; at 20℃; for 2h;	Step 1: synthesis of 4-chloro-2-fluoro-6-iodoaniline To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silversulphate (1.7 g, 8.3 mmol), then followed by addition of ?2 (2.1 g, 8.3 mmol) in portions. Afterthe addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL x 2), saturated Na25203 (40 mL x 2) and water (40 mL x 2). The resulting solution was dried over Mg504 and thenevaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
87%	With iodine; silver sulfate; In ethanol; at 20℃; for 1.5h;	4-Chloro-2-fluoroaniline (2.9 g, 20 mmol) was dissolved in ethanol (200 mL). Silver sulphate (6.22 g, 20 mmol) was added and then iodine (5.08 g, 20 mmol) was added in small portions. After the addition was complete the reaction mixture was stirred at ambient temperature for 90min. The reaction mixture was filtered through Celite and evaporated to leave a dark oil which was taken up in DCM (200 mL). and washed with 2M sodium hydroxide (2 x 50 mL), saturated sodium thiosulphate (2x50 mL) and water (2x50 mL). The solution was dried (MgSO4) and evaporated to leave the title compound as a dark oil (4.73g, 87%).1H NMR (400 MHz, DMSO-d6) delta 5.30 (2H, s), 7.25 - 7.29 (IH, m), 7.47 (IH, t)
40%	With iodine; silver sulfate; In ethanol; at 20℃; for 2h;	To a solution of 4-chloro-2-fluoroaniline (2 g, 14 mmol) in EtOH (40 mL) was added Ag2S04 (12.9 g, 42 mmol), followed by the addition of I2 (10.5 g, 42 mmol). The reaction mixture was stirred at RT for 2 h and then filtered through Celite. The filtrate was evaporated to give a dark oil. The residue was dissolved in DCM (70 mL), washed with 2M NaOH (40 mL x 2), Na2S203 (40 mL x 2) and water (40 mL x 2). The resulting solution was dried over MgS04, filtered and concentrated. The residue was purified by column chromatography on silica gel (PE/EA = 5/1) to give 4-chloro-2-fluoro-6-iodoaniline (1.5 g, 40% yield) as a dark oil. 1H NMR (400 MHz, DMSO-i): d 7.47-7.46 (m, 1H), 7.28-7.25 (m, 1H), 5.31 (brs, 2H).

	With iodine; silver sulfate; In ethanol; at 20℃; for 2h;	Step 1: synthesis of 4-chloro-2-fluoro-6-iodoaniline To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL2), saturated Na2S2O3 (40 mL2) and water (40 mL*2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).
	With iodine; silver sulfate; In ethanol; at 20℃; for 2h;	To a solution of 4-chloro-2-fluoroaniline (1.15 g, 7.9 mmol) in 125 mL of ethanol added silver sulphate (1.7 g, 8.3 mmol), then followed by addition of I2 (2.1 g, 8.3 mmol) in portions. After the addition was completed, the mixture was stirred at RT for 2 hours. The mixture was filtered through celite and the filtration was evaporated to give dark oil which was dissolved in 125 mL of DCM. The solution was washed with 2M sodium hydroxide (40 mL×2), saturated Na2S2O3 (40 mL×2) and water (40 mL×2). The resulting solution was dried over MgSO4 and then evaporated to give the crude 4-chloro-2-fluoro-6-iodoaniline as dark oil (2.1 g, yield: 98%).

References: [1]Patent: WO2014/9302,2014,A1 .Location in patent: Page/Page column 119.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5088 - 5109.
[3]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 56.
[4]Patent: WO2019/152883,2019,A1 .Location in patent: Paragraph 00135.
[5]Patent: US2015/158879,2015,A1 .Location in patent: Paragraph 0581; 0582.
[6]Patent: US2016/200741,2016,A1 .Location in patent: Paragraph 0582-0583.

3
[ 216393-67-8 ]
[ 127-17-3 ]
[ 383132-37-4 ]

Yield	Reaction Conditions	Operation in experiment
97%	With 1,4-diaza-bicyclo[2.2.2]octane; palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 3h;	4-Chloro-2-fluoro-6-iodoaniline (2.5 g, 9.2 mmol), pyruvic acid (2.5 g, 27 mmol) and DABCO (3.1 g, 27 mmol) were dissolved in DMF (15 mL). The solution was degassed and palladium acetate (500 mg) was added. The reaction mixture was heated at 100 C for 3 h, cooled to RT and then filtered. The filtrate was diluted with EA (90 mL), washed with 2M HC1 (20 mL x 3), water (40 mL) and brine (40 mL). The organic phase was dried over MgS04, filtered and evaporated to give 5-chloro-7-fluoro-lH-indole-2-carboxylic acid (1.9 g, 97% yield) as a dark solid. 1H NMR (400 MHz, DMSO^): d 13.06 (br s, 1H), 12.50 (s, 1H), 7.59 (s, 1H), 7.21 (d, = 1.2 Hz, 1H), 7.16-7.15 (t, 7= 3.2 Hz, 1H).
85%	With 1,4-diaza-bicyclo[2.2.2]octane; palladium diacetate; In N,N-dimethyl-formamide; at 100℃; for 3h;	4~Chloro-2-fluoro-6-iodoaniline (Intermediate 30, 1.35 g, 5 mmol), pyruvic acid (1.32 g,15 mmol) and DABCO (1.68 g,15 mmol) were dissolved in DMF(15 mL). The solution was degassed and palladium acetate (56 mg) was added. The mixture was then heated to 1000C for 3h., cooled to ambient and filtered. The filtrate was diluted with EtOAc (100 mL), washed with 2M HCl (2 x 2OmL), water (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave the title compound as a dark solid (0.9g, 85% ). 1H NMR (400 MHz, DMSO-de) delta 7.16 (IH, t), 7.21 - 7.24 (IH, m), 7.59 (IH, d), 12.52 (IH, s), 13.27 (IH, s); MS m/z 212 (M-H)"

References: [1]Patent: WO2019/152883,2019,A1 .Location in patent: Paragraph 00136.
[2]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 56.

4
[ 216393-67-8 ]
[ 82483-66-7 ]
[ 1029433-57-5 ]

References: [1]Tetrahedron Letters,2008,vol. 49,p. 3172 - 3175.

5
[ 216393-67-8 ]
[ 660866-51-3 ]
[ 1093942-90-5 ]

References: [1]Organic Letters,2009,vol. 11,p. 221 - 224.

6
[ 216393-67-8 ]
[ 628-71-7 ]
C₁₃H₁₅ClFN [ No CAS ]

References: [1]Synlett,2008,p. 3006 - 3010.

7
[ 216393-67-8 ]
[ 536-74-3 ]
C₁₄H₉ClFN [ No CAS ]

References: [1]Synlett,2008,p. 3006 - 3010.

8
[ 216393-67-8 ]
[ 2510-23-8 ]
[ 1202551-89-0 ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; for 1h;Reflux;	To a mixture of 3-ethynylpyridine (1.13 g, 11 mmol) and 2-fluoro^-chloro-6-iodoaniline (2.71 g, 10 mmol) in triethylamine (100 mL) is added PdCI2(PPh3)2 (175 mg, 0.25 mmol) and CuI (95 mg, 0.50 mmol) and the mixture is refluxed for 1 h. The solvent is removed in vacuo and the residue is purified by silica gel flash chromatography (dichloromethane- methanol, 1 :0 to 24:1 ) to give 4-chloro-2-fluoro-6-pyridin-3-ylethynyl-phenylamine. MS (ESI) m/z 247 (M+H)+.

References: [1]Patent: WO2009/156462,2009,A2 .Location in patent: Page/Page column 125.

9
[ 216393-67-8 ]
[ 14395-57-4 ]
[ 1219602-19-3 ]

References: [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 1291 - 1294.

10
[ 216393-67-8 ]
[ 6320-02-1 ]
[ 1219602-18-2 ]

References: [1]Angewandte Chemie - International Edition,2010,vol. 49,p. 1291 - 1294.

12
[ 216393-67-8 ]
[ 58635-45-3 ]
C₁₈H₁₆ClFIN₃O₂ [ No CAS ]

References: [1]Journal of the American Chemical Society,2010,vol. 132,p. 7119 - 7137.

13
[ 216393-67-8 ]
[ 1258504-27-6 ]
[ 1258504-28-7 ]

Yield	Reaction Conditions	Operation in experiment
25%	With sodium carbonate; lithium chloride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100℃;	INTERMEDIATE 150 - PREPARATION of Lambda/-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1 H-indol- 3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide; A mixture of <strong>[216393-67-8]4-chloro-2-fluoro-6-iodoaniline</strong> (0.100 g; 0.368 mmol), 5-(2,5-difluorobenzyl)- N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide (0.150 g; 0.347 mmol), Bis(diphenylphosphino)ferrocene]palladium(ll) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol), sodium carbonate (0.078 g; 0.737 mmol) in DMF (5 ml.) was stirred at 100 0C overnight. The solution was reparted between ethyl acetate and brine, washed with sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60 % ethyl acetate in heptane) to yield 0.05 g (25%) of Lambda/-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1 H- indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a yellow oil. ESI/APCI(+): 549(M+H).

References: [1]Patent: WO2010/142801,2010,A1 .Location in patent: Page/Page column 193.

14
[ 216393-67-8 ]
[ 1202551-92-5 ]

References: [1]Patent: WO2009/156462,2009,A2 .

15
[ 216393-67-8 ]
[ 906779-61-1 ]

References: [1]Patent: WO2009/156462,2009,A2 .

16
[ 216393-67-8 ]
[ 1202550-40-0 ]

References: [1]Patent: WO2009/156462,2009,A2 .

17
[ 216393-67-8 ]
[ 74-99-7 ]
[ 1297275-38-7 ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at -78℃;	In a 350 mL glass pressure vessel with a threaded Teflon cap, <strong>[216393-67-8]4-chloro-2-fluoro-6-iodoaniline</strong> (3.25 g, 12.0 mmol), CuI (30 mg, 0.16 mmol), and Pd(PPh3)2Cl2 (0.101 g, 0.144 mmol) were taken up in 165 mL triethylamine and cooled to -78 C. Propyne (2.7 mL, 1.9 g, 48 mmol) was condensed into a graduated cylinder and added to the reaction vessel. The vessel was then capped, the cooling bath removed, and the reaction mixture allowed to stir while warming to room temperature overnight behind a safety shield. Removal of the triethylamine by evaporation gave a crude material that was purified by flash chromatography over silica gel (1-10% ethyl acetate in hexanes) to give pure product (2.00 g, 91% yield): 1H NMR (CHLOROFORM-d) delta 7.00-7.04 (m, 1H), 6.95 (dd, J=10.6, 2.3 Hz, 1H), 4.18 (br. s., 2H), 2.13 (s, 3H).

References: [1]Patent: US2011/105509,2011,A1 .Location in patent: Page/Page column 20.

18
[ 216393-67-8 ]
[ 74-99-7 ]
[ 1297282-80-4 ]

Yield	Reaction Conditions	Operation in experiment
91%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at -78℃;	In a 350 mL glass pressure vessel with a threaded Teflon cap, <strong>[216393-67-8]4-chloro-2-fluoro-6-iodoaniline</strong> (3.25 g, 12.0 mmol), CuI (30 mg, 0.16 mmol), and Pd(PPh3)2Cl2 (0.101 g, 0.144 mmol) were taken up in 165 mL triethylamine and cooled to -78 C. Propyne (2.7 mL, 1.9 g, 48 mmol) was condensed into a graduated cylinder and added to the reaction vessel. The vessel was then capped, the cooling bath removed, and the reaction mixture allowed to stir while warming to room temperature overnight behind a safety shield. Removal of the triethylamine by evaporation gave a crude material that was purified by flash chromatography over silica gel (1-10% ethyl acetate in hexanes) to give pure product (2.00 g, 91% yield): 1H NMR (CHLOROFORM-d) delta 7.00-7.04 (m, 1H), 6.95 (dd, J=10.6, 2.3 Hz, 1H), 4.18 (br. s., 2H), 2.13 (s, 3H).

References: [1]Patent: US2011/105509,2011,A1 .Location in patent: Page/Page column 18; 19.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5088 - 5109.

19
[ 216393-67-8 ]
[ 74-99-7 ]
[ 1297282-90-6 ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at -78℃;	In a 350 mL glass pressure vessel with a threaded Teflon cap, <strong>[216393-67-8]4-chloro-2-fluoro-6-iodoaniline</strong> (3.25 g, 12.0 mmol), CuI (30 mg, 0.16 mmol), and Pd(PPh3)2Cl2 (0.101 g, 0.144 mmol) were taken up in 165 mL triethylamine and cooled to -78 C. Propyne (2.7 mL, 1.9 g, 48 mmol) was condensed into a graduated cylinder and added to the reaction vessel. The vessel was then capped, the cooling bath removed, and the reaction mixture allowed to stir while warming to room temperature overnight behind a safety shield. Removal of the triethylamine by evaporation gave a crude material that was purified by flash chromatography over silica gel (1-10% ethyl acetate in hexanes) to give pure product (2.00 g, 91% yield): 1H NMR (CHLOROFORM-d) delta 7.00-7.04 (m, 1H), 6.95 (dd, J=10.6, 2.3 Hz, 1H), 4.18 (br. s., 2H), 2.13 (s, 3H).

References: [1]Patent: US2011/105509,2011,A1 .Location in patent: Page/Page column 20.

20
[ 216393-67-8 ]
[ 74-99-7 ]
[ 1297282-92-8 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at -78℃;	In a 350 mL glass pressure vessel with a threaded Teflon cap, <strong>[216393-67-8]4-chloro-2-fluoro-6-iodoaniline</strong> (3.25 g, 12.0 mmol), CuI (30 mg, 0.16 mmol), and Pd(PPh3)2Cl2 (0.101 g, 0.144 mmol) were taken up in 165 mL triethylamine and cooled to -78 C. Propyne (2.7 mL, 1.9 g, 48 mmol) was condensed into a graduated cylinder and added to the reaction vessel. The vessel was then capped, the cooling bath removed, and the reaction mixture allowed to stir while warming to room temperature overnight behind a safety shield. Removal of the triethylamine by evaporation gave a crude material that was purified by flash chromatography over silica gel (1-10% ethyl acetate in hexanes) to give pure product (2.00 g, 91% yield): 1H NMR (CHLOROFORM-d) delta 7.00-7.04 (m, 1H), 6.95 (dd, J=10.6, 2.3 Hz, 1H), 4.18 (br. s., 2H), 2.13 (s, 3H).

References: [1]Patent: US2011/105509,2011,A1 .Location in patent: Page/Page column 20.

21
[ 216393-67-8 ]
[ 74-99-7 ]
[ 1297282-94-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at -78℃;	In a 350 mL glass pressure vessel with a threaded Teflon cap, <strong>[216393-67-8]4-chloro-2-fluoro-6-iodoaniline</strong> (3.25 g, 12.0 mmol), CuI (30 mg, 0.16 mmol), and Pd(PPh3)2Cl2 (0.101 g, 0.144 mmol) were taken up in 165 mL triethylamine and cooled to -78 C. Propyne (2.7 mL, 1.9 g, 48 mmol) was condensed into a graduated cylinder and added to the reaction vessel. The vessel was then capped, the cooling bath removed, and the reaction mixture allowed to stir while warming to room temperature overnight behind a safety shield. Removal of the triethylamine by evaporation gave a crude material that was purified by flash chromatography over silica gel (1-10% ethyl acetate in hexanes) to give pure product (2.00 g, 91% yield): 1H NMR (CHLOROFORM-d) delta 7.00-7.04 (m, 1H), 6.95 (dd, J=10.6, 2.3 Hz, 1H), 4.18 (br. s., 2H), 2.13 (s, 3H).

References: [1]Patent: US2011/105509,2011,A1 .Location in patent: Page/Page column 20.

22
[ 216393-67-8 ]
[ 1297282-82-6 ]

References: [1]Patent: US2011/105509,2011,A1 .
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 5088 - 5109.

23
[ 216393-67-8 ]
[ 100-10-7 ]
[ 1374581-32-4 ]

References: [1]European Journal of Organic Chemistry,2012,p. 1984 - 1993.

24
[ 216393-67-8 ]
[ 1382991-52-7 ]
[ 1382991-58-3 ]

Yield	Reaction Conditions	Operation in experiment
51%	With sodium carbonate; lithium chloride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 100℃; for 18h;	INTERMEDIATE 65 - PREPARATION of A/-(2-(5-Chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3- yl)ethyl)-4-(3-fluorobenzyl)benzamide. 4-Chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 4-(3-fluorobenzyl)-N-(4- (triethylsilyl)but-3-ynyl)benzamide (0.145 g; 0.368 mmol), bis(diphenylphosphino)ferrocene]palladium(ll) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol) and sodium carbonate (0.078 g; 0.737 mmol) were suspended in DMF (5 ml_) and the mixture was stirred at 100C for 18 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60 % ethyl acetate in heptane) to afford 0.102 g (51 %) of the title compound as a yellow oil. ESI/APCI(+): 539(M+H).
51%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; lithium chloride; In N,N-dimethyl-formamide; at 100℃; for 18h;	4-Chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 4-(3-fluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)benzamide (0.145 g; 0.368 mmol), bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol) and sodium carbonate (0.078 g; 0.737 mmol) were suspended in DMF (5 mL) and the mixture was stirred at 100 C. for 18 hours. The solution was concentrated under reduced pressure and diluted in ethyl acetate. The organic layer was successively washed with brine, sodium thiosulfate, dried and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (eluent 2 to 60% ethyl acetate in heptane) to afford 0.102 g (51%) of the title compound as a yellow oil. [0672] ESI/APCI(+): 539 (M+H).

References: [1]Patent: WO2012/80221,2012,A1 .Location in patent: Page/Page column 92.
[2]Patent: US2013/274260,2013,A1 .Location in patent: Paragraph 0671-0672.

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