[ CAS No. 71759-89-2 ] {[proInfo.proName]}

Name: 71759-89-2|5-Iodo-1H-imidazole|97%
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Quality Control of [ 71759-89-2 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 71759-89-2 ]

SDS Specification

Alternatived Products of [ 71759-89-2 ]

Product Details of [ 71759-89-2 ]

CAS No. :	71759-89-2	MDL No. :	MFCD01632213
Formula :	C₃H₃IN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	BHCMXJKPZOPRNN-UHFFFAOYSA-N
M.W :	193.97	Pubchem ID :	606522
Synonyms :	5-Iodo-1H-imidazole

Calculated chemistry of [ 71759-89-2 ]

Physicochemical Properties

Num. heavy atoms :	6
Num. arom. heavy atoms :	5
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	31.3
TPSA :	28.68 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-7.11 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.85
Log Po/w (XLOGP3) :	0.52
Log Po/w (WLOGP) :	1.01
Log Po/w (MLOGP) :	0.21
Log Po/w (SILICOS-IT) :	2.24
Consensus Log Po/w :	0.97

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.99
Solubility :	2.0 mg/ml ; 0.0103 mol/l
Class :	Very soluble
Log S (Ali) :	-0.69
Solubility :	39.3 mg/ml ; 0.203 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.19
Solubility :	1.26 mg/ml ; 0.00649 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	2.63

Safety of [ 71759-89-2 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 71759-89-2 ]

* 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.

Upstream synthesis route of [ 71759-89-2 ]
Downstream synthetic route of [ 71759-89-2 ]

[ 71759-89-2 ] Synthesis Path-Upstream 1~14

1
[ 1746-25-4 ]
[ 71759-89-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium sulfite In N,N-dimethyl-formamide at 110℃; Inert atmosphere	2,4,5-triiodo-1H-imidazole was reacted with Na₂SO₃in DMF (250 mL) and stirring at 110° C. for over night under N₂atmosphere. The reactin mixture was filtered, the filtrate was concentrated and poured into water, then extracted with EtOAc, the organic was washed with water, dried over Na₂SO₄, concentrated and purified by silica gel column to give 4-iodo-1H-imidazole (Yield=55percent). LC-MS: m/z=195 [M+H⁺]

Reference： [1] Patent: US2012/245144, 2012, A1, . Location in patent: Page/Page column 118
[2] Journal of Medicinal Chemistry, 1996, vol. 39, # 15, p. 3001 - 3013
[3] Patent: WO2006/38100, 2006, A1, . Location in patent: Page/Page column 78

2
[ 15813-09-9 ]
[ 71759-89-2 ]

Yield	Reaction Conditions	Operation in experiment
48.1%	With water; sodium sulfite In ethanol for 72 h; Reflux	A mixture of 2 (12.0 g, 37.5 mmol)and Na2SO3 (23.6 g, 187.3 mmol) in EtOH (120 mL) and H2O (20 mL)was refluxed for 72 h. The mixture was concentrated in vacuo andthe residue was extracted with ethyl acetate. The crude productwas purified by recrystallization from dichloromethane to afford 3as a white solid (3.5 g, 48.1percent). Mp 137e139 C. 1H NMR (300 MHz,Chloroform-d) d(ppm) 7.0 (s, 1H), 7.5 (s, 1H). MS (EI) m/z 194.9[MH].
48.1%	With sodium sulfite In ethanol; water for 72 h; Reflux	1 (12.0 g, 37.5 mmol) was dissolved in a reaction system of ethanol (120 mL) and water (20 mL)Na2SO3 (23.6 g, 188.0 mmol),The reaction was refluxed for 72 hours,Ethanol was removed under reduced pressure,Ethyl acetate extraction,Dried over anhydrous magnesium sulfate,Remove the solvent,Methylene chloride was recrystallized to give a white solid,Yield 48.1percent.
38 kg	With sodium sulfite In water; isopropyl alcoholReflux; Large scale	(2) The product of the previous step (4-iodo-1H-imidazole and a little diiodo-substituted imidazole, 78 kg)60 kg of isopropyl alcohol and 240 kg of water were added,Adding 67.5 kg of sodium sulfite,Reflux reaction to raw material disappears.Cooled and filtered (the filtrate used as solvent in the next batch, no emissions)Extraction (using ethyl acetate extraction),Concentration under reduced pressure gave the compound 4-iodo-1H-imidazole (38 kg, purity was 99.2percent by high performance liquid phase).

Reference： [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 21, p. 4658 - 4666
[2] Synthesis, 1994, # 7, p. 681 - 682
[3] Tetrahedron Asymmetry, 2004, vol. 15, # 13, p. 2021 - 2028
[4] Medicinal Chemistry Research, 2011, vol. 20, # 4, p. 401 - 407
[5] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 293 - 304
[6] Patent: CN107501272, 2017, A, . Location in patent: Paragraph 0085; 0086; 0089; 0090
[7] Patent: CN106674121, 2017, A, . Location in patent: Paragraph 0031; 0034

3
[ 288-32-4 ]
[ 71759-89-2 ]

Reference： [1] European Journal of Organic Chemistry, 2015, vol. 2015, # 21, p. 4658 - 4666
[2] Synthetic Communications, 2008, vol. 38, # 17, p. 2881 - 2888
[3] Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 2944 - 2953
[4] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3741 - 3749
[5] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507

4
[ 15813-09-9 ]
[ 71759-89-2 ]

Reference： [1] Patent: US6313312, 2001, B1,

5
[ 1443425-57-7 ]
[ 71759-89-2 ]

Reference： [1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 2-3, p. 499 - 507

6
[ 71759-89-2 ]
[ 1692-25-7 ]
[ 51746-85-1 ]

Yield	Reaction Conditions	Operation in experiment
52%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾; sodium carbonate In water; N,N-dimethyl-formamide at 110℃; for 2 h; Microwave irradiation; Inert atmosphere	General procedure: Method B: In a20 mL microwave Biotage tube, a 1M Na₂CO₃ aqueous solution(5 mL) purged with argon were introduced into a mixture purged with argon of 4-iodo-1H-imidazole (1a) (0.194 g, 1.0 mmol), a boronicacid 2 (1.6 mmol) and Pd(PPh₃)₄ (0.80 g, 0.05 mmol) in DMF (15 mL). The mixture washeated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3j and 3p-3u in yields ranging from 30 to 95percent. Time and temperaturereactions were collected in Table 1.

Reference： [1] Tetrahedron Letters, 2014, vol. 55, # 46, p. 6347 - 6350

7
[ 71759-89-2 ]
[ 74-88-4 ]
[ 71759-87-0 ]
[ 71759-88-1 ]

Reference： [1] Tetrahedron Letters, 2004, vol. 45, # 28, p. 5529 - 5532
[2] Patent: WO2017/87837, 2017, A1, . Location in patent: Paragraph 00394

8
[ 77-78-1 ]
[ 71759-89-2 ]
[ 71759-87-0 ]
[ 71759-88-1 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 4, p. 735 - 739
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 4, p. 735 - 739

9
[ 71759-89-2 ]
[ 74-88-4 ]
[ 71759-87-0 ]
[ 71759-88-1 ]

Reference： [1] Tetrahedron Letters, 2004, vol. 45, # 28, p. 5529 - 5532
[2] Patent: WO2017/87837, 2017, A1, . Location in patent: Paragraph 00394

10
[ 77-78-1 ]
[ 71759-89-2 ]
[ 71759-88-1 ]

Reference： [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1983, # 4, p. 735 - 739

11
[ 333-27-7 ]
[ 71759-89-2 ]
[ 71759-88-1 ]

Reference： [1] Journal of Organic Chemistry, 2013, vol. 78, # 23, p. 12220 - 12223

12
[ 77-78-1 ]
[ 71759-89-2 ]
[ 71759-87-0 ]
[ 71759-88-1 ]

13
[ 71759-89-2 ]
[ 76-83-5 ]
[ 96797-15-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 24 h;	To a solution of 3 (3.5 g,18.0 mmol) in DMF (70 mL) was added TEA (3.0 mL, 21.7 mmol) andtrityl chloride (5.5 g, 19.7 mmol). After stirring at 20 C for 24 h, thesolution was poured into water. The solid was filtered to yield thecrude compound that was purified by flash column chromatographyon silica gel to afford 4 as a white solid (7.4 g, 94.0percent). Mp148e150 C. 1H NMR (300 MHz, Chloroform-d) d(ppm) 6.9 (m, 1H),7.0e7.2 (m, 6H), 7.25e7.4 (m, 10H). MS (EI) m/z 437.1 [MH].
94%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 24 h;	2 (3.5 g, 18.0 mmol) was dissolved in DMF (70 mL),Triethylamine (3.0 mL, 21.6 mmol) was added dropwise,Trityl chloride (5.5 g, 19.7 mmol) was added,After 24 hours at room temperature,Poured into 200mL water,Precipitation of a large number of solids,Suction filtration,Ether filtered and washed,Drying gives a white solid,Yield 94.0percent
93%	With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 48 h;	To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-IODO-1-TRITYL-LH-IMIDAZOLE (104.1, 93percent) as a white solid. ME (437)

93%	With triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 48 h;	To a solution of 4-iodoimidazole (50 g, 258 mmoles) in DMF (500 ML) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-IODO-1-TRITYL-LH-IMIDAZOLE (104.1, 93percent) as a white solid. MH+ (437)
93%	With triethylamine In dichloromethane at 25℃; for 17 h; Cooling with ice; Inert atmosphere	After dissolving 4-iodo -1Himidazole(compound 1) (1.9g, 10mmol) in dichloromethane (40mL), under ice-cooling,triethylamine (2.1mL, 15mmol), trityl chloride (3.4g, 12mmol) It was added, under argon, andstirred for 17 hours at room temperature (25 ° C). After completion of the reaction, water wasadded, and the mixture was extracted twice with dichloromethane. The combineddichloromethane layers were dried anhydrous sodium sulfate and concentrated under reducedpressure, silica and the resulting crude product was gel column chromatography (eluent:chloroform / n-hexane = 1/1 → chloroform) at Purification, Compound 2 It was obtained (4.1g,9.3mmol, 93percent yield).
93%	With triethylamine In dichloromethane at 25℃; for 17 h; Inert atmosphere	4-Iodo-1H-imidazole (Compound 25, manufactured by Wako Pure Chemical Industries, Ltd.) (1.9 g, 10 mmol) was dissolved in dichloromethane (40 mL)Triethylamine (2.1 mL, 15 mmol) and trityl chloride (3.4 g, 12 mmol) were added and the mixture was stirred at room temperature (25 ° C.) for 17 hours under an argon gas atmosphere. After completion of the reaction, water was added and the mixture was extracted twice with dichloromethane. The combined dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform / n-hexane = 1/1 → chloroform) to obtain compound 26 (4.1 g, 9.3 mmol, yield 93percent).
93%	With triethylamine In dichloromethane at 25℃; for 17 h; Inert atmosphere	4-iodo-1H-imidazole (Compound 13, manufactured by Wako Pure Chemical Industries, Ltd.) (1.9 g, 10 mmol) was dissolved in dichloromethane (40 mL)below freezing,Triethylamine (2.1 mL, 15 mmol),Trityl chloride (3.4 g, 12 mmol) was added,Under an argon gas atmosphere,And the mixture was stirred at room temperature (25 ° C.) for 17 hours.After completion of the reaction,Add water,Extraction was carried out twice with dichloromethane.The combined dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure,The obtained crude product was purified by silica gel column chromatography (eluent (volume ratio): chloroform / n-hexane = 1/1 → chloroform) to obtain Compound 14 (4.1 g, 9.3 mmol, yield 93percent).
92%	at 20℃; for 24 h;	To a solution of 4-iodoimidazole (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 h, the solution was poured into ice water and left stirring for 30 min. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-iodo-1- TRITYL-LH-IMIDAZOLE (92percent) as a white solid. MH+ (437).
92%	Stage #1: With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.166667 h; Stage #2: at 20℃; for 16 h;	At 0° C., to a solution of 4-iodo-1H-imidazole (5 g, 25.8 mmol) in DMF (100 mL) was added triethylamine (3.13 g, 30.9 mmol) slowly. After stirring for additional 10 min at 0° C., the reaction mixture was added by TrtCl (7.17 g, 25.7 mmol). The resulting solution was then stirred at room temperature for 16 h. The reaction mixture was poured into 1 L water. A white solid precipitated out and were collected by filtration. The solid was rinsed with MeOH (50 mL×2) and Et₂O (50 mL×3), and then dried in vacuo to yield 4-iodo-1-(triphenylmethyl)-1H-imidazole as white solid (10.4 g, 92percent).
90%	at 0 - 20℃;	4-lodo-1tf-imidazole (2.8g, 14.6mmol) and trityl chloride (5.Og, 20.5mmol) were dissolved in λ/,λ/-dimethylacetamide (45mL). The solution was cooled to 0"C and triethylamine (4mL, 29.2mmol) added slowly. The reaction mixture was slowly warmed to room temperature. After 48 hours the solution was poured to water(15OmL). The solid was filtered, washed with water, hexane and dried to give a white solid (5.7g) with a yield of 90percent. The product was pure enough for the next step reaction without further purification.
88.9%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 48 h;	4-iodo-1H-imidazole (20 g, 103 mmoles) was dissolved in DMF (100 mL) then triethylamine (15.1 mL, 108 mmoles) and triphenylmethyl chloride (27.8 g, 100 mmoles). The reaction mixture was stirred at room temperature for 48 h, then poured into ice water (500 mL), and then evaporated to dryness, and filtered, and dried to give white crystals of 4-iodo-1-triphenylmethyl-1H-imidazole (40 g, 91.7 mmol, 88.9percent).
81%	With triethylamine In tetrahydrofuran at 70℃; for 3 h; Inert atmosphere	Triethylamine (36.0 mL, 258 mmol) was added to a mixture of 4-iodoimidazole (24.8 g, 128 mmol) and trityl chloride (39.2 g, 141 mmol) in THF (275 mL), the resulting mixture was heated at 70 °C for 3 hours under nitrogen. The reaction was cooled to 45 °C and filtered to remove thesuspended white solid (Et3N.HCI). The filtrate was concentrated in vacuo, dissolved in DCM (500 mL) and washed with 5 wtpercent aq. sodium thiosulfate solution (300 mL). The aqueous layer was extracted with DCM (150 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford an off white solid. Hot filtration was carried out with methanol (500 ml) at 90°C to afford a white solid characterised as 4-iodo-1-trityl-imidazole (45.2 g, 104 mmol, 81percentyield). 1H NMR (CDCI3, 400 MHz) O: 7.36-7.44 (m, 9H), 7.28-7.32 (m, 1H), 7.10-7.15 (m, 6H), 6.94 (5, 1 H). LCMS purity >95percent, [M+H] = 437.0, 4.47 mm (analytical long).
71%	With triethylamine In tetrahydrofuran at 80℃;	4-Iodoimidazole (0101-1) (10.0 g, 51.6 mmol, 1.0 eq.)Dissolved in 150 ml of tetrahydrofuran,Triphenylmethyl chloride (17.2 g, 61.7 mmol, 1.2 equivalents) andTriethylamine (14.5 ml, 10.4 mmol, 2.0 eq),Heat to 80°C and react overnight.Cooled to room temperature, concentrated under reduced pressure, added ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol and a small amount of dichloromethane were added and stirred for half an hour. The solid was collected by suction, washed twice with methanol, and vacuum dried. ,4-Iodo-1-trityl-1H-imidazole (16 g, yield: 71percent) was obtained as a white solid.
66%	With triethylamine In N,N-dimethyl-formamide at 20℃; for 14 h;	After dissolving 4-iodo-1H-imidazole (3.0 g, 0.015 mol) and triphenylmethyl chloride (6.0 g, 0.021 mol) in anhydrous N, N-dimethylformamide (50 mL) Deg.] C, triethylamine (7.2 mL, 0.052 mol) was added slowly, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and then distilled water (100 mL) was added thereto. After stirring at room temperature for 20 minutes, the solid was filtered The filtrate was washed with distilled water and diethyl ether to give the title compound 60-a (4.4 g, 66percent) as a white solid.
59%	With triethylamine In water; N,N-dimethyl-formamide	Preparation 72 4-Iodo-1-triphenylmethyl-1H-imidazole To 4-iodo-1H-imidazole (Preparation 71, 3.0 g, 15.3 mmol) in N,N-dimethylformamide (25 ml) was added triphenylmethyl chloride (4.72 g, 16.9 mmol) and then triethylamine (2.5 ml, 18.4 mmol). After stirring at room temperature for 2.5 h, water (200 ml) was added and the reaction mixture was filtered and washed with water. The crude solid was chromatographed on silica gel eluding with hexane:ethyl acetate (5:1 and then 2:1). The material was then recrystallized from hexane and dichloromethane to give the title compound as a white solid (4.0 g, 59percent). NMR (CDCl₃, selected data for the free base: 6.9 (m, 1H), 7.0-7.2 (m, 6H), 7.25-7.4 (m, 10H). MS (TSP): M/Z (MH⁺): 436.3; C₂₂H₁₇¹²⁹IN₂+H requires 437.1.
55.57%	With triethylamine In tetrahydrofuran at 70℃; for 3 h;	4-iodoimidazole (5.38g, 27.72mmol) was dissolved in THF (86ml_). Trityl chloride, (8.5g, 30.49mmol) and triethylamine (7.73ml_, 55.44mmol) were added and the reaction was heated at 70 °C. After 3 h, TLC showed that the reaction had gone to completion. Therefore, the reaction mixture was allowed to cool to 45 C and filtered to remove the suspended white solid. The filtrate was concentrated, redissolved in DCM (300 mL) and washed with 5 wtpercent aq. sodium thiosulfate solution (300 mL), which was back-extracted with DCM (150 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield the crude product. The white solid was taken up in EtOAc (300ml) and heated to reflux for 30 minutes. The mixture was cooled and the solid was obtained by vacuum filtration. The white solid was dried in the vacuum oven for 3 hours affording 4- iodo-1 -trityl-imidazole (6.721 g, 15.40mmol, 55.57percent yield). MS Method 2: RT 2.08 min, ES⁺ m/z 459 [M+Na]⁺ H NMR (400MHz, DMSO) δ/ppm: 7.35-7.40 (m, 10H), 7.06-7.1 1 (m, 7H).

Reference： [1] Journal of Heterocyclic Chemistry, 1985, vol. 22, p. 57 - 59
[2] European Journal of Medicinal Chemistry, 2017, vol. 140, p. 293 - 304
[3] Patent: CN107501272, 2017, A, . Location in patent: Paragraph 0085; 0086; 0091; 0092
[4] Patent: WO2004/96822, 2004, A2, . Location in patent: Page 262
[5] Patent: WO2004/96823, 2004, A2, . Location in patent: Page 44; 45
[6] Patent: JP2015/93833, 2015, A, . Location in patent: Paragraph 0057; 0058
[7] Patent: JP2015/93831, 2015, A, . Location in patent: Paragraph 0016; 0100; 0101
[8] Patent: JP2015/110563, 2015, A, . Location in patent: Paragraph 0016; 0078; 0079
[9] Patent: WO2004/96822, 2004, A2, . Location in patent: Page 239; 240
[10] Patent: US2016/75711, 2016, A1, . Location in patent: Paragraph 0216-0217
[11] Patent: WO2009/93981, 2009, A1, . Location in patent: Page/Page column 96
[12] Patent: CN108203438, 2018, A, . Location in patent: Paragraph 0142; 0143; 0144; 0145
[13] Patent: WO2016/59412, 2016, A1, . Location in patent: Paragraph 00200; 00201
[14] Synthesis, 1994, # 7, p. 681 - 682
[15] Patent: CN107383024, 2017, A, . Location in patent: Paragraph 0112
[16] Patent: KR101798840, 2017, B1, . Location in patent: Paragraph 1139-1142
[17] Journal of Medicinal Chemistry, 2008, vol. 51, # 10, p. 2944 - 2953
[18] Patent: US6313312, 2001, B1,
[19] Patent: WO2016/55786, 2016, A1, . Location in patent: Paragraph 00231
[20] Journal of Medicinal Chemistry, 1996, vol. 39, # 15, p. 3001 - 3013
[21] Journal of Organic Chemistry, 2007, vol. 72, # 10, p. 3741 - 3749
[22] Patent: US5932606, 1999, A,
[23] Patent: US2002/19527, 2002, A1,

14
[ 71759-89-2 ]
[ 60-29-7 ]
[ 76-83-5 ]
[ 96797-15-8 ]

Reference： [1] Patent: US2003/125266, 2003, A1,

[ 71759-89-2 ] Synthesis Path-Downstream 1~87

1
[ 71759-89-2 ]
[ 76-83-5 ]
[ 96797-15-8 ]

Yield	Reaction Conditions	Operation in experiment
94%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	To a solution of 3 (3.5 g,18.0 mmol) in DMF (70 mL) was added TEA (3.0 mL, 21.7 mmol) andtrityl chloride (5.5 g, 19.7 mmol). After stirring at 20 C for 24 h, thesolution was poured into water. The solid was filtered to yield thecrude compound that was purified by flash column chromatographyon silica gel to afford 4 as a white solid (7.4 g, 94.0%). Mp148e150 C. 1H NMR (300 MHz, Chloroform-d) d(ppm) 6.9 (m, 1H),7.0e7.2 (m, 6H), 7.25e7.4 (m, 10H). MS (EI) m/z 437.1 [MH].
94%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;	2 (3.5 g, 18.0 mmol) was dissolved in DMF (70 mL),Triethylamine (3.0 mL, 21.6 mmol) was added dropwise,Trityl chloride (5.5 g, 19.7 mmol) was added,After 24 hours at room temperature,Poured into 200mL water,Precipitation of a large number of solids,Suction filtration,Ether filtered and washed,Drying gives a white solid,Yield 94.0%
93%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h;	To a solution of <strong>[71759-89-2]4-iodoimidazole</strong> (50 g, 258 mmoles) in DMF (500 ml) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-IODO-1-TRITYL-LH-IMIDAZOLE (104.1, 93%) as a white solid. ME (437)

93%	With triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h;	To a solution of <strong>[71759-89-2]4-iodoimidazole</strong> (50 g, 258 mmoles) in DMF (500 ML) was added triethyl amine (37.7 ml, 270.6 mmoles) and than triphenylmethyl chloride (69.7 g, 250 mmoles). After stirring at room temperature for 48 hours, the solution was poured into ice water (2.5 L). The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether (200 ml) was added to the crude compound and the solution was filtered to yield 4-IODO-1-TRITYL-LH-IMIDAZOLE (104.1, 93%) as a white solid. MH+ (437)
93%	With triethylamine; In dichloromethane; at 25℃; for 17h;Cooling with ice; Inert atmosphere;	After dissolving 4-iodo -1Himidazole(compound 1) (1.9g, 10mmol) in dichloromethane (40mL), under ice-cooling,triethylamine (2.1mL, 15mmol), trityl chloride (3.4g, 12mmol) It was added, under argon, andstirred for 17 hours at room temperature (25 C). After completion of the reaction, water wasadded, and the mixture was extracted twice with dichloromethane. The combineddichloromethane layers were dried anhydrous sodium sulfate and concentrated under reducedpressure, silica and the resulting crude product was gel column chromatography (eluent:chloroform / n-hexane = 1/1 ? chloroform) at Purification, Compound 2 It was obtained (4.1g,9.3mmol, 93% yield).
93%	With triethylamine; In dichloromethane; at 25℃; for 17h;Inert atmosphere;	4-Iodo-1H-imidazole (Compound 25, manufactured by Wako Pure Chemical Industries, Ltd.) (1.9 g, 10 mmol) was dissolved in dichloromethane (40 mL)Triethylamine (2.1 mL, 15 mmol) and trityl chloride (3.4 g, 12 mmol) were added and the mixture was stirred at room temperature (25 C.) for 17 hours under an argon gas atmosphere. After completion of the reaction, water was added and the mixture was extracted twice with dichloromethane. The combined dichloromethane layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (eluent: chloroform / n-hexane = 1/1 ? chloroform) to obtain compound 26 (4.1 g, 9.3 mmol, yield 93%).
93%	With triethylamine; In dichloromethane; at 25℃; for 17h;Inert atmosphere;	<strong>[71759-89-2]4-iodo-1H-imidazole</strong> (Compound 13, manufactured by Wako Pure Chemical Industries, Ltd.) (1.9 g, 10 mmol) was dissolved in dichloromethane (40 mL)below freezing,Triethylamine (2.1 mL, 15 mmol),Trityl chloride (3.4 g, 12 mmol) was added,Under an argon gas atmosphere,And the mixture was stirred at room temperature (25 C.) for 17 hours.After completion of the reaction,Add water,Extraction was carried out twice with dichloromethane.The combined dichloromethane layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure,The obtained crude product was purified by silica gel column chromatography (eluent (volume ratio): chloroform / n-hexane = 1/1 ? chloroform) to obtain Compound 14 (4.1 g, 9.3 mmol, yield 93%).
92%	In DMF (N,N-dimethyl-formamide); at 20℃; for 24h;	To a solution of <strong>[71759-89-2]4-iodoimidazole</strong> (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 h, the solution was poured into ice water and left stirring for 30 min. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-iodo-1- TRITYL-LH-IMIDAZOLE (92%) as a white solid. MH+ (437).
92%		At 0 C., to a solution of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (5 g, 25.8 mmol) in DMF (100 mL) was added triethylamine (3.13 g, 30.9 mmol) slowly. After stirring for additional 10 min at 0 C., the reaction mixture was added by TrtCl (7.17 g, 25.7 mmol). The resulting solution was then stirred at room temperature for 16 h. The reaction mixture was poured into 1 L water. A white solid precipitated out and were collected by filtration. The solid was rinsed with MeOH (50 mL×2) and Et2O (50 mL×3), and then dried in vacuo to yield 4-iodo-1-(triphenylmethyl)-1H-imidazole as white solid (10.4 g, 92%).
90%	In ISOPROPYLAMIDE; at 0 - 20℃;	4-lodo-1tf-imidazole (2.8g, 14.6mmol) and trityl chloride (5.Og, 20.5mmol) were dissolved in lambda/,lambda/-dimethylacetamide (45mL). The solution was cooled to 0"C and triethylamine (4mL, 29.2mmol) added slowly. The reaction mixture was slowly warmed to room temperature. After 48 hours the solution was poured to water(15OmL). The solid was filtered, washed with water, hexane and dried to give a white solid (5.7g) with a yield of 90%. The product was pure enough for the next step reaction without further purification.
88.9%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48h;	<strong>[71759-89-2]4-iodo-1H-imidazole</strong> (20 g, 103 mmoles) was dissolved in DMF (100 mL) then triethylamine (15.1 mL, 108 mmoles) and triphenylmethyl chloride (27.8 g, 100 mmoles). The reaction mixture was stirred at room temperature for 48 h, then poured into ice water (500 mL), and then evaporated to dryness, and filtered, and dried to give white crystals of 4-iodo-1-triphenylmethyl-1H-imidazole (40 g, 91.7 mmol, 88.9%).
88%	With triethylamine; In dichloromethane; at 20℃; for 15h;	To a stirred suspension of compound 40 (5.00 g, 25.78 mmol), Triphenylmethyl chloride (8.63 g, 30.94 mmol) in DCM (100 mL) was added TEA (3.91 g, 38.67 mmol), the resulting mixture was stirred at rt for 15 h, TLC showed that the start materials was consumed up, stopped the reaction, poured into a mixture of DCM (200 mL) and H20 (150 mL), the organic layer was separated and washed with brine, dried over anhydrous Na2S04, concentrate in vacuo, the residue was purified by column (EtOAc/Hex 1/30 to 1/5) to give compound 41 (10.00 g, 88% yield) as a white solid. MS (ESI) (M/Z): [M+H]+ =437.0; 1H NMR (400 MHz, CDCI3) delta 7.41 - 7.34 (m, 10H), 7.18 - 7.11 (m, 6H), 6.94 (d, = 1.4 Hz, 1H).
81%	With triethylamine; In tetrahydrofuran; at 70℃; for 3h;Inert atmosphere;	Triethylamine (36.0 mL, 258 mmol) was added to a mixture of <strong>[71759-89-2]4-iodoimidazole</strong> (24.8 g, 128 mmol) and trityl chloride (39.2 g, 141 mmol) in THF (275 mL), the resulting mixture was heated at 70 C for 3 hours under nitrogen. The reaction was cooled to 45 C and filtered to remove thesuspended white solid (Et3N.HCI). The filtrate was concentrated in vacuo, dissolved in DCM (500 mL) and washed with 5 wt% aq. sodium thiosulfate solution (300 mL). The aqueous layer was extracted with DCM (150 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to afford an off white solid. Hot filtration was carried out with methanol (500 ml) at 90C to afford a white solid characterised as 4-iodo-1-trityl-imidazole (45.2 g, 104 mmol, 81%yield). 1H NMR (CDCI3, 400 MHz) O: 7.36-7.44 (m, 9H), 7.28-7.32 (m, 1H), 7.10-7.15 (m, 6H), 6.94 (5, 1 H). LCMS purity >95%, [M+H] = 437.0, 4.47 mm (analytical long).
78%	With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	4-Iodo-1H-imidazole (5 g, 25.8 mmol) and N,N-diisopropylethylamine (6.65 g, 51.5 mmol) wereadded to dry dimethylformamide (30 mL), and (chloromethanetriyl)tribenzene (7.89 g, 28.4 mmol)was added to reaction mixture gradually at 20 C. After the reaction mixture was stirred at 20 Cuntil the starting material disappeared in thin layer chromatography (TLC), the reaction mixture wasdistilled in vacuo, ethyl acetate (200 mL) was added to the mixture. The organic extract was washedtwice with saturated aqueous NaCl (40 mL), and the organic extract was dried over Na2SO4. Aftersolvent was removed under vacuum, the product was purified as a white solid by silica gel columnchromatography, 8.77 g, yield 78%. 1H-NMR (400 MHz, CDCl3): = 7.38-7.33 (m, 10H, H-phenyl,H-imidazolyl), 7.13-7.09 (m, 6H, H-phenyl), 6.92 (d, J = 1.4 Hz, 1H, H-imidazolyl). 13C-NMR (101 MHz,CDCl3): = 141.83, 140.56, 129.72 (6C), 128.29 (3C), 128.18 (6C), 127.91, 126.89 (3C), 75.84. HRMS (ESI):m/z [M + H]+ calculated for C22H18N2I: 437.05092; found: 437.04934.
71%	With triethylamine; In tetrahydrofuran; at 80℃;	4-Iodoimidazole (0101-1) (10.0 g, 51.6 mmol, 1.0 eq.)Dissolved in 150 ml of tetrahydrofuran,Triphenylmethyl chloride (17.2 g, 61.7 mmol, 1.2 equivalents) andTriethylamine (14.5 ml, 10.4 mmol, 2.0 eq),Heat to 80C and react overnight.Cooled to room temperature, concentrated under reduced pressure, added ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol and a small amount of dichloromethane were added and stirred for half an hour. The solid was collected by suction, washed twice with methanol, and vacuum dried. ,4-Iodo-1-trityl-1H-imidazole (16 g, yield: 71%) was obtained as a white solid.
66%	With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 14h;	After dissolving <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (3.0 g, 0.015 mol) and triphenylmethyl chloride (6.0 g, 0.021 mol) in anhydrous N, N-dimethylformamide (50 mL) Deg.] C, triethylamine (7.2 mL, 0.052 mol) was added slowly, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated, and then distilled water (100 mL) was added thereto. After stirring at room temperature for 20 minutes, the solid was filtered The filtrate was washed with distilled water and diethyl ether to give the title compound 60-a (4.4 g, 66%) as a white solid.
59%	With triethylamine; In water; N,N-dimethyl-formamide;	Preparation 72 4-Iodo-1-triphenylmethyl-1H-imidazole To <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (Preparation 71, 3.0 g, 15.3 mmol) in N,N-dimethylformamide (25 ml) was added triphenylmethyl chloride (4.72 g, 16.9 mmol) and then triethylamine (2.5 ml, 18.4 mmol). After stirring at room temperature for 2.5 h, water (200 ml) was added and the reaction mixture was filtered and washed with water. The crude solid was chromatographed on silica gel eluding with hexane:ethyl acetate (5:1 and then 2:1). The material was then recrystallized from hexane and dichloromethane to give the title compound as a white solid (4.0 g, 59%). NMR (CDCl3, selected data for the free base: 6.9 (m, 1H), 7.0-7.2 (m, 6H), 7.25-7.4 (m, 10H). MS (TSP): M/Z (MH+): 436.3; C22H17129IN2+H requires 437.1.
58%		Et3N (0.59 mL, 4.25 mmol) was added to a solution of <strong>[71759-89-2]4-iodoimidazole</strong> [71759-89-2] (750 mg, 3.87 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 5 min and trytil chloride (1.19 g, 4.25 mmol) was added. The reaction mixture was stirred at 40 C for 16 h. The reaction mixture was diluted with NaHCCh (sat., aq.) and extracted with DCM. The organic layer was dried (MgS04), filtered and the solvent were evaporated in vacuo. The crude mixture was purified by flash column chromatography (silica, heptane/EtOAc, gradient from 100:0 to 60:40) to afford 1-169 (976 mg, 58%).
55.57%	With triethylamine; In tetrahydrofuran; at 70℃; for 3h;	<strong>[71759-89-2]4-iodoimidazole</strong> (5.38g, 27.72mmol) was dissolved in THF (86ml_). Trityl chloride, (8.5g, 30.49mmol) and triethylamine (7.73ml_, 55.44mmol) were added and the reaction was heated at 70 C. After 3 h, TLC showed that the reaction had gone to completion. Therefore, the reaction mixture was allowed to cool to 45 C and filtered to remove the suspended white solid. The filtrate was concentrated, redissolved in DCM (300 mL) and washed with 5 wt% aq. sodium thiosulfate solution (300 mL), which was back-extracted with DCM (150 mL). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield the crude product. The white solid was taken up in EtOAc (300ml) and heated to reflux for 30 minutes. The mixture was cooled and the solid was obtained by vacuum filtration. The white solid was dried in the vacuum oven for 3 hours affording 4- iodo-1 -trityl-imidazole (6.721 g, 15.40mmol, 55.57% yield). MS Method 2: RT 2.08 min, ES+ m/z 459 [M+Na]+ H NMR (400MHz, DMSO) delta/ppm: 7.35-7.40 (m, 10H), 7.06-7.1 1 (m, 7H).
	With triethylamine; In dichloromethane;	Step D 1-Trityl-<strong>[71759-89-2]4-iodoimidazole</strong> Trityl chloride (3.8 g, 13.6 mmol) was added to a cooled (0 C.) solution of <strong>[71759-89-2]4-iodoimidazole</strong> (2.25 g, 11.6 mmol) and triethylamine (2 ml, 14.3 mmol) in methylene chloride (25 ml). After stirring for 30 min the reaction mixture was warmed to room temperature and stirred ther for 2 h. The reaction mixture was washed well with water and saturated NaHCO3 then dried (Na2 SO4). Concentration gave the product as a white solid. 1 H NMR (CDCl3) d 6.92 (s, 1 H), 7.08-7.20 (m, 6 H), 7.28-7.40 (m, 10 H).
	With triethylamine; In N,N-dimethyl-formamide;	EXAMPLE 49A 4-iodo-1-trityl-1H-imidazole A suspension of <strong>[71759-89-2]4-iodoimidazole</strong> (3.38 g, 17.4 mmol) and triphenylmethyl chloride (5.56 g, 19.9 mmol) in DMF (15 mL) at 0 C. was treated with triethylamine (1.5 mL, 10.8 mmol), warmed to room temperature, stirred for 16 hours, poured into ice water, filtered, and dried in a vacuum oven at 50 C. to provide the desired product of sufficient purity for subsequent use without further purification.

Reference： [1]Journal of Heterocyclic Chemistry,1985,vol. 22,p. 57 - 59
[2]European Journal of Medicinal Chemistry,2017,vol. 140,p. 293 - 304
[3]Patent: CN107501272,2017,A .Location in patent: Paragraph 0085; 0086; 0091; 0092
[4]Patent: WO2004/96822,2004,A2 .Location in patent: Page 262
[5]Patent: WO2004/96823,2004,A2 .Location in patent: Page 44; 45
[6]Patent: JP2015/93833,2015,A .Location in patent: Paragraph 0057; 0058
[7]Patent: JP2015/93831,2015,A .Location in patent: Paragraph 0016; 0100; 0101
[8]Patent: JP2015/110563,2015,A .Location in patent: Paragraph 0016; 0078; 0079
[9]Patent: WO2004/96822,2004,A2 .Location in patent: Page 239; 240
[10]Patent: US2016/75711,2016,A1 .Location in patent: Paragraph 0216-0217
[11]Patent: WO2009/93981,2009,A1 .Location in patent: Page/Page column 96
[12]Patent: CN108203438,2018,A .Location in patent: Paragraph 0142; 0143; 0144; 0145
[13]Patent: WO2018/217439,2018,A1 .Location in patent: Page/Page column 40-41
[14]Patent: WO2016/59412,2016,A1 .Location in patent: Paragraph 00200; 00201
[15]Molecules,2019,vol. 24
[16]Synthesis,1994,p. 681 - 682
[17]Patent: CN107383024,2017,A .Location in patent: Paragraph 0112
[18]Patent: KR101798840,2017,B1 .Location in patent: Paragraph 1139-1142
[19]Journal of Medicinal Chemistry,2008,vol. 51,p. 2944 - 2953
[20]Patent: US6313312,2001,B1
[21]Patent: WO2019/243535,2019,A1 .Location in patent: Page/Page column 87
[22]Patent: WO2016/55786,2016,A1 .Location in patent: Paragraph 00231
[23]Journal of Medicinal Chemistry,1996,vol. 39,p. 3001 - 3013
[24]Journal of Organic Chemistry,2007,vol. 72,p. 3741 - 3749
[25]Patent: US5932606,1999,A
[26]Patent: US2002/19527,2002,A1

2
[ 77-78-1 ]
[ 71759-89-2 ]
[ 71759-87-0 ]
[ 71759-88-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1983,p. 735 - 739
[2]Journal of the Chemical Society. Perkin transactions I,1983,p. 735 - 739

3
[ 77-78-1 ]
[ 71759-89-2 ]
[ 71759-88-1 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1983,p. 735 - 739

4
[ 71759-89-2 ]
[ 98-59-9 ]
[ 163854-63-5 ]

Yield	Reaction Conditions	Operation in experiment
66.8%	With triethylamine; In dichloromethane; at 0 - 20℃; for 48h;	Step 1.To a mixture of 13a (5 g, 0.026 mol) in DCM (100 mL) was added Et3N (3.9 g, 0.038 mol) and TsCI (5.87 g, 0.030 mol) at 0 C, and the mixture stirred at rt for 48 h. The reaction was poured into water (100 mL) and extracted with EtOAc (200 mL). The organic layer was dried with Na2S04 and concentrated under reduced pressure. The residue was purified by flash column to afford 14a (6.0 g, 66.8%).
7.64 g	With pyridine; In chloroform; for 2h;Cooling with ice;	1) 4-Iodo-1-[(4-methylphenyl)sulfonyl]-1H-imidazole 4-Methylbenzenesulfonyl chloride (5.40 g) was added to a chloroform (50 mL) and pyridine (4.17 mL) solution that contained <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (5.00 g) under cooling in an ice bath, and the obtained solution was then stirred for 2 hours. Thereafter, the reaction solution was added to water, and the obtained mixture was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and was then concentrated under a reduced pressure. The obtained solid was recrystalllized from ethyl acetate-hexane, so as to obtain the title compound (7.64 g) in the form of a colorless solid. 1H NMR (600 MHz, CHLOROFORM-d) delta ppm 2.45 (s, 3H) 7.35 (d, J=1.38 Hz, 1H) 7.37 (d, J=8.25 Hz, 2H) 7.82 (d, J=8.25 Hz, 2H) 7.86 (d, J=1.38 Hz, 1H)

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 2378 - 2383
[2]Journal of Organic Chemistry,2007,vol. 72,p. 3741 - 3749
[3]European Journal of Organic Chemistry,2015,vol. 2015,p. 4658 - 4666
[4]Patent: WO2015/58163,2015,A2 .Location in patent: Paragraph 282
[5]Patent: US2013/137865,2013,A1 .Location in patent: Paragraph 0639; 0640

5
[ 71759-89-2 ]
[ 3188-13-4 ]
[ 163854-61-3 ]
1-(Ethoxymethyl)-5-iodoimidazole [ No CAS ]

Reference： [1]Journal of Organic Chemistry,1995,vol. 60,p. 2378 - 2383

6
[ 1746-25-4 ]
[ 71759-89-2 ]

Yield	Reaction Conditions	Operation in experiment
55%	With sodium sulfite; In N,N-dimethyl-formamide; at 110℃;Inert atmosphere;	2,4,5-triiodo-1H-imidazole was reacted with Na2SO3 in DMF (250 mL) and stirring at 110 C. for over night under N2 atmosphere. The reactin mixture was filtered, the filtrate was concentrated and poured into water, then extracted with EtOAc, the organic was washed with water, dried over Na2SO4, concentrated and purified by silica gel column to give 4-iodo-1H-imidazole (Yield=55%). LC-MS: m/z=195 [M+H+]
	With sodium sulfite; In ethanol; water; at 80℃; for 24h;	To the compound (35 g) obtained from the step a above in ethanol was added a saturated aqueous solution of sodium sulfite. The reaction mixture was refluxed at 80 0C for 24 hours, filtered and the filtrate was evaporated in vacuo to remove ethanol. The residual aqueous layer was extracted with ethyl acetate, dried over anhydrous sodium sulfate. The solvent removal in vacuo yielded the title compound (5.5 g)

Reference： [1]Patent: US2012/245144,2012,A1 .Location in patent: Page/Page column 118
[2]Journal of Medicinal Chemistry,1996,vol. 39,p. 3001 - 3013
[3]Patent: WO2006/38100,2006,A1 .Location in patent: Page/Page column 78

7
[ 71759-89-2 ]
[ 98-09-9 ]
[ 183060-05-1 ]

Reference： [1]Tetrahedron,1996,vol. 52,p. 13703 - 13712

8
[ 71759-89-2 ]
[ 183622-26-6 ]
[ 1025818-05-6 ]

Reference： [1]Journal of Medicinal Chemistry,1996,vol. 39,p. 4583 - 4591

9
[ 71759-89-2 ]
[ 999-97-3 ]
1-(trimethylsilanyl)-4-iodoimidazole [ No CAS ]

Reference： [1]Journal of Organic Chemistry,2006,vol. 71,p. 5000 - 5003

10
[ 2949-92-0 ]
[ 71759-89-2 ]
4-methylsulfanyl-1H-imidazole [ No CAS ]

Reference： [1]Synlett,2007,p. 980 - 982

11
[ 71759-89-2 ]
[ 630-19-3 ]
C₈H₁₄N₂O [ No CAS ]

Reference： [1]Synlett,2007,p. 980 - 982

12
[ 71759-89-2 ]
[ 100-44-7 ]
[ 941286-76-6 ]
[ 536760-32-4 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 3741 - 3749

13
[ 288-32-4 ]
[ 71759-89-2 ]

Reference： [1]European Journal of Organic Chemistry,2015,vol. 2015,p. 4658 - 4666
[2]Synthetic Communications,2008,vol. 38,p. 2881 - 2888
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 2944 - 2953
[4]Journal of Organic Chemistry,2007,vol. 72,p. 3741 - 3749
[5]Advanced Synthesis and Catalysis,2013,vol. 355,p. 499 - 507

14
[4-(1-benzenesulfonyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-dimethyl-amine [ No CAS ]
[ 71759-89-2 ]
[4-(1-benzenesulfonyl-3-(1H-imidazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-phenyl]-dimethyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%	With sodium carbonate; lithium chloride;bis-triphenylphosphine-palladium(II) chloride; In ethanol; water; toluene; at 120℃; for 0.25h;Microwaves;	A mixture of 16 (150 mg, 0. 298 mmol), 4-IODOIMIDAZOLE (86.7 mg, 0.447 mmol), dichlorobis (triphenylphosphine) palladium (II) (20.9 mg, 0.0298 mmol), LiCl (37.9 mg, 0. 894 MMOL) 9 M AQ. NA2CO3 (0.75 mL, 0.75 mmol) in toluene (1.8 ML) and EtOH (1. 8 ML) was microwaved at 120 C for 15 min. The reaction mixture was cooled, brine (3 mL) was added and the aqueous layer extracted with ethyl acetate (3 X 5 ML). Sorbent (HM-N, Jones Chromatography) was added, the solvent evaporated and the product purified by silicagel chromatography using MEOH : CH2CL2 (3: 97) (gradient elution) to give product 17 as A brown foam (111 mg, 84%); 1H NMR (400 MHz, CDCl3) 62. 96 (s, 6H), 6.77 (d, J = 8. 8 Hz, 2H), 7.48-7. 35 (m, 5H), 7.52 (t, J = 7. 6 Hz, 1H), 7.81 (s, 1H), 7.99 (s, 1H), 8. 11 (d, J = 7.5 Hz, 2H), 8. 27 (d, J = 2.0 Hz, 1H), 8.61 (d, J = 2. 1 HZ, 1H).

Reference： [1]Patent: WO2004/78756,2004,A2 .Location in patent: Page 107-109

15
[ 71759-89-2 ]
[ 24424-99-5 ]
[ 840481-77-8 ]

Yield	Reaction Conditions	Operation in experiment
46.2%	With sodium hydrogencarbonate; In tetrahydrofuran; water; at 20℃; for 18h;	To a flask was added 4-iodo-lH-imidazole (500 mg, 3.402 mmol) in 100 mL of THF followed by the addition of di-tert-butyl dicarbonate (1.485 g, 6. 804 mmol) and 5 mL of saturated NAHC03 solution. The reaction mixture was stirred at room temperature for 18 h and then diluted with EtOAc, and washed with HA0 and brine. The organic phase was dried over anhydrous MGS04, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-10% EtOAc/hexane. The product fractions were collected and concentrated to afford 388 mg (46.2 %) OF 4-IODO-IMIDAZOLE-1- carboxylic acid tert-butyl ester as a white solid.

Reference： [1]Organic and Biomolecular Chemistry,2011,vol. 9,p. 5129 - 5136
[2]Patent: WO2005/12283,2005,A1 .Location in patent: Page/Page column 70

16
[ 71759-89-2 ]
[ 60-29-7 ]
[ 76-83-5 ]
[ 96797-15-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	In N,N-dimethyl-formamide;	EXAMPLE 90 Synthesis of 4-Iodo-1-trityl-1H-imidazole To a solution of <strong>[71759-89-2]4-iodoimidazole</strong> (1 eq) in DMF at room temperature was added triphenylmethyl chloride (1.2 eq). After stirring at room temperature for 24 hours, the solution was poured into ice water and left stirring for 30 minutes. The solid was filtered and pumped on for several hours to yield the crude compound. Ethyl ether was added to the crude compound and the solution was filtered to yield 4-Iodo-1-trityl-1H-imidazole (92%) as a white solid. MH+(437).

Reference： [1]Patent: US2003/125266,2003,A1

Yield	Reaction Conditions	Operation in experiment
		Step C 4-Iodoimidazole A hot saturated solution of the diodide (12 g) in ethanol (60 ml) was mixed together with a solution of sodium thiosulfate (29 g) in water (10 ml). A white precipitate separated. The resulting mixture was heated at 100 C. for 24 h. then cooled and filtered. The filtrate was evaporated and the residue boiled three times with chloroform (400 ml portions) each time followed by a hot filtration. Concentration of the filtrate gave 4-iodoimidazole as a white solid. 1 H NMR (CD3 OD) d 7.20 (s, 1 H), 7.63 (s, 1 H).

18
[ 624-28-2 ]
[ 71759-89-2 ]
[ 883230-85-1 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In 1-methyl-pyrrolidin-2-one; at 100 - 110℃;	2,5-Dibromopyridine (2 g) and 4-iodo-lH-imidazole (2.45 g) obtained from step b above was dissolved in N-methylpyrrolidin-2-one (5 mL). To the reaction mixture was added anhydrous potassium carbonate (3.5 g) and the reaction mixture was heated overnight at about 100-110 0C. The reaction mixture was poured into cooled water and the solid that separated out was filtered and dried over phosphorous pentaoxide to yield the title compound. (670 mg).

Reference： [1]Patent: WO2006/38100,2006,A1 .Location in patent: Page/Page column 78

19
[ 71759-89-2 ]
[ 888312-81-0 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 47 Benzo[1,3]dioxol-5-ylmethyl-(3-[3-(4-iodo-imidazol-1-yl)-[1,2,4]thiadiazol-5-yl]-methyl-amino}-propyl)-carbamic Acid tert-butyl Ester Example 47 was prepared following the procedures described in the preparation of Example 1 using <strong>[71759-89-2]4-iodo-1H-imidazole</strong>. [M+H]+598.90.

Reference： [1]Patent: US2007/123572,2007,A1 .Location in patent: Page/Page column 28

20
[ 71759-89-2 ]
[ 1068103-70-7 ]
[ 1068104-41-5 ]

Yield	Reaction Conditions	Operation in experiment
97%	With potassium carbonate; In N,N-dimethyl-formamide; at 130℃; for 0.75h;	A stirred mixture of a compound of formulae VI (1 eq), a imidazole derivative (1.5 eq) and potassium carbonate (1 eq) in an organic solvent (e.g. DMF) is heated at 1300C for around 45 min, cooled, poured into water and extracted three times with ethyl acetate. The combined organic layers are washed two times with brine, dried (e g. MgSCU) and evaporated. The crude product is further purified by flash chromatography on silica gel (ethyl acetate/ heptane) and crystallization (e.g. ethyl acetate/ hexane) to give a compound of formulae X; 4-(5-Chloro-thiophen-2-yl)-2-(4-iodo-imidazol-l-yl)-6-trifluoromethyl-pyrimidine The title compound was prepared from 2-chloro-4-(5-chloro-thiophen-2-yl)-6- trifluoromethyl-pyrimidine (example A.I) (1.2 g, 4.0 mmol) and commercially available 4-iodo-imidazole (0.85 g, 4.4 mmol) according to the general procedure Ha. Obtained as an off-white solid (1.78 g, 97%). MS (ISP) 457.0 [(M+H)+]; mp 251 0C.

Reference： [1]Patent: WO2008/119689,2008,A1 .Location in patent: Page/Page column 21; 22

21
[ 860025-99-6 ]
[ 71759-89-2 ]
[ 868601-07-4 ]

Yield	Reaction Conditions	Operation in experiment
22%		EXAMPLE 1; [4-(1-{3-[2-(3-phenylsulphonylamino-phenyl)-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-imidazol-4-yl)-phenyl]-acetic acid-hydrotrifluoroacetate; a. Tert-butyl [3-(4-iodo-imidazol-1-yl)-1,1-dimethyl-propyl]-carbamate; 3.88 g (20 mmol) <strong>[71759-89-2]4-iodoimidazole</strong> are dissolved in 30 ml DMPU and at 5 C., 556 mg (22 mmol) 95% sodium hydride are added batchwise. After the development of gas has died down the reaction mixture is stirred for 1 hour at 10 C. Then a solution of 4.44 g (20 mmol) tert-butyl (3-chloro-1,1-dimethyl-propyl)-carbamate in 5 ml DMPU and 739 mg (2.0 mmol) tetrabutylammonium iodide are added. The reaction mixture is stirred for 16 hours at ambient temperature and then heated to 80 C. for 24 hours. After cooling to ambient temperature the reaction solution is poured onto a mixture of 500 ml ice water and 250 ml of ethyl acetate. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried on sodium sulphate and evaporated down using the rotary evaporator. The residue is chromatographed on silica gel (petroleum ether/ethyl acetate=80:20?0:100).Yield: 1.66 g (22% of theory)C13H22IN3O2 (379.24)Mass spectrum: (M+H)+=380Rf value: 0.45 (silica gel; petroleum ether/ethyl acetate=1:1)

Reference： [1]Patent: WO2005/108373,2005,A1 .Location in patent: Page/Page column 36-37
[2]Patent: US2008/300290,2008,A1 .Location in patent: Page/Page column 8

22
[ 71759-89-2 ]
[ 98-80-6 ]
[ 670-95-1 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,4-dioxane; water; at 90℃; for 3h;	4-lodo-1H-imidazole (194mg, LOmmol), phenylboronic acid (158.5 mg, 1.3mmol), potassium carbonate (345mg, 2.5mmol) and Pd (PPh3)2Cl2 (42 mg, 6%) were taken up in a degassed mixture of 1 ,4-dioxane (5mL) and water (0.8mL) under an atmosphere of nitrogen. The resulting mixture was heated at 901C for 3 hours. The reaction mixture was cooled to room temperature, and taken up in ethyl acetate and water. The organic phase was separated and the aqueous layer further extracted with 3x20 ml portions of ethyl acetate. The combined ethyl acetate layers were washed with water, brine, dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue was purified by flash chromatography to give the product (112 mg) with a yield of 78%.

Reference： [1]Patent: WO2009/93981,2009,A1 .Location in patent: Page/Page column 97

23
[ 381721-57-9 ]
[ 71759-89-2 ]
[ 701298-81-9 ]

Yield	Reaction Conditions	Operation in experiment
47%		A 1 M solution (22 mL) of ethylmagnesium bromide in THF was added to a solution of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (2.1 g) and tetramethylethylenediamine (1.7 mL) in THF (15 mL) at 25C or lower. After the reaction solution was stirred at 60C for 1 hour, a solution of tert-butyl 4-[(N-methoxy-N-methylcarbamoyl)methyl]piperazine-1-carboxylate (2.0 g) in THF (15 mL) was added at room temperature and stirred at room temperature for 16 hours. After an aqueous ammonium chloride solution was added, the reaction solution was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified with a silica gel column to obtain the title compound (41.0 g, 47%) as an oil. NMR (200 MHz, CDCl3) delta: 1.20-1.27 (2H, m), 1.47 (9H, s), 1.71-1.78 (2H, m), 2.75-2.85 (4H, m), 3.31-3.39 (1H, m), 4.07-4.13 (2H, m), 7.19 (1H, s), 7.65 (1H, s).

Reference： [1]Patent: EP1564213,2005,A1 .Location in patent: Page/Page column 59

24
[ 71759-89-2 ]
[ 824-94-2 ]
[ 1236042-08-2 ]
[ 1214247-82-1 ]

Reference： [1]Archiv der Pharmazie,2010,vol. 343,p. 40 - 47

25
[ 71759-89-2 ]
[ 824-94-2 ]
[ 1214247-82-1 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1:To a 000 mixture of <strong>[71759-89-2]4-iodoimidazole</strong> AlOa (5.0 g, 25.8 mmol) (Synthonix) in anhydrous THF (100 mL) is added NaH (60% in oil, 1 .24 g, 30.9 mmol). The resulting mixture is stirred for 10 mm before the addition of 4-methoxybenzyl chloride (4.37 mL, 32.2 mmol) (Aldrich). This mixture is allowed to warm to RT and is stirred overnight. An aqueous solution of saturated NH4CI (50 mL) is added and this mixture is stirred for 10 mm. The mixture is extracted with EtOAc (3x) and the layers are separated. The organic layer is washed with water and brine, dried with Mg504 and concentrated to provide crude material that is purified by Combif lash (20:80 to 80:20, EtOAc/hexanes) to provide AlOb.

Reference： [1]Archiv der Pharmazie,2010,vol. 343,p. 40 - 47
[2]Patent: WO2014/70978,2014,A1 .Location in patent: Page/Page column 27; 28

26
[ 71759-89-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
1-methyl-5-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-4-yl]-1H-pyrazole [ No CAS ]
[ 1254162-31-6 ]

Yield	Reaction Conditions	Operation in experiment
		Example 91 -Methyl-4-[1 -(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-4-yl]-1 H-p yrazol e (as a mixture with the 5-regioisomer) By following General procedure A (SEM Protection), <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (500 mg, 2.58 mmol) was used to prepare 4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1H- imidazole product (462 mg and 305 mg) (as a mixture with the 5-regioisomer). In a three separate tubes, a suspension of 4-iodo-1-(2-trimethylsilanyl-ethoxymethyl)- 1H-imidazole (100 mg, 0.308 mmol), 1-benzyl-4-(4,4,5,5-tetramethyl)-1,3,2- dioxaborolan-2-yl-1H-pyrazole (97 mg, 0.463 mmol) Pd2(dba)3 (3.0 mg, 0.003 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (5.0 mg, 0.012 mmol) in 2M aqueous K3PO4 (2 mol. eq.; 0.30 ml.) and 1,4-dioxane (0.6 ml.) was degassed with nitrogen. Each tube was heated in a microwave reactor at 80 0C for 1 hour. The combined reactions were diluted with H2O and CHCI3, filtered and extracted into CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The product was purified by SiO2 chromatography providing the title compound (as a mixture with the 5-regioisomer) (88 mg).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 112-113

27
[ 71759-89-2 ]
[ 1254163-00-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
[2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[4-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanol [ No CAS ]
[ 1254163-08-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 48[2-(2,6-Difluoro-phenyl)-pyridin-4-yl]-[5-(1 -methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl]- methanoneStep 1 : To a stirred solution of Example 9 (84 mg, 0.302 mmol; as a mixture of two regioisomers) in THF (2 ml.) at -78 0C was added n-BuLi (2.5M in hexanes; 0.262 ml_, 0.654 mmol) dropwise. The mixture was stirred at -78 0C for 1 hour before a solution of 2-(2,6-difluoro-phenyl)-pyridine-4-carbaldehyde (Example 42) (70 mg, 2.52 mmol) in THF (1 ml.) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and the mixture extracted with CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SiC>;2 chromatography providing [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5- (1 -methyl-1 H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]- methanol (78 mg, as a mixture with the 4-regioisomer).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 133

28
[ 71759-89-2 ]
[ 1254163-00-2 ]
[ 76513-69-4 ]
[ 761446-44-0 ]
[2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[4-(1-methyl-1H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-methanone [ No CAS ]
[ 1254163-10-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 48[2-(2,6-Difluoro-phenyl)-pyridin-4-yl]-[5-(1 -methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl]- methanoneStep 1 : To a stirred solution of Example 9 (84 mg, 0.302 mmol; as a mixture of two regioisomers) in THF (2 ml.) at -78 0C was added n-BuLi (2.5M in hexanes; 0.262 ml_, 0.654 mmol) dropwise. The mixture was stirred at -78 0C for 1 hour before a solution of 2-(2,6-difluoro-phenyl)-pyridine-4-carbaldehyde (Example 42) (70 mg, 2.52 mmol) in THF (1 ml.) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and the mixture extracted with CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SiC>;2 chromatography providing [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5- (1 -methyl-1 H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]- methanol (78 mg, as a mixture with the 4-regioisomer).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 133-134

29
[ 71759-89-2 ]
[ 1254163-00-2 ]
[ 761446-44-0 ]
[ 1254160-35-4 ]

Yield	Reaction Conditions	Operation in experiment
		Example 48[2-(2,6-Difluoro-phenyl)-pyridin-4-yl]-[5-(1 -methyl-1 H-pyrazol-4-yl)-1 H-imidazol-2-yl]- methanoneStep 1 : To a stirred solution of Example 9 (84 mg, 0.302 mmol; as a mixture of two regioisomers) in THF (2 ml.) at -78 0C was added n-BuLi (2.5M in hexanes; 0.262 ml_, 0.654 mmol) dropwise. The mixture was stirred at -78 0C for 1 hour before a solution of 2-(2,6-difluoro-phenyl)-pyridine-4-carbaldehyde (Example 42) (70 mg, 2.52 mmol) in THF (1 ml.) was added and the reaction was allowed to warm to room temperature overnight. The reaction was quenched with water and the mixture extracted with CHCI3 (x3). The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SiC>;2 chromatography providing [2-(2,6-difluoro-phenyl)-pyridin-4-yl]-[5- (1 -methyl-1 H-pyrazol-4-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1 H-imidazol-2-yl]- methanol (78 mg, as a mixture with the 4-regioisomer).

Reference： [1]Patent: WO2010/125402,2010,A1 .Location in patent: Page/Page column 133-134

30
[ 71759-89-2 ]
[ 213318-44-6 ]
[ 1300728-16-8 ]

Yield	Reaction Conditions	Operation in experiment
37%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 85℃;Inert atmosphere;	Example 30 2-(lH-imidazol-4-yl)-lH-indole; [0353] A mixture of DMF (3 mL) and 2M Na2C03 (0.75 mL) was purged with nitrogen for 10 minutes. <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (145.5 mg, 0.75 mmol), (l-(tert-butoxycarbonyl)-1H-indol- 2-yl)boronic acid (235.0 mg, 0.9 mmol) and Pd(PPh3)4 (86.7 mg, 75.0 mu?iotaomicron) were added followed by purging with nitrogen for an additional 2 minutes. The solution was heated at 85 C over night. The solution was poured into water (20 mL) and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with water (2 x 10 mL), brine and dried. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography on silica gel using 10% MeOH/DCM as the eluent. The BOC protecting group was lost during the reaction sequence. Yield = 37%. NMR:6.66 (s, 1 H), 7.07-7.15 (m, 2H), 7.32 (s, 1H), 7.33 (d, 1 H, JHz), 7.63 (s, 1 H), 9.47 (s, 1 H).

Reference： [1]Patent: WO2011/56652,2011,A1 .Location in patent: Page/Page column 117-118

31
[ 71759-89-2 ]
2,5-difurorboronic acid [ No CAS ]
[ 1334675-73-8 ]

Yield	Reaction Conditions	Operation in experiment
20%	With copper(l) chloride; In methanol; at 60℃; for 3h;	Step 1 Following a procedure similar to that outlined in Chem. Comm. 2004, 188-189: A solution of 2,5-difluorophenylboronic acid (47 mg, 0.30 mmol), <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (46 mg, 0.24 mmol), copper(I) chloride (1.8 mg, 0.018 mmol), and 1 mL of methanol was stirred under air at 60 C. for 3 h, then concentrated. Column chromatography (0-33% EtOAc/hexanes) afforded 14.5 mg (20%) of 1-(2,5-difluorophenyl)-<strong>[71759-89-2]4-iodo-1H-imidazole</strong> as a white solid.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 110-111

32
[ 71759-89-2 ]
(2,3,5-trifluorophenyl)boronic acid [ No CAS ]
[ 1334675-81-8 ]

Yield	Reaction Conditions	Operation in experiment
27%	With copper(I) oxide; In methanol; for 21h;	Step 2 Following a procedure similar to that outlined in Synthesis 2008, 795-799: A mixture of 2,3,5-trifluorophenylboronic acid (0.302 g, 1.72 mmol), <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (0.498 g, 2.57 mmol), 2 mL of methanol, and Cu2O (0.049 g, 0.34 mmol) was stirred under air for 21 h, then filtered through Celite and concentrated to an oily white solid. Column chromatography (0->33% EtOAc/hexanes) afforded 0.150 g (27%) of 4-iodo-1-(2,3,5-trifluorophenyl)-1H-imidazole as a white solid. MS: (M+H)+=325.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 112

33
[ 71759-89-2 ]
[ 7051-34-5 ]
[ 1334675-62-5 ]
[ 1334675-63-6 ]

Yield	Reaction Conditions	Operation in experiment
58%; 22%	With caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 3h;	Step 1 To a solution of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (800 mg, 4.12 mmol) in DMF (50 mL) was added cesium carbonate (5.37 g, 16.5 mmol) and (bromomethyl)cyclopropane (1.6 mL, 16.5 mmol). The reaction mixture was stirred at room temperature for 3 h then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed sequentially with water, sat'd LiCl and sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/heptane) to isolate first 590 mg (58%) of 1-cyclopropylmethyl-<strong>[71759-89-2]4-iodo-1H-imidazole</strong> as a pale yellow oil followed by 227 mg (22%) of 1-cyclopropylmethyl-5-iodo-1H-imidazole as a pale yellow oil.

Reference： [1]Patent: US2011/230462,2011,A1 .Location in patent: Page/Page column 107

34
[ 71759-89-2 ]
[ 2032-35-1 ]
[ 1341216-32-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide;	Step 1. 1-(2,2-diethoxyethyl)-<strong>[71759-89-2]4-iodo-1H-imidazole</strong> (260) To a stirred solution of <strong>[71759-89-2]4-iodoimidazole</strong> (10 g, 51.6 mmol) and bromoacetaldehyde diethyl acetal (9.31 mL) in DMSO (30 mL) was added K2CO3 (10.69 g, 77 mmol). The reaction mixture was heated at 110 C. for 16 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 50/50 over 20 CV). The desired fractions were collected and concentrated to afford title compound 260 (11.29 g, 36.4 mmol, 71% yield) as yellow oil. MS (m/z): 310.97 (M+H).

Reference： [1]Patent: US2011/257100,2011,A1

35
[ 71759-89-2 ]
[ 107-04-0 ]
[ 1342837-87-9 ]

Yield	Reaction Conditions	Operation in experiment
60%	With NaH; In tetrahydrofuran;	Step 1. 2-(4-iodo-1H-imidazol-1-yl)-N-(2-methoxyethyl)ethanamine (248) To a stirred solution of <strong>[71759-89-2]4-iodoimidazole</strong> (8.8 g, 45.4 mmol) in THF (200 mL) at 0 C. under nitrogen was added portion-wise NaH 60% (1.99 g, 49.9 mmol). After 15 min, 1-bromo-2-chloroethane (4.53 mL, 54.4 mmol) was added at 0 C. The reaction mixture was heated at 60 C. for 20 h. After cooling to RT, the reaction mixture was diluted with water and extracted with AcOEt. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; MeOH/AcOEt: 0/100 to 5/95 over 20 CV), to afford crude 1-(2-chloroethyl)-<strong>[71759-89-2]4-iodo-1H-imidazole</strong> not shown in the scheme 57 (7 g, 27.26 mmol, 60% yield) as colorless oil. MS (m/z): 256.83 (M+H).

Reference： [1]Patent: US2011/257100,2011,A1

36
[ 71759-89-2 ]
[ 107-04-0 ]
[ 57260-71-6 ]
[ 1342836-78-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In dimethyl sulfoxide;	Step 1. tert-butyl 4-(2-(4-iodo-1H-imidazol-1-yl)ethyl)piperazine-1-carboxylate (304) To a stirred solution of <strong>[71759-89-2]4-iodoimidazole</strong> (25 g, 129 mmol) and 1-bromo-2-chloroethane (12.87 ml, 155 mmol) in DMSO (250 ml) under nitrogen was added K2CO3 (26.7 g, 193 mmol). The reaction mixture was heated at 80 C. for 30 min. More 1-bromo-2-chloroethane (1.28 ml, 15.5 mmol) was added and the reaction mixture was heated at 80 C. for an additional 30 min. Finally, 1-Boc-piperazine (28.8 g, 155 mmol) was added and the reaction mixture heated at 80 C. for 1 h, cooled to RT and partitioned between water and AcOEt. The organic layer was collected, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 340 g cartridge; Hexane/AcOEt:40/60 to 0/100 over 15 CV) followed by another purification under different conditions (SNAP 100 g cartridge; MeOH/DCM: 0/100 to 5/95 over 15 CV), to afford title compound 304 (4 g, 9.85 mmol, 8% yield) as white solid. MS (m/z): 407.18 (M+H).

Reference： [1]Patent: US2011/257100,2011,A1

37
[ 71759-89-2 ]
[ 63503-60-6 ]
[ 1350712-79-6 ]

Yield	Reaction Conditions	Operation in experiment
48%	With oxygen;di-mu-hydroxo-bis[(N,N,N?,N?-tetramethylethylenediamine)copper(II)] chloride; In tetrahydrofuran; at 20℃; for 23.4167h;	Example 147.2-[l-(3-Chlorophenyl)-lH-imidazol-4-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)- 1 ,2,2-trimethyl-propyl)-amideStep 14-Iodo-lH-imidazole (1.0 g, 5.16 mmol) was dissolved in THF (32 mL). Copper TMEDA catalyst (480 mg, 1.03 mmol, Aldrich) and then 3-chlorophenylboronic acid (0.56 g, 3.6 mmol) were added. Oxygen gas was bubbled into the reaction mixture for 20 min, then the mixture was stirred for 90 min. An additional 0.28 g of 3-chlorophenylboronic acid was added followed by an additional 20 min of oxygen gas bubbling and 75 min of stirring at room temperature. An additional 0.28 g of 3-chlorophenylboronic acid was added followed by an additional 20min of oxygen gas bubbling and then stirring at room temperature for 20 h. The reaction mixture was filtered through a bed of neutral alumina and the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes) to give 0.76 g (48%) of 4-iodo-l-(3-chlorophenyl)-lH-imidazole.

Reference： [1]Patent: WO2011/144585,2011,A1 .Location in patent: Page/Page column 217

38
[ 558-30-5 ]
[ 71759-89-2 ]
[ 1282516-90-8 ]

Yield	Reaction Conditions	Operation in experiment
71%	With caesium carbonate; at 120℃; for 0.333333h;irradiation with microwave;	A mixture of <strong>[71759-89-2]4-iodo-1H-imidazole</strong>, Cs2CO3 in 2,2-dimethyl oxirane was stirred at 120 C. for 20 min under irradiation with microwave. The reaction mixture was concentrated, and purified to give 1-(4-iodo-1H-imidazol-1-yl)-2-methylpropan-2-ol (Yield=71%). LC-MS: m/z=266 [M+H+ ] 1H NMR (CDCl3, 400 MHz): delta7.36 (s, 1H), 7.06 (s, 1H), 3.84 (s, 2H), 1.22 (s, 6H).

Reference： [1]Patent: US2012/245144,2012,A1 .Location in patent: Page/Page column 118

39
[ 71759-89-2 ]
[ 1443425-57-7 ]

Reference： [1]Advanced Synthesis and Catalysis,2013,vol. 355,p. 499 - 507

40
[ 1443425-57-7 ]
[ 71759-89-2 ]

Reference： [1]Advanced Synthesis and Catalysis,2013,vol. 355,p. 499 - 507

41
[ 71759-89-2 ]
[ 6628-86-0 ]
[ 1443255-53-5 ]

Yield	Reaction Conditions	Operation in experiment
		Intermediate 4.1 : (5-chloro-2-nitro-phenyl)-(lH-imidazol-4-yl) methanol To a solution of 4-iodo-lH-imidazole (2 g, 10.3 mmol) in THF (20 mL) was added dropwise isopropylmagnesiumchloride (2 M in THF, 12 mL, 23.7 mmol) at room temperature. The reaction solution was stirred at rt for 2 h. To this solution was added 5-chloro-2-nitro-benzaldehyde (2.9 g, 15.5 mmol) in 10 mL THF. The solution was stirred at room temperature for 2 h. The reaction was quenched with aqueous NH4CI solution. The mixture was extracted twice with EA. The combined organic phases were dried and concentrated in vacuo. The residue was purified silica gel chromatography column (PE/EA, 3/1 to 1/1) to give the title compound as a brown solid

Reference： [1]Patent: WO2013/82751,2013,A1 .Location in patent: Page/Page column 21; 28

42
[ 74-96-4 ]
[ 71759-89-2 ]
[ 918643-51-3 ]

Yield	Reaction Conditions	Operation in experiment
		Step 1 To a solution of 113a (Synthonix, 5.0 g, 25.8 mmol) in THF (100 mL) at 0C is added portion wise NaH (60% in oil, 1.13 g, 28.3 mmol). The reaction is warmed to RT for 30 min and then cooled to 0C. EtBr is added and the reaction is stirred for 1 h at 0C, and then warmed to RT. The reaction is diluted ammonium chloride (10 mL) and NaHC03 (saturated) is added. The aqueous phase is extracted with EtOAc (100 mL). The organic layer is washed with water (2 x 20 mL), brine, dried (MgS04), filtered and concentrated under reduced pressure. Purification by chromatography (40-100% EtOAc/Hexanes) affords imidazole 113b.

Reference： [1]Patent: WO2013/91096,2013,A1 .Location in patent: Page/Page column 115

43
[ 71759-89-2 ]
[ 6226-25-1 ]
[ 1450739-58-8 ]
4-iodo-1-(2,2,2-trifluoroethyl)-1H-imidazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80 mg; 619 mg		Intermediate le 5-Iodo- l-(2,2,2-trifluoroethyl)- lH-imidazole In a 50 mL three-necked flask, 4-iodo-lH-imidazole (0.500 g, 2.58 mmol, Eq: 1.00) was combined under Ar with THF (7 ml) to give a colorless solution. Sodium hydride 55% (337 mg, 7.73 mmol, Eq: 3) was added at 0C (exothermic reaction, temperature rose to 17C). The reaction mixture was stirred at RT for 30 min. and then cooled down again to 0C, before 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.2 g, 5.16 mmol, Eq: 2), dissolved in THF (3 ml), was added. The white suspension was stirred at RT for additional 1.5 hours when TLC indicated that the reaction was complete. Work up: The reaction mixture was poured into 10 mL H20 and extracted with EtOAc (2 x 15 mL). The organic layers were combined, washed with brine, dried over Na2S04, and concentrated i. V. Purification : The crude product was purified by flash chromatography (silica gel, 70 g, 0% to 60% EtOAc in heptane) to yield 80 mg of the desired title compound as off-white solid, besides 619 mg of the unwanted 4-iodo-l-(2,2,2-trifluoro-ethyl)-lH-imidazole. MS (ESI): 276.9 [M+H]+.
80 mg; 619 mg		In a 50 mL three-necked flask, <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (0.500 g, 2.58 mmol, Eq: 1.00) was combined under Ar with THF (7 ml) to give a colorless solution. Sodium hydride 55% (337 mg, 7.73 mmol, Eq: 3) was added at 0 C. (exothermic reaction, temperature rose to 17 C.). The reaction mixture was stirred at RT for 30 min. and then cooled down again to 0 C., before 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.2 g, 5.16 mmol, Eq: 2), dissolved in THF (3 ml), was added. The white suspension was stirred at RT for additional 1.5 hours when TLC indicated that the reaction was complete. Work up: The reaction mixture was poured into 10 mL H2O and extracted with EtOAc (2*15 mL). The organic layers were combined, washed with brine, dried over Na2SO4, and concentrated i. V. Purification: The crude product was purified by flash chromatography (silica gel, 70 g, 0% to 60% EtOAc in heptane) to yield 80 mg of the desired title compound as off-white solid, besides 619 mg of the unwanted 4-iodo-1-(2,2,2-trifluoro-ethyl)-1H-imidazole. MS (ESI): 276.9 [M+H]+.

Reference： [1]Patent: WO2013/120771,2013,A1 .Location in patent: Page/Page column 48-49
[2]Patent: US2014/128429,2014,A1 .Location in patent: Paragraph 0326; 0327

44
[ 71759-89-2 ]
[ 1446333-39-6 ]
[ 1446333-41-0 ]

Yield	Reaction Conditions	Operation in experiment
51%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In 1,4-dioxane; at 85℃; for 48h;	Step D: A mixture of 7-fluoro-3-(tributylstannyl)-2H-chromen-2-one (1.15 g, 2.53 mmol), <strong>[71759-89-2]4-iodoimidazole</strong> (600 mg, 3.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (285 mg, 0.41 mmol), copper(I) iodide (115 mg, 0.60 mmol), and 1,4-dioxane (7 mL) was heated at 85 C for 2 d. The reaction mixture was partitioned between NH4OH and CH2CI2. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (30%> MeOH in CH2CI2). The product was triturated with CH2CI2, yielding 7- fluoro-3-(lH-imidazol-4-yl)-2H-chromen-2-one (298 mg, 51%) as a yellow solid. MS m/z 231.1 [M+H]+.
51%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In 1,4-dioxane; at 85℃; for 48h;	Step D: A mixture of 7-fluoro-3-(tributylstannyl)-2H-chromen-2-one (1.15 g, 2.53 mmol), <strong>[71759-89-2]4-iodoimidazole</strong> (600 mg, 3.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (285 mg, 0.41 mmol), copper(I) iodide (115 mg, 0.60 mmol), and 1,4-dioxane (7 mL) was heated at 85 C. for 2 d. The reaction mixture was partitioned between NH4OH and CH2Cl2. The organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography (30% MeOH in CH2Cl2). The product was triturated with CH2Cl2, yielding 7-fluoro-3-(1H-imidazol-4-yl)-2H-chromen-2-one (298 mg, 51%) as a yellow solid. MS m/z 231.1 [M+H]+.

Reference： [1]Patent: WO2013/101974,2013,A1 .Location in patent: Paragraph 00711; 00715
[2]Patent: US9617268,2017,B2 .Location in patent: Page/Page column 349; 350

45
[ 333-27-7 ]
[ 71759-89-2 ]
[ 71759-88-1 ]

Reference： [1]Journal of Organic Chemistry,2013,vol. 78,p. 12220 - 12223

46
[ 71759-89-2 ]
[ 54314-84-0 ]
[ 1609271-73-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; mineral oil; at 20℃; for 0.166667h;	Step 1:To a 000 mixture of AlOa (2.0 g, 10.3 mmol) (Synthonix) in anhydrous THF (40 mL) is added NaH (60% in oil, 495 mg, 12.4 mmol). The resulting mixture is stirred for 10 mm before the addition of (3-bromo-propoxymethyl)benzene (2.3 mL, 12.9 mmol) (Chembridge-BB). The resulting mixture is allowed to warm to RT, and then is stirred overnight. An aqueous solution of saturated NH4CI (20 mL) is added, and this mixture is stirred for 10 mm. The mixture is extracted with EtOAc (3x) and the layers are separated. The organic layer is washed with water,brine, dried with MgSO4 and concentrated to provide crude material that is purified by Combif lash (20:80 to 80:20, EtOAc/hexanes) to provide A22a.

Reference： [1]Patent: WO2014/70978,2014,A1 .Location in patent: Page/Page column 42

47
[ 71759-89-2 ]
[ 126747-14-6 ]
[ 34443-07-7 ]