[ CAS No. 90-99-3 ] {[proInfo.proName]}

Name: 90-99-3|Benzhydryl Chloride|95%
Brand: Ambeed
SKU: A674425
Rating: 99 (32 reviews)

,{[proInfo.pro_purity]}

Cat. No.: {[proInfo.prAm]}

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Quality Control of [ 90-99-3 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 90-99-3 ]

SDS Specification

Alternatived Products of [ 90-99-3 ]

Product Details of [ 90-99-3 ]

CAS No. :	90-99-3	MDL No. :	MFCD00000855
Formula :	C₁₃H₁₁Cl	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZDVDCDLBOLSVGM-UHFFFAOYSA-N
M.W :	202.68	Pubchem ID :	7035
Synonyms :

Calculated chemistry of [ 90-99-3 ]

Physicochemical Properties

Num. heavy atoms :	14
Num. arom. heavy atoms :	12
Fraction Csp3 :	0.08
Num. rotatable bonds :	2
Num. H-bond acceptors :	0.0
Num. H-bond donors :	0.0
Molar Refractivity :	60.69
TPSA :	0.0 Å²

Pharmacokinetics

GI absorption :	Low
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) :	-4.74 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.5
Log Po/w (XLOGP3) :	3.94
Log Po/w (WLOGP) :	3.69
Log Po/w (MLOGP) :	4.41
Log Po/w (SILICOS-IT) :	4.23
Consensus Log Po/w :	3.76

Druglikeness

Lipinski :	1.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-4.08
Solubility :	0.0168 mg/ml ; 0.000083 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.64
Solubility :	0.0465 mg/ml ; 0.000229 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.58
Solubility :	0.000528 mg/ml ; 0.00000261 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	2.0
Synthetic accessibility :	1.94

Safety of [ 90-99-3 ]

Signal Word:	Danger	Class:	8
Precautionary Statements:	P501-P234-P264-P280-P390-P303+P361+P353-P301+P330+P331-P363-P304+P340+P310-P305+P351+P338+P310-P406-P405	UN#:	3265
Hazard Statements:	H314-H290	Packing Group:	Ⅱ
GHS Pictogram:

Application In Synthesis of [ 90-99-3 ]

* 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 [ 90-99-3 ]
Downstream synthetic route of [ 90-99-3 ]

[ 90-99-3 ] Synthesis Path-Upstream 1~16

1
[ 90-99-3 ]
[ 7431-45-0 ]

Reference： [1] Journal of the Chemical Society - Perkin Transactions 1, 1997, # 24, p. 3581 - 3585

2
[ 142-64-3 ]
[ 90-99-3 ]
[ 841-77-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate In tetrahydrofuranReflux	Compound, 2 (250 mg, 1.23 mmol) was taken in THF, and piperazinedihydrochloride (199 mg, 1.25 mmol) and K₂CO₃(690mg, 5 mmol) were added. The reaction mixture was refluxed overnight.After complete reaction the solvent was removed under reduced pressure and theprecipitate obtained was washed with water and hexane (5 x 3ml). The crudeproduct was purified by column chromatographyusing gradient of ethylacetate andhexane (20 percent v/v) to obtain off white color compound. Yield 80 percent (250mg). M.p. 91-92C.¹H NMR(300 MHz, CDCl₃) δ (ppm): 7.38-7.12 (m, 10 H), 4.21 (s, 1H),2.40 (Br, 8 H).

Reference： [1] Tetrahedron Letters, 2013, vol. 54, # 28, p. 3688 - 3693
[2] Medicinal Chemistry Research, 2007, vol. 16, # 4, p. 179 - 187
[3] European Journal of Medicinal Chemistry, 2009, vol. 44, # 3, p. 1223 - 1229
[4] Medicinal Chemistry Research, 2014, vol. 23, # 6, p. 3207 - 3219

3
[ 110-85-0 ]
[ 90-99-3 ]
[ 841-77-0 ]

Yield	Reaction Conditions	Operation in experiment
215 g	at 60 - 100℃;	General procedure: NaBH4 (0.6mol) was added to a stirred solution of benzophenones (1.0 mol)in methanol (2 vol) portionwise at room temperature for 45 min. The mixture was stirred for 2–3 h at ambient temperature (completion of reaction was monitoredby TLC), and was diluted with water (750 ml), acidified with acetic acid to pH 4,and extracted with dichloromethane (2x400 ml). The organic layer was washed with water (200 ml) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to get pure benzhydrol derivatives as a white to off-white solid in 93–97percent yield. To the benzhydrol derivatives (1.0 mol) in toluene (370 ml) was added concentrated HCl (35percent in H2O, 370 ml) and tetrabutylammonium bromide(0.01 mol) at room temperature under stirring. Stirring was continued at 40–45 °C for 6–7 h. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature. The organic layer was separated and concentrated under vacuum to obtain crude benzhydryl chloride derivatives as a light brown liquid in 95–97percent yield. To this benzhydryl chloride (0.96 mol) derivatives in toluene (380 ml) was added anhydrous piperazine (5.0 mol) at 60–70 °C for 45–60 min. The resulting mixture was heated under stirring at 90–100 °C for 8–10 h. The mixture was cooled after completion of the reaction. Water (380 ml) was added, and the organic layer was separated. The latter was washed with a 1:1 mixture of concentrated HCl/water(2x350 ml) and neutralized with 20percent NaOH solution (750 ml). The water layer was re-extracted into toluene (2x300 ml), dried over anhydrous sodium sulfate, and concentrated under vacuum to result pure diphenylmethylpiperazine compounds (2a–c) as a white to off-white solid with yields up to 88percent.

Reference： [1] Chemical and Pharmaceutical Bulletin, 1999, vol. 47, # 2, p. 177 - 181
[2] ChemSusChem, 2016, vol. 9, # 1, p. 67 - 74
[3] Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562
[4] Analytical Chemistry, 2014, vol. 86, # 17, p. 8693 - 8699
[5] Arzneimittel-Forschung/Drug Research, 1987, vol. 37, # 10, p. 1103 - 1107
[6] Journal of Medicinal Chemistry, 1997, vol. 40, # 13, p. 2047 - 2052
[7] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2519 - 2525
[8] Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 2, p. 371 - 385
[9] Molecular Crystals and Liquid Crystals, 2007, vol. 474, # 1, p. 67 - 76
[10] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1378 - 1383
[11] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1822 - 1826
[12] Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 2, p. 205 - 214
[13] Synthetic Communications, 2014, vol. 44, # 5, p. 600 - 609
[14] Journal of Chemistry, 2016, vol. 2016,
[15] Bioorganic and Medicinal Chemistry, 2018,

4
[ 90-99-3 ]
[ 841-77-0 ]

Reference： [1] Archiv der Pharmazie, 1988, vol. 321, # 3, p. 171 - 174
[2] Yakugaku Zasshi, 1954, vol. 74, p. 1049[3] Chem.Abstr., 1955, p. 11666

5
[ 7755-92-2 ]
[ 90-99-3 ]
[ 841-77-0 ]

Reference： [1] Patent: US5147876, 1992, A,

6
[ 90-99-3 ]
[ 750512-44-8 ]
[ 298-57-7 ]

Reference： [1] Synthetic Communications, 2014, vol. 44, # 5, p. 600 - 609

7
[ 90-99-3 ]
[ 298-57-7 ]

Reference： [1] ChemSusChem, 2016, vol. 9, # 1, p. 67 - 74

8
[ 108-01-0 ]
[ 90-99-3 ]
[ 58-73-1 ]

Reference： [1] Chemical Science, 2013, vol. 4, # 7, p. 2822 - 2827
[2] Patent: US2751388, 1950, ,
[3] Patent: DE927689, 1952, ,
[4] Chemical Science, 2017, vol. 8, # 6, p. 4363 - 4370
[5] Patent: DE927689, 1952, ,
[6] Patent: US2751388, 1950, ,

9
[ 108-01-0 ]
[ 90-99-3 ]
[ 58-73-1 ]
[ 574-42-5 ]

Reference： [1] Chemical Science, 2013, vol. 4, # 7, p. 2822 - 2827

10
[ 90-99-3 ]
[ 27329-60-8 ]

Reference： [1] Patent: JP2005/200358, 2005, A, . Location in patent: Page/Page column 35-36

11
[ 90-99-3 ]
[ 122-52-1 ]
[ 27329-60-8 ]

Reference： [1] Patent: JP2005/298421, 2005, A, . Location in patent: Page/Page column 40
[2] Patent: JP2005/213183, 2005, A, . Location in patent: Page/Page column 40
[3] European Journal of Medicinal Chemistry, 1993, vol. 28, # 12, p. 943 - 948

12
[ 60-29-7 ]
[ 762-04-9 ]
[ 90-99-3 ]
[ 27329-60-8 ]

Reference： [1] Uchenye Zapiski, Kazanskii Gosudarstvennyi Universitet, 1956, vol. 116, # 2, p. 71,108, 109[2] Chem.Abstr., 1957, p. 6581

13
[ 108-01-0 ]
[ 90-99-3 ]
[ 147-24-0 ]

Reference： [1] Science, 2016, vol. 352, # 6281, p. 61 - 67

14
[ 108-01-0 ]
[ 90-99-3 ]
[ 147-24-0 ]
[ 2498-25-1 ]

Reference： [1] Chemical Science, 2013, vol. 4, # 7, p. 2822 - 2827

15
[ 90-99-3 ]
[ 147-24-0 ]

Reference： [1] Recueil des Travaux Chimiques des Pays-Bas, 1952, vol. 71, p. 431

16
[ 108-01-0 ]
[ 90-99-3 ]
[ 147-24-0 ]
[ 2498-25-1 ]

Reference： [1] Chemical Science, 2013, vol. 4, # 7, p. 2822 - 2827

[ 90-99-3 ] Synthesis Path-Downstream 1~88

1
[ 5570-78-5 ]
[ 90-99-3 ]
4-benzhydryloxy-1-isopropyl-piperidine; hydrochloride [ No CAS ]

Reference： [1]Patent: US2751388,1950,

2
[ 122-96-3 ]
[ 90-99-3 ]
[ 96773-57-8 ]

Reference： [1]Chemicke Listy,1949,vol. 43,p. 257,260
Chem.Abstr.,1951,p. 577

3
[ 91-01-0 ]
[ 90-99-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With 1,2,3-Benzotriazole; thionyl chloride In dichloromethane at 20℃;
100%	With hydrogenchloride; tetrabutylammonium bromide In lithium hydroxide monohydrate at 40 - 45℃;
97%	With hydrogenchloride; tetrabutylammonium bromide In lithium hydroxide monohydrate; toluene at 40 - 45℃;	General Method for the Preparation of 1-Benzhydrylpiperazine Derivatives (2a-c) General procedure: NaBH4 (0.6mol) was added to a stirred solution of benzophenones (1.0 mol)in methanol (2 vol) portionwise at room temperature for 45 min. The mixture was stirred for 2-3 h at ambient temperature (completion of reaction was monitoredby TLC), and was diluted with water (750 ml), acidified with acetic acid to pH 4,and extracted with dichloromethane (2x400 ml). The organic layer was washed with water (200 ml) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to get pure benzhydrol derivatives as a white to off-white solid in 93-97% yield. To the benzhydrol derivatives (1.0 mol) in toluene (370 ml) was added concentrated HCl (35% in H2O, 370 ml) and tetrabutylammonium bromide(0.01 mol) at room temperature under stirring. Stirring was continued at 40-45 °C for 6-7 h. After completion of the reaction as indicated by TLC, the mixture was cooled to room temperature. The organic layer was separated and concentrated under vacuum to obtain crude benzhydryl chloride derivatives as a light brown liquid in 95-97% yield. To this benzhydryl chloride (0.96 mol) derivatives in toluene (380 ml) was added anhydrous piperazine (5.0 mol) at 60-70 °C for 45-60 min. The resulting mixture was heated under stirring at 90-100 °C for 8-10 h. The mixture was cooled after completion of the reaction. Water (380 ml) was added, and the organic layer was separated. The latter was washed with a 1:1 mixture of concentrated HCl/water(2x350 ml) and neutralized with 20% NaOH solution (750 ml). The water layer was re-extracted into toluene (2x300 ml), dried over anhydrous sodium sulfate, and concentrated under vacuum to result pure diphenylmethylpiperazine compounds (2a-c) as a white to off-white solid with yields up to 88%.

97%	With hydrogenchloride In lithium hydroxide monohydrate; propan-2-one at 100℃; for 0.166667h; Flow reactor;
96%	With anhydrous tin tetrachloride for 1h;
96%	With chloro-trimethyl-silane In neat (no solvent) at 20℃; for 4h; Green chemistry; chemoselective reaction;	General procedure for the halo functionalization of organic compounds using halosilanes on half mmol scale General procedure: A mixture of alcohol (0.5 mmol) in the case of solids, which had been powedered for 1-2 min and halosilanes (0.55 mmol) was transferred to a 4 mL screw-capped vial, and stirred at rt or heated at 70-75 °C for 0.5 h-24 h. The progress of the reaction mixture was monitored by TLC. Upon completion of the reaction, the crude reaction mixture was cooled down to the room temperature and volatile product (TMS)2O was removed by evaporation at 30-35oC under reduced pressure and the remaining was analysed by 1H NMR. Finally, if necessary, the pure final product was obtained after column chromatography on dried silica. Detailed experimental information such as isolated yields, and spectroscopic and other identification data are given in Characterization Data of Isolated Final Products chapter in the SI.
95%	With chloro-trimethyl-silane; dimethyl sulfoxide In acetonitrile Heating;
93%	With thionyl chloride In toluene for 20h;
93%	With 1-chloro-1-(dimethylamino)-2-methyl-1-propene In dichloromethane at 20℃; Inert atmosphere;
90%	With thionyl chloride In dichloromethane at 20℃; for 5h;	Biphenylmethylchloride (2): Compound 1 (300 mg, 1.63 mmol) was taken in DCMand thionyl chloride (213 mg, 1.79 mmol) was added drop wise for 30 min. Thereaction mixture was stirred at room temperature for 5 h. After completereaction (monitored on TLC) excess thionyl chloride was removed by distillationto obtain compound 2 as a yellow color liquid. Yield 90 % (296mg). 1H NMR (300 MHz, CDCl3) δ (ppm): 7.40-7.22 (m, 10 H), 6.11 (s, 1H).
90%	With pyrrolidine-1-carbaldehyde; benzoyl chloride In 1,4-dioxane at 80℃; for 24h; Sealed tube;	4.4.4.8 Synthesis of Chlorodiphenylmethane (226) General procedure: Entry 1: According to general procedure II (chapter 2.1.2) diphenylmethanol (126, 372 mg, 2.00 mmol,1.0 equiv), FPyr (19.7 ilL, 20.4 mg, 0.20 mmol, 10 mol%), dioxane (1 mL, 2 M) and BzCI (282 ilL,341 mg, 2.40 mmol, 1.2 equiv) were combined and then heated to 80 °C for 24 h. ‘H-N MR of the crude product (623 mg) revealed full conversion and a chloride 226 to ester 326 ratio of 96:4. Rapid chromatographic purification (mass crude material/Si02 1:9) with Et20/nPen 3:97 delivered the chloride 226 as a colorless liquid in 90% yield (366 mg, 1.81 mmol).
89%	With silicium tetrachloride In chloroform at 20℃; for 5h;
88%	With 4-aminophenyl diphenylphosphinite; N-chloro-succinimide In dichloromethane for 15h; Heating;
85%	With tungsten hexachloride In dichloromethane for 2h; Heating;
76%	With thionyl chloride In dichloromethane at 20℃; for 22h;	To a solution of diphenylmethanol (4.60g, 24.97mmol, 1.0eq.) in DCM (50mL) cooled on an ice-bath, SOCl2 (9.06mL, 124.84mmol, 5.0eq.) was added. After stirring the reaction mixture at room temperature for 22h, the volatile components were removed in vacuo. The residue was dissolved in DCM (50mL), washed with saturated NaHCO3(aq) (50mL), saturated brine (50mL), dried over Na2SO4, filtered and volatile components evaporated in vacuo to give (chloromethylene)dibenzene 10.Yield: 3.85g (76%) of yellow oil.1H NMR (400MHz, DMSO-d6): δ 6.52 (s, 1H), 7,28-7,33 (m, 2H), 7.35-7.40 (m, 4H), 7.46-7.49 (m, 4H).
76%	With thionyl chloride In dichloromethane at 20℃; for 22h;	To a solution of diphenylmethanol (4.60g, 24.97mmol, 1.0eq.) in DCM (50mL) cooled on an ice-bath, SOCl2 (9.06mL, 124.84mmol, 5.0eq.) was added. After stirring the reaction mixture at room temperature for 22h, the volatile components were removed in vacuo. The residue was dissolved in DCM (50mL), washed with saturated NaHCO3(aq) (50mL), saturated brine (50mL), dried over Na2SO4, filtered and volatile components evaporated in vacuo to give (chloromethylene)dibenzene 10.Yield: 3.85g (76%) of yellow oil.1H NMR (400MHz, DMSO-d6): δ 6.52 (s, 1H), 7,28-7,33 (m, 2H), 7.35-7.40 (m, 4H), 7.46-7.49 (m, 4H).
74%	With 1-methoxy-2-(methylsulfinyl)benzene; benzoyl chloride In acetonitrile at 20℃; for 20h; Sealed tube;
50%	With 2,2,4,6-Tetrachloro-1,3,5,2λ⁵-triazaphosphorin; N,N-dimethyl-formamide In dichloromethane at 20℃; for 2h;
36%	With 4-dimethylaminopyridine; triethylamine; 4-methylbenzene-1-sulfonyl chloride In dichloromethane at 0 - 15℃; for 12.5h;
31%	With dimethylsilicon dichloride In dichloromethane; propan-2-one Ambient temperature;
	With hydrogenchloride; calcium(II) chloride; benzene
	With beryllium(II) chloride at 100 - 110℃;
	With thionyl chloride; toluene
	With hydrogenchloride; benzene
	With phosphorus(V) chloride; trichlorophosphate
	With hydrogenchloride
	With thionyl chloride In Carbon tetrachloride Yield given;
	With hydrogenchloride In Petroleum ether
97 % Chromat.	With selenium tetrachloride; triethylamine In toluene at 25℃; for 3h;
	With thionyl chloride In Carbon tetrachloride
	With hydrogenchloride; calcium(II) chloride In benzene
	With thionyl chloride In dichloromethane at 0℃; for 1h;
	With thionyl chloride In dichloromethane at 20℃; for 2h;
	With thionyl chloride In benzene for 12h; Heating;
	With hydrogenchloride; calcium(II) chloride In dichloromethane; Petroleum ether; benzene
	With thionyl chloride In dichloromethane at 0 - 5℃; for 4h;
	With thionyl chloride In dichloromethane at 0 - 5℃; for 4h;
	With thionyl chloride In dichloromethane at 0℃; for 4h;	1.2 Chlorodiphenylmethane: At about 0° C., thionyl chloride (1.98 mL, 27.17 mmol) was added slowly to a solution of diphenyl-methanol (1.0 g, 5.44 mmol) in dichloromethane (10 mL). The mixture was stirred at ambient temperature for about 4 hours. Excess thionyl chloride was removed in vacuo, and the title product was used in the next step without further purification.
	With thionyl chloride In dichloromethane at 0 - 5℃; for 4h;
	With thionyl chloride In dichloromethane
	With thionyl chloride In dichloromethane at 20℃; Inert atmosphere;
	With thionyl chloride In benzene Reflux;
	With thionyl chloride In dichloromethane at 0 - 5℃; for 4h;
195 mg	With oxalyl dichloride; chlorotriphenylphosphonium chloride In chloroform at 20℃; for 7h;
	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃;	4,4'-(Chloromethylene)bis(chlorobenzene) (8y) General procedure: Bis(4-chlorophenyl)methanol (2.83 g, 11.18 mmol) was dissolved in dichloromethane (30 ml) at room temperature. Oxalyl chloride (975 μL, 11.18 mmol) was added followed by addition of a drop of dimethylformamide. After stirring overnight, the mixture was concentrated and co-evaporated with chloroform to afford 3.0 g of 8 as an off-white solid (11.05 mmol, 99%), which was carried to the next step without further purification.
	With hydrogenchloride; calcium(II) chloride In lithium hydroxide monohydrate at 85℃; for 4h;
	With thionyl chloride at 0 - 20℃; for 12h;
	With thionyl chloride In dichloromethane at 20℃; for 4.5h;
	With thionyl chloride In dichloromethane
99 %Spectr.	With chloro-trimethyl-silane In dichloromethane; lithium hydroxide monohydrate at 20℃; for 0.666667h;	A Representative Procedure for the Chlorination of 1a with TMSCl in the Presence of Na-Mont In a flask was placed Na-Mont (30 mg), 1a (1 mmol, 0.18 g),TMSCl (2 mmol, 0.22 g, 0.25 mL), and CH2Cl2 (5 mL). The mixture was stirred at r.t. for 40 min. The solid material was filtered off, and the filtrate was concentrated. Compound 3a was isolated by Kugelrohr distillation under vacuum in 90% yield as a colorless liquid. NMR Data of 3a: 1H NMR (500 MHz, CDCl3): δ = 7.42-7.18 (m, 10 H), 6.08(s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 141.1, 128.6,128.1, 127.8, 64.3.

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[22]Bredereck et al. [Chemische Berichte, 1939, vol. 72, p. 1414,1424]
[23]Gilman; Kirby [Journal of the American Chemical Society, 1926, vol. 48, p. 1735]
[24]Montagne [Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 402] Boeseken [Recueil des Travaux Chimiques des Pays-Bas, 1903, vol. 22, p. 312]
[25]Montagne [Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 402]
[26]Engler [Chemische Berichte, 1878, vol. 11, p. 922] Engler; Bethge [Chemische Berichte, 1874, vol. 7, p. 1128]
[27]Okamoto, Akio; Snow, Miles S.; Arnold, Donald R. [Tetrahedron, 1986, vol. 42, # 22, p. 6175 - 6187]
[28]Mayr, Herbert; Pock, Rudolf [Chemische Berichte, 1986, vol. 119, # 8, p. 2473 - 2496]
[29]Yamauchi, Takayoshi; Hattori, Kaneaki; Mizutaki, Shoichi; Tamaki, Kentaro; Uemura, Sakae [Bulletin of the Chemical Society of Japan, 1986, vol. 59, p. 3617 - 3620]
[30]Liu, Kwang-Ting; Lin, Yen-Shyi; Tsao, Meng-Lin [Journal of Physical Organic Chemistry, 1998, vol. 11, # 3, p. 223 - 229]
[31]Spange, Stefan; Adolph, Simone; Walther, Ralph; Zimmermann, Yvonne [Journal of Physical Chemistry B, 2003, vol. 107, # 1, p. 298 - 305]
[32]Chern, Jyh-Haur; Shia, Kak-Shan; Hsu, Tsu-An; Tai, Chia-Liang; Lee, Chung-Chi; Lee, Yen-Chun; Chang, Chih-Shiang; Tseng, Sung-Nien; Shih, Shin-Ru [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 10, p. 2519 - 2525]
[33]Lee, Jeewoo; Kang, Sang-Uk; Lim, Ju-Ok; Choi, Hyun-Kyung; Jin, Mi-Kyung; Toth, Attila; Pearce, Larry V.; Tran, Richard; Wang, Yun; Szabo, Tamas; Blumberg, Peter M. [Bioorganic and Medicinal Chemistry, 2004, vol. 12, # 2, p. 371 - 385]
[34]Cai, Xiao-Hua; Xie, Bing [Canadian Journal of Chemistry, 2006, vol. 84, # 9, p. 1106 - 1109] Cai, Xiao-Hua; Xie, Bing; Guo, Hui [Canadian Journal of Chemistry, 2006, vol. 84, # 9, p. 1110 - 1113]
[35]Denegri, Bernard; Streiter, Andre; Juric, Sandra; Ofial, Armin R.; Kronja, Olga; Mayr, Herbert [Chemistry - A European Journal, 2006, vol. 12, # 6, p. 1648 - 1656]
[36]Naveen; Sridhar; Prasad, J. Shashidhara; Kumar, C. S. Ananda; Prasad, S. B. Benaka; Thimmegowda; Rangappa [Molecular Crystals and Liquid Crystals, 2007, vol. 474, # 1, p. 67 - 76]
[37]Ananda Kumar; Nanjunda Swamy; Thimmegowda; Benaka Prasad; Yip, George W.; Rangappa [Medicinal Chemistry Research, 2007, vol. 16, # 4, p. 179 - 187]
[38]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - US2009/176792, 2009, A1 Location in patent: Page/Page column 26
[39]Location in patent: body text Kumar, C.S. Ananda; Prasad, S.B. Benaka; Vinaya; Chandrappa; Thimmegowda; Kumar, Y.C. Sunil; Swarup, Sanjay; Rangappa [European Journal of Medicinal Chemistry, 2009, vol. 44, # 3, p. 1223 - 1229]
[40]Streidl, Nicolas; Antipova, Anna; Mayr, Herbert [Journal of Organic Chemistry, 2009, vol. 74, # 19, p. 7328 - 7334]
[41]Location in patent: scheme or table Meng, Tao; Wang, Jue; Peng, Hongli; Fang, Guanghua; Li, Min; Xiong, Bing; Xie, Xin; Zhang, Yongliang; Wang, Xin; Shen, Jingkang [European Journal of Medicinal Chemistry, 2010, vol. 45, # 3, p. 1133 - 1139]
[42]Location in patent: scheme or table Pajouhesh, Hassan; Feng, Zhong-Ping; Ding, Yanbing; Zhang, Lingyun; Pajouhesh, Hossein; Morrison, Jerrie-Lynn; Belardetti, Francesco; Tringham, Elizabeth; Simonson, Eric; Vanderah, Todd W.; Porreca, Frank; Zamponi, Gerald W.; Mitscher, Lester A.; Snutch, Terrance P. [Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 4, p. 1378 - 1383]
[43]Location in patent: scheme or table Vinaya; Veeresh; Ananda Kumar; Prasanna; Ranganatha; Benaka Prasad; Patil; Rangappa [Letters in drug design and discovery, 2010, vol. 7, # 2, p. 109 - 115]
[44]Location in patent: experimental part Denton, Ross M.; An, Jie; Adeniran, Beatrice; Blake, Alexander J.; Lewis, William; Poulton, Andrew M. [Journal of Organic Chemistry, 2011, vol. 76, # 16, p. 6749 - 6767]
[45]Weïwer, Michel; Bittker, Joshua A.; Lewis, Timothy A.; Shimada, Kenichi; Yang, Wan Seok; MacPherson, Lawrence; Dandapani, Sivaraman; Palmer, Michelle; Stockwell, Brent R.; Schreiber, Stuart L.; Munoz, Benito [Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1822 - 1826]
[46]Gurdal, Enise Ece; Durmaz, Irem; Cetin-Atalay, Rengul; Yarim, Mine [Journal of Enzyme Inhibition and Medicinal Chemistry, 2014, vol. 29, # 2, p. 205 - 214]
[47]Santhoshi, Amlipur; Kumar, Singam Naveen; Sujitha, Pombala; Poornachandra, Yedla; Sadhu, Partha Sarathi; Kumar, C. Ganesh; Rao, Vaidya Jayathirtha [Medicinal Chemistry Research, 2014, vol. 23, # 6, p. 3207 - 3219]
[48]Perlmutter, Jessamyn I.; Forbes, Lauren T.; Krysan, Damian J.; Ebsworth-Mojica, Katherine; Colquhoun, Jennifer M.; Wang, Jenna L.; Dunman, Paul M.; Flaherty, Daniel P. [Journal of Medicinal Chemistry, 2014, vol. 57, # 20, p. 8540 - 8562]
[49]Srivastava, Priyanka; Razi, Syed S.; Ali, Rashid; Gupta, Ramesh C.; Yadav, Suresh S.; Narayan, Gopeshwar; Misra, Arvind [Analytical Chemistry, 2014, vol. 86, # 17, p. 8693 - 8699]
[50]Tandiary, Michael Andreas; Masui, Yoichi; Onaka, Makoto [Synlett, 2014, vol. 25, # 18, p. 2639 - 2643]

4
[ 574-42-5 ]
[ 90-99-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; benzene at 20℃;
99 %Spectr.	With chloro-trimethyl-silane In dichloromethane; water at 20℃; for 0.666667h;	A Representative Procedure for the Chlorination of 1a with TMSCl in the Presence of Na-Mont General procedure: In a flask was placed Na-Mont (30 mg), 1a (1 mmol, 0.18 g),TMSCl (2 mmol, 0.22 g, 0.25 mL), and CH2Cl2 (5 mL). The mixture was stirred at r.t. for 40 min. The solid material was filtered off, and the filtrate was concentrated. Compound 3a was isolated by Kugelrohr distillation under vacuum in 90% yield as a colorless liquid.
73 %Spectr.	With tetrachlorosilane; NbCl₃(N,N′-bis-(2,6-diisopropylphenyl)-1,4-diaza-2,3-dimethyl-1,3-butadiene) In chloroform-d1 at 80℃; for 24h;

Reference： [1]Ward [Journal of the Chemical Society, 1927, p. 2289,2294]
[2]Tandiary, Michael Andreas; Masui, Yoichi; Onaka, Makoto [Synlett, 2014, vol. 25, # 18, p. 2639 - 2643]
[3]Parker, Bernard F.; Hosoya, Hiromu; Arnold, John; Tsurugi, Hayato; Mashima, Kazushi [Inorganic Chemistry, 2019, vol. 58, # 19, p. 12825 - 12831]

5
[ 60-29-7 ]
[ 762-04-9 ]
[ 90-99-3 ]
[ 27329-60-8 ]

Reference： [1]Uchenye Zapiski, Kazanskii Gosudarstvennyi Universitet,1956,vol. 116,p. 71,108, 109
Chem.Abstr.,1957,p. 6581

6
[ 108-01-0 ]
[ 90-99-3 ]
[ 58-73-1 ]

Reference： [1]Chemical Science,2013,vol. 4,p. 2822 - 2827
[2]Chemical Science,2017,vol. 8,p. 4363 - 4370
[3]Patent: DE927689,1952,

7
[ 6335-76-8 ]
[ 90-99-3 ]
[ 858216-70-3 ]

Reference： [1]Journal of the American Chemical Society,1949,vol. 71,p. 2129

8
[ 90-99-3 ]
[ 119-61-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With N-Bromosuccinimide; water In chloroform for 5h; Reflux;	General procedure for synthesis of diaryllketones (3a-x) General procedure: In around-bottom flask, diarylmethanes (1.0 mmol), NBS (889.9 mg, 5.0 mmol) andwater (0 or 5.0 mmol) were dissolved in CHCl3 (4.0 mL). After refluxingfor 3 h in the air, the reaction mixture was quenched withNa2S2O3·5H2O, cooled to roomtemperature, washed with 5mL CH2Cl2, dried with MgSO4,and filtered to get clear organic solution. The solvent was removed reducedpressure by a rotary evaporator, and the resulting residue was subjected tocolumn chromatography on silica gel using co-solvent(ethyl acetate / petroleum ether, v/v) as eluent to give the correspondingdiaryllketones.
98%	With water; sodium hydroxide at 20℃; for 0.0833333h; Microwave irradiation;	general procedure for the oxidation of benzyl halides with 4-hydroxypyridinium nitrate SiO₂under microwave irradiation General procedure: A mixture of benzyl halide (10 mmol) and H2O (20 ml) was stirred, and then the mixture was added to 4-hydroxypyridinium nitrate functionalized silica gel (2.46 g,11 mmol) and stirred. The reaction was done at ambient temperature for half the time indicated in Table 2 by microwave and then sodium hydroxide solution (0.440 g,11 mmol, in 10 ml H2O) was added dropwise over a period of 5 min at room temperature with vigorous stirring. The mixture was irradiated again for the other half time indicated in Table 2. The progress of the reaction was monitored by TLC (silica gel,n-hexane: pet. ether (1:3) as eluent). When the reaction was complete, the reaction mixture was cooled and extracted with diethyl ether (320 ml), washed with cold water, and dried over anhydrous sodium sulfate After filtration, the removal of solvent gave a crude product which was passed through a short silica gel column with n-hexane:diethyl ether (1: 1) as solvent to afford the pure product. The retrieved regent (4-hydroxypyridinesilica gel) was activated by treatment with 1.25 ml of concentrated HNO3 to provide 4-hydroxypyridinium nitrate SiO2, then reused for the oxidation.
95%	With 1-dodecyl-3-methylimidazolium iron chloride; periodic acid at 30℃; for 2.5h;

93%	Stage #1: diphenylchloromethane With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium bromide In water for 0.0833333h; Reflux; Stage #2: With dihydrogen peroxide In water for 1h;
90%	With dihydrogen peroxide; potassium bromide In ethanol for 1h; Heating;
87%	With dihydrogen peroxide; trimethylamine In water for 4h; Reflux;
84%	With 4Na⁽¹⁺⁾6H⁽¹⁺⁾NiMo₆O₂₄^(10-)=Na₄H₆NiMo₆O₂₄; oxygen In water; acetonitrile at 20℃; for 12h; Irradiation;
80%	With sodium periodate In N,N-dimethyl-formamide at 150℃; for 0.833333h;
79%	With (NH₄)₄[ZnMo₆O₁₈(OH)₆]; oxygen In water; acetonitrile at 60℃; for 12h;
	With dimethyl sulfoxide
		3 Oxidation of chlorodiphenylmethane. Example 3 Oxidation of chlorodiphenylmethane. The catalyst prepared as described in Example 1 was used, with the same quantities and conditions, to oxidize chlorodiphenylmethane. It was oxidised at between 4% and 5% per hour. After 6 hours, 31% of the chlorodiphenylmethane was converted to benzophenone.

Reference： [1]He, Chao; Zhang, Xiaohui; Huang, Ruofeng; Pan, Jing; Li, Jiaqiang; Ling, Xuege; Xiong, Yan; Zhu, Xiangming [Tetrahedron Letters, 2014, vol. 55, # 32, p. 4458 - 4462]
[2]Ghalehbandi, Shermineh sadat; Ghazanfari, Dadkhoda; Ahmadi, Sayed Ali; Sheikhhosseini, Enayatollah [Organic Preparations and Procedures International, 2021, vol. 53, # 2, p. 176 - 183]
[3]Location in patent: experimental part Hu, Yu Lin; Liu, Qi Fa; Lu, Ting Ting; Lu, Ming [Catalysis Communications, 2010, vol. 11, # 10, p. 923 - 927]
[4]He, Ying; Liu, Qifa; Ma, Xiaoyun; Lu, Ming [Journal of Chemical Research, 2013, vol. 37, # 1, p. 22 - 24]
[5]Tang, Jingting; Zhu, Jinlong; Shen, Zongxuan; Zhang, Yawen [Tetrahedron Letters, 2007, vol. 48, # 11, p. 1919 - 1921]
[6]Location in patent: experimental part Zheng, Pengwu; Yan, Li; Ji, Xiujie; Duan, Xuemin [Synthetic Communications, 2011, vol. 41, # 1, p. 16 - 19]
[7]Yu, Han; Wang, Jingjing; Zhai, Yongyan; Zhang, Mengqi; Ru, Shi; Han, Sheng; Wei, Yongge [ChemCatChem, 2018, vol. 10, # 19, p. 4274 - 4279]
[8]Das, Sasmita; Panigrahi; Maikap, Golak C. [Tetrahedron Letters, 2003, vol. 44, # 7, p. 1375 - 1377]
[9]Wang, Jingjing; Zhai, Yongyan; Wang, Ying; Yu, Han; Zhao, Wenshu; Wei, Yongge [Dalton Transactions, 2018, vol. 47, # 38, p. 13323 - 13327]
[10]Nace; Monagle [Journal of Organic Chemistry, 1959, vol. 24, p. 1792]
[11]Current Patent Assignee: KNOWSLEY CONTRACT CHEM - EP336768, 1989, A1

9
[ 90-99-3 ]
[ 632-50-8 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium iodide In acetone Heating;
95%	With iron(II) oxalate dihydrate In N,N,N,N,N,N-hexamethylphosphoric triamide at 155 - 160℃; for 0.166667h;
95%	With hydrogen In benzene at 90℃; for 24h;

95%	With hydrogen In benzene at 90℃; for 24h;
95%	With 1-dodecyl-3-methylimidazolium cuprous chloride; copper; zinc at 70℃; for 2h;
94%	With sodium hydroxide; dicobalt octacarbonyl; carbon monoxide; benzyltrimethylammonium chloride In toluene at 45℃; for 20h;
85%	With bis(cyclopentadienyl)titanium dichloride; samarium In tetrahydrofuran for 1h; Ambient temperature;
79%	With sodium dithionite In N,N,N,N,N,N-hexamethylphosphoric triamide at 155 - 160℃; for 0.0833333h;
76%	With dicyclopentadienyltitanium bromide In tetrahydrofuran for 5h; Ambient temperature; other benzylic and allylic chlorides;
76%	With dicyclopentadienyltitanium bromide In tetrahydrofuran for 5h; Ambient temperature;
76%	With nickel In 1,2-dimethoxyethane for 9h;
67%	With chlorotris(triphenylphosphine)cobalt(I) In benzene for 17h; Ambient temperature;
	With sodium; benzene
	beim Destillieren;
	With sodium; benzene
	With copper; benzene
	bei der Grignardierung in Gegenwart von etwas Jod;
	With silver; benzene
	With diethyl ether; ammonia; sodium
	With diethyl ether; magnesium
	With sodium In diethyl ether for 48h; Heating; Yield given;
79 % Chromat.	With tetrahydrofuran; titanium(II) hydride; magnesium chloride In tetrahydrofuran at -68 - 20℃;
	With ortho-tolylmagnesium bromide; C₇₆H₈₈Cl₂FeN₈P₄ In tetrahydrofuran at 0℃; for 1h; Schlenk technique; Inert atmosphere;

Reference： [1]Smith, William B.; Branum, Gary D. [Tetrahedron Letters, 1981, vol. 22, # 22, p. 2055 - 2058]
[2]Khurana, Jitender M.; Chauhan, Sushma; Maikap, Golak C. [Organic and Biomolecular Chemistry, 2003, vol. 1, # 10, p. 1737 - 1740]
[3]Li, Yanjun; Izumi, Taeko [Synthetic Communications, 2003, vol. 33, # 20, p. 3583 - 3588]
[4]Li, Yanjun; Kijima, Tatsuro; Izumi, Taeko [Journal of Organometallic Chemistry, 2003, vol. 687, # 1, p. 12 - 15]
[5]Location in patent: experimental part Hu, Yu-Lin; Li, Fu; Gu, Guo-Liang; Lu, Ming [Catalysis Letters, 2011, vol. 141, # 3, p. 467 - 473]
[6]Francalanci, F.; Foa, M. [Journal of Organometallic Chemistry, 1982, vol. 232, # 1, p. 59 - 70]
[7]Zhang; Yu; Bao [Synthetic Communications, 1995, vol. 25, # 12, p. 1825 - 1830]
[8]Khurana, Jitender M.; Bansal, Geeti; Sahoo, Prabhat K. [Journal of Chemical Research, 2004, # 2, p. 139 - 140]
[9]Yanlong, Qian; Guisheng, Li; Huang, Yao-Zeng [Journal of Organometallic Chemistry, 1990, vol. 381, # 1, p. 29 - 34]
[10]Yanlong, Qian; Guisheng, Li; Huang, Yao-Zeng [Journal of Organometallic Chemistry, 1990, vol. 381, # 1, p. 29 - 34]
[11]Inaba, Shin-ichi; Matsumoto, Hideyuki; Rieke, Reuben D. [Journal of Organic Chemistry, 1984, vol. 49, # 12, p. 2093 - 2098]
[12]Yamada, Yasuji; Momose, Den-ichi [Chemistry Letters, 1981, p. 1277 - 1278] Momose, Den-ichi; Iguchi, Kazuo; Sugiyama, Toshikazu; Yamada, Yasuji [Chemical and pharmaceutical bulletin, 1984, vol. 32, # 5, p. 1840 - 1853]
[13]Engler [Chemische Berichte, 1878, vol. 11, p. 922]
[14]Anschuetz [Justus Liebigs Annalen der Chemie, 1886, vol. 235, p. 163]
[15]Montagne [Recueil des Travaux Chimiques des Pays-Bas, 1906, vol. 25, p. 411]
[16]Mel'kanowizkaja; Zukerwanik [Zhurnal Obshchei Khimii, 1958, vol. 28, p. 11,14; engl. Ausg. S. 10, 13]
[17]Gilman; Kirby [Journal of the American Chemical Society, 1926, vol. 48, p. 1735]
[18]Nauta; Mulder [Recueil des Travaux Chimiques des Pays-Bas, 1939, vol. 58, p. 1062,1065]
[19]Dean; Berchet [Journal of the American Chemical Society, 1930, vol. 52, p. 2823,2825]
[20]Lapkin; Ljubimowa [Zhurnal Obshchei Khimii, 1948, vol. 18, p. 701,704][Chem.Abstr., 1949, p. 188] Kinney; Mayhue [Journal of the American Chemical Society, 1931, vol. 53, p. 190,194, 198]
[21]Okamoto, Akio; Snow, Miles S.; Arnold, Donald R. [Tetrahedron, 1986, vol. 42, # 22, p. 6175 - 6187]
[22]Becker, Beate; Bogdanovic, Borislav [Zeitschrift fur Naturforschung, B: Chemical Sciences, 1995, vol. 50, # 3, p. 476 - 482]
[23]Kawamura, Shintaro; Nakamura, Masaharu [Chemistry Letters, 2013, vol. 42, # 2, p. 183 - 185]

10
[ 124-38-9 ]
[ 90-99-3 ]
[ 117-34-0 ]

Yield	Reaction Conditions	Operation in experiment
92.6%	With salcomine; tetrabutylammonium perchlorate In acetonitrile at 25℃; electrochemical reaction;
66%	With samarium; chloro-trimethyl-silane; tetra-(n-butyl)ammonium iodide In acetonitrile at 20℃; for 2h; Electrochemical reaction; Cooling with ice;
	(i) tBuCl, Li, Et₂O, (ii) /BRN= 1900390/; Multistep reaction;

Reference： [1]Isse, Abdirisak Ahmed; Gennaro, Armando; Vianello, Elio [Journal of the Chemical Society, Dalton Transactions, 1996, # 8, p. 1613 - 1618]
[2]Bazzi, Sakna; Schulz, Emmanuelle; Mellah, Mohamed [Organic Letters, 2019, vol. 21, # 24, p. 10033 - 10037]
[3]Bartlett,P.D. et al. [Journal of the American Chemical Society, 1969, vol. 91, # 23, p. 6362 - 6366]

11
[ 29683-23-6 ]
[ 90-99-3 ]
[ 116197-04-7 ]

Reference： [1]Collection of Czechoslovak Chemical Communications,1987,vol. 52,p. 2758 - 2774

12
[ 288-32-4 ]
[ 90-99-3 ]
[ 7189-67-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With potassium hydroxide; potassium carbonate In xylene Heating;
66.6%	With tetraethylammonium iodide; potassium carbonate; sodium hydroxide In acetonitrile for 24h; Reflux;
59%	In acetonitrile for 2h; Heating;

	In 1,4-dioxane Reflux;
	Stage #1: 1H-imidazole With potassium hydroxide In dimethyl sulfoxide at 20℃; for 0.5h; Stage #2: diphenylchloromethane In dimethyl sulfoxide at 20℃;	General method for the synthesis of N-alkyl/aryl benzimidazole (I-II) General procedure: Imidazole (0.76 g, 11.1 mmol) and potassium hydroxide (0.9 g, 16 mmol) were stirred for 0.5 h in 20mL DMSO, then benzhydryl chloride/cyclohexyl bromide was added andthe reaction mixture further stirred for 3.5 h. Finally, the reaction mixture was poured into 250 mL chilled distilled water. White or beige powders appeared, which were separatedby filtering (for details, see Supplementary Data).

Reference： [1]Claramunt, Rosa M.; Elguero, Jose; Garceran, Rafael [Heterocycles, 1985, vol. 23, # 11, p. 2895 - 2906]
[2]Location in patent: experimental part Rezaei, Zahra; Khabnadideh, Soghra; Zomorodian, Kamiar; Pakshir, Kyvan; Kashi, Giti; Sanagoei, Narges; Gholami, Sanaz [Archiv der Pharmazie, 2011, vol. 344, # 10, p. 658 - 665]
[3]Jones, C. David; Winter, Mark A.; Hirsch, Kenneth S.; Stamm, Nancy; Taylor, Harold M.; et al. [Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 416 - 429]
[4]Location in patent: experimental part El Hage, Salome; Lajoie, Barbora; Feuillolay, Catherine; Roques, Christine; Baziard, Genevieve [Archiv der Pharmazie, 2011, vol. 344, # 6, p. 402 - 410]
[5]Kamal, Amna; Iqbal, Muhammad Adnan; Bhatti, Haq Nawaz; Ghaffar, Abdul [Journal of Coordination Chemistry, 2022]

13
[ 147-24-0 ]
[ 108-01-0 ]
[ 91-01-0 ]
[ 90-99-3 ]

Reference： [1]Pharmazie,1984,vol. 39,p. 816 - 818

14
[ 111-74-0 ]
[ 90-99-3 ]
[ 90749-73-8 ]

Yield	Reaction Conditions	Operation in experiment
	Heating;
		10.a 5-(3-[N-(2-(N-Diphenylmethyl-N-ethylamino)ethyl)-N-ethylamino]-2-hydroxypropoxy)quinoline (a) Reaction and treatment were carried out using 21 g of N,N'-diethylethylenediamine and 7.3 g of diphenylmethyl chloride in accordance with the same procedure as in Example 3-(a), in order to obtain 4.2 g of N-diphenylmethyl-N,N'-diethylethylenediamine. NMR δ ppm (CDCl3): 0.9-1.4 (m,6H), 2.4-3.2 (m,8H), 4.8 (s,1H), 7.1-7.8 (m,10H)

Reference： [1]Regnier, Gilbert L.; Guillonneau, Claude G.; Duhault, Jacques L.; Tisserand, Francoise P.; Saint-Romas, Guy; Holstorp, Sophie M. [European Journal of Medicinal Chemistry, 1987, vol. 22, p. 243 - 250]
[2]Current Patent Assignee: BAYER AG - US5112817, 1992, A

15
[ 7677-24-9 ]
[ 90-99-3 ]
[ 86-29-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With iodine; lithium carbonate In dichloromethane at 35℃; for 5h;	4.4 General procedure of this method for synthesizing the desired products (2 and 3) General procedure: To a round-bottom flask was charged with compounds 1 (0.3mmol) in DCM (5mL), Li2CO3 (0.06mmol), TMSCN (or TMSN3, or RO-H) (1.35mmol), and I2 (0.54mmol) in sequence successively. Then the resulting mixture was stirred under closed conditions at 35°C (water bath temperature) for 5h. The reaction was quenched with saturated solution of Na2S2O3. The organic phase was separated, and the aqueous layer was extracted with DCM (5mL×3). The combined organic solution was dried with Mg2SO4 and concentrated in vacuo. The resulting residue was purified by a column chromatography to give the corresponding products.
93%	With titanium tetrachloride In dichloromethane at 0℃; for 2h;

Reference： [1]Hu, Liangzhen; Hussain, Muhammad Ijaz; Deng, Qingfu; Liu, Qing; Feng, Yangyang; Zhang, Xiaohui; Xiong, Yan [Tetrahedron, 2019, vol. 75, # 2, p. 308 - 314]
[2]Zieger, Herman E.; Wo, Shiming [Journal of Organic Chemistry, 1994, vol. 59, # 14, p. 3838 - 3840]

16
[ 766-90-5 ]
[ 90-99-3 ]
[ 62677-54-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With titanium tetrachloride In dichloromethane at -78℃;

Reference： [1]Pock,R.; Mayr,H.; Rubow,M. [Journal of the American Chemical Society, 1986, vol. 108, p. 7767]

17
[ 544-97-8 ]
[ 90-99-3 ]
[ 612-00-0 ]

Yield	Reaction Conditions	Operation in experiment
95%	With titanium tetrachloride In dichloromethane at 0℃; for 2h;

Reference： [1]Reetz, M. T.; Steinbach, R.; Wenderoth, B. [Synthetic Communications, 1981, vol. 11, # 3, p. 261 - 266]

18
[ 29368-59-0 ]
[ 90-99-3 ]
[ 85686-16-4 ]

Yield	Reaction Conditions	Operation in experiment
	In dimethyl sulfoxide at 25℃; ΔG⁰;
	With potassium dimsylate In dimethyl sulfoxide at 25℃; for 48h;

Reference： [1]Bordwell, F.G.; Harrelson, John A. [Journal of Organic Chemistry, 1989, vol. 54, # 20, p. 4893 - 4898]
[2]Bordwell, F.G.; Harrelson, John A. [Journal of Organic Chemistry, 1989, vol. 54, # 20, p. 4893 - 4898]

19
[ 114474-26-9 ]
[ 90-99-3 ]
[ 154019-55-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With potassium hydroxide; tetrabutylammomium bromide; sodium carbonate In xylene Heating;

Reference： [1]Cerrada, Luisa; Cudero, Jose; Elguero, Jose; Pardo, Carmen [Journal of the Chemical Society. Chemical communications, 1993, # 23, p. 1713 - 1714]

20
[ 90-99-3 ]
[ 75-05-8 ]
[ 91-01-0 ]
[ 2286-54-6 ]
[ 101-81-5 ]
[ 5267-35-6 ]
[ 632-50-8 ]

Reference： [1]Journal of the American Chemical Society,1990,vol. 112,p. 6918 - 6928

21
[ 90-99-3 ]
[ 122-52-1 ]
[ 27329-60-8 ]

Reference： [1]Patent: JP2005/298421,2005,A .Location in patent: Page/Page column 40
[2]European Journal of Medicinal Chemistry,1993,vol. 28,p. 943 - 948

22
[ 90-99-3 ]
[ 896-65-1 ]
[ 101-81-5 ]
[ 19120-39-9 ]
[ 5424-75-9 ]

Yield	Reaction Conditions	Operation in experiment
1: 27% 2: 32% 3: 27% 4: 5%	With styrene; hydrogenchloride; acetic acid; mercury; zinc for 2h; Heating; Further byproducts given;
1: 27% 2: 5% 3: 32% 4: 27%	With styrene; hydrogenchloride; acetic acid; mercury; zinc for 2h; Heating; also of deuteriochlorodiphenylmethane; Further byproducts given;
1: 27% 2: 5% 3: 27% 4: 32%	With hydrogenchloride; acetic acid; mercury; zinc for 2h; Heating; Further byproducts given;

Reference： [1]Vona, Maria Luisa Di; Rosnati, Vittorio [Journal of Organic Chemistry, 1991, vol. 56, # 13, p. 4269 - 4273]
[2]Vona, Maria Luisa Di; Rosnati, Vittorio [Journal of Organic Chemistry, 1991, vol. 56, # 13, p. 4269 - 4273]
[3]Vona, Maria Luisa Di; Rosnati, Vittorio [Journal of Organic Chemistry, 1991, vol. 56, # 13, p. 4269 - 4273]

23
[ 75-15-0 ]
[ 90-99-3 ]
[ 100-49-2 ]
[ 34886-60-7 ]

Reference： [1]Canadian Journal of Chemistry,1971,vol. 49,p. 3362 - 3366

24
[ 90-99-3 ]
[ 38385-95-4 ]
[ 1026904-51-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 707 - 718

26
[ 90-99-3 ]
(R)-<PhCH2-<cyclo(N-CH2CH2CH2CH)>-CONH-o-C6H4-CH=N-CH2CO2H>Ni(II) [ No CAS ]
[ 149597-91-1 ]

Reference： [1]Tetrahedron Asymmetry,1997,vol. 8,p. 79 - 83

27
[ 90-99-3 ]
(S)-<PhCH2-<cyclo(N-CH2CH2CH2CH)>-CONH-o-C6H4-CH=N-CH2CO2H>Ni(II) [ No CAS ]
[ 149597-92-2 ]
(S)-2-N-(N-benzyl-L-prolyl)aminobenzophenone hydrochloride [ No CAS ]

Reference： [1]Tetrahedron Asymmetry,1997,vol. 8,p. 79 - 83

28
[ 524-38-9 ]
[ 90-99-3 ]
[ 2041-21-6 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In N,N-dimethyl-formamide at 60℃; for 8h;
85%	With triethylamine In DMF (N,N-dimethyl-formamide) at 60℃; for 8h;	N-Benzhydryloxyphthalimide A solution of 1-chloro-1, 1-diphenylmethane (3.42 g, 16.93 mmol), N-hydroxyphthalimide (2.30 g, 14.11 mmol) and Et3N (3.0 ml) in DMF (50 ml) was stirred at 60° C. under N2 for 8 hours. After the reaction mixture was cooled to room temperature, water (100 ml) was added. The mixture was extracted with Et2O. The combined organic phase was dried over Na2SO4. After evaporation of the solvent, the crude product was purified by chromatography(Hexane/Benzene/EtOAc=20/10/3) to give a white solid, 3.95 g (85% yield). 1H NMR (CD3Cl) δ 7.72-7.63 (1H, m), 7.56-7.53 (1H, m), 7.40-7.24 (12H, m), 5.85 (1H, s, Ph2CH).

Reference： [1]Dutta; Fei; Beardsley; Newman; Reith [Journal of Medicinal Chemistry, 2001, vol. 44, # 6, p. 937 - 948]
[2]Current Patent Assignee: WAYNE STATE UNIVERSITY - US2003/225133, 2003, A1 Location in patent: Page 10

29
[ 119-61-9 ]
[ 90-99-3 ]
[ 632-50-8 ]

Yield	Reaction Conditions	Operation in experiment
90%	With hydrogenchloride; hydrogen In xylene at 180℃; for 24h;

Reference： [1]Li, Yanjun; Izumi, Taeko [Synthetic Communications, 2003, vol. 33, # 20, p. 3583 - 3588]

30
[ 534-22-5 ]
[ 90-99-3 ]
[ 90499-97-1 ]

Yield	Reaction Conditions	Operation in experiment
87%	With ammonium bicarbonate In 2,2,2-trifluoroethanol at 20℃; for 2h;

Reference： [1]Hofmann, Matthias; Hampel, Nathalie; Kanzian, Tanja; Mayr, Herbert [Angewandte Chemie - International Edition, 2004, vol. 43, # 40, p. 5402 - 5405]

31
[ 26348-61-8 ]
[ 90-99-3 ]
[ 938056-62-3 ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6169 - 6172

32
[ 557-98-2 ]
[ 90-99-3 ]
3,3-dichloro-1,1-diphenylbutane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With gallium(III) trichloride; N-benzyl-N,N,N-triethylammonium chloride In dichloromethane at -78℃; for 1h;

Reference： [1]Mayr; Bug; Gotta; Hering; Irrgang; Janker; Kempf; Loos; Ofial; Remennikov; Schimmel [Journal of the American Chemical Society, 2001, vol. 123, # 39, p. 9500 - 9512]

33
[ 2212-32-0 ]
[ 110-16-7 ]
[ 90-99-3 ]
di-{N,N,N-[(2-diphenylmethoxyethyl)-(2-dimethylaminoethyl)methyl]amine} maleate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
10%	Stage #1: 2-[2-(dimethylamino)ethyl]methylamino}ethanol With sodium hydride In toluene at 95℃; for 0.5h; Stage #2: diphenylchloromethane In toluene at 95℃; for 4h; Stage #3: maleic acid In diethyl ether Further stages.;

Reference： [1]Doege, Ulrica; Eger [Pharmazie, 2007, vol. 62, # 3, p. 174 - 178]

34
[ 61903-11-5 ]
[ 90-99-3 ]
1-[4-(diphenylmethyl)-1,4-diazepin-1-yl]ethanone [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 7258 - 7273

35
[ 90-99-3 ]
[ 147-24-0 ]

Reference： [1]Recueil des Travaux Chimiques des Pays-Bas,1952,vol. 71,p. 431

36
[ 3088-15-1 ]
[ 90-99-3 ]
4,6-dibenzoyl-2-(diphenylmethyl)resorcinol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
13%	With sodium hydroxide In water at 80℃; for 4h;	16 Example 16 Example 16 This example is similar to example 15, and involved the preparation of 4,6-dibenzoyl-2-(diphenylmethyl)resorcinol (XIV, structure I with Ar1, Ar2, A, and R=phenyl).. 4,6-Dibenzoylresorcinol (3.18 g, 10 mmol), chlorodiphenylmethane (2.22 g, 11 mmol) and about 30 mg of tetrabutylammonium bromide were added to a solution of 0.8 g (20 mmol) of sodium hydroxide in 10 ML of water.. The temperature was brought to about 80° C. and stirred vigorously for 2 hours whereupon 1 g more of the chlorodiphenylmethane was added.. Heating and stirring were continued for another 2 hours.. The reaction mixture was then cooled, acidified with concentrated hydrochloric acid, and extracted into chloroform.. The organic layer was separated, dried, and evaporated to give a solid that was twice recrystallized from ethanol/chloroform to yield 0.62 g (13%) of solid in two crops.. The NMR spectrum was consistent with the assigned structure.
0.62 g (13%)	With sodium hydroxide; tetrabutylammomium bromide In water	16 Example 16 Example 16 This example is similar to example 15, and involved the preparation of 4,6-dibenzoyl-2-(diphenylmethyl)resorcinol (XIV, structure I with Ar1, Ar2, A, and R=phenyl). 4,6-Dibenzoylresorcinol (3.18 g, 10 mmol), chlorodiphenylmethane (2.22 g, 11 mmol) and about 30 mg of tetrabutylammonium bromide were added to a solution of 0.8 g (20 mmol) of sodium hydroxide in 10 mL of water. The temperature was brought to about 80° C. and stirred vigorously for 2 hours whereupon 1 g more of the chlorodiphenylmethane was added. Heating and stirring were continued for another 2 hours. The reaction mixture was then cooled, acidified with concentrated hydrochloric acid, and extracted into chloroform. The organic layer was separated, dried, and evaporated to give a solid that was twice recrystallized from ethanol/chloroform to yield 0.62 g (13%) of solid in two crops. The NMR spectrum was consistent with the assigned structure.

Reference： [1]Current Patent Assignee: GENERAL ELECTRIC CO - US6395922, 2002, B1 Location in patent: Page column 16
[2]Current Patent Assignee: GENERAL ELECTRIC CO - US6143918, 2000, A

37
[ 149366-79-0 ]
[ 90-99-3 ]
[ 802983-61-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; potassium iodide; In butanone; for 18h;Heating / reflux;	To a solution OFCHLORODIPHENYLMETHANE (0.68 g, 3.39 mmol) in butanone (15 ml) was added 3-AMINOMETHYL-3-TERT-BUTOXYCARBONYLPYRROLIDINE (0.68 g, 3.39 mmol), K2C03 (0.56 g, 4.07 mmol) and KI (0.56, 3.39 mmol). The mixture was heated under reflux for 18 hours, then filtered and the solvent was removed . VACZLO. The residue was dissolved in CH2CL2 (50 ml) and washed with water (10 ml). Drying over MGS04 and removal of solvent under reduced pressure followed by column chromatography using Hex: EtOAc (3: 1) gives the desired product.

Reference： [1]Patent: WO2004/105750,2004,A1 .Location in patent: Page 29

38
[ 90-99-3 ]
[ 27329-60-8 ]

Reference： [1]Patent: JP2005/200358,2005,A .Location in patent: Page/Page column 35-36

39
[ 90-99-3 ]
[ 198989-07-0 ]
[ 198989-05-8 ]

Yield	Reaction Conditions	Operation in experiment
78%	With triethylamine; In tetrahydrofuran; sodium bicarbonate;	2-tBoc-5-diphenylmethyl-2,5-diazabicyclo[2.2.1]heptane (145) Triethylamine (0.8 g) and 1.55 g of diphenylmethyl chloride are added to a solution of 1.5 g of 2-tBoc-2,5-diazabicyclo[2.2.1]heptane in anhydrous THF and refluxed with stirring for 4 hours. The THF was then evaporated off, taken up in 50 mL of saturated sodium hydrogen carbonate solution and extracted 3 times with 30 mL of ether. Evaporation resulted in 2.2 g of yellowish crystals of 145 (78% of the theoretical yield). 1H-NMR (CDCl3): 7.48-7.11 (10 H, m), 4.81 (H, b), 4.31 (H, d), 3.40 (H, d), 3.18 (H, dd), 2.92 (H, dd), 2.56 (H, d), 1.84 (H, d), 1.72 (H, d), 1.54 (9H, s)

Reference： [1]Patent: US2003/92700,2003,A1

40
[ 75-44-5 ]
[ 132924-44-8 ]
[ 132924-55-1 ]
[ 90-99-3 ]

Yield	Reaction Conditions	Operation in experiment
70.1%	With potassium carbonate In ligroin; dichloromethane	18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride Preparation 18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride A solution of 14 g (0.144 mole) of phosgene in 200 ml of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 hr, then 45.9 g (0.12 mole) of 1-diphenylmethyl-3-(3,4-dichlorophenoxy)azetidine in 100 ml of methylene chloride was added dropwise and stirring was continued for 72 hr. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing, an additional 13.3 g of tacky material was obtained. After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, in 70.1% yield, m.p. 96°-99° C. Analysis: Calculated for C10 H18 Cl3 NO2: C,42.81; H,2.87; N,4.99 Found: C,43.32; H,2.89; N,4.99
70.1%	With potassium carbonate In ligroin; dichloromethane	18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride PREPARATION 18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride A solution of 14 g (0.144 mole) of phosgene in 200 ml of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 hr, then 45.9 g (0.12 mole) of 1-diphenylmethyl-3-(3,4-dichlorophenoxy)azetidine in 100 ml of methylene chloride was added dropwise and stirring was continued for 72 hr. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing, an additional 13.3 g of tacky material was obtained. After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, in 70.1% yield, m.p. 96°-99° C. Analysis: Calculated for C10 H18 Cl3 NO2: C,42.81; H,2.87; N,4.99. Found: C,43.32; H,2.89; N,4.99.
70.1%	With potassium carbonate In ligroin; dichloromethane	18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride. PREPARATION 18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride. A solution of 14 g (0.144 mole) of phosgene in 200 ml of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 hr, then 45.9 g (0.12 mole) of 1-diphenylmethyl-3-(3,4-dichlorophenoxy)azetidine in 100 ml of methylene chloride was added dropwise and stirring was continued for 72 hr. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing, an additional 13.3 g of tacky material was obtained. After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, in 70.1% yield, m.p. 96°-99° C. Analysis: Calculated for C10 H18 Cl3 NO2: C,42.81; H,2.87;N,4.99. Found: C,43.32; H,2.89; N,4.99.

With potassium carbonate In ligroin; dichloromethane

18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride PREPARATION 18 3-(3,4-Dichlorophenoxy)-1-azetidinecarbonyl chloride A solution of 14 g (0.144 mole) of phosgene weighed into 200 mL of methylene chloride was treated with 19.9 g (0.144 mole) of anhydrous potassium carbonate and stirred for 1 h then 45.9 g (0.12 mole) of 1-(diphenylmethyl)-3-(3,4-dichlorophenoxy)azetidine in 100 mL of methylene chloride was added dropwise and stirring was continued for 72 h. The reaction mixture was filtered to remove the inorganic salts and then concentrated in vacuo to a pale yellow oil (67 g). Trituration of the residue with cyclohexane yielded a crude pale yellow solid (23.6 g). The filtrate was treated with ligroin and upon standing an additional 13.3 g of tacky material was obtained (contaminated with diphenylmethyl chloride). After several recrystallizations from cyclohexane to remove traces of diphenylmethyl chloride a portion was obtained as fine white crystals, mp 96°-99° C. Analysis: Calculated for C10 H18 Cl3 NO2: C, 42.81; H, 2.87; N, 4.99. Found: C, 43.32; H, 2.89; N, 4.99.

Reference： [1]Current Patent Assignee: PFIZER INC - US5183902, 1993, A
[2]Current Patent Assignee: PFIZER INC - US4956359, 1990, A
[3]Current Patent Assignee: PFIZER INC - US5068231, 1991, A
[4]Current Patent Assignee: PFIZER INC - US5095014, 1992, A

41
[ 90-99-3 ]
[ 10111-08-7 ]
[ 169378-53-4 ]

Yield	Reaction Conditions	Operation in experiment
10.8 g (39%)	In tetrahydrofuran; dichloromethane;	(a) To a stirred solution of 2-imidazolylcarboxaldehyde (9.6 g, 0.1 mol) in dry THF (200 ml) at 0 C. under argon was added portionwise 4 g (0.1 mol) of 60% sodium hydride and the mixture was stirred at 0 C. for 15 minutes and at room temperature for 2 hours, and cooled to 0 C. To the above mixture was added diphenylmethyl chloride (20.27 g, 0.1 mol) in 15 ml of THF and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was heated in an oil-bath at 60-70 C. for 24 hours. The solvent was concentrated in vacuo, the residue was dissolved in methylene chloride and washed with water. The organic layer was dried over sodium sulfate, concentrated in vacuo, and the residual oil was passed through a silica column (methylene chloride/ether, 9:1) and crystallized from methylene chloride/hexane to afford 10.8 g (39%) of 1-(1,1-diphenylmethyl)-2-imidazolyl-carboxaldehyde.

Reference： [1]Patent: US5569655,1996,A

42
[ 3304-70-9 ]
[ 90-99-3 ]
[ 69840-42-2 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In acetonitrile;	(a) 1-Benzhydryl-4,5-dimethoxycarbonyl-imidazole 20.3 g of benzhydryl chloride were added dropwise to a suspension of 18.4 g (0.1 mol) of 4,5-dimethoxycarbonyl-imidazole in 60 cc of acetonitrile and 14 cc of triethylamine and the reaction mixture was heated for 8 hours at 80 C. The solvent was then removed under reduced pressure and triethylammonium chloride was separated by washing with water. 30 g (85% of the theory) of 1-benzhydryl-4,5-dimethoxycarbonyl-imidazole, m.p. 93 C., were obtained. The following compound was obtained in analogous manner with the use of 2-chlorotrityl chloride (=2-chlorotriphenylmethyl chloride):

Reference： [1]Patent: US4182624,1980,A

43
[ 5670-78-0 ]
[ 1499-21-4 ]
[ 5849-36-5 ]
[ 90-99-3 ]

Reference： [1]Gazizov; Ibragimov; Bagautdinova; Karimova; Khairullina; Sinyashin [Doklady Chemistry, 2008, vol. 418, # 1, p. 17 - 18]

44
[ 1016-09-7 ]
[ 1499-21-4 ]
[ 5849-36-5 ]
[ 90-99-3 ]

Yield	Reaction Conditions	Operation in experiment
	at 150℃; for 23h;

Reference： [1]Gazizov; Ibragimov; Bagautdinova; Karimova; Khairullina; Sinyashin [Doklady Chemistry, 2008, vol. 418, # 1, p. 17 - 18]

45
[ 142-64-3 ]
[ 90-99-3 ]
[ 841-77-0 ]

Yield	Reaction Conditions	Operation in experiment
80%	With potassium carbonate; In tetrahydrofuran;Reflux;	Compound, 2 (250 mg, 1.23 mmol) was taken in THF, and piperazinedihydrochloride (199 mg, 1.25 mmol) and K2CO3 (690mg, 5 mmol) were added. The reaction mixture was refluxed overnight.After complete reaction the solvent was removed under reduced pressure and theprecipitate obtained was washed with water and hexane (5 x 3ml). The crudeproduct was purified by column chromatographyusing gradient of ethylacetate andhexane (20 % v/v) to obtain off white color compound. Yield 80 % (250mg). M.p. 91-92C. 1H NMR(300 MHz, CDCl3) delta (ppm): 7.38-7.12 (m, 10 H), 4.21 (s, 1H),2.40 (Br, 8 H).

Reference： [1]Tetrahedron Letters,2013,vol. 54,p. 3688 - 3693
[2]Medicinal Chemistry Research,2007,vol. 16,p. 179 - 187
[3]European Journal of Medicinal Chemistry,2009,vol. 44,p. 1223 - 1229
[4]Medicinal Chemistry Research,2014,vol. 23,p. 3207 - 3219

46
(S)-N-(2-formyl-benzyl-4-chlorophenyl)-1-benzyl-pyrrolidine-2-carboxamide-glycine nickel complex [ No CAS ]
[ 90-99-3 ]
Ni-(S)-2-[(N-benzylprolyl)amino]-5-chlorobenzophenone-(S)-diphenylalanine complex [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium methylate In methanol; N,N-dimethyl-formamide at 25℃; for 6h;	1 Example 1 Production of Ni-(S)-2-[(N-benzylprolyl)amino]-5-chlorobenzophenone-(S)-diphenylalanine complex (Ni-(S)-BPC-(S)-DIP) [Show Image] To a solution of Ni-(S)-2-[(N-benzylprolyl)amino]-5-chlorobenzophenone-glycine complex (Ni-(S)-BPC-Gly) (532 mg, 1.0 mmol) in N,N-dimethylformamide (1.25 mL) was added diphenylmethyl chloride (117 µL, 1.0 mmol), and the mixture was stirred at 25°C, a solution (245 µL, 1.2 mmol) of 28% sodium methoxide in methanol was added dropwise, and the mixture was stirred for 6 hours. After completion of the reaction, the reaction mixture was quenched with water, adjusted to pH 7.0 with aqueous citric acid solution, and the suspension was filtered. The filtrated solid was washed with water and vacuum dried to give Ni-BPC-DIP as red crystals (642 mg, yield 92%). The diastereomeric excess of Ni-(S)-BPC-(S)-DIP was 96%d.e.

Reference： [1]Current Patent Assignee: AJINOMOTO COMPANY INC - EP1918275, 2008, A1 Location in patent: Page/Page column 15

47
[ 90-99-3 ]
[ 113451-59-5 ]
[ 1024010-87-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With sodium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 110℃; for 2h;	To a stirred solution of chlorodiphenylmethane (0.39 g, 1.94 mmol) in DMF (5 mL) was added (IS, 4S)-diazabicyclo[2,2,l]-heptane (0.5 g, 2.52 mmol), Na2CO3 (0.41 g, 3.88 mmol) and NaI (0.31 g, 2.04 mmol). The mixture was stirred for 2 h at 1100C, then cooled to room temperature and diluted with 75% AcOEt in Hexanes. The mixture was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (0-30%) in hexanes to afford 200 (0.5 g, 71%) as a beige solid. LRMS (ESI): (calc) 364.2 (found) 365.5 (MH)+.
71%	With sodium carbonate;sodium iodide; In N,N-dimethyl-formamide; at 110℃; for 2h;	To a stirred solution of chlorodiphenylmethane (0.39 g, 1.94 mmol) in DMF (5 rnL) was added (IS, 4S)-diazabicyclo[2,2,l]-heptane (0.5 g, 2.52 mmol), Na2CO3 (0.41 g, 3.88 mmol) and NaI (0.31 g, 2.04 mmol). The mixture was stirred for 2 h at 1100C, then cooled to room temperature and diluted with 75% AcOEt in Hexanes. The mixture was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (0-30%) in hexanes to afford 200 (0.5 g, 71%) as a beige solid. LRMS (ESI): (calc) 364.2 (found) 365.5 (MH)+.
71%	With sodium carbonate; sodium iodide; In N,N-dimethyl-formamide; at 110℃; for 2h;	To a stirred solution of chlorodiphenylmethane (0.39 g, 1.94 mmol) in DMF (5 mL) was added (1S,4S)-diazabicyclo[2,2,1]-heptane (0.5 g, 2.52 mmol), Na2CO3 (0.41 g, 3.88 mmol) and NaI (0.31 g, 2.04 mmol). The mixture was stirred for 2 h at 110 C., then cooled to room temperature and diluted with 75% AcOEt in Hexanes. The mixture was washed with water, brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography with gradient of EtOAc (0-30%) in hexanes to afford 200 (0.5 g, 71%) as a beige solid. LRMS (ESI): (calc) 364.2 (found) 365.5 (MH)+

Reference： [1]Patent: WO2008/55068,2008,A2 .Location in patent: Page/Page column 166
[2]Patent: WO2009/137503,2009,A1 .Location in patent: Page/Page column 47
[3]Patent: US2017/749,2017,A1 .Location in patent: Paragraph 0529

48
[ 1004755-00-3 ]
[ 90-99-3 ]
[ 1004755-24-1 ]

Yield	Reaction Conditions	Operation in experiment
30%	With sodium hexamethyldisilazane In tetrahydrofuran at -20 - 0℃; for 5.58333h;	26.1 Step 1: Under nitrogen stream, sodium disilazide (1.9 mol/L; tetrahydrofuran solution, 10.6 mmol) was added dropwise at -20°C over 20 minutes to an anhydrous tetrahydrofuran solution (25 ml) containing a very small amount of 1, 10-phenanthroline (5 mg or less), 1-dimethylethyl-(2R)-(2,6-dichlorophenyl)-5-oxo-3-((1'R)-phenylethyl)tetrahydro-1H-1-imidazolecarboxylate (4.0 g, 9.2 mmol) obtained in Example 10 and benzhydryl chloride (3.1 g, 15.3 mmol); and then, reaction was carried out at -20°C for 15 hours and further at -10°C for 1 hour and at 0°C for 4 hours. To the reaction mixture, 6.5 ml of a 4 M acetic acid / tetrahydrofuran solution was added to stop the reaction. The reaction mixture was diluted with 100 ml of ethyl acetate, and then successively washed with distilled water and saturated brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed in reduced pressure to obtain 7.0 g of a crude product. The crude product was purified by silica gel column chromatography (silica gel 60, 200 g, eluent: hexane / ethyl acetate = 5 / 1 by volume ratio) twice and further purified once in the same manner except that 300 g of silica gel was used to obtain 1,1-dimethylethyl- (2R)-(2,6-dichlorophenyl)-(4S)-(diphenylmethyl)-5-oxo-3-((1'R)-phenylethyl)tetrahydro-1H-1-imidazolecarboxylate in total amount of 1.63 g as a white solid (yield: 30%). 1H-NMR (400MHz, CDCl3): δ7.50-7.05(18H, m), 6.25(1H, d, J=2.2Hz), 4.67(1H, dd, J=1.5Hz, 2.0Hz), 4.62(1H, d, J=1.5Hz), 4.06(1H, q, J=6.8Hz), 1.29(3H, d, J=6.8Hz), 1.16(9H, s)

Reference： [1]Current Patent Assignee: KANEKA CORPORATION - EP2050738, 2009, A1 Location in patent: Page/Page column 39

49
[ 121-44-8 ]
[ 90-99-3 ]
[ 79-07-2 ]
[ 68524-30-1 ]

Yield	Reaction Conditions	Operation in experiment
81.4%		Thiourea (20.0 g) is loaded into a 500 ml round-bottom flask and water (60 ml) and potassium iodide are added (0.7 g). The resulting suspension is heated to 70 C. (at 35-40 C. complete dissolution is observed) and benzhydryl chloride (44.0 g) is added in 30 minutes. After the addition of the first one-quarter aliquot the mixture first becomes clear, then the product precipitates with exothermic reaction and heating (95 C.) is continued for 90 minutes. [0027] The mixture, which is not easily stirrable, is cooled to 15-20 C., thereafter water (45 ml) is added, followed by 30% sodium hydroxide (29.0 g, i.e. the amount necessary to hydrolyse the isothiouronium salt) at a temperature of 24 C. The mixture is heated to 70 C. (at 50-60 C. the compound dissolves, and separation of a gluey but stirrable phase is observed) and triethylamine (24.1 g) is added (the gluey phase becomes an oil). A hot solution of chloroacetamide (22.0 g) in water (66 ml) is added in about 1 hour. An oil separates from the mixture and at the end of the addition compound (II) solidifies. Refluxing is continued for 30 minutes, until all the solid becomes an oil again. Heating is stopped and at 80 C. crystallization is triggered with 2-(benzhydrylthio)acetamide crystals, thereafter stirring is continued overnight. The following day the mixture is cooled to 15 C., and the product is filtered after 1 hour and washed with water. Wet product: 64 g (HPLC: 81.4%).The product is dissolved in boiling toluene, distilling off the amount of solvent necessary to remove the water. Decolorizing carbon (0.5 g) is added, then the mixture is hot filtered. Crystallisation is accomplished by slow cooling, then the product is filtered at 0-5 C. and dried at 40 C. under reduced pressure. Dry product: 45.6 g (HPLC: 99.3%).

Reference： [1]Patent: US2004/106829,2004,A1 .Location in patent: Page 3

50
[ 90-99-3 ]
[ 79-07-2 ]
[ 68524-30-1 ]

Yield	Reaction Conditions	Operation in experiment
97.9%		Thiourea (20.0 g) is loaded into a 500 ml round-bottom flask and water (60 ml) and potassium iodide (0.7 g) are added. The resulting suspension is on heated to 70 C. (at 35-40 C. complete dissolution is observed) and benzhydryl chloride (44.0 g) is added in 30 minutes. After the addition of the first one-quarter aliquot the mixture first becomes clear, then the product precipitates with exothermic reaction and heating (70-75 C.) is continued for 60 minutes. The mixture, which is not easily stirrable, is cooled to 15-20 C., thereafter water (45 ml) is added, followed by 30% sodium hydroxide (29.0 g, i.e. the amount necessary to hydrolyse the isothiouronium salt), at a temperature of 24 C. The mixture is heated to 70 C. (at 50-60 C. the product dissolves, and the separation of a gluey but stirrable phase is observed) and 24.1 g of triethylamine is added (the gluey phase becomes an oil). The temperature is raised to 80 C. and a solution of chloroacetamide (22.0 g) in dimethylsulfoxide (33 ml) is added over approximately 1 hour; an oil separates from the mixture. The temperature is kept at 80 C. for 60 minutes and then toluene (250 ml) is added. The phases are separated at 80 C. and the organic one is washed with 150 ml of hot water. The phases are separated and the aqueous one is re-extracted with toluene (80 ml), then separated at 80 C. The organic phase from the first extraction is concentrated by distilling off 150 ml of toluene at atmospheric pressure, to obtain a clear solution, which is allowed to cool to room temperature overnight. After further cooling to 0-5 C. for 30 minutes, the crystallized product is filtered and washed, first with 15 ml of toluene at 0 C. and then with 50 ml of hexane at 0 C. Wet product: 54.1 g. After drying at 50 C. under reduced pressure for 4 hours and 30 minutes 42.3 g of dry product is obtained (HPLC: 97.9%).

Reference： [1]Patent: US2004/106829,2004,A1 .Location in patent: Page 3
[2]ACS Combinatorial Science,2015,vol. 17,p. 348 - 354

51
[ 3612-20-2 ]
[ 90-99-3 ]
[ 562838-53-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	Stage #1: 1-phenylmethyl-4-piperidone With trimethylsilyl trifluoromethanesulfonate In toluene at 5 - 10℃; Stage #2: In toluene at 20℃; for 0.5h; Stage #3: diphenylchloromethane In toluene at 78 - 80℃; for 4h;	200 Example 200; 3-Benzhydryl-1-benzyl-4-piperidinone The title compound described in Example 4 can also be produced by the method described below.. A 1 L flask was charged with 250 ml of toluene and 73.7 g (389 mmol) of 1-benzyl-4-piperidinone and to the mixture was added dropwise 85.5 ml (467 mmol) of trimethylsilyl triflate with stirring under ice-cooling (internal temperature 5 to 10°C).. The cooling bath was removed and the mixture was warmed to room temperature and then stirred for 30 minutes.. Then, 87.0 g (429 mmol) of benzhydryl chloride was added thereto and the mixture was stirred at an internal temperature of 78 to 80°C for 4 hours.. To the mixture.were added 580 ml of ethyl acetate and a 10% aqueous solution of sodium carbonate with stirring under ice-cooling.. After separating into layers, the aqueous layer was washed with 580 ml of ethyl acetate.. The organic layers were combined and washed with 580 ml of water.. The mixture was decolorized by treating with 7.4 g of an active charcoal SHIRASAGI A. After concentration under reduced pressure, 390 ml of ethanol and 47 ml of conc. hydrochloric acid were added to the residue, and the mixture was ice-cooled, and allowed to stand in a refrigerator overnight.. The precipitated crystals were collected by filtration, washed with 200 ml of ethanol and 100 ml of IPE and dried under reduced pressure to obtain 107 g of the hydrochloride of the title compound (yield: 70%). The compounds obtained in the above Examples are summarized in the following Tables 1 to 3.

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED - EP1460062, 2004, A1 Location in patent: Page 82

52
[ 1615-14-1 ]
[ 90-99-3 ]
1-[2-(diphenylmethoxy)ethyl]imidazole hydrochloride [ No CAS ]

Reference： [1]Russian Chemical Bulletin,2009,vol. 58,p. 936 - 939

53
[ 114875-62-6 ]
[ 90-99-3 ]
1,5-bis(benzhydryloxy)-2-(hydroxymethyl)pyridin-4(1H)-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium carbonate; sodium iodide In dimethyl sulfoxide at 20 - 25℃; for 20h;
99%	With potassium carbonate; sodium iodide In dimethyl sulfoxide at 20 - 110℃; for 17h;	1.3 1.3 Intermediate 1-hydroxy-2-hydroxymethyl-5-diphenylmethoxy-4-pyridoneSynthesis Suspend 1-hydroxy-2-hydroxymethyl-5-dibenzyloxy-4-pyridone (16.2g, 0.05mol) in dimethyl sulfoxide (160ml),Heat to 110 to dissolve, cool to room temperature,Add potassium carbonate (10.37g, 0.075mol) one by one,Sodium iodide (11.25g, 0.075mol), diphenylchloromethane (15.2g, 0.075mol), react for 17 hours at room temperature,TLC monitors the reaction. After the reaction is complete, pour the reaction solution into ice water (500ml), and the glass rod is stirred to precipitate solids.Then filtered, the filter cake was washed with a mixed solution of ethyl acetate and petroleum ether (2:1) for 1 hour, filtered,Dry under vacuum at 40°C to obtain an off-white solid (24.23g, yield 99%).
98%	With potassium carbonate; sodium iodide In dimethyl sulfoxide at 20℃;

92%	With potassium carbonate; sodium iodide In dimethyl sulfoxide at 20 - 100℃;	3.3 Step 3: Preparation of C13. A suspension of C12 (1.91 g, 5.91 mmol) in dimethyl sulfoxide (30 ml.) was heated at 100 °C to dissolve the compound. The reaction mixture was cooled to room temperature and treated with potassium carbonate (1.22 g, 8.85 mmol), sodium iodide (1.33 g, 8.90 mmol) and chlorodiphenylmethane (1.60 ml_, 9.00 mmol). The mixture was stirred at room temperature overnight and then treated with ice cold water. The yellow solid was filtered, dissolved in excess ethyl acetate and washed twice with water and once with brine solution. Theorganic layer wasconcentrated to dryness and the resulting solid was suspended in a minimal amount of ethyl acetate, collected by filtration and washed with ethyl acetate to afford C13 as a light yellow solid. Yield: 2.66 g, 5.43 mmol, 92%. 1H NMR (400 MHz, CD3OD) δ 7.33- 7.43 (m, 15H), 7.26-7.31 (m, 2H), 7.19-7.24 (m, 4H), 6.43-6.44 (m, 1 H), 6.18 (s, 1 H), 6.04 (s, 1 H), 4.27 (s, 2H).
92%	With potassium carbonate; sodium iodide In dimethyl sulfoxide at 100℃;

Reference： [1]Tan, Liang; Tao, Yunliang; Wang, Ting; Zou, Feng; Zhang, Shuhua; Kou, Qunhuan; Niu, Ao; Chen, Qian; Chu, Wenjing; Chen, Xiaoyan; Wang, Haidong; Yang, Yushe [Journal of Medicinal Chemistry, 2017, vol. 60, # 7, p. 2669 - 2684]
[2]Current Patent Assignee: CHONGQING MEDICAL PHARMACEUTICAL COLLEGE; SPECIAL SCHOOL FOR CHONGQING MEDICINE AND LIKE - CN111620893, 2020, A Location in patent: Paragraph 0051-0053; 0058-0059
[3]Ding, Shi; Wang, Wen-Ke; Cao, Qiao; Chu, Wen-Jing; Lan, Le-Fu; Hu, Wen-Hao; Yang, Yu-She [Chinese Chemical Letters, 2015, vol. 26, # 6, p. 763 - 767]
[4]Current Patent Assignee: PFIZER INC - WO2012/73138, 2012, A1 Location in patent: Page/Page column 48
[5]Brown, Matthew F.; Mitton-Fry, Mark J.; Arcari, Joel T.; Barham, Rose; Casavant, Jeffrey; Gerstenberger, Brian S.; Han, Seungil; Hardink, Joel R.; Harris, Thomas M.; Hoang, Thuy; Huband, Michael D.; Lall, Manjinder S.; Lemmon, M. Megan; Li, Chao; Lin, Jian; McCurdy, Sandra P.; McElroy, Eric; McPherson, Craig; Marr, Eric S.; Mueller, John P.; Mullins, Lisa; Nikitenko, Antonia A.; Noe, Mark C.; Penzien, Joseph; Plummer, Mark S.; Schuff, Brandon P.; Shanmugasundaram, Veerabahu; Starr, Jeremy T.; Sun, Jianmin; Tomaras, Andrew; Young, Jennifer A.; Zaniewski, Richard P. [Journal of Medicinal Chemistry, 2013, vol. 56, # 13, p. 5541 - 5552]

54
[ 108-01-0 ]
[ 90-99-3 ]
[ 58-73-1 ]
[ 574-42-5 ]

Reference： [1]Chemical Science,2013,vol. 4,p. 2822 - 2827

55
[ 108-01-0 ]
[ 90-99-3 ]
[ 147-24-0 ]
[ 2498-25-1 ]

Reference： [1]Chemical Science,2013,vol. 4,p. 2822 - 2827

56
[ 90-99-3 ]
[ 750512-44-8 ]
[ 298-57-7 ]

Reference： [1]Synthetic Communications,2014,vol. 44,p. 600 - 609

57
[ 90-99-3 ]
[ 157303-86-1 ]
[ 1629873-36-4 ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium carbonate In neat (no solvent) at 140℃; for 18h;	N-Alkylation of Secondary Amines: (R)-N-Benzhydryl-1-phenylethylamine Hydrochloride [(R)-3·HCl);²⁷ Typical Procedure General procedure: Anhydrous K2CO3 (3.04 g, 22.0 mmol) was added to a mixture of (R)-(+)-α-methylbenzylamine (6; 6.45 mL, 6.06 g, 50.0 mmol) and benzhydryl chloride (11.6 mL, 13.2 g, 65.0 mmol). The suspension was heated at 140 °C for 18 h, and then poured into EtOH (1 L) and H2O (150 mL). The mixture was loaded on activated Dowex-50WX2 (ion-exchange resin), washed with MeOH (300 mL) and EtOAc (100 mL), and then eluted with MeOH-NH3·H2O (9:1) until no product was observable by TLC (eluent: MeOH-CH2Cl2 sat.with NH3, 5.95). Collected ammonia solutions were concentrated. Then 10% aq HCl (4.5 mL) was added to the crude product, and H2O was evaporated in vacuo. The product was crystallized from a mixture of EtOH and EtOAc to give (R)-3·HCl as a white solid.