1798-06-7|2-(4-Iodophenyl)acetic acid| Ambeed

Structure of 1798-06-7

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Quality Control of [ 1798-06-7 ] Purity: 95% SDS Specification

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Product Details of [ 1798-06-7 ]

CAS No. :	1798-06-7
Formula :	C₈H₇IO₂
M.W :	262.04
SMILES Code :	O=C(O)CC1=CC=C(I)C=C1
MDL No. :	MFCD00082985
InChI Key :	FJSHTWVDFAUNCO-UHFFFAOYSA-N
Pubchem ID :	137214

Safety of [ 1798-06-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1798-06-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	2
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	50.7
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.61
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	2.64
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.92
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	2.55
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	2.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.24

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.4
Solubility	0.104 mg/ml ; 0.000399 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-3.07
Solubility	0.221 mg/ml ; 0.000843 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	-3.13
Solubility	0.195 mg/ml ; 0.000745 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	No
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.02 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.56

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<0.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.67

Application In Synthesis of [ 1798-06-7 ]

* 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 [ 1798-06-7 ]

[ 1798-06-7 ] Synthesis Path-Downstream 1~35

1
[ 103-82-2 ]
[ 1798-06-7 ]

References: [1]Journal of the American Chemical Society,2001,vol. 123,p. 1828 - 1833.
[2]Journal of the American Chemical Society,1943,vol. 65,p. 1273,1274.
[3]Journal of the American Chemical Society,1919,vol. 41,p. 295.

2
[ 1798-06-7 ]
[ 84863-81-0 ]

References: [1]Bollettino Chimico Farmaceutico,1958,vol. 97,p. 602,607.
[2]Journal of the American Chemical Society,1984,vol. 106,p. 3344 - 3353.

3
[ 1197-55-3 ]
[ 1798-06-7 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7898 - 7909.
[2]Chemistry - A European Journal,2013,vol. 19,p. 15565 - 15571.
[3]Journal of the Chemical Society,1934,p. 161,164.
[4]Journal of Organic Chemistry,1980,vol. <22> 45,p. 4492 - 4494.

4
[ 1798-06-7 ]
[ 37051-38-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride; for 2h;Heating; Inert atmosphere;	A mixture of 4-iodophenylacetic acid (3 g, 11.5 mmol, 1 e.q.) and thionyl chloride (5 mL, 49 mmol, 4.5 e.q.) was heated in an 80 C oil bath under argon for 2 h. The reaction is then allowed to cool to room temperature. The excess thionyl chloride is removed in vacuum to give 6 as a dark yellow oil (3.2 g, 100%) which is used without further purification. NMR (300 MHz, CDCb) d 4.11 (2 H, s, CH2), 7.03 & 7.73(4 H, AA'XX', Ph-H).
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;	G2. DMF (5 drops) was added to a dichloromethane solution (30 mL) containing acid Gl (4.02 g, 15 mmol) and oxalyl chloride (1.61 mL, 18 mmol) at room temperature. After stirring for 1 h., excess dichloromethane was removed using reduced pressure. The remaining residue was dissolved in a dry THF and was added to a THF solution containing ethyl cuperate (23 mmol) at -20 C. After 20 min., a saturated copper sulfate solution was then added at -20 C, and the mixture was warmed to room temperature. The resulting solution was extracted with ethyl acetate, dried over sodium sulfate, and concentrated. The remaining residue was purified on silica eluting with 30% ethyl acetate/hexane solution to give 2.29 g (56 % yield) of ketone G2: ESI (MH+) m/z 275.
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 1h;Inert atmosphere;	Under an inert atmosphere and at room temperature, 4 ml (43.8 mmol) of oxalyl chloride are added to 3.8 g (14.6 mmol) of 4-iodophenylacetic acid suspended in dichloromethane (54 ml). Two drops of DMF are introduced and the reaction mixture is heated for one hour at room temperature, and then concentrated under reduced pressure. The residue is taken up in toluene and concentrated again. The acid chloride thus obtained is dissolved in dichloromethane (10 ml) and added dropwise to 5 g (14.6 mmol) of the compound obtained from step 1.9 suspended in dichloromethane (30 ml) in the presence of 2.45 g (29.2 mmol) of NaHCO3, under cold conditions (ice bath) and under an inert atmosphere. The reaction medium is stirred overnight at room temperature, and is then filtered through Celite and concentrated under reduced pressure. 8.5 g of product are obtained in the form of a yellow foam, and are used directly in the following step without purification. MH+: 586

With thionyl chloride; at 100℃; for 1.5h;Inert atmosphere;

Under an argon atmosphere, to 4-iodophenylacetic acid (11) (prepared by the process described in Chen, Q.-H. et al., Bioorg. Med. Chem. 14, 7898-7909 (2006)) (1.06 g, 4.05 mmol) was added thionyl chloride (5.00 mL, 68.6 mmol) and heated to reflux (100 C.) for 1.5 h. After cooling to room temperature, the mixture was concentrated under reduced pressure to give 4-iodophenylacetyl chloride (12) as a brown oily crude product, which was used in the next reaction without further purification.

References: [1]Patent: WO2021/62491,2021,A1 .Location in patent: Paragraph 00194.
[2]Journal of the American Chemical Society,1984,vol. 106,p. 3344 - 3353.
[3]Archiv der Pharmazie,1992,vol. 325,p. 751 - 760.
[4]Journal of medicinal chemistry,1996,vol. 39,p. 1220 - 1226.
[5]Canadian Journal of Chemistry,1999,vol. 77,p. 634 - 638.
[6]European Journal of Organic Chemistry,2004,p. 1298 - 1307.
[7]Journal of Medicinal Chemistry,2006,vol. 49,p. 5080 - 5092.
[8]Patent: WO2007/2701,2007,A2 .Location in patent: Page/Page column 52-53.
[9]Patent: US2011/124643,2011,A1 .Location in patent: Page/Page column 15.
[10]Patent: US8546568,2013,B2 .Location in patent: Page/Page column 29.
[11]Chemistry - A European Journal,2013,vol. 19,p. 15565 - 15571.
[12]Advanced Synthesis and Catalysis,2017,vol. 359,p. 1990 - 1995.
[13]European Journal of Organic Chemistry,2020,vol. 2020,p. 937 - 943.

5
[ 1798-06-7 ]
[ 62349-86-4 ]

References: [1]Journal of Organic Chemistry,1980,vol. <22> 45,p. 4492 - 4494.

6
[ 1798-06-7 ]
[ 530-62-1 ]
1-Imidazol-1-yl-2-(4-iodo-phenyl)-ethanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In acetonitrile; at 20℃; for 0.166667h;	intermediate 35; yV-[2-(4-Hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)-ethyl]-2-(4-iodo-phenyl)- acetamide; A solution of (4-iodo-phenyl)-acetic acid (5 g, 19.08 mmol) in MeCN was treated with CDI (3.40 g, 21 mmol) and allowed to stir at RT for 10 min after which a voluminous precipitate was produced. Triethylamine (5.80 ml_, 42 mmol) was added, followed by 7-(2-aminoethyl)-4-hydroxybenzo[d]thiazol-2(3H)-one hydrobromide (5.56 g, 19.08 mmol) and the reaction slurry was stirred at RT for 18 h. The reaction mixture was then partitioned between water (200 ml_) and EtOAc (2 x 300 ml_). The combined organic extracts were washed with 10% aqueous Na2SO4 (2 x 100 ml_) and brine (100 ml_), dried (Na2SO4), filtered and concentrated in vacuo to afford the title product.Yield: 6.18 g (71%).LC-MS (Method 2): Rt 2.98 min, m/z 455 [M+H] 496 [M+H+MeCN]+.

References: [1]Journal of Medicinal Chemistry,1982,vol. 25,p. 618 - 621.
[2]Patent: WO2008/149110,2008,A1 .Location in patent: Page/Page column 90.

7
[ 1798-06-7 ]
[ 52914-23-5 ]

Yield	Reaction Conditions	Operation in experiment
33%		To a stirred solution of 2-<strong>[1798-06-7](4-iodophenyl)acetic acid</strong> (2.00 g, 7.63 mmol) in tetrahydrofuran (150 ml_) at room temperature was added borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 7.63 ml_, 7.63 mmol). The resulting solution was stirred for 6 hours prior to dilution with brine, adjustment to pH = 13 with NaOH, and extraction with ethyl εicetate. The combined organic extracts were dried (Na2SO4), filtered, and concentrated to afford 192a (620 mg, 33%) as a light orange solid which was used in the subsequent reaction without further purification. LRMS (ESI): (calc) 248.1 ; (found) 271.1 (M+Na)+

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 7865 - 7869.
[2]Journal of the American Chemical Society,2001,vol. 123,p. 1828 - 1833.
[3]Liebigs Annalen der Chemie,1994,p. 1075 - 1092.
[4]Patent: WO2006/102760,2006,A1 .Location in patent: Page/Page column 121.
[5]Bioorganic and Medicinal Chemistry Letters,1999,vol. 9,p. 647 - 652.
[6]Journal of Medicinal Chemistry,2002,vol. 45,p. 2319 - 2324.
[7]Angewandte Chemie - International Edition,2015,vol. 54,p. 12777 - 12781.
Angew. Chem.,2015,vol. 127,p. 12968 - 12972,5.

8
[ 67-56-1 ]
[ 1798-06-7 ]
[ 63349-52-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h;	To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.
98%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h;	Preparation 38 Methyl 4-Iodophenylacetate To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.
98%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h;	To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.

98%	hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h;	To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MeOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.
98%	With hydrogenchloride; In 1,4-dioxane; at 20℃; for 24h;	To a stirred solution of 4-iodophenylacetic acid (5.0 g, 19.1 mmol) in MEOH (200 mL) was added 4N hydrochloric acid in dioxane (10 mL). The reaction mixture was stirred for 24 h at room temperature and then the solvent was removed under reduced pressure to give the title compound (5.17 g, 98% yield), which was used without further purification.
93%	With thionyl chloride; at 0 - 20℃; for 1h;	Methyl (4-iodophenyl)acetate (13).; To a solution of <strong>[1798-06-7](4-iodophenyl)acetic acid</strong> (12) (15.0 g, 57.0 mmol) in dry methanol (50 mL) was added SOCl2 (20.7 mL, 285 mmol, 5 equiv) drop wise at 00C. After stirring for 1 h at room temperature, the solvent was removed under reduced pressure and the residue dissolved in Et2O (400 mL). The organic phase was subsequently washed with saturated aqueous NaHCO3 (400 mL), saturated aqueous NH4Cl (400 mL) and brine (400 mL) and dried over MgSO4. Concentration under reduced pressure gave 13 (14.7 g, 93%). Rf=O.57 (EtOAc/hexane, 1 :4); 1H NMR (360 MHz, CDCl3) δ 7.65 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.3 Hz, 2H), 3.69 (s, 3H), 3.56 (s, 3H); 13C NMR (90 MHz, CDCl3) δ 171.3, 137.6, 133.5, 131.2, 92.5, 52.0, 40.5.
90%	With tert.-butylnitrite; at 40℃; for 48h;	Add compound 1z (0.5 mmol, 131.1 mg) and methanol containing 40 mol% tert-butyl nitrite to the reaction tube; then react for 48 hours at 40C in air; after the reaction, add sodium thiosulfate and stir. After quenching, using a rotary evaporator to remove the solvent, silica gel adsorption, and finally column chromatography with a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3z, the yield is 90%
86%	With thionyl chloride; at 20℃; for 36h;	A solution of 5 g (19 mmol) of [(4-IODO-PHENYL)-ACETIC ACID] in 50 mL of methanol [(MEOH)] was added dropwise 3.5 mL [(48] mmol) of [THIENYL] [CHLORIDE (SOCL2),] and the resulting mixture was stirred at rt for 36 h, after which time analysis by thin layer chromatography (TLC) indicated product formation. The mixture was concentrated to give 4.5 g [(86%] yield) of (4-iodo-phenyl)-acetic acid methyl ester as a pale beige oil as indicated by H NMR. A solution of 2. 88 mL (20.5 mmol) [OF DIISOPROPYLAMINE (IPR2NH)] in 50 mL of tetrahydrofuran [(THF)] was flushed with argon and cooled [TO-78 C.] To this solution was added dropwise 8.2 mL (20.5 mmol) [OF N-BUTYLLITHIUM (NBULI)] 2. 5 M solution in hexane, and the resulting mixture was stirred at-78 [C] for 20 min, after which time a solution of 4.5 g (16.3 mmol) of [(4-IODO-PHENYL)-ACETIC ACID METHYL ESTER] in 25 mL of THF was added dropwise. The mixture was allowed to warm up to rt for 40 min, then it was cooled again [TO-78 C,] and 2.62 mL (19.6 mmol) [OF CYCLOHEXANECARBONYL CHLORIDE] was added dropwise, and the resulting mixture was allowed to warm up to rt, and stirred at rt overnight under argon. The reaction mixture was quenched on ice by the addition of saturated ammonium chloride solution, and extracted with ethyl acetate. The combined organic extracts were washed with water, brine, dried over sodium sulfate and concentrated to give 7 g of a burgundy oil which was chromatographed on silica gel (Biotage; 10% ethyl acetate in hexane) to afford 5.06 g [(80%] yield) of desired [3-CYCLOHEXYL-2-(4-IODO-PHE72YL)-3-OXO-PROPIONIC ACID METHYL ESTER AS] a pale yellow solid as indicated [BY 1HNMR] (1: 2.6 keto: enol ratio). LC-MS-calcd for C16Hl9IO3 [[M++H] +] : 387.04, found: 387.0. According to a modified literature procedure (Collins, [1.] et al [J. MED. CHENA.] 2002, 45, 1887-1900) a solution of 5.06 g (13.1 mmol) of 3-cyclohexyl-2-(4-iodo-phenyl)-3-oxo- [PROPIONIC ACID METHYL ESTER] in 80 mL of dimethylsulfoxide (DMSO) was added a solution of 1.53 g (26.2 mmol) of sodium chloride (NaCI) in 5.8 mL of water (H2O), and the resulting mixture was heated at [150 C] for 3 h during which time a white solid formed. The reaction mixture was cooled to rt, poured into 500 mL of water, and extracted thoroughly with ethyl acetate. The combined organic extracts were washed with water (3 times), brine, dried over sodium sulfate and concentrated to give 4.13 g (96% yield) of desired 1-cyclohexyl-2- (4-iodo- phenyl)-ethanone as a yellow solid as indicated by 1H NMR (containing small traces of impurities). The product was used without any further purification in the next step. According to a modified literature procedure (Wasserman, H. H.; Ives, J. L. [J.] Org. Chem. 1985, 50, 3573-3580) a solution of 4.13 g (12.6 mmol) of [1-CYCLOHEXYL-2- (4-IODO-] [PHENYL)-ETHANONE] in 20 mL of toluene was flushed with argon. To this solution was added 2.7 mL (17.6 mmol) [OF METHOXY BIS (DIMETHYLAMINOQ7WLETHA7LE,] and the resulting mixture was stirred at 70C under argon overnight. The reaction mixture was concentrated to give 5.07 g of crude 1-cyclohexyl-3-dimethylamino-2-(4-iodo-phenyl)-propenone as indicated [BY'H NMR] (containing traces of starting material). The product was used without any further purification in the next step. A solution of 2.55 g (6.32 mmol max) of crude 1-cyclohexyl-3-dimethylamino-2-(4- [IODO-PHEENYL)-PROPENONE,] and 0.98 g (6.32 mmol) [OF 5-AFNINO-IH-PYRAZOLE-4-CARBOXYLIC ACID] ethyl ester in 30 mL of acetic acid [(HOAC)] was heated at reflux for 66 h, during which time a precipitate formed. The precipitate was filtered off and discarded, and the acetic acid filtrate was concentrated to a solid residue, which was washed with 1: 1 ethyl acetate: hexane and dried to give 1.67 g (55% yield) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3- carboxylic acid ethyl ester as a pale yellow [SOLID.'H] NMR (CDC13) [5] 8.57 (s, [1H),] 8. 53 (s, 1H), 7.86-7. 83 (d, J= 8.4 Hz, 2H), 7.1-7. 06 (d, J= 8.4 Hz, 2H), 4.46 (q, 2H, J= 7.2 Hz), 3.31- 3.21 [(M,] 1H), 2.62-2. 41 [(M,] 2H), 1.87-1. 82 [(M,] 2H), 1.74-1. 66 [(IN,] 3H), 1.44 (t, 3H, J= 7.2 Hz), 1.41-1. 21 [(M,] 3H). A solution of 1.66 g (4.1 mmol max) of crude 1-cyclohexyl-3-dimethylamino-2-(4-iodo- [PHENYL)-PROPENONE,] and 0.44 g (4.1 mmol) [OF 5-AMI7LO-LH-PYRAZOLE-4-CARBONITRILE IN] 20 mL of acetic acid [(HOAC)] was heated at reflux for [66 H,] during which time a finely dispersed precipitate formed. Since all attempts to filter off the precipitate were unsuccessful, the reaction mixture was concentrated to give a brown residue which was chromatographed on silica gel (Biotage; 2% ethyl acetate in dichloromethane) to afford 1.09 g (62% yield) of 7- cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a yellow solid NMR (CDC13) [6] 8.49 (s, 1H), 8.39 (s, 1H), 7.88-7. 86 (d, J= 8.4 Hz, 2H), 7.07-7. 05 (d, J= 8.4 Hz, [2H),] 4.13 (q, 2H, J= 7.2 Hz), 3.28-3. 21 [(M,] 1H), 2.59-2. 47 [(M,] 2H), 1.87-1. 8...
	With sulfuric acid; at 85℃; for 16h;Inert atmosphere;	A vessel was charged with Compound Q21A (10 g, 38.1 mmol, 1.00 eq ) in MeOH (60 mL). H2SO4 (3.74 g, 38.1 mmol, 2.03 mL, 1.00 eq ) was added to the mixture under N2. The reaction was stirred at 85 C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and then reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with saturated aq NaHCCh (70, 50mL). The final organic phase was concentrated under reduced pressure to give Compound Q21B. NMR (400 MHz, CDCh) d 7.65 (d, J= 8.4 Hz, 2H), 7.04 (d, J= 8.4 Hz, 2H), 3.70 (s, 3H), 3.57 (s, 2H).

References: [1]European Journal of Organic Chemistry,2018,vol. 2018,p. 6194 - 6198.
[2]Patent: US2004/242622,2004,A1 .Location in patent: Page 38.
[3]Patent: US2005/113417,2005,A1 .Location in patent: Page/Page column 45.
[4]Patent: US2006/35933,2006,A1 .Location in patent: Page/Page column 29.
[5]Patent: WO2006/23457,2006,A1 .Location in patent: Page/Page column 74.
[6]Patent: WO2004/89892,2004,A2 .Location in patent: Page 113.
[7]Bioorganic and Medicinal Chemistry Letters,2010,vol. 20,p. 896 - 902.
[8]Journal of the American Chemical Society,2019,vol. 141,p. 17295 - 17304.
[9]Patent: US6359135,2002,B1 .Location in patent: Page column 54.
[10]Patent: US6369261,2002,B1 .Location in patent: Page column 52.
[11]Patent: US6369225,2002,B1 .Location in patent: Page column 25,53.
[12]Chemistry - A European Journal,2007,vol. 13,p. 6082 - 6089.
[13]Patent: WO2008/68516,2008,A1 .Location in patent: Page/Page column 15; 28.
[14]Patent: CN112552171,2021,A .Location in patent: Paragraph 0048-0049.
[15]European Journal of Organic Chemistry,2021,vol. 2021,p. 2713 - 2718.
[16]Patent: WO2003/101993,2003,A1 .Location in patent: Page 42.
[17]Journal of Medicinal Chemistry,1997,vol. 40,p. 1422 - 1438.
[18]Journal of Medicinal Chemistry,1995,vol. 38,p. 1837 - 1840.
[19]Journal of Medicinal Chemistry,2007,vol. 50,p. 856 - 864.
[20]Pharmaceuticals,2017,vol. 10.
[21]Patent: WO2020/176510,2020,A1 .Location in patent: Paragraph 0345.
[22]Journal of the American Chemical Society,2021,vol. 143,p. 20616 - 20621.
[23]Chemical Communications,2021,vol. 57,p. 12643 - 12646.
[24]Organic Letters,2022,vol. 24,p. 1706 - 1710.

9
[ 1798-06-7 ]
[ 5720-05-8 ]
2-(4'-methyl-biphenyl-4-yl)-acetamide [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2001,vol. 40,p. 938 - 941.

10
[ 1798-06-7 ]
[ 98-80-6 ]
[ 63780-50-7 ]

References: [1]Angewandte Chemie - International Edition,2001,vol. 40,p. 938 - 941.

11
[ 50541-93-0 ]
[ 1798-06-7 ]
N-(1-benzyl-piperidin-4-yl)-2-(4-iodo-phenyl)-acetamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2001,vol. 44,p. 4404 - 4415.

12
[ 110-91-8 ]
[ 1798-06-7 ]
[ 364793-89-5 ]

Yield	Reaction Conditions	Operation in experiment
62.1%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;	2-(4-Iodo-phenyl)-l-morpholin-4-yl-ethano Triethylamine (5.30 mL, 38.0 mmol), HOBt (3.96 g, 28.5 mmol) and EDC.HCl (5.47 g, 28.5 mmol) were added to a solution of (4-iodo-phenyl)-acetic acid (5.0 g, 19.0 mmol) in DMF (100 mL) and stirred. After 5 min morpholine (2.0 mL, 22.9 mmol) was added at RT. The reaction mixture was stirred at RT for 16 h. The reaction mixture was poured into ice-cold water (50 mL) and obtained solid was filtered, dried to get 3.92 g (Yield: 62.1 %) of the title compound as a white solid. 1H NMR (DMSO-dg, 400 MHz, TMS) δ: 7.66-7.64 (2H, d), 7.04-7.02 (2H, d), 3.68 (2H, s), 3.54-3.42 (8H, m).

References: [1]Patent: WO2014/106612,2014,A1 .Location in patent: Page/Page column 31.
[2]Bioorganic and Medicinal Chemistry Letters,2002,vol. 12,p. 2989 - 2992.

13
[ 1798-06-7 ]
[ 75-65-0 ]
[ 856250-87-8 ]

References: [1]Journal of Medicinal Chemistry,2004,vol. 47,p. 18 - 21.
[2]Angewandte Chemie - International Edition,2021,vol. 60,p. 22236 - 22240.
Angew. Chem.,2021,vol. 133,p. 22410 - 22414.

14
[ 696-63-9 ]
[ 1798-06-7 ]
[ 252973-19-6 ]

References: [1]Organic Letters,2005,vol. 7,p. 2719 - 2722.

15
(5-mercapto-4-phenyl-4H-[1,2,4]triazol-3-ylmethyl)-carbamic acid tert-butyl ester [ No CAS ]
[ 1798-06-7 ]
(4-[5-(aminomethyl)-4-phenyl-4H-1,2,4-triazol-3-yl]thio}phenyl)acetic acid [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 2719 - 2722.

16
[ 1798-06-7 ]
[ 7217-59-6 ]
{4-[(2-methoxyphenyl)thio]phenyl}acetic acid [ No CAS ]
[4-(2-methoxy-benzenesulfinyl)-phenyl]-acetic acid [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 2719 - 2722.

17
[ 1798-06-7 ]
[ 825-83-2 ]
(4-[4-(trifluoromethyl)phenyl]thio}phenyl)acetic acid [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 2719 - 2722.

18
[ 1798-06-7 ]
[ 106-45-6 ]
{4-[(4-methylphenyl)thio]phenyl}acetic acid [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 2719 - 2722.

19
[ 1798-06-7 ]
[ 137-06-4 ]
{4-[(2-methylphenyl)thio]phenyl}acetic acid [ No CAS ]

References: [1]Organic Letters,2005,vol. 7,p. 2719 - 2722.

20
[ 64-17-5 ]
[ 1798-06-7 ]
[ 15250-46-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sulfuric acid; for 7h;Heating / reflux;	1. 25 ml (0. 023 mol) of concentrated sulphuric acid are added dropwise to a mixture of 6. 14 g (0. 023 mol) of 4-iodophenylacetic acid in 50 ml of ethanol. The reaction medium is then heated under reflux for 7 h, and then concentrated in a rotary evaporator under vacuum. Water is added to the residue obtained. The solution is neutralized by adding sodium bicarbonate. The desired product is extracted by adding ethyl ether. The organic phase is washed with water, dried over magnesium sulphate and concentrated in a rotary evaporator. The product is purified by filtration on a silica column, eluted with a dichloromethane 8/heptane 2 mixture. After evaporation of the solvents, 6. 2 G (96%) of the expected compound are recovered in the form of a colourless oil.
90%	With sulfuric acid;Heating / reflux; Neat (no solvent);	[4-IODOPHENYLACETIC] acid (3 g), ethanol (20 mL) and conc. [H2SO4] (5 mL) were refluxed overnight. Ca. 15 mL ethanol was then evaporated, the residue was extracted with dichloromethane (3 x 100 mL), the combined organic extracts were washed with sat. aq. [NAHCO3,] dried over [NA2S04] and evaporated in vacuo to afford 2.97 g (90 %) of 121JP58 as a yellow oil. Characterization Data [: 1H-NMR (CDC13) ] 7.62 (d, 2H, J= 8.4), 7.02 (d, 2H, J = 8.4), 4.07 (q, 2 H, [J=] 7.0), 3.59 (s, 2H), 1.12 (t, 3H, [J=] 7.0).
43%	With sulfuric acid;Reflux; Inert atmosphere;	To a solution of A (50 g, 0.2 mol, 1 .Oeq) in EtOH (200m1, 2.Omol, 10.0 eq) was added catalytic H2S04 and the reaction heated at ref lux under N2 overnight. The mixture was diluted with 250 mL water and extracted with 2x1 50 mL EtOAc. The combined organic fractions were concentrated and purified by column chromatography (EtOAc: PE1 :50 to 1:10) to give the title compound (24 g, 43%) as a colorless solid.

With hydrogenchloride; for 16h;Reflux;

A solution of 2f1 (Lancaster; 4.54 g, 17.3 mmol) and concentrated HCI in EtOH (100 mL) is heated to reflux for 16 h. The cooled mixture is concentrated under reduced pressure and the residue diluted with EtOAc. The solution is washed with aqueous saturated NaHC03 solution, water and brine, dried (MgS04), filtered and concentrated under reduced pressure. The resulting ethyl ester is transformed into compound 2f2 using the procedure described in step 1 of example 2c.

References: [1]Journal of Medicinal Chemistry,2005,vol. 48,p. 7153 - 7165.
[2]Patent: WO2004/71504,2004,A1 .Location in patent: Page/Page column 31.
[3]Patent: WO2004/808,2003,A2 .Location in patent: Page 86.
[4]Patent: WO2018/28,2018,A1 .Location in patent: Page/Page column 30.
[5]Patent: WO2011/100838,2011,A1 .Location in patent: Page/Page column 36.

21
[ 1798-06-7 ]
[ 2028-63-9 ]
[ 915038-35-6 ]

References: [1]Bioorganic and Medicinal Chemistry,2006,vol. 14,p. 7898 - 7909.

22
(1R)-1-{5-[(2,2,2-trifluoroethyl)oxy]pyridin-2-yl}ethylamine dihydrochloride [ No CAS ]
[ 1798-06-7 ]
[ 953780-66-0 ]

Yield	Reaction Conditions	Operation in experiment
92%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 20℃; for 3h;	EXAMPLE 32; <n="68"/>2-r4-riH-Pyrazol-l-vnphenyll-N-UlR)-l-r5-f2.2.2-trifluoroethoxy)pyridin-2-yl1ethvnacetamxde; To a 50 ml round bottom flask equipped with a magnetic stir bar were added 4- iodophenylacetic acid (1.048 g, 4.000 mmol), (lR)-l-{5-[(2,2,2-trifluoroethyl)oxo]pyridin-2- yl}ethylamine dihydrochloride (1.172 g, 4.000 mmol). l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.767 g, 4.000 mmol), l-hydroxy-7-azabenzotriazole (0.544 g, 4.000 mmol) and triethylamine (1.115 ml, 8.000 mmol) into 10.0 ml OfCH2Cl2. The resulting solution was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and the two layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. The residue was dissolved into CH2C12 (20 ml). Hexanes was added while stirring until slightly cloudy. A white crystal gradually crystallized on the wall of the flask. The mixture was allowed to sit overnight. The solvent was decanted and the crystal was washed with hexanes (3 x 10 ml). Dried under vacuum to give 2-(4-iodophenyl)-N-((l R)-I- {5-[(2,2,2-trifluoroethyl)oxo]pyridin-2-yl}ethyl)acetamide as a white solid (1.700 g, 92%). 1HNMR (CDCl3, 400 MHz) δ 8.226 (d, J= 2.75 Hz5 IH); 7.657 (d, J= 8.33 Hz, 2H); 7.223 (dd, J= 2.89 Hz, J= 8.57 Hz5 IH); 7.169 (d, J= 8.51 Hz3 2H); 7.031 (d, J= 8.15 Hz, 2H); 6.736 (d, J= 6.87 Hz, IH); 5.091 (dq, J= 7.01 Hz, IH); 4.387 (dd, J= 7.97 Hz, J= 15.93 Hz, 2H); 3.513 (s, 2H); 1.400 (d, J= 6.77 Hz, 3H); MS (Electrospray): m/z 465.0 (M+H).

References: [1]Patent: WO2007/120729,2007,A2 .Location in patent: Page/Page column 66-67.

23
[ 1798-06-7 ]
⁽¹⁵⁾NC₈H₈OI [ No CAS ]

References: [1]Journal of labelled compounds and radiopharmaceuticals,2007,vol. 50,p. 273 - 276.

24
[ 1798-06-7 ]
[ 192804-75-4 ]