[ CAS No. 20289-26-3 ] {[proInfo.proName]}

Name: 20289-26-3|4-Benzyloxyindole|97%
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Quality Control of [ 20289-26-3 ]

COA NMR CNMR HPLC LC-MS

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Product Citations

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders

Raithatha, Sheetal A. ; Hagel, Jillian M. ; Matinkhoo, Kaveh , et al. J. Med. Chem.,2023, 67(2): 1024-1043. DOI: 10.1021/acs.jmedchem.3c01225 PubMed ID: 37983270

Abstract: The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite pos. clin. end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chem. entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacol. exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.

Purchased from AmBeed: 7693-46-1 ; 33657-49-7 ; 38871-41-9 ; 20289-26-3 ; 2251-50-5 ; 35180-01-9 ; 4090-55-5 ; 54322-65-5 ; 77877-94-2 ; 52061-51-5 ; 63881-16-3 ; 5402-53-9 ; 7693-46-1

Product Details of [ 20289-26-3 ]

CAS No. :	20289-26-3	MDL No. :	MFCD00047200
Formula :	C₁₅H₁₃NO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LJFVSIDBFJPKLD-UHFFFAOYSA-N
M.W :	223.27	Pubchem ID :	88465
Synonyms :

Calculated chemistry of [ 20289-26-3 ] Expand+

Physicochemical Properties

Num. heavy atoms :	17
Num. arom. heavy atoms :	15
Fraction Csp3 :	0.07
Num. rotatable bonds :	3
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	69.28
TPSA :	25.02 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	Yes
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	Yes
CYP3A4 inhibitor :	Yes
Log Kp (skin permeation) :	-5.18 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.3
Log Po/w (XLOGP3) :	3.49
Log Po/w (WLOGP) :	3.6
Log Po/w (MLOGP) :	2.66
Log Po/w (SILICOS-IT) :	3.99
Consensus Log Po/w :	3.2

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.88
Solubility :	0.0296 mg/ml ; 0.000132 mol/l
Class :	Soluble
Log S (Ali) :	-3.7
Solubility :	0.0447 mg/ml ; 0.0002 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.95
Solubility :	0.000249 mg/ml ; 0.00000111 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.71

Safety of [ 20289-26-3 ]

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

Application In Synthesis of [ 20289-26-3 ]

* 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 [ 20289-26-3 ]
Downstream synthetic route of [ 20289-26-3 ]

[ 20289-26-3 ] Synthesis Path-Upstream 1~4

1
[ 20289-26-3 ]
[ 7556-37-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 17, p. 4090 - 4094
[2] Patent: CN103254191, 2016, B,

2
[ 20289-26-3 ]
[ 68-12-2 ]
[ 7042-71-9 ]

Reference： [1] Journal of Medicinal Chemistry, 2012, vol. 55, # 23, p. 10700 - 10715
[2] Heterocycles, 1984, vol. 22, # 4, p. 797 - 801
[3] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 9, p. 2571 - 2574

3
[ 20289-26-3 ]
[ 98-09-9 ]
[ 79315-62-1 ]

Yield	Reaction Conditions	Operation in experiment
45%	Stage #1: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1 h; Stage #2: for 1 h;	1. To a cooled solution of 4-(benzyloxy)-lH-indole (1.12 g, 5.00 mmol) in 10 mL of DMF, was added sodium hydride (60 wt dispersion, 220 mg, 5.50 mmol) at 0 °C. After lhr, phenylsulfonylchloride (0.77 mL, 6.00 mmol) was added. After lhr, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was dried (MgS0₄), and concentrated The residue was purified over 25 g Si0₂(25 percentEtOAc/Hexanes) to give 4-(benzyloxy)-l-(phenylsulfonyl)-lH-indole (0.820 g, 2.26 mmol, 45percent) as an off white solid. *H NMR (399 MHz, CHLOROFORM-d) δ ppm 7.79 - 7.89 (2 H, m), 7.56 - 7.64 (1 H, m), 7.46 - 7.55 (2 H, m), 7.28 - 7.46 (5 H, m), 7.15 - 7.28 (2 H, m), 6.99 - 7.14 (1 H, m), 6.75 - 6.88 (1 H, m), 6.62 - 6.74 (1 H, m), 6.58 (1 H, d, 7=7.8 Hz), 5.13 (2 H, s)

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 10, p. 2858 - 2860
[2] Patent: WO2016/114816, 2016, A1, . Location in patent: Paragraph 0277
[3] Patent: WO2016/207217, 2016, A1, . Location in patent: Page/Page column 106-107

4
[ 20289-26-3 ]
[ 889675-05-2 ]

Reference： [1] Journal of Medicinal Chemistry, 2006, vol. 49, # 10, p. 2858 - 2860

[ 20289-26-3 ] Synthesis Path-Downstream 1~108

1
[ 20289-26-3 ]
[ 2380-94-1 ]

Yield	Reaction Conditions	Operation in experiment
89.4%	With palladium on activated charcoal; hydrogen In methanol at 20℃; for 12h;	1.5 (1) Compound 6 (15g, 1eq) under N2 protectionDissolved in 100ML MeOH,Add Pd/C (0.15g, 0.1eq) to the reaction system,H2 replacement 3 times,React at room temperature for 12 hours under the protection of H2 (15psi);(2) TLC monitors the completion of the reaction;(3) The Pd/C is filtered, the mother liquor is concentrated to obtain a crude product, and the crude product is slurried with petroleum ether ethyl acetate (PE:EA-10:1) to obtain 8 g of product, with a yield of 89.4%.
	With methanol; magnesium hydrosilicate; palladium Hydrogenation;

Reference： [1]Current Patent Assignee: ASTATECH CHENGDU BIOPHARMACEUTICAL - CN112552224, 2021, A Location in patent: Paragraph 0039; 0077-0083
[2]Stoll et al. [Helvetica Chimica Acta, 1955, vol. 38, p. 1452,1469]

2
[ 20289-26-3 ]
[ 13523-93-8 ]

Reference： [1]Helvetica Chimica Acta,1959,vol. 42,p. 2073,2098

3
[ 2380-94-1 ]
[ 100-39-0 ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 2h;	To a stirred solution of <strong>[2380-94-1]1H-indol-4-ol</strong> 1 (3.2 g, 12.9 mmol) in DMF (17 mL) at RT, were added benzyl bromide (2.43 g, 14.2 mmol) and K2C03 (5.35 g, 38.7 mmol). The reaction mixture was stirred at RT for 1.5 h. Additional benzyl bromide (0.40 g, 2.33 mmol) was added and the mixture stirred at RT for 30 mm. The mixture was diluted with water (200 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was purified (silica gel; eluting 0-60% EtOAc/ hexanes) to afford compound 2 as an amber oil (2.88 g, 100%). ?HNIVIR (500 IVIHz, DMSO-d6): 11.08 (s, 1H), 7.20-7.55 (m, 5H), 6.93-7.10 (m, 3H), 6.58 (m, 1H), 6.48 (m, 1H), 5.19 (s, 2H).
59%	With potassium carbonate; In acetone; at 30℃; for 20h;	To a 250-mL round-bottom flask was placed asolution of 1H -indol-4-ol (3 g,22.53 mmol) in acetone (100 mL),then K2C03 (6.225 g,45.04mmol) and BnBr (3.47 1 g,20.29 mmol) were added. The reaction was stirred for 20 h at 30Cthen the solids were removed by filtration and the filtrate was concentrated under reducedpressure. The residue was purified by column chromatography eluting with EtOAc/petroleumether (1:20) affording 2.95 g (59%) of the title compound as a brown oil. Mass Spectrum (LCMS,ESI pos): Calcd. for C15H14NO: 224.1 (M+H); Found: 224.1.
41%	With potassium carbonate; In acetone; for 12h;Reflux;	To a stirred solution of lH-indol-4-ol 1 (1 g, 7.52 mmol) in acetone (50 mL) were added benzyl bromide (1.54 g, 8.95 mmol) and K2C03 (3.11 g, 22.56 mmol) at RT under inert atmosphere. The reaction mixture was heated to reflux temperature and stirred for 12 h. The mixture was diluted with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine (20 mL), dried (Na2S04), filtered, and concentrated under reduced pressure. The crude was purified (silica gel; eluting 1-6% EtOAc/ hexanes) to afford compound 2 (650 mg, 41%) as colorless sticky solid. 1H MR (500 MHz, DMSO-i): delta 11.08 (br s, 1H), 7.49 (d, J= 7.5 Hz, 2H), 7.39 (t, J= 7.5 Hz, 2H), 7.34-7.29 (m, 1H), 7.21 (t, J = 2.6 Hz, 1H), 7.01-6.92 (m, 2H), 6.55 (d, J= 7.2 Hz, 1H), 6.45-6.43 (m, 1H), 5.20 (s, 2H); LC- MS: m/z 224.3 (M + H+).

Reference： [1]Patent: WO2016/144702,2016,A1 .Location in patent: Paragraph 00363
[2]Tetrahedron,1993,vol. 49,p. 11155 - 11168
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 2858 - 2860
[4]Patent: WO2017/62581,2017,A1 .Location in patent: Paragraph 0205
[5]Patent: WO2016/144703,2016,A1 .Location in patent: Paragraph 00348
[6]Tetrahedron Letters,1996,vol. 37,p. 7099 - 7102
[7]ACS Medicinal Chemistry Letters,2014,vol. 5,p. 178 - 182

4
[ 22630-08-6 ]
[ 20876-37-3 ]
[ 20289-26-3 ]

Reference： [1]Archiv der Pharmazie,1988,vol. 321,p. 487 - 489
[2]Journal of Heterocyclic Chemistry,1987,vol. 24,p. 1499 - 1501

5
[ 20289-26-3 ]
[ 100-39-0 ]
[ 30000-78-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydride In N,N-dimethyl-formamide; benzene for 5h; Ambient temperature;
90%	Stage #1: 4-benzyloxy-1H-indole With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; Stage #2: benzyl bromide In tetrahydrofuran at 20℃;	4.1.3 General procedure for the synthesis of compounds 2, 3 and 4 (GP1) General procedure: To an ice-bath solution of potassium tert-butoxide (1.2 equiv) and 18-crown-6 ether (0.2 equiv) in THF, 4-(benzyloxy)-1H-indole (1.0 equiv) dissolved in THF was added dropwise; after 30min, appropriate chloride or bromide (1.3-1.5 equiv) was added and the mixture was stirred at ambient temperature for 18h. After that time, the solvent was removed in vacuo, the residue was dissolved in DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by crystallization or flash chromatography according to methods described below.
86%	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.25h; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 2h;	46.2 Step 2: 1-benzyl-4-(benzyloxy)-1H-indole (3) To a stirred solution of compound 2 (250 mg, 1.12 mmol) in DMF (2 mL) at RT were added NaH (56 mg of a 60% dispersion in mineral oil, 1.40 mmol). The mixture was stirred at RT for 15 mm, before cooling to 0 °C. A solution of benzyl bromide (210 mg, 1.23 mmol) in DMF (0.7 mL) was added and the mixture warmed to RT and stirred for 2 h. The mixture was concentrated under reduced pressure, then partitioned between water (50 mL) and EtOAc (25 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was purified (silica gel; eluting 0-60% EtOAc/ hexanes) to afford compound 3 as a white solid (302 mg, 86%). LCMS Mass: 314.0 (M+1).

Reference： [1]Somei; Tsuchiya [Chemical and Pharmaceutical Bulletin, 1981, vol. 29, # 11, p. 3145 - 3157]
[2]Wichur, Tomasz; Godyń, Justyna; Góral, Izabella; Latacz, Gniewomir; Bucki, Adam; Siwek, Agata; Głuch-Lutwin, Monika; Mordyl, Barbara; Śniecikowska, Joanna; Walczak, Maria; Knez, Damijan; Jukič, Marko; Sałat, Kinga; Gobec, Stanislav; Kołaczkowski, Marcin; Malawska, Barbara; Brazzolotto, Xavier; Więckowska, Anna [European Journal of Medicinal Chemistry, 2021, vol. 225]
[3]Current Patent Assignee: PHARMAKEA INC - WO2016/144702, 2016, A1 Location in patent: Paragraph 00364

6
[ 20289-26-3 ]
[ 68-12-2 ]
[ 7042-71-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 10700 - 10715
[2]Heterocycles,1984,vol. 22,p. 797 - 801
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 2571 - 2574
[4]Journal of Pharmacology and Experimental Therapeutics,2019,vol. 370,p. 864 - 875

7
[ 79-37-8 ]
[ 20289-26-3 ]
[ 74-89-5 ]
[ 118052-07-6 ]

Yield	Reaction Conditions	Operation in experiment
46%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: methylamine In diethyl ether; dichloromethane; water at 20℃; Cooling with ice;	13.1 Step 1 : 2-(4-(benzyloxy)-1 H-indol-3-yl)-N-methyl-2-oxoacetamide To a solution of 4-(benzyloxy)-1H-indole (12.0 g, 53.7 mmol) in diethyl ether (400 ml_) under ice-salt bath cooling was added a solution of oxalyl chloride (13.6 g, 108 mmol) in ether dropwise. The resulting brown solution was stirred for 3h, and then added dropwise into 40% aqueous methylamine (70 ml_) under ice-salt bath cooling. The resulting mixture was diluted with DCM (40 ml_) and then allowed to warm up to room temperature. After stirring overnight, the mixture was concentrated under reduced pressure. The concentrate was dissolved in DCM, washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: DCM/MeOH = 30/1) to afford the title compound as a brown solid (7.7 g, 46%) and used directly in the next step.
	1.) Et₂O, -10 deg C, 1 h; Yield given. Multistep reaction;

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00168-00170
[2]Brenneisen; Borner; Peter-Oesch; Schlunegger [Archiv der Pharmazie, 1988, vol. 321, # 8, p. 487 - 489]

8
[ 117609-04-8 ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
90%	With nickel boride; hydrazine hydrate In ethanol Heating;
	With titanium(III) chloride; ammonium acetate In acetone Yield given;

Reference： [1]Lloyd, David H.; Nicholas, David E. [Journal of Organic Chemistry, 1986, vol. 51, # 22, p. 4294 - 4295]
[2]Lloyd, David H.; Nichols, David E. [Tetrahedron Letters, 1983, vol. 24, # 42, p. 4561 - 4562]

9
[ 20876-37-3 ]
[ 4637-24-5 ]
[ 20289-26-3 ]

Reference： [1]Journal of Heterocyclic Chemistry,1982,vol. 19,p. 845 - 848

10
[ 79315-62-1 ]
[ 20289-26-3 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1994,vol. 42,p. 271 - 276

11
[ 13154-24-0 ]
[ 20289-26-3 ]
[ 270588-32-4 ]

Yield	Reaction Conditions	Operation in experiment
100%	With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 2h;
	With sodium hydride In tetrahydrofuran for 1h;	45A EXAMPLE 45 A1 -(triisopropylsilyl)- 1 H-indol-4-ol; 4-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) and triisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 rnL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.
	With sodium hydride In tetrahydrofuran; mineral oil	16A 4-Benzyloxyindole (1 g) was treated with 60% oily NaH (135 mg) and triisopropylsilyl chloride (1 g) in THF, purified by flash chromatography (98/2 ethyl acetate/hexanes), then debenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and a hydrogen balloon.

Reference： [1]Vedejs, Edwin; Barda, David A. [Organic Letters, 2000, vol. 2, # 8, p. 1033 - 1035]
[2]Current Patent Assignee: ABBVIE INC - WO2010/65865, 2010, A2 Location in patent: Page/Page column 262
[3]Current Patent Assignee: ABBVIE INC - US2010/160322, 2010, A1 Location in patent: Page/Page column 90

12
[ 20289-26-3 ]
[ 329015-28-3 ]
2-(4-benzyloxy-1H-indol-3-yl)-5-(2-tert-butyl-1H-indol-3-yl)-3,6-dichloro-[1,4]benzoquinone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
34%	With Celite; zinc trifluoromethanesulfonate; silver carbonate In tetrahydrofuran Heating;

Reference： [1]Pirrung, Michael C.; Liu, Yufa; Deng, Liu; Halstead, Diana K.; Li, Zhitao; May, John F.; Wedel, Michael; Austin, Darrell A.; Webster, Nicholas J. G. [Journal of the American Chemical Society, 2005, vol. 127, # 13, p. 4609 - 4624]

13
(E)-6-benzyloxy-2-nitro-β-pyrrolidinostyrene [ No CAS ]
[ 2380-94-1 ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
6%; 88%	With hydrogen;5% rhodium-on-charcoal; nickel(II) nitrate; In tetrahydrofuran; water; at 20℃; for 32h;	Following a procedure similar to Example 32, 3-benzyloxy-2-(2-pyrrolidinylvinyl)nitrobenzene as a starting material was reduced in the presence of 5 % rhodium/carbon powder and as a metal compound, ferrous(II) acetate, nickel(II) nitrate or cobalt (III) acetylacetonate as the catalyst of the present invention. The results are shown in the following Table 4, and in the case where the reducing agent of the present invention was used, 4-benzyloxyindole was obtained in a higher yield and 4-hydroxyindole was byproduced in a lower yield, compared to Comparison Example 3.
5%; 83%	With hydrogen;5% rhodium-on-charcoal; iron(II) acetate; In tetrahydrofuran; at 20℃; for 31h;	Following a procedure similar to Example 32, 3-benzyloxy-2-(2-pyrrolidinylvinyl)nitrobenzene as a starting material was reduced in the presence of 5 % rhodium/carbon powder and as a metal compound, ferrous(II) acetate, nickel(II) nitrate or cobalt (III) acetylacetonate as the catalyst of the present invention. The results are shown in the following Table 4, and in the case where the reducing agent of the present invention was used, 4-benzyloxyindole was obtained in a higher yield and 4-hydroxyindole was byproduced in a lower yield, compared to Comparison Example 3.
3%; 80%	With hydrogen;5% rhodium-on-charcoal; tris(acetylacetonato)cobalt; In tetrahydrofuran; at 20℃; for 38h;	Following a procedure similar to Example 32, 3-benzyloxy-2-(2-pyrrolidinylvinyl)nitrobenzene as a starting material was reduced in the presence of 5 % rhodium/carbon powder and as a metal compound, ferrous(II) acetate, nickel(II) nitrate or cobalt (III) acetylacetonate as the catalyst of the present invention. The results are shown in the following Table 4, and in the case where the reducing agent of the present invention was used, 4-benzyloxyindole was obtained in a higher yield and 4-hydroxyindole was byproduced in a lower yield, compared to Comparison Example 3.

38%; 43%

With hydrogen;5% rhodium-on-charcoal; In tetrahydrofuran; at 20℃; for 167h;

Following a procedure similar to Example 32, 3-benzyloxy-2-(2-pyrrolidinylvinyl)nitrobenzene as a starting material was reduced in the presence of 5 % rhodium/carbon powder and as a metal compound, ferrous(II) acetate, nickel(II) nitrate or cobalt (III) acetylacetonate as the catalyst of the present invention. The results are shown in the following Table 4, and in the case where the reducing agent of the present invention was used, 4-benzyloxyindole was obtained in a higher yield and 4-hydroxyindole was byproduced in a lower yield, compared to Comparison Example 3.

Reference： [1]Patent: EP1541582,2005,A1 .Location in patent: Page/Page column 38
[2]Patent: EP1541582,2005,A1 .Location in patent: Page/Page column 38
[3]Patent: EP1541582,2005,A1 .Location in patent: Page/Page column 38
[4]Patent: EP1541582,2005,A1 .Location in patent: Page/Page column 38
[5]Tetrahedron Letters,2006,vol. 47,p. 969 - 972
[6]Tetrahedron Letters,2006,vol. 47,p. 969 - 972

14
acetic acid 2-methylene-3-oxobutyl ester [ No CAS ]
[ 20289-26-3 ]
4-(4-benzyloxy-1H-indol-3-yl)-3-(4-benzyloxy-1H-indol-3-ylmethyl)butan-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 20℃; for 24h;

Reference： [1]Ma, Shengming; Yu, Shichao; Peng, Zhihua [Organic and Biomolecular Chemistry, 2005, vol. 3, # 10, p. 1933 - 1936]

15
[ 20289-26-3 ]
[ 840538-48-9 ]

Yield	Reaction Conditions	Operation in experiment
77%	Stage #1: 4-benzyloxy-1H-indole With potassium hydroxide In N,N-dimethyl-formamide at 75℃; for 0.25h; Stage #2: With iodine In N,N-dimethyl-formamide at 20℃; for 0.75h;	1.B.1 Step 1. Synthesis of tert-butyl 4-benzyloxy-3-iodo-indole-l-carboxylate (C91) 4-benzyloxy-lH-indole C90 (2.5 g, 11.2 mmol) in DMF (25 mL) at it. was added KOH (1.6 g, 28.5 mmol) and the mixture was heated to 75 °C for 15 minutes. Upon cooling to room temperature, a solution of I2 (3.1 g, 12.2 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred for 45 minutes. The mixture was then poured into ice water containing 1% v/v NH4OH and 0.2% w/v sodium metabisulfite and stirred for 20 minutes. A pink solid was collected by filtration and dried to give 4-benzyloxy-3-iodo-lH-indole (3 g, 77%) which was used without further purification. To a solution of 4-benzyloxy-3-iodo-lH-indole (3 g, 77%) and hoc anhydride (2.5 g, 11.5 mmol) in dichloromethane (25 mL) was added DMAP (150 mg, 1.23 mmol) and the solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Purification by silica gel chromatography (Gradient: 10- 50%) EtOAc in heptane) afforded tert-butyl 4-benzyloxy-3-iodo-indole-l-carboxylate (3.3 g, 63%) as light brown solid. NMR (400 MHz, DMSO- e) d 7.72 (d, J = 2.0 Hz, 2H), 7.63-7.61 (m, 2H), 7.45 - 7.38 (m, 2H), 7.35 - 7.21 (m, 2H), 6.95 (m, 1H), 5.28 (s, 2H), 1.61 (s, 9H). LCMS m/z 450.16 [M+H]+.
77%	Stage #1: 4-benzyloxy-1H-indole With potassium hydroxide In N,N-dimethyl-formamide at 75℃; for 0.25h; Stage #2: With iodine In N,N-dimethyl-formamide at 20℃; for 0.75h;	1.B.1 Step 1. Synthesis of tert-butyl 4-benzyloxy-3-iodo-indole-l-carboxylate (C91) 4-benzyloxy-lH-indole C90 (2.5 g, 11.2 mmol) in DMF (25 mL) at it. was added KOH (1.6 g, 28.5 mmol) and the mixture was heated to 75 °C for 15 minutes. Upon cooling to room temperature, a solution of I2 (3.1 g, 12.2 mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirred for 45 minutes. The mixture was then poured into ice water containing 1% v/v NH4OH and 0.2% w/v sodium metabisulfite and stirred for 20 minutes. A pink solid was collected by filtration and dried to give 4-benzyloxy-3-iodo-lH-indole (3 g, 77%) which was used without further purification. To a solution of 4-benzyloxy-3-iodo-lH-indole (3 g, 77%) and hoc anhydride (2.5 g, 11.5 mmol) in dichloromethane (25 mL) was added DMAP (150 mg, 1.23 mmol) and the solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. Purification by silica gel chromatography (Gradient: 10- 50%) EtOAc in heptane) afforded tert-butyl 4-benzyloxy-3-iodo-indole-l-carboxylate (3.3 g, 63%) as light brown solid. NMR (400 MHz, DMSO- e) d 7.72 (d, J = 2.0 Hz, 2H), 7.63-7.61 (m, 2H), 7.45 - 7.38 (m, 2H), 7.35 - 7.21 (m, 2H), 6.95 (m, 1H), 5.28 (s, 2H), 1.61 (s, 9H). LCMS m/z 450.16 [M+H]+.
	With pyridine; Iodine monochloride In dichloromethane

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203023, 2021, A1 Location in patent: Paragraph 00234; 00316; 00350
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203023, 2021, A1 Location in patent: Paragraph 00234; 00316; 00350
[3]Zhang, Xiaoyan; Urbanski, Maud; Patel, Mona; Cox, Geoffrey G.; Zeck, Roxanne E.; Bian, Haiyan; Conway, Bruce R.; Beavers, Mary Pat; Rybczynski, Philip J.; Demarest, Keith T. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 6, p. 1696 - 1701]

16
[ 20289-26-3 ]
[ 98-09-9 ]
[ 79315-62-1 ]

Yield	Reaction Conditions	Operation in experiment
45%		1. To a cooled solution of 4-(benzyloxy)-lH-indole (1.12 g, 5.00 mmol) in 10 mL of DMF, was added sodium hydride (60 wt dispersion, 220 mg, 5.50 mmol) at 0 C. After lhr, phenylsulfonylchloride (0.77 mL, 6.00 mmol) was added. After lhr, the reaction was quenched with saturated sodium bicarbonate solution, and extracted with EtOAc. The organic layer was dried (MgS04), and concentrated The residue was purified over 25 g Si02(25 %EtOAc/Hexanes) to give 4-(benzyloxy)-l-(phenylsulfonyl)-lH-indole (0.820 g, 2.26 mmol, 45%) as an off white solid. *H NMR (399 MHz, CHLOROFORM-d) delta ppm 7.79 - 7.89 (2 H, m), 7.56 - 7.64 (1 H, m), 7.46 - 7.55 (2 H, m), 7.28 - 7.46 (5 H, m), 7.15 - 7.28 (2 H, m), 6.99 - 7.14 (1 H, m), 6.75 - 6.88 (1 H, m), 6.62 - 6.74 (1 H, m), 6.58 (1 H, d, 7=7.8 Hz), 5.13 (2 H, s)
		7.0 g 4-benzyloxy-lH- indole (31.35 mmol) was dissolved in 60 mL dry DMF and 1.317 g NaH (32.92 mmol, 60 % on mineral oil) was added at 0 C. The mixture was stirred for 1 hour, then 6.09 g benzenesulfonyl chloride (34.48 mmol) was added dropwise and the mixture was stirred at 0 C until no further conversion was observed. Then it was diluted with water and extracted with DCM. The combined organic phases were dried over Na2S04, filtered and the filtrate was concentrated under reduced pressure and purified via flash chromatography using heptane and EtOAc as eluents to obtain l-(benzenesulfonyl)- 4-benzyloxy- indole. 1H NMR (400 MHz, DMSO-d6) delta: 7.97 (d, 2H), 7.72 (d, 1H), 7.69 (t, 1H), 7.59 (t, 2H), 7.54 (d, 1H), 7.47 (d, 2H), 7.39 (t, 2H), 7.33 (d, 1H), 7.27 (t,lH), 6.89 (d, 1H), 6.85 (d, 1H), 5.20 (s, 2H) MS (EI, 70 eV) m/z (% relative intensity, [ion]): 77 (32), 91 (100), 141 (18), 222 (6), 272 (11), 363 (10, [M+])

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2858 - 2860
[2]Patent: WO2016/114816,2016,A1 .Location in patent: Paragraph 0277
[3]Patent: WO2016/207217,2016,A1 .Location in patent: Page/Page column 106-107

17
[ 20289-26-3 ]
[ 30982-08-2 ]
3-(2'-methoxycarbonyl-2'-propenyl)-4-benzyloxyindole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	In toluene at 80℃; for 12h;

Reference： [1]Ma, Shengming; Yu, Shichao; Peng, Zhihua; Guo, Hao [Journal of Organic Chemistry, 2006, vol. 71, # 26, p. 9865 - 9868]

18
[ 90-46-0 ]
[ 20289-26-3 ]
4-(benzyloxy)-3-(9H-xanthen-9-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	In water at 20℃; for 1h;
76%	With ammonium cerium(IV) nitrate In methanol at 20℃; for 1h;

Reference： [1]Wang, Shun-Yi; Ji, Shun-Jun [Synthetic Communications, 2008, vol. 38, # 3, p. 465 - 472]
[2]Wang, Shun-Yi; Ji, Shun-Jun [Synlett, 2007, # 14, p. 2222 - 2226]

19
[ 20289-26-3 ]
[ 889675-05-2 ]

Reference： [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2858 - 2860

20
[ 20876-37-3 ]
[ 20289-26-3 ]

Reference： [1]Journal of Organic Chemistry,1986,vol. 51,p. 4294 - 4295
[2]Chemical and Pharmaceutical Bulletin,1981,vol. 29,p. 726 - 738
[3]Chemical and Pharmaceutical Bulletin,1981,vol. 29,p. 726 - 738
[4]Chemical and Pharmaceutical Bulletin,1981,vol. 29,p. 726 - 738
[5]Chemical and Pharmaceutical Bulletin,1981,vol. 29,p. 726 - 738
[6]Tetrahedron Letters,1983,vol. 24,p. 4561 - 4562
[7]Helvetica Chimica Acta,1955,vol. 38,p. 1452,1469

21
[ 20289-26-3 ]
[ 2905-21-7 ]
4-benzyloxy-1-(2-fluorobenzenesulfonyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In dichloromethane at 20℃; for 19h;	1.1 Synthesis of 4-benzyloxy-1-(2-fluorobenzenesulfonyl)-1H-indole Step 1: Synthesis of 4-benzyloxy-1-(2-fluorobenzenesulfonyl)-1H-indole To a magnetically stirred mixture of 4-benzyloxyindole (13.80 g, 0.062 mol), tetrabutylammonium hydrogen sulfate (1.05 g, 0.0031 mol) and finely ground sodium hydroxide (2.72 g, 0.068 mol) in 100 ML of dichloromethane at 0° C., was added 2-fluorobenzenesulfonyl chloride (13.25 g, 0.068 mol).After 18 hours stirring at ambient temperature, 2-fluorobenzenesulfonyl chloride (3.96 g, 0.020 mol) and finely ground sodium hydroxide (0.82 g, 0.020) were added.One hour later, the reaction mixture was washed sequentially with water (2100 ML) and an aqueous K2CO3 solution (2 M, 100 ML).The aqueous fractions were combined and extracted with CH2Cl2 (245 ML).The organic fractions were combined, dried over MgSO4 and concentrated in vacuo.The resulting solid was recrystallized from 10:2 ethyl acetate/hexanes (100 ML) to give 4-benzyloxy-1-(2-fluorobenzenesulfonyl)-1H-indole as an off-white powder (21.48 g, 91%). MP 117-120° C.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - US2003/229069, 2003, A1 Location in patent: Page 14

22
[ 20289-26-3 ]
[ 3132-64-7 ]
[ 627501-46-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride In tetrahydrofuran Heating / reflux;	19.a EXAMPLE 19; 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-oxiranylmethyl-4H-pyrrolo[2,3-h]chromene; a) 1-Oxiranylmethyl-4-hydroxy-indole:; A mixture of 4-benzyloxyindole (223 mg, 1.0 mmol), 2-bromomethyl-oxirane (168 mg, 1.2 mmol) and 60% sodium hydride (60 mg, 1.5 mmol) in 5 mL THF was refluxed overnight. The solution was poured into NaHCO3 saturated solution (20 mL) and extracted with EtOAc. The organic layer was separated, washed with brine and dried over Na2SO4. The solvent was removed in vacuo. The crude material was purified by column chromatography (1:4, hexane:ethyl acetate) to yield 200 mg of 4-benzyloxy-1-oxiranylmethylindole, which was hydrogenated by 5% Pd/C in 20 mL methanol under H2 (50 psi) to yield 70 mg (37%) of the title compound. 1H NMR (CDCl3): 7.10-7.03 (m, 2H), 6.95 (d, J=8.4 Hz, 1H), 6.56 (dd, J=0.9 Hz, J=3.3 Hz, 1H), 6.51 (dd, J=0.9 Hz, J=7.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.17-4.10 (m, 1H), 3.29-3.26 (m, 1H), 2.81-2.78 (m, 1H), 2.46-2.44 (m, 1H).

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; IMMUNE PHARMACEUTICALS INC - US2006/104998, 2006, A1 Location in patent: Page/Page column 21

23
[ 50-00-0 ]
[ 20289-26-3 ]
[ 627501-45-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide In ethanol; water at 20℃; for 4h;	17.a EXAMPLE 17; 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-7-hydroxymethyl-4H-pyrrolo[2,3-h]chromene; a) 1-Hydroxymethyl-4-hydroxy-indole:; A solution of 4-benzyloxyindole (1.0 g, 4.48 mmol), formaldehyde (2.0 mL, 26.8 mmol) and 2 N NaOH (2.24 mL, 4.48 mmol) in 10 mL EtOH was stirred at the room temperature for 4 h. The solvent was removed in vacuo. The crude material was purified by flash column chromatography (3:1, hexane:ethyl acetate) to yield 1.13 g of 4-benzyloxy-1-hydroxymethylindole, which was hydrogenated by 5% Pd/C in 40 mL methanol under H2 (50 psi) to yield 580 mg (79.5%) of the title compound. 1H NMR (CDCl3): 7.15-7.07 (m, 3H), 6.60-6.55 (m, 2H), 5.62 (d, J=7.5 Hz, 2H), 4.93 (s, 1H), 2.37 (t, J=7.2 Hz, 1H).
	With sodium hydroxide In ethanol at 20℃; for 4h;

Reference： [1]Current Patent Assignee: TAKEDA PHARMACEUTICAL COMPANY LIMITED; IMMUNE PHARMACEUTICALS INC - US2006/104998, 2006, A1 Location in patent: Page/Page column 20
[2]Kemnitzer, William; Drewe, John; Jiang, Songchun; Zhang, Hong; Crogan-Grundy, Candace; Labreque, Denis; Bubenick, Monica; Attardo, Giorgio; Denis, Real; Lamothe, Serge; Gourdeau, Henriette; Tseng, Ben; Kasibhatla, Shailaja; Sui, Xiong Cai [Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 417 - 423]

24
[ 539-74-2 ]
[ 20289-26-3 ]
[ 501031-27-2 ]

Yield	Reaction Conditions	Operation in experiment
77%	With potassium hydroxide; acetic acid In dimethyl sulfoxide	53.d (d) (d) 3-(4-Benzyloxy-indol-1-yl)-propionic acid (136) A solution of 4-Benzyloxyindole (1.61 g, 7.21 mmol) and potassium hydroxide (2.02 g, 36.1 mmol) in DMSO (12 mL) was stirred at room temperature for 1.5 hours. Ethyl 3-bromopropionate (1.11 mL, 8.65 mmol) was added and the mixture stirred overnight. The reaction was diluted with water, acidified with 2N HCl, extracted with ethyl acetate, dried over MgSOs, and concentrated under reduced pressure. The crude oil was chromatographed eluding with 25%-30% EtOAc (with 20% HOAc) in hexanes to yield the desired propionic acid (1.65 g, 77%). 400 MHz 1H NMR (DMSO-d6) δ7.44 (m, 2H), 7.35 (m, 2H), 7.27 (m, 1H), 7.18 (d, 1H, J=3.2 Hz), 7.04 (d, 1H, J=8.3 Hz), 6.97 (m, 1H), 6.55 (d, 1H, J=7.3 Hz), 6.39 (m, 1H), 5.16 (s, 2H), 4.30 (t, 2H, J=6.8 Hz), 2.67 (t, 2H, J=6.8 Hz). MS m/z 296 (M+1).

Reference： [1]Current Patent Assignee: PFIZER INC - US2003/171377, 2003, A1

25
[ 20289-26-3 ]
[ 138474-46-1 ]

Yield	Reaction Conditions	Operation in experiment
82.7%		2 Example 2 Example 2 Analogously to example 1, 43.2 g (yield 82.7% of theory) of N-[1-(4-benzyloxy-indolyl-3-yl)-2-methoxyethyl]-N-isopropylamine of a melting point of 138.4-139.3° C is obtained from 34.47 g of 4-benzyloxy-indole.

Reference： [1]Current Patent Assignee: BAYER AG - US5401854, 1995, A

26
semicarbazone [ No CAS ]
[ 5762-56-1 ]
[ 20876-37-3 ]
[ 4426-72-6 ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; hydrazine hydrate;aluminum nickel; In tetrahydrofuran; N-methyl-acetamide; methanol; ethanol; water;	5. 4-Benzyloxy-1H-indole STR57 A solution of <strong>[20876-37-3]2-nitro-6-benzyloxytoluene</strong> (13.0 g, 53 mmol) and tris(dimethylamino)methane (13.9 mL, 80 mmol) in dimethylformamide (30 mL) was heated at 115 C. under Nitrogen for 3 h. Upon cooling to ambient temperature, a solution of semicarbazide hydochloride (6.26 g, 56 mmol) and concentrated hydrochloric acid (4.8 mL) in water (70 mL) was added dropwise with vigorous stirring. Ethanol (25 mL) was added and the heterogeneous mixture stirred for 2 h. After cooling in an ice bath, the precipitate was filtered, rinsed with, in sequence, ice water, cold 50% aqueous ethanol, cold ethanol, then ether and dried to give a semicarbazone. A slurry of this semicarbazone (17.64 g, 54 mmol), Raney nickel (18 g of a 50% aqueous slurry) in 1:1 tetrahydrofuran:methanol (145 mL) was heated to 55 C. Hydrazine monohydrate was added in four equal portions (2.7 mL each) at 0.5 h intervals. The mixture was cooled, then filtered through a small pad of silica gel using ether. The filtrate was dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue purified by flash chromatography to afford 4-benzyloxy-1H-indole as a low melting solid.

Reference： [1]Patent: US5750702,1998,A

27
[ 74-96-4 ]
[ 20289-26-3 ]
[ 627500-94-1 ]

Yield	Reaction Conditions	Operation in experiment
52%	With sodium hydride In tetrahydrofuran at 0 - 20℃;

Reference： [1]Kemnitzer, William; Drewe, John; Jiang, Songchun; Zhang, Hong; Crogan-Grundy, Candace; Labreque, Denis; Bubenick, Monica; Attardo, Giorgio; Denis, Real; Lamothe, Serge; Gourdeau, Henriette; Tseng, Ben; Kasibhatla, Shailaja; Sui, Xiong Cai [Journal of Medicinal Chemistry, 2008, vol. 51, # 3, p. 417 - 423]

28
[ 20289-26-3 ]
[ 74-88-4 ]
[ 13523-93-8 ]

Yield	Reaction Conditions	Operation in experiment
55%		At 0degrees C to contain has sodium hydride 8.9g, 0 . 22mol) of DMF (150 ml)suspensionliquid adding -4- benzyloxy-1H- indole X XI (50g0. 22mol ) Stirringat room temperature 30 minutes later add iodomethane28mL0. 45mol )Then continue stirring for5 hours,again add 2equivalent iodomethane 28mL0. 45mol)The reaction mixturewas stirred for 1 hours , use Ethyl acetate (2200mL X) extraction,then drying, filtration, concentration, to obtain brown oily residue. Residueby column chromatography (use EtOAc/ Petroleum ether 1:4 for elution agent) obtain brown oily thing18g yield 55%
		To a solution of 4-benzyloxy-1H-indole (CASNo. 20289-26-3, 10.85 g, 48.6 mmol) in N. N- dimethylformamide (200 mL) at 0 C, was added sodium hydride (60% dispersion in oil 2.24 g, 55 9 mmol). The reaction was permitted to stir for 15 minutes at 0 C Then iodomethane (3.19 mL, 51.0 mmol) was added to the reaction mixture. The reaction was put at room temperature and permitted to stir 30 minutes, The reaction was then quenched with saturated aqueous ammonium chloride. The mixture was diluted with water and extracted with diethyl ether The layers were separated and the aqueous layer was then extracted two additional times with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford A- benzyloxy-1-methyMH-ιndole, MS' (ES+) m/z 238.4 (M+H)*

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4090 - 4094
[2]Patent: CN103254191,2016,B .Location in patent: Paragraph 0132; 0133
[3]Journal of Medicinal Chemistry,2008,vol. 51,p. 417 - 423
[4]Patent: WO2010/130794,2010,A1 .Location in patent: Page/Page column 103

29
[ 20289-26-3 ]
[ 588-72-7 ]
[ 1058666-99-1 ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 36h; Inert atmosphere;

Reference： [1]Location in patent: scheme or table Mao, Jincheng; Hua, Qiongqiong; Guo, Jun; Shi, Daqing; Ji, Shunjun [Synlett, 2008, # 13, p. 2011 - 2016]

30
[ 20289-26-3 ]
ammonium thiocyanate [ No CAS ]
[ 1112908-15-2 ]

Yield	Reaction Conditions	Operation in experiment
91%	With manganese(III) acetate In acetic acid at 25℃; for 2h; regioselective reaction;

Reference： [1]Location in patent: experimental part Pan, Xiang-Qiang; Lei, Mao-Yi; Zou, Jian-Ping; Zhang, Wei [Tetrahedron Letters, 2009, vol. 50, # 3, p. 347 - 349]

31
[ 99045-18-8 ]
[ 20289-26-3 ]
[ 1181567-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; copper(l) iodide; <i>L</i>-proline In N,N-dimethyl-formamide at 140℃; for 3h; Microwave irradiation;	21.b b) 4-[(phenylmethyl)oxy]-1H-indole (500 mg, 2.24 mmoL), 4-bromo-2,6-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL) and L-Proline (43 mg, 0.373 mmoL) were dissolved in DMF (5 ml.) in a microwave vial and degassed by sonication under a flow of argon. To this was added CuI (71 mg, 0.373 mmoL) and the solution was heated to 140 0C in the microwave reactor. After 3 hours the mixture was partitioned between ethyl acetate (100 ml_)/water (100 ml_), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 ml_). The combined organic phases were washed with sat. NH4CI (2x100 ml_), water (100 ml.) and brine (2x100 ml.) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4, 40+S Cartridge) eluting with a gradient of 0 to 20% Et2O in hexane to give the title compound (D21 ), (299 mg). LC-MS: MH+ = 442 (C28H21F2NO2 = 441 )

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/103710, 2009, A1 Location in patent: Page/Page column 24

32
[ 20289-26-3 ]
[ 133057-82-6 ]
[ 1181566-72-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate; copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane In toluene for 24h; Reflux;	1 Description 1. 1-{3-Fluoro-4-[(phenylmethyl)oxy]phenyl}-4-[(phenylmethyl)oxy]- 1H-indole (D1) A mixture of 4-benzyloxyindole (3.35 g, 15 mmol), 4-bromo-2-fluoro-1- [(phenylmethyl)oxy]benzene (4.22 g, 15 mmol) and potassium phosphate (6.68 g, 31.5 mmol) in toluene (25 mL) was degassed by bubbling argon through the solution for 3 minutes. Copper (I) iodide (143 mg, 0.75 mmol) and (1 S,2S)-λ/,/V-dimethyl-1 ,2- cyclohexanediamine (426 mg, 0.479 ml, 3.0 mmol) were added and the mixture was refluxed under argon for 24 hrs. After cooling, the mixture was filtered through a plug of silica gel (elution with ethyl acetate) and concentrated. Chromatography (2 columns, elution with 0-50% ethyl acetate in hexane and then a gradient of diethyl ether in hexane) gave the title compound (D1 ) 2.32 g. LC-MS: MH+ = 424 (C28H22FNO2 = 423) NMR (δH), (CDCI3): 5.21 (2H, s), 5.26 (2H, s), 6.64 (1 H, m), 6.83 (1 H, d, J = 3.2 Hz), 7.08-7.19 (5H,m), 7.28-7.53 (11 H, m)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/103710, 2009, A1 Location in patent: Page/Page column 14; 15

33
[ 6793-92-6 ]
[ 20289-26-3 ]
[ 1181567-07-6 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: p-benzyloxyphenylbromide; 4-benzyloxy-1H-indole With potassium phosphate; copper(l) iodide; <i>L</i>-proline In 1,4-dioxane at 100℃; for 5h; Microwave irradiation; Stage #2: With copper(l) iodide; <i>L</i>-proline In 1,4-dioxane for 2h; Heating;	24 Description 23. 1-{2,3-difluoro-4-[(phenylmethyl)oxy]phenyl}-4- [(phenylmethyl)oxy]-1 H-indole ((D23) 4-[(phenylmethyl)oxy]-1 H-indole (432 mg, 1.94 mmoL), 4-bromo-2,3-difluorophenyl phenylmethyl ether (486 mg, 1.63 mmoL), K3PO4 (863 mg, 4.06 mmoL) and L-Proline (38 mg, 0.329 mmoL) were dissolved in DMF (5 mL) in a microwave vial and degassed by sonication under a flow of argon for 5 minutes. To this was added CuI (62.7 mg, 0.329 mmoL) and the solution was heated to 140 0C in the microwave reactor. After 6 hours a second portion of CuI (62.7 mg, 0.329 mmoL) and L-Proline (38 mg, 0.329 mmoL) were added and heated for 2 more hours. The mixture was partitioned between ethyl acetate (75 mL)/water (75 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (3x75 mL). The combined organic phases were washed with sat. NH4CI (2x75 mL), water (75 mL) and brine (2x75 mL) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4, 40+S Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane and then further purified by MDAP to give the title compound (D23), (142 mg). LC-MS: MH+ = 442 (C28H2IF2NO2 = 441 )

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/103710, 2009, A1 Location in patent: Page/Page column 26

34
[ 901238-24-2 ]
[ 20289-26-3 ]
[ 1181567-04-3 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-(benzyloxy)-4-bromo-2,5-difluorobenzene; 4-benzyloxy-1H-indole With potassium phosphate; copper(l) iodide; <i>L</i>-proline In N,N-dimethyl-formamide at 140℃; for 4h; Microwave irradiation; Stage #2: With <i>L</i>-proline In N,N-dimethyl-formamide for 1h; Heating;	22.b ) In two microwave vials were placed 4-[(phenylmethyl)oxy]-1 H-indole (500 mg, 2.24 mmoL), 4-bromo-2,5-difluorophenyl phenylmethyl ether (prepared as described in part a), 559 mg, 1.87 mmoL), K3PO4 (990 mg, 4.67 mmoL), L-Proline (43 mg, 0.373 mmoL) and DMF (5 mL) and the mixture was degassed by sonication under a flow of argon. To each vial was added CuI (71 mg, 0.373 mmoL) and the solutions were heated to 140 0C in the microwave reactor. After 4 hours a second portion of L-Proline (43 mg, 0.373 mmoL) was added and heated for an additional hour. The two mixtures were partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with sat. NH4CI (2x100 mL), water (100 mL) and brine (2x100 mL) and finally dried over MgSO4. The combined crude materials were purified by flash chromatography (Biotage SP4, 40+M Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D22), (258 mg).NMR (δH), (CDCI3): 7.3-7.6 (11 H, m), 7.12 (2 H, m), 6.92 (2H, m), 6.85 (1 H, dd), 6.65 (1 H, d), 5.25 (2H, s), 5.20 (2H, s)

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/103710, 2009, A1 Location in patent: Page/Page column 25

35
[ 20289-26-3 ]
[ 941294-52-6 ]
[ 1181567-06-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-benzyloxy-1H-indole; 1-(benzyloxy)-4-bromo-2,3-difluorobenzene With potassium phosphate; copper(l) iodide; <i>L</i>-proline In N,N-dimethyl-formamide at 140℃; for 6h; Microwave irradiation; Stage #2: With copper(l) iodide; <i>L</i>-proline In N,N-dimethyl-formamide for 2h; Heating;	23 Description 23. 1-{2,3-difluoro-4-[(phenylmethyl)oxy]phenyl}-4- [(phenylmethyl)oxy]-1 H-indole ((D23) 4-[(phenylmethyl)oxy]-1 H-indole (432 mg, 1.94 mmoL), 4-bromo-2,3-difluorophenyl phenylmethyl ether (486 mg, 1.63 mmoL), K3PO4 (863 mg, 4.06 mmoL) and L-Proline (38 mg, 0.329 mmoL) were dissolved in DMF (5 mL) in a microwave vial and degassed by sonication under a flow of argon for 5 minutes. To this was added CuI (62.7 mg, 0.329 mmoL) and the solution was heated to 140 0C in the microwave reactor. After 6 hours a second portion of CuI (62.7 mg, 0.329 mmoL) and L-Proline (38 mg, 0.329 mmoL) were added and heated for 2 more hours. The mixture was partitioned between ethyl acetate (75 mL)/water (75 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (3x75 mL). The combined organic phases were washed with sat. NH4CI (2x75 mL), water (75 mL) and brine (2x75 mL) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4, 40+S Cartridge) eluting with a gradient of 0 to 30% Et2O in hexane and then further purified by MDAP to give the title compound (D23), (142 mg). LC-MS: MH+ = 442 (C28H2IF2NO2 = 441 )

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/103710, 2009, A1 Location in patent: Page/Page column 25; 26

36
[ 20289-26-3 ]
[ 4124-31-6 ]
C₁₇H₁₂Cl₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide at 0℃; for 6h;	4-(benzyloxy)-1H-indole-3-carboxylate (16) To a solution of 4-benzyloxy-1H-indole 15 (5.00 g, 22.3 mmol) in anhydrous N, N-dimethylformamide (10 ml), trichloroacetic acid anhydride (10.4 g, 33.5 mmol) was added and the mixture was stirred for 6 hours at 0 °C. The saturated sodium bicarbonate solution was added to the mixture and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated in vacuo. To a solution of the residue (8.00 g) in tetrahydrofurane (135 ml) , 4M sodium hydroxide solution (16.3 ml, 65.2 mmol) was added and stirred at room temperature for 6 hours. The mixture was diluted with diethyl ether and 1M sodium hydroxide solution. The aqueous layer was washed with diethyl ether and neutralized with 1M hydrochloric acid. The precipitate was separated from the resultant aqueous solution and dried in vacuo to give compound 16 as a colorless solid in 17% yield.

Reference： [1]Honda, Takahiro; Nagahara, Hironori; Mogi, Hiroyuki; Ban, Masakazu; Aono, Hiroyuki [Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 6, p. 1782 - 1785]

37
[ 1189-71-5 ]
[ 20289-26-3 ]
4-benzyloxy-3-cyano-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	Stage #1: isocyanate de chlorosulfonyle; 4-benzyloxy-1H-indole In acetonitrile at -45℃; for 0.166667h; Inert atmosphere; Stage #2: With N,N-dimethyl-formamide In acetonitrile at -45 - 20℃;	Experimental procedure for the synthesis of 16: Chlorosulfonyl isocyanate (4.08 mL, 47.0 mmol) in acetonitrile (10 mL) was added dropwise over 15 min to an acetontrile/CO2-cooled (ca. -45 °C), stirred solution of 4-benzyloxy-1H-indole (10.0 g, 44.8 mmol) in acetonitrile (100 mL). Over the course of the addition a fine precipitate formed. The mixture was stirred at ca. -45 °C under nitrogen for 10 min. DMF (100 mL) was then slowly added, and the mixture was removed from the bath and allowed to warm to room temperature. It was then poured into a mixture of ice and water (500 mL), and extracted with ethyl acetate (3 × 250 mL). The combined organics were washed with water, satd NaHCO3, and brine, then dried (MgSO4), filtered, and evaporated. The crude material was purified by dissolving in chloroform and passing through silica gel (10 cm diam. × 10 cm thick), eluting with 0-3% ethyl acetate in chloroform to give 4-benzyloxy-3-cyano-1H-indole (12, 8.03 g, 32.3 mmol, 72%) as an off-white solid. LC-MS (ES) m/z = 271 [M+Na]+. 1H NMR (400 MHz, CDCl3) δ 5.31 (s, 2H), 6.74 (d, J = 7.8 Hz, 1H), 7.07 (d, J = 8.3 Hz, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.31 (t, J = 7.3 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.58-7.67 (m, 3H), 8.93 (br s, 1H). Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87; N, 11.28. Found: C, 76.98; H, 4.80; N, 11.16.

Reference： [1]Location in patent: experimental part Grant, Seth W.; Gallagher, Timothy F.; Bobko, Mark A.; Duquenne, Celine; Axten, Jeffrey M. [Tetrahedron Letters, 2011, vol. 52, # 26, p. 3376 - 3378]

38
[ 20289-26-3 ]
[ 67-68-5 ]
[ 1355345-32-2 ]

Yield	Reaction Conditions	Operation in experiment
56%	With bromotris(triphenylphosphine)copper(I); ammonium acetate; sodium methylate at 120℃; for 12h; Inert atmosphere; regioselective reaction;	4.2. General procedure for the synthesis of 3-methylthiomethyl substituted indoles by using dimethylsulfoxide General procedure: All reactions were performed on a 0.40 mmol scale relative to 1a. To a solution of ammonium acetate in dry DMSO (NH4OAc, 1.6 mmol in 1.2 mL DMSO) in a 10 mL general branch reaction vial was added indole 1a (0.40 mmol), CuBr(PPh3)3 (0.06 mmol) and CH3ONa (0.40 mmol). The reaction vial was strictly sealed with the air in it drived away. Then the reaction vial was heated in an oil bath at 120 °C for 12 h with stirring. Following, to the reaction mixture was added H2O (2 mL) and it was extracted with methylene dichloride (3×10 mL). The combined organic phases were washed with saturated brine (2×3 mL), dried over anhydrous NaSO4 and concentrated in vacuo. The residue was subjected to flash column chromatography on silica gel with petroleum ether/EtOAc (v/v 8/1) as eluent to obtain the pure 3-(methylthiomethyl)-1H-indole product 2a as a white solid (50 mg, 71% yield).19

Reference： [1]Liu, Jin; Wang, Xianxue; Guo, Han; Shi, Xiaokang; Ren, Xiaoyu; Huang, Guosheng [Tetrahedron, 2012, vol. 68, # 5, p. 1560 - 1565]

39
[ 20289-26-3 ]
[ 124-38-9 ]
[ 24370-72-7 ]

Yield	Reaction Conditions	Operation in experiment
19%	With lithium tert-butoxide In N,N-dimethyl-formamide at 100℃; for 24h;	Representative procedure for the direct C-H carboxylation of indole derivatives 1a-p General procedure: In a dried two-necked test tube was charged with LiOtBu (160 mg, 2.00 mmol) and indole 1a (23.4 mg, 0.4 mmol). The reaction vessel was evacuated under high vacuum and the atmosphere was replace with a balloon of CO2. Then DMF (2 mL) was added and the mixture was stirred for 24 h at 100°C. Then the result mixture was cooled and carefully quenched with a solution of HCl (2 N) and extracted with EtOAc (5x). The combined organic layers were washed with water (2x), brine (1x) and dry over MgSO4. The dried organics were concentrated under reduce pressure and the residue was purified by preparative TLC (hexane:acetone = 1:1) to afford the desired product 2a (153.0 mg, 95%) as a white solid.
19%	Stage #1: 4-benzyloxy-1H-indole; carbon dioxide With lithium tert-butoxide In N,N-dimethyl-formamide at 100℃; for 24h; Stage #2: With hydrogenchloride In water; N,N-dimethyl-formamide

Reference： [1]Yoo, Woo-Jin; Nguyen, Thanh V. Q.; Guiteras Capdevila, Montse; Kobayashi, Shu [Heterocycles, 2015, vol. 90, # 2, p. 1196 - 1204]
[2]Yoo, Woo-Jin; Capdevila, Montse Guiteras; Du, Xiangwei; Kobayashi, Shu [Organic Letters, 2012, vol. 14, # 20, p. 5326 - 5329,4]

40
[ 20289-26-3 ]
[ 99-97-8 ]
[ 1415753-77-3 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 4-benzyloxy-1H-indole; Dimethyl-p-toluidine With tert-Butyl peroxybenzoate; potassium iodide; Trimethylacetic acid In dimethyl sulfoxide at 60℃; for 16h; Stage #2: With sodium hydrogencarbonate In dimethyl sulfoxide

Reference： [1]Li, Lan-Tao; Li, Hong-Ying; Xing, Li-Juan; Wen, Li-Juan; Wang, Peng; Wang, Bin [Organic and Biomolecular Chemistry, 2012, vol. 10, # 48, p. 9519 - 9522]

41
[ 20289-26-3 ]
[ 33513-42-7 ]
[ 1520083-65-1 ]

Yield	Reaction Conditions	Operation in experiment
68%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 4-benzyloxy-1H-indole In N,N-dimethyl-formamide at 0 - 20℃; for 1h; Inert atmosphere;

Reference： [1]Pouwer, Rebecca H.; Deydier, Sophie M.; Le, Phuc Van; Schwartz, Brett D.; Franken, Nicole C.; Davis, Rohan A.; Coster, Mark J.; Charman, Susan A.; Edstein, Michael D.; Skinner-Adams, Tina S.; Andrews, Katherine T.; Jenkins, Ian D.; Quinn, Ronald J. [ACS Medicinal Chemistry Letters, 2014, vol. 5, # 2, p. 178 - 182]

42
[ 20289-26-3 ]
[ 1610457-25-4 ]

Yield	Reaction Conditions	Operation in experiment
71%	With tert.-butylhydroperoxide; iodine In dimethyl sulfoxide at 80℃; for 16h;	B B. 4-(Benzyloxy)-2,3-d1H ydro-1H -indole-2,3-dione. To a 100-mL round-bottom flask was placed a solution of 4-(benzyloxy)-1H -indole (1 g,4.48 mmol,as prepared in theprevious step) in DMSO (20 mL),then ‘2 (1.36 g) and TBHP (2.02 g,22.41 mmol) were added. The reaction was stirred at 80°C for 16 h,quenched by the addition of 50 mL of aqueous Na2S2O3,and extracted with EtOAc. The organic extracts were combined,dried over anhydrous Na2SO4,and concentrated under reduced pressure. The residue was purified by column chromatography eluting with EtOAc/petroleum ether (1:2) affording 801 mg (71%) ofthe title compound as a brown solid. Mass Spectrum (LCMS,ESI pos): Calcd. for C15H12NO3: 254.1 (M+H); Found: 254.1.
57%	With tert.-butylhydroperoxide; iodine In dimethyl sulfoxide at 80℃; for 24h;

Reference： [1]Current Patent Assignee: YUMANITY THERAPEUTICS INC - WO2017/62581, 2017, A1 Location in patent: Paragraph 0206
[2]Zi, You; Cai, Zhong-Jian; Wang, Shun-Yi; Ji, Shun-Jun [Organic Letters, 2014, vol. 16, # 11, p. 3094 - 3097]

43
[ 20289-26-3 ]
[ 124-38-9 ]
[ 1616115-77-5 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-benzyloxy-1H-indole With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; hexane at 0℃; for 1h;
	Stage #1: 4-benzyloxy-1H-indole With n-butyllithium In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere; Stage #2: carbon dioxide In tetrahydrofuran; hexane at 0℃; for 1h; Inert atmosphere;
	Stage #1: 4-benzyloxy-1H-indole With n-butyllithium In tetrahydrofuran at 0℃; Stage #2: carbon dioxide In tetrahydrofuran Stage #3: With hydrogenchloride In tetrahydrofuran; water

Reference： [1]Zheng, Jing; Zhang, Yan; Cui, Sunliang [Organic Letters, 2014, vol. 16, # 13, p. 3560 - 3563]
[2]Xie, Yanan; Wu, Xiaowei; Li, Chunpu; Wang, Jiang; Li, Jian; Liu, Hong [Journal of Organic Chemistry, 2017, vol. 82, # 10, p. 5263 - 5273]
[3]Zeng, Linwei; Sajiki, Hironao; Cui, Sunliang [Organic Letters, 2019, vol. 21, # 13, p. 5269 - 5272]

44
[ 20289-26-3 ]
[ 7556-37-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4090 - 4094
[2]Patent: CN103254191,2016,B

45
[ 20289-26-3 ]
2-((trifluoromethyl)thio)benzo[d]isothiazol-3(2H)-one 1,1-dioxide [ No CAS ]
4-(benzyloxy)-3-(trifluoromethylthio)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With iron(III) chloride In 1,2-dichloro-ethane at 50℃; for 12h; Inert atmosphere; Sealed tube;

Reference： [1]Wang, Qiang; Qi, Zisong; Xie, Fang; Li, Xingwei [Advanced Synthesis and Catalysis, 2015, vol. 357, # 2-3, p. 355 - 360]

46
[ 7629-81-4 ]
[ 20289-26-3 ]
C₂₉H₂₁N₃O₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With 10-camphorsufonic acid In tetrahydrofuran at 20℃; for 16h;	Friedel-Crafts reaction of indoles to α-ketimino esters General procedure: To a stirring mixture of indole (5a, 23.4mg, 0.2mmol) and phenyl-ketimino ester (4a, 26.8mg,0.1mmol) in THF was added DL-camphorsulfonic acid (3.3mg, 0.01mmol), the reaction was stirred under room temperature until 4a was disappeared on TLC (about 12 hours), the crude product was purified by flash chromatograghy on silica gel (petroleum ether-EA, 5:1) to give 6a as yellow solid (35.4mg, 92%).

Reference： [1]Yang, Jin-Hui; Lou, Qin-Xin; Chen, Yan-Xue; Tang, Kang-Kang [Synthetic Communications, 2015, vol. 45, # 16, p. 1887 - 1892]

47
[ 1722-12-9 ]
[ 20289-26-3 ]
[ 1451369-26-8 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h;
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.666667h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 0 - 130℃; for 24h;	2. General procedure for synthesis of the starting materials (1a-m) General procedure: NaH (60% dispersion in mineral oil, 300 mg, 7.5 mmol) was added in portions at 0 °C to a stirred solution of indole (5.0 mmol) in DMF (8.0 mL). After stirring for 40 min at 0 °C, 2-chloropyrimidine (687.18 g, 6.0 mmol) was added and the mixture was stirred at 130 °C for 24 h. The reaction mixture was cooled to ambient temperature, quenched with H2O (90 mL) and then extracted with EtOAc (3×30 mL). The combined organic phase was dried over with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was directly purified by column chromatography on silica gel (with EtOAc/petroleum) to get the corresponding product.1
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃;

	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil for 0.666667h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h;	3 In the reaction vessel, was added 4-benzyloxy-indole (6mmol, 1339.68mg), NaH (content 60%, 9mmol, 360mg) for 40 minutes, DMF solvent, low temperature; then 2-chloropyrimidine (7.2 mmol, 824.616g), after the mixture was reacted at 130 24 hours, cooled to room temperature, the solvent was removed by extraction, separation by column to give compound 4-benzyloxy-1- (pyrimidin-2-yl) lH-indole
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h; Inert atmosphere;
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide for 1h; Cooling with ice; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide at 130℃; for 24h;	2 A 100 mL round-bottomed flask and a magnet of a suitable size were weighed and 4- (benzyloxy)-1H-indole (5 mmol, 1115 mg) was weighed out and dissolved in N, N-dimethylformamide And placed in an ice-water bath slowly added NaH (mass fraction 60%, 7.5mmol, 300mg) hydrogen extraction reaction, the reaction 1 hour after the transfer to a 130 °C oil bath, 24h after completion of the reaction was monitored by TLC, with ethyl acetate After dilution, the solution was transferred to a 250 mL separatory funnel and washed three times with water. After DMF was washed, the organic phase was collected and dried over anhydrous sodium sulfate. The organic solvent was removed by rotary evaporation under reduced pressure to give a crude product, which was purified by column chromatography (ethyl acetate : Petroleum ether = 3:95) to give the product 4-(benzyloxy)-1H-(pyrimidin-2-yl)-1H-indole. The 4- (benzyloxy) -1H- (pyrimidin-2-yl) -1H-indole reactant (0.3 mmol, 90.3 mg) was weighed accurately with a one-thousandth electronic balance and transferred to a pressure vessel Tube, PhI (OAc) 2 (3eq, 289.5mg) was added dropwise to the reaction vessel with a mixed solvent of acetic acid / acetic anhydride = 7/3, the reaction tube plug was tightened to seal the reaction system, heated to 60 °C, The reaction conditions 36h. After the reaction was completed, the reaction solution was cooled to room temperature, a short silica gel column was used to remove some metal impurities for preliminary purification, the solvent was extracted and the solvent was removed, and the solvent was distilled off under reduced pressure to give a crude product. The crude product was subjected to column chromatography Deprotecting: ethyl acetate / petroleum ether = 15: 75) gave pure and dried product in 71% yield.
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 120 - 140℃; for 12h;
	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: 2-chloropyrimidine In N,N-dimethyl-formamide; mineral oil at 130℃; for 24h;

Reference： [1]Zhao, Jing; Cheng, Xiuzhi; Le, Jun; Yang, Wei; Xue, Fengtian; Zhang, Xuan; Jiang, Chao [Organic and Biomolecular Chemistry, 2015, vol. 13, # 34, p. 9000 - 9004]
[2]Le, Jun; Gao, Yadong; Ding, Yousong; Jiang, Chao [Tetrahedron Letters, 2016, vol. 57, # 15, p. 1728 - 1731]
[3]Tu, Daoquan; Cheng, Xiuzhi; Gao, Yadong; Yang, Panpan; Ding, Yousong; Jiang, Chao [Organic and Biomolecular Chemistry, 2016, vol. 14, # 31, p. 7443 - 7446]
[4]Current Patent Assignee: NANJING UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN105622585, 2016, A Location in patent: Paragraph 0016; 0046; 0049
[5]Zhu, Chuan; Song, Shengjin; Zhou, Lu; Wang, Ding-Xing; Feng, Chao; Loh, Teck-Peng [Chemical Communications, 2017, vol. 53, # 68, p. 9482 - 9485]
[6]Current Patent Assignee: NANJING UNIVERSITY OF SCIENCE AND TECHNOLOGY - CN106279116, 2017, A Location in patent: Paragraph 0044; 0046
[7]Liu, Ruixing; Liu, Jiaxin; Wei, Yin; Shi, Min [Organic Letters, 2019, vol. 21, # 11, p. 4077 - 4081]
[8]Lu, Ming-Zhu; Ding, Xin; Shao, Changdong; Hu, Zhengsong; Luo, Haiqing; Zhi, Sanjun; Hu, Huayou; Kan, Yuhe; Loh, Teck-Peng [Organic Letters, 2020, vol. 22, # 7, p. 2663 - 2668] Zhang, Dong; Fang, Zheng; Cai, Jinlin; Liu, Chengkou; He, Wei; Duan, Jindian; Qin, Ning; Yang, Zhao; Guo, Kai [Chemical Communications, 2020, vol. 56, # 58, p. 8119 - 8122]

48
[ 20289-26-3 ]
[ 79893-97-3 ]
4-(benzyloxy)-1-(3-methyl-4,6-diphenylpyridin-2-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With sodium hydroxide In dimethyl sulfoxide at 20℃; for 0.0833333h;

Reference： [1]Cheng, Guolin; Weng, Yunxiang; Yang, Xifa; Cui, Xiuling [Organic Letters, 2015, vol. 17, # 15, p. 3790 - 3793]

49
[ 20289-26-3 ]
2-((difluoromethyl)thio)isoindoline-1,3-dione [ No CAS ]
4-(benzyloxy)-3-((difluoromethyl)thio)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With chloro-trimethyl-silane In 1,2-dichloro-ethane at 80 - 120℃; for 16h; Schlenk technique;
93%	With chloro-trimethyl-silane at 80 - 120℃; Inert atmosphere; Sealed tube;	3-4 Example 3-4 Preparation of 3-difluoromethylthio-4-benzyloxyindole (Compound b4) Procedure: Under argon conditions, 0.5 mmol of 4-benzyloxyindole, 0.6 mmol of difluoromethylthio reagent 1 and0.75 mmol trimethylchlorosilane was placed in a 25 mL sealed tube, followed by the addition of 3.0 mL of dichloromethane or 1,2-dichloroethane,80-120 ° C for 12-24 hours. After completion of the reaction, the solvent was removed by rotary evaporation under reduced pressure, and the residue was purified by flash silica gel column To give 142 mg of the corresponding difluoromethylthiylated product with an isolated yield of 93% and a hydrogen spectrum showing a purity of greater than 98%.

Reference： [1]Zhu, Dianhu; Gu, Yang; Lu, Long; Shen, Qilong [Journal of the American Chemical Society, 2015, vol. 137, # 33, p. 10547 - 10553]
[2]Current Patent Assignee: CHINESE ACADEMY OF SCIENCES - CN105985280, 2016, A Location in patent: Paragraph 0165; 0166; 0167; 0168

50
[ 108-01-0 ]
[ 20289-26-3 ]
[ 28383-23-5 ]

Yield	Reaction Conditions	Operation in experiment
61%	With bis[dichloro(pentamethylcyclopentadienyl)iridium(III)]; caesium carbonate at 150℃; for 48h; Inert atmosphere;	4.2.2 _{RRN 52,55,58,60,62,65,68,73,76,78}General procedure for the synthesis of N-Substituted tryptamines General procedure: A mixture of the suitable indole 1a or 6a-b (0.25mmol), Cs2CO3 (90mg, 0.275mmol), [Cp*IrCl2]2 (5mg, 0.00625mmol) and the appropriate N-protected ethanolamine 2a-c, 4a-e or 7a-b (0.75mmol) was stirred under N2 atmosphere at 150°C for 48h in a sealed vial. After cooling to room temperature the reaction mixture was dissolved in EtOAc/MeOH 9:1 (1mL) and filtered through a silica gel pad. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel.

Reference： [1]Bartolucci, Silvia; Mari, Michele; Di Gregorio, Giovanni; Piersanti, Giovanni [Tetrahedron, 2016, vol. 72, # 18, p. 2233 - 2238]

51
[ 1796-25-4 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-1-yl)-1-(piperidin-1-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
48%	With tetrabutylammomium bromide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	51.2 Step 2: 2-(4-(Benzyloxy)-lH-indol-l-yl)-l-(piperidin-l-yl)ethan-l-one (3) To a stirred solution of compound 2 (200 mg, 0.9 mmol) in DMF (10 mL) at RT were added 2-bromo-l-(piperidin-l-yl)ethan-l-one (277 mg, 1.34 mmol), Cs2C03 (584 mg, 1.8 mmol) and n-Bu4NBr (catalytic amount). The mixture was stirred at RT for 12 h. The mixture was diluted with water (30 mL), stirred well and filtered. The obtained solid was dissolved in CH2C12, dried (Na2S04), filtered and concentrated under reduced pressure. The crude was purified (silica gel; eluting 30% EtOAc/ hexanes) to afford compound 3 (150 mg, 48%) as an off-white solid. 1H NMR (500 MHz, OMSO-d6): δ 7.64 (d, J= 7.2 Hz, 2H), 7.54 (t, J= 7.5 Hz, 2H), 7.49-7.44 (m, 1H), 7.29 (d, J= 2.9 Hz, 1H), 7.15-7.05 (m, 2H), 6.73 (d, J= 7.5 Hz, 1H), 6.60 (d, J= 3.2 Hz, 1H), 5.36 (s, 2H), 5.24 (s, 2H), 3.64 (br t, J= 4.9 Hz, 2H), 3.55 (t, J= 5.2 Hz, 2H), 1.76-1.65 (m, 4H), 1.58-1.56 (m, 2H); LC-MS (ESI): m/z 349.0 (M + H+).
48%	With tetrabutylammomium bromide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	23.1 Step 1: 2-(4-(Benzyloxy)-1H-indol-1-yl)- 1-(piperidin- 1-yl)ethan- 1-one (2) To a stirred solution of 4-(benzyloxy)-1H-indole 1 (200 mg, 0.9 mmol) in DMF (10 mL) atRT, were added 2-bromo-1-(piperidin-1-yl)ethan-1-one (277 mg, 1.34 mmol), Cs2CO3 (584 mg, 1.8 mmol) and n-Bu4NBr (catalytic amount). The mixture was stirred at RT for 12 h. The mixture was diluted with water (30 mL), stirred well and filtered. The obtained solid was dissolved in CH2C12, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified (silica gel; eluting 30% EtOAc in hexanes), to afford compound 2 (150 mg, 48%) as an off-white solid. ‘HNMR (500 IVIFIz, DMSO-d6): 7.64 (d, J 7.2 Hz, 2H), 7.54 (t, J = 7.5 Hz, 2H), 7.49-7.44 (m, 1H), 7.29 (d, J 2.9 Hz, 1H), 7.15-7.05 (m, 2H), 6.73 (d, J= 7.5 Hz, 1H), 6.60 (d, J= 3.2 Hz, 1H), 5.36 (s, 2H), 5.24 (s, 2H), 3.64 (br t, J 4.9 Hz, 2H), 3.55 (t, J= 5.2 Hz, 2H), 1.76-1.65 (m, 4H), 1.58-1.56 (m, 2H); LCMS Mass: 349.0 (M+1).

Reference： [1]Current Patent Assignee: PHARMAKEA INC - WO2016/144703, 2016, A1 Location in patent: Paragraph 00349
[2]Current Patent Assignee: PHARMAKEA INC - WO2017/3862, 2017, A1 Location in patent: Paragraph 00349

52
[ 20289-26-3 ]
[ 75-03-6 ]
[ 627500-94-1 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: 4-benzyloxy-1H-indole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: ethyl iodide In N,N-dimethyl-formamide at 20℃; for 2h;	20.1 Step 2: Ethyl 2-(5-(benzyloxy)-2-oxo-3,4-dihydroquinolin-1 (211)-yl)acetate (3) j00343j To a stirred solution of 4-(benzyloxy)-1H-indole 1 (175 mg, 0.783 mmol) in DMF (1.5 mL) at RT, was added NaH (40 mg of a 60% dispersion in mineral oil, 1.0 mmol) and the mixture stirred atRT for 20mm A solution of iodomethane (171 mg, 1.10 mmol) in DMF (0.5 mL) was added and the mixture stirred at RT for 2 h. The mixture was partitioned between water (20 mL) and EtOAc (20 mL). The organic layer was separated, dried over Na2504, filtered, and the filtrate concentrated under reduced pressure. The residue was purified (silica gel; eluting 0 to 100% EtOAc in hexanes), to afford compound 2 (185 mg, 97%) as an amber oil.

Reference： [1]Current Patent Assignee: PHARMAKEA INC - WO2017/3862, 2017, A1 Location in patent: Paragraph 00343

53
[ 20289-26-3 ]
[ 29182-97-6 ]
2-(4-(benzyloxy)-1H-indol-1-yl)-N-methyl-N-phenylacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With tetra-(n-butyl)ammonium iodide; caesium carbonate; In N,N-dimethyl-formamide; at 20℃; for 12h;	To a stirred solution of 4-(benzyloxy)-1H-indole 1 (1.5 g, 5.49 mmol) in DMF (40 mL) atRT, were added <strong>[29182-97-6]2-bromo-N-methyl-N-phenylacetamide</strong> (1.88 g, 8.24 mmol), Cs2CO3 (3.58 g, 10.99 mmol) and n-Bu4NI (88 mg, 0.27 mmol). The mixture was stirred at RT for 12 h. The reaction mixture was quenched with water (60 mL) and extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine (30 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in Hexanes), to afford compound 2 (2.3 g, 95%) as an off-white solid. ‘H NIVIR (500 MHz, CDC13): 7.48 (br dd, J= 18.5, 7.5 Hz, 4H), 7.43-7.29 (m, 4H), 7.23 (br d, J 7.5 Hz, 2H), 7.05 (t, J= 8.0 Hz, 1H), 6.82 (br d, J= 2.6 Hz, 1H), 6.70 (br d, J= 8.1 Hz, 1H), 6.63 (br d, J = 2.6 Hz, 1H), 6.56 (d, J= 7.8 Hz, 1H), 5.22 (s, 2H), 4.62 (s, 2H), 3.30 (s, 3H); LCMS Mass:371.1 (M+1).

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00354

54
[ 16523-02-7 ]
[ 20289-26-3 ]
4-(benzyloxy)-1-(2-(methylsulfonyl)ethyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;	25.1 Step 1: 4-(Benzyloxy)- 1-(2-(methylsulfonyl)ethyl)- 1H-indole (3) To a stirred solution of 4-(benzyloxy)-1H-indole 1 (300 mg, 1.34 mmol) in DMF (3 mL) at 0 °C, were added 1-bromo-2-(methylsulfonyl)ethane 2 (300 mg, 1.61 mmol), Cs2CO3 (873 mg, 2.68 mmol) and n-Bu4NI (25 mg, 0.07 mmol). The reaction mixture was gradually warmed to RT and stirred for an additional 12 h. The reaction mixture was quenched with ice water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2 SO4, filtered and concentrated under reduced pressure to afford compound 3 (440 mg) as an off-white solid. This crude material was taken to next step without further purification. ‘H NIVIR (500 MHz, DMSO-d6): 7.48 (d, J= 7.2 Hz, 2H), 7.39 (t, J 7.5 Hz, 2H), 7.34-7.29 (m, 2H), 7.13-7.04 (m, 2H), 6.64 (d, J= 7.5 Hz, 1H), 6.49 (d, J= 3.2 Hz, 1H), 5.21 (s, 2H), 4.56 (t, J= 6.9 Hz, 2H), 3.63 (t, J= 6.9 Hz, 2H), 2.83 (s, 3H); LCMS Mass: 329.9 (M+1).

Reference： [1]Current Patent Assignee: PHARMAKEA INC - WO2017/3862, 2017, A1 Location in patent: Paragraph 00358

55
[ 15803-02-8 ]
[ 20289-26-3 ]
4-(benzyloxy)-1-(1-methyl-1H-pyrazol-4-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
88%	With potassium phosphate; copper(l) iodide; N,N`-dimethylethylenediamine In toluene at 150℃; for 12h; Inert atmosphere; Sealed tube;	32.1 Step 1: 4-(Benzyloxy)- 1-(1-methyl- 1H-pyrazol-4-yl)- 1H-indole (2) j00377j To a stirred solution of 4-(benzyloxy)-1H-indole 1 (200 mg, 0.89 mmol) in toluene (5 mL) at RT, were added 4-bromo-1-methyl-1H-pyrazole (185 mg, 0.98 mmol), N,N’dimethylethylenediamine (31 mg, 0.36 mmol), potassium phosphate (478 mg, 2.23 mmol) and CuT (17 mg, 0.09 mmol). The reaction mixture was degassed under argon for 15 mm, then sealed and heated at 150 °C for 12 h. The reaction mixture was diluted with EtOAc (50 mL) and filteredthrough a pad of celite, and the celite washed with EtOAc (10 mL). The filtrate was concentrated under reduced pressure. The residue was washed with water (20 mL) and extracted with EtOAc (2 x 30 mL). The organic layer was separated, dried over Na2 SO4, filtered and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 20% EtOAc in hexanes), to afford compound 2 (240 mg, 88%) as pale brown sticky solid. ‘H NMR (500 MHz, DMSO-d6): 8.21 (s, 1H), 7.80 (s, 1H), 7.51 (br d, J= 7.5 Hz, 2H), 7.43-7.39 (m, 3H), 7.36-7.3 1 (m, 1H), 7.09 (d, J 4.0 Hz, 2H), 6.70 (t, J 4.2 Hz, 1H), 6.66 (d, J= 3.2 Hz, 1H), 5.26 (s, 2H), 3.91 (s, 3H); LCMS Mass: 303.9 (M+1).

Reference： [1]Current Patent Assignee: PHARMAKEA INC - WO2017/3862, 2017, A1 Location in patent: Paragraph 00377

56
[ 20289-26-3 ]
[ 86864-60-0 ]
4-(benzyloxy)-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
82%	With tetra-(n-butyl)ammonium iodide; caesium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;	48.1 Step 1: 4-(Benzyloxy)- 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)- 1H-indole (3) To a stirred solution of 4-(benzyloxy)-1H-indole 1 (700 mg, 3.12 mmol) in DMF (6 mL) at RT, were added (2-bromoethoxy)(tert-butyl)dimethylsilane 2 (2.97 g, 12.5 mmol), Cs2CO3 (3.05 g, 9.37 mmol) and tetrabutylammonium iodide (576 mg, 1.56 mmol). The reaction mixture was heated at 80 °C for 12 h. The reaction mixture was quenched with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2 SO4, filtered, and concentrated under reduced pressure. The crude was purified (silica gel; eluting with 2% EtOAc in hexanes), to afford compound compound 3 (900 mg, 82%) as pale yellow sticky liquid. ‘H NIVIR (500MHz, CDC13): 7.53 (d, J 7.5 Hz, 2H), 7.41 (t, J= 7.5 Hz, 2H), 7.37-7.32 (m, 1H), 7.14-7.07 (m, 2H), 7.00 (d, J= 8.1 Hz, 1H),6.66 (d, J= 2.9 Hz, 1H), 6.59 (d, J= 7.8 Hz, 1H), 5.25 (s, 2H), 4.23 (t, J 5.8 Hz, 2H), 3.92 (t, J = 5.6 Hz, 2H), 0.86 (s, 9H), 0.10 (m, 6H); LCMS Mass: 382.1 (M+1).

Reference： [1]Current Patent Assignee: PHARMAKEA INC - WO2017/3862, 2017, A1 Location in patent: Paragraph 00404

57
[ 26272-83-3 ]
[ 20289-26-3 ]
4-(benzyloxy)-1-(oxetan-3-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
32%	With 1-methyl-pyrrolidin-2-one; tetra-(n-butyl)ammonium iodide; caesium carbonate; at 150℃; for 2h;Sealed tube; Microwave irradiation;	To a solution of 4-(benzyloxy)-1H-indole 1 (550 mg, 2.45 mmol) in N-methyl-2- pyrrolidone (5 mL) were added <strong>[26272-83-3]oxetan-3-yl 4-methylbenzenesulfonate</strong> (840 mg, 3.68 mmol), Cs2CO3 (1.6 g, 4.91 mmol) and tetrabutylammonium iodide (453 mg, 1.23 mmol). The reaction mixture was sealed, placed in a microwave synthesizer, and heated at 150 C for 2 h. The reaction mixture was cooled to RT, diluted with ice cold water (30 mL) and extracted with Et20 (2 x 30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified (silica gel; eluting with 2-4% EtOAc in hexanes), to afford compound 2 (200 mg, 32%) as pale yellow sticky liquid. ?HNMR (500MHz, CDC13): 7.50 (d, J= 7.2 Hz, 2H), 7.40 (t, J= 7.5 Hz, 2H), 7.36-7.31 (m, 2H), 7.16-7.07 (m, 2H), 6.78 (d, J= 3.2 Hz, 1H), 6.61 (d, J= 7.5 Hz, 1H), 5.60-5.53 (m, 1H), 5.24 (s, 2H), 5.16 (t, J 7.2 Hz, 2H), 5.09 (t, J= 6.1 Hz, 2H); LCMS Mass: 279.9

Reference： [1]Patent: WO2017/3862,2017,A1 .Location in patent: Paragraph 00409

58
[ 20289-26-3 ]
[ 479423-30-8 ]
C₂₇H₂₇BrN₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With potassium fluoride; C₄₆H₃₄I₄O₆ In m-xylene at 20℃; for 12h; Schlenk technique; enantioselective reaction;

Reference： [1]Kim, Mun Jong; Xue, Lu; Liu, Yidong; Paladhi, Sushovan; Park, Si Joon; Yan, Hailong; Song, Choong Eui [Advanced Synthesis and Catalysis, 2017, vol. 359, # 5, p. 811 - 823]

59
(E)-6-benzyloxy-2-nitro-β-pyrrolidinostyrene [ No CAS ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: (E)-6-benzyloxy-2-nitro-β-pyrrolidinostyrene With hydrazine hydrate In tetrahydrofuran; methanol at 30 - 50℃; for 3.66667h; Inert atmosphere; Stage #2: In tetrahydrofuran; methanol Inert atmosphere;

Reference： [1]Batcho, Andrew D.; Leimgruber, Willy [Organic Syntheses, 1985, vol. 63, p. 214 - 214]

60
[ 20289-26-3 ]
[ 7175-47-5 ]
(E)-1-(4-(benzyloxy)-1H-indol-1-yl)-N-(p-tolyl)methanimine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	Stage #1: 4-benzyloxy-1H-indole With 2-phenyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate; sodium t-butanolate In 1,4-dioxane at 28℃; for 0.0833333h; Inert atmosphere; Sealed tube; Glovebox; Stage #2: 4-methylphenyl isocyanide In 1,4-dioxane at 28℃; for 24h; Inert atmosphere; Sealed tube; Glovebox; chemoselective reaction;

Reference： [1]Kim, Jungwon; Hong, Soon Hyeok [Organic Letters, 2017, vol. 19, # 12, p. 3259 - 3262]

61
[ 20289-26-3 ]
[ 275818-95-6 ]
4-(benzyloxy)-3-((difluoromethyl)thio)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With chloro-trimethyl-silane; phosphonic acid diethyl ester In toluene at 85℃; for 3h; Sealed tube;

Reference： [1]Yan, Qiang; Jiang, Lvqi; Yi, Wenbin; Liu, Qiran; Zhang, Wei [Advanced Synthesis and Catalysis, 2017, vol. 359, # 14, p. 2471 - 2480]

62
[ 67-56-1 ]
[ 50-00-0 ]
[ 20289-26-3 ]
4-(benzyloxy)-3-(methoxymethyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
94%	With sodium hydroxide at 20℃; for 2h; Schlenk technique; Green chemistry;	6 Example 6 A process for producing a 3-alkoxyalkylindole derivative of the present example: specifically, 0.1 mmol of 4-benzyloxyindole, 0.2 mmol of paraformaldehyde, 0.2 mmol of sodium hydroxide was added to a Schlenk tube containing 1.0 ml of methanol solvent and dissolved at room temperature. The reaction was carried out for 2 h, neutralized with excess sodium bicarbonate and filtered through celite. The filtrate was concentrated and purified by column chromatography to give 25.1 mg, target product yield 94%.
94%	With sodium hydroxide at 120℃; for 2h; Sealed tube; Green chemistry; regioselective reaction;

Reference： [1]Current Patent Assignee: ZHENGZHOU UNIVERSITY - CN106957254, 2017, A Location in patent: Paragraph 0043; 0067; 0068; 0069; 0070
[2]Pi, Chao; Yin, Xiaohang; Cui, Xiuling; Ma, Yuwen; Wu, Yangjie [Organic Letters, 2019, vol. 21, # 7, p. 2081 - 2084]

63
[ 20289-26-3 ]
[ 6626-84-2 ]
dimethyl 2-[4-(benzyloxy)-1H-indol-3-yl](phenyl)methyl}malonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With magnesium iodide In tetrahydrofuran at -40℃; for 8h;	Friedel-Crafts Alkylation Reaction; General Procedure General procedure: The calcium or magnesium salt (0.025 mmol, 10 mol%) and Michael acceptor (0.25 mmol) were dissolved in solvent (0.5 mL), and the mixture was stirred at r.t. for 30 min in a glass vial. The aromatic compound (0.5 mmol) was added and the reaction was stirred at the temperature indicated in Tables 2-9; reaction progress was monitored by TLC. When the reaction was complete, the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography to afford the product.

Reference： [1]Feofanov, Mikhail N.; Anokhin, Maxim V.; Averin, Alexei D.; Beletskaya, Irina P. [Synthesis, 2017, vol. 49, # 22, p. 5045 - 5058]

64
[ 20289-26-3 ]
4,4′-bis(benzyloxy)-1H,1'H-2,3′-biindole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With N-Bromosuccinimide In chloroform at 15℃; for 6h; regioselective reaction;

Reference： [1]Huang, Panpan; Peng, Xiangjun; Hu, Dan; Liao, Huiwu; Tang, Shaobin; Liu, Liangxian [Organic and Biomolecular Chemistry, 2017, vol. 15, # 45, p. 9622 - 9629]

65
[ 20289-26-3 ]
C₁₆H₂₄O₃ [ No CAS ]
C₃₁H₃₅NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
613 mg	With boron trifluoride diethyl etherate In dichloromethane at -78 - 20℃; for 24h; Inert atmosphere;	General procedure: BF3-Et2O (945μL, 7.52mmol) was added via syringe to a stirred mixture of 12 (331mg, 1.25mmol) and ethyl 1H-pyrrole-2-carboxylate (531mg, 3.82mmol) in anhydrous CH2Cl2 (15mL) at -78°C under an Ar atmosphere. The solution was allowed to warm to room temperature and stirred for 24h. Then, the reaction mixture was cooled to 0°C, quenched with aqueous sat. NaHCO3, extracted with CH2Cl2, and dried over MgSO4. Removal of solvents gave an oily residue, which was purified by column chromatography on silica gel. The fraction eluted with 20% EtOAc in n-hexane gave crude acetyl-protected 5 (613mg) as an oily residue, which was used in the next reaction without further purification. The mixture of potassium carbonate (1.33g, 9.62mmol) and crude acetyl-protected 5 (613mg) in EtOH (30mL) was stirred for 51h at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (20% EtOAc in n-hexane) to give 5 (248mg, 58%) as colorless solids;Compound 9 was prepared from 12 and 4-benzyloxyindole in a manner similar to that described for the preparation of 5.

Reference： [1]Eto, Ryo; Misawa, Takashi; Noguchi-Yachide, Tomomi; Ohoka, Nobumichi; Kurihara, Masaaki; Naito, Mikihiko; Tanaka, Masakazu; Demizu, Yosuke [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 8, p. 1638 - 1642]

66
[ 948-65-2 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-2-phenylindolin-3-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With tert.-butylhydroperoxide In water at 90℃; for 0.5h; Microwave irradiation;
56%	With tert.-butylhydroperoxide In water at 100℃; for 24h;	11 Embodiment 11 in order to 2 - phenyl indole and 4 - benzyloxy indole as substrate for the synthesis of 2 - (1H- Indole -4 - benzyloxy -3 - yl) -2 - phenyl indole -3 - ketone A microfiltration at room temperature 25 ml reaction tube by adding 0.4 ml TBHP (70% aq), add 1 ml water, stirring and mixing. The reaction tube is arranged after the 100oC in oil bath, and then sequentially weighing 2 - phenyl indole (97 mg, 0.5 mmol) and 4 - benzyloxy indole (223 mg, 1 mmol) is added to the reaction tube, and coupled with the built-in condensing tube, for 100 °C reaction in oil bath 24 hours. TLC display raw material after the reaction is complete, the reaction is cooled down to the room temperature, add 10 ml saturated aqueous solution of sodium bicarbonate quenching reaction. For 20 ml ethyl acetate extraction, the combined organic layer after and drying with anhydrous sodium sulfate. The organic layer after concentrating column separation (hexane: ethyl acetate=6:1) to obtain yellow powdery solid 2 - (1H- Indole -4 - benzyloxy -3 - yl) -2 - phenyl indole -3 - ketone 121 mg, yield is 56%.

Reference： [1]Jiang, Xinpeng; Zhu, Bingbin; Lin, Kai; Wang, Guan; Su, Wei-Ke; Yu, Chuanming [Organic and Biomolecular Chemistry, 2019, vol. 17, # 8, p. 2199 - 2203]
[2]Current Patent Assignee: ZHEJIANG UNIVERSITY OF TECHNOLOGY - CN108218762, 2018, A Location in patent: Paragraph 0022

67
[ 20289-26-3 ]
[ 133057-82-6 ]
[ 1181566-47-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium phosphate; copper(l) iodide; (1S,2S)-N,N'-dimethyl-1,2-diaminocyclohexane / toluene / 24 h / Reflux 2: hydrogen / palladium 10% on activated carbon / ethanol; ethyl acetate / 20 °C / 760.05 Torr

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2009/103710, 2009, A1

68
[ 536-57-2 ]
[ 20289-26-3 ]
4-(benzyloxy)-2-tosyl-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With dihydrogen peroxide; potassium iodide In water at 20℃; for 0.0833333h; Green chemistry;

Reference： [1]Zhang, Jun; Wang, Zhong; Chen, Lingjuan; Liu, Yan; Liu, Ping; Dai, Bin [RSC Advances, 2018, vol. 8, # 72, p. 41651 - 41656]

69
[ 635-46-1 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-3-yl)quinoline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
53%	With C₂₅H₂₉ClIrNO In 2,2,2-trifluoroethanol at 50℃; for 16h; Inert atmosphere; Schlenk technique;

Reference： [1]Chen, Xiuwen; Li, Yibiao; Chen, Lu; Zhu, Zhongzhi; Li, Bin; Huang, Yubing; Zhang, Min [Journal of Organic Chemistry, 2019, vol. 84, # 6, p. 3559 - 3565]

70
[ 20289-26-3 ]
[ 63468-90-6 ]
(4-(benzyloxy)-1H-indol-3-yl)(phenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	With oxygen; copper(II) acetate monohydrate; sodium chloride In acetonitrile Autoclave;

Reference： [1]Yu, Jingbo; Zhang, Chao; Yang, Xinjie; Su, Weike [Organic and Biomolecular Chemistry, 2019, vol. 17, # 18, p. 4446 - 4451]

71
[ 20289-26-3 ]
[ 762-04-9 ]
S-(4-(benzyloxy)-1H-indol-3-yl) O,O-diethyl phosphorothioate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 4-benzyloxy-1H-indole; phosphonic acid diethyl ester With sulfur; triethylamine; sodium iodide In ethanol at 60℃; for 0.166667h; Stage #2: With tert.-butylhydroperoxide; trifluoroacetic acid In ethanol; water at 60℃; for 8h;
80%	Stage #1: 4-benzyloxy-1H-indole; phosphonic acid diethyl ester With sulfur; triethylamine; sodium iodide In acetonitrile at 60℃; for 0.333333h; Stage #2: With tert.-butylhydroperoxide; sulfuric acid In acetonitrile at 80℃; for 5h;	10 Method 3: Example 3: Preparation of S-substituted 3-indoledithiophosphate (Compound 7) In a 150 mL reaction flask,First, diethyl hydrogen phosphite (2.07 g, 15 mmol) was added in order.Sulphur powder (0.48g, 15mmol),Triethylamine (1.52 g, 15 mmol),Sodium iodide (0.15 g, 1 mmol), (1.17g, 10mmol),Add 20 mL of acetonitrile and incubate at 60 ° C for 20 min.Then add trifluoroacetic acid,Adjust to pH<3,Add tert-butyl peroxide (70% strength, 3.9 g, 30 mmol),The reaction was incubated at 80 ° C for 5 h.The TLC detection reaction has ended.Stop the reaction.The reaction solution was cooled to room temperature.80 mL of ethyl acetate was added under stirring.And adjusting the pH to 7-8 with sodium bicarbonate;After liquid filtration, liquid separation,Organic phase with 15g anhydrous sulfurSodium is dried for 0.5 h,filter,The solid obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (eluent: petroleum ether: ethyl acetate = 3:1, v/v).Obtained 2.82 g of S-substituted 3-indole thiophosphate.The yield was 80%.

Reference： [1]Shi, Shanshan; Chen, Jun; Zhuo, Shaohua; Wu, Zi'ang; Fang, Meijuan; Tang, Guo; Zhao, Yufen [Advanced Synthesis and Catalysis, 2019, vol. 361, # 13, p. 3210 - 3216]
[2]Current Patent Assignee: XIAMEN UNIVERSITY - CN109970794, 2019, A Location in patent: Paragraph 0030; 0031; 0032; 0045; 0046

72
[ 20289-26-3 ]
[ 622-58-2 ]
4-(benzyloxy)-N-(p-tolyl)-1H-indole-1-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With copper(l) iodide In dimethyl sulfoxide at 20℃; for 9h; Schlenk technique;

Reference： [1]Chen, Jinyang; Hu, Li; Wang, Haiying; Liu, Lingrong; Yuan, Binfang [European Journal of Organic Chemistry, 2019, vol. 2019, # 24, p. 3949 - 3954]

73
2-hydroxychalcone [ No CAS ]
[ 20289-26-3 ]
C₃₀H₂₃NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With diphenyl hydrogen phosphate In tetrahydrofuran at 20℃; Irradiation;

Reference： [1]Gao, Yu-Qi; Hou, Yi; Zhu, Liming; Chen, Guzhou; Xu, Dongyang; Zhang, Sheng-Yong; He, Yupeng; Xie, Weiqing [RSC Advances, 2019, vol. 9, # 50, p. 29005 - 29009]

74
[ 20289-26-3 ]
C₇H₁₄O₃S₂ [ No CAS ]
C₂₁H₂₃NO₃S₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With methanesulfonic acid In tert-Amyl alcohol at 0℃; for 5h;	17 Synthesis of compound 3d: 1a (42.1 mg, 0.2 mmol), 4-benzyloxyindole (67.0 mg, 0.3 mmol), methanesulfonic acid (2.0 mg, 0.02 mmol), tert-amyl alcohol (0.5) were added to the reaction tube under an air atmosphere. (M)), the reaction system was stirred at 0 ° C for 5 hours. After completion of the reaction, the mixture was diluted with dichloromethane, and the solvent was evaporated to give a white solid compound 3d (60.1 mg, 75%).

Reference： [1]Current Patent Assignee: EAST CHINA NORMAL UNIVERSITY - CN110117247, 2019, A Location in patent: Paragraph 0146-0149

75
[ 20289-26-3 ]
[ 78-94-4 ]
C₁₉H₁₉NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With aluminum oxide In hexane at 68℃; for 12h;

Reference： [1]Zhang, Xiong; Jones-Mensah, Ebenezer; Deobald, Jackson; Magolan, Jakob [Advanced Synthesis and Catalysis, 2019, vol. 361, # 24, p. 5548 - 5551]

76
[ 20289-26-3 ]
[ 111-30-8 ]
(6R/S,10S/R)-1-benzyloxy-6,10-bis(4-benzyloxy-1H-indol-3-yl)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
54%	With acetic acid at 20℃;	3.1. General Procedure for the Formation of the BisindolylCycloheptane Indoles (4) General procedure: 2 mmol of freshly distilled glutardialdehyde was dissolvedin 15 mL of glacial acetic acid in a round bottomflask. 5 mmol of the respective indole compound was addedto result in a color change of the mixtue to dark brown. Thesolution was stirred at room temperature and the reactionproceeding was followed by the compound fluorescencequenching at 254 nm on TLC using dichloromethane as eluent.The reaction was stopped when no more changes in theappearance of product amounts were detectable by TLC. Thework-up procedure started with the addition of diluted sodiumhydroxide solution to give a dark colored precipitateincluding the formed product. Then the mixture was extractedwith dichoromethane for three times. The unifiedorganic layer was extracted with a saturated solution of sodiumchloride and dried over sodium sulfate. Then it wasfiltered and evaporated to dryness to give an oil. The oilyresidue was purified by column chromatography using silicagel and eluent mixtures of either ethyl acetate and cyclohexaneor diethyl ether and cyclohexane. The unified compound-containing fractions were evaporated to give the targetcompounds 4.

Reference： [1]Hertlein, Tobias; Hilgeroth, Andreas; Lalk, Michael; Ohlsen, Knut; Suzen, Sibel; Yasrebi, Kaveh [Medicinal Chemistry, 2019, vol. 15, # 8, p. 833 - 839]

77
[ 20289-26-3 ]
[ 503315-79-5 ]
C₂₆H₁₈F₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 45℃; for 0.833333h;

Reference： [1]Liu, Xiaobiao; Liu, Ying; Pan, Zhenliang; Shi, Lijun; Wang, Caixia; Wu, Lulu; Xu, Cuilian; Yang, Guoyu; Yu, Qicheng; Yuan, Xinxin [RSC Advances, 2020, vol. 10, # 24, p. 13929 - 13935]

78
[ 20289-26-3 ]
C₁₁H₄ClF₃O₃ [ No CAS ]
C₂₆H₁₇ClF₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 45℃; for 1h;

79
[ 20289-26-3 ]
[ 530141-47-0 ]
C₂₆H₁₇BrF₃NO₄ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 45℃; for 1h;

80
[ 20289-26-3 ]
7-methoxy-3-(trifluoroacetyl)coumarin [ No CAS ]
C₂₇H₂₀F₃NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 45℃; for 0.833333h;

81
[ 20289-26-3 ]
C₁₂H₇F₃O₄ [ No CAS ]
C₂₇H₂₀F₃NO₅ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
80%	With scandium tris(trifluoromethanesulfonate) In dichloromethane at 45℃; for 0.266667h;

82
[ 79-37-8 ]
[ 20289-26-3 ]
3,3-dimethoxypropan-1-ammonium bromide [ No CAS ]
2-(4-(benzyloxy)-1H-indol-3-yl)-N-(3,3-dimethoxypropyl)-2-oxoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether at 0℃; for 2.33333h; Inert atmosphere; Stage #2: 3,3-dimethoxypropan-1-ammonium bromide With triethylamine In diethyl ether; dichloromethane at 0 - 20℃; for 1.33333h;	N-(2-(4-(Benzyloxy)-1H-indol-3-yl)ethyl)-3,3-dimethoxypropan-1-amine (S14) A solution of oxalyl chloride (0.57 g, 4.5 mmol) in ether (1 mL) was added dropwise over 20 min to a solution of 4- benzyloxyindole (1.40 g, 4.5 mmol) in ether (10 mL) at 0°C. The reaction was stirred for 2 h at 0°C, at which point the solution was transferred dropwise over 20 min via cannula into a solution of 9 (0.73 g, 3.7 mmol) and triethylamine (1.9 g, 19 mmol) in CH2Cl2 (50 mL) at 0°C. During the transfer, HCl gas was removed from the reaction through intermittent ventilation with a stream of nitrogen. The reaction was warmed to room temperature and stirred for 1 h. Saturated aqueous NaHCO3 (100 mL) was added, and the solution was stirred for 20 min at room temperature. The mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic fractions were washed with aqueous NaOH (1 M, 100 mL), water (100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give crude 2-(4-(benzyloxy)-1H-indol-3- yl)-N-(3,3-dimethoxypropyl)-2-oxoacetamide as a thick orange semi-solid, which was carried onto the next step without further purification. A solution of crude 2-(4-(benzyloxy)-1H-indol-3-yl)-N-(3,3-dimethoxypropyl)-2-oxoacetamide (0.37 g, 0.93 mmol) in THF (5 mL) was added dropwise over 10 min to a suspension of lithium aluminum hydride (0.35 g, 9.3 mmol) in THF (20 mL) at 0°C. The reaction was heated to 60°C for 14 h. The reaction was then cooled to 0°C, and the Fieser work-up was performed by successive addition of water (0.3 mL), aqueous NaOH (15%, 0.3 mL), and water (1 mL). The suspension was warmed to room temperature, and MgSO4 was added. The solids were removed by vacuum filtration through a fritted funnel and washed with copious amounts of CH2Cl2. The filtrate was concentrated in vacuo to give crude S14 as an opaque viscous oil. The crude residue was taken up into aqueous HCl (0.2 M, 100 mL), and washed with ether (2 x 50 mL). The aqueous fraction was basified to pH 12-14 by dropwise addition of aqueous NaOH (40% w/v), as judged by pH paper. The basic solution was extracted with CH2Cl2 (4 x 100 mL). The combined organic fractions were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL), brine (100 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give 230 mg (67%) of S14 as a viscous oil (>95% purity, by 1H NMR).

Reference： [1]Lepovitz, Lance T.; Martin, Stephen F.; Meis, Alan R.; Mensa-Wilmot, Kojo; Pham, Alexandra; Thomas, Sarah M.; Wiedeman, Justin [Tetrahedron, 2020]

83
[ 20289-26-3 ]
halomethane [ No CAS ]
[ 13523-93-8 ]

Reference： [1]Chemical Communications,2020,vol. 56,p. 2807 - 2810

84
[ 20289-26-3 ]
[ 36635-61-7 ]
4-(benzyloxy)-3-(tosylmethyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
76%	With ferrous(II) sulfate heptahydrate In water at 110℃; for 24h; Schlenk technique; Inert atmosphere; Sealed tube;	General Procedure for Preparation of Products 3 and 4 General procedure: To a 15 mL two-necked Schlenk tube fitted with glass stopper were added indoles 1 (0.1 mmol),TosMIC derivatives 2 (0.3 mmol), and FeSO4·7H2O (0.015 mmol, 4.2 mg) in a mixed solvent of H2O and PEG400 (v/v = 3/2, 2 mL) under an Ar atmosphere using the standard Schlenk techniques. The Schlenk tube was capped and heated at 110 °C for 24 h. The reaction mixture was then cooled toroom temperature and concentrated directly. After removal of solvent, the residue was purified by preparative thin-layer chromatography (petroleum ether/EtOAc = 1:1) to give the desiredproduct 3 and 4.

Reference： [1]Cui, Tian-Wei; Hao, Xin-Qi; Lu, Shuai; Song, Mao-Ping; Yan, Ke-Xin; Zhu, Xinju; Zhu, Yu-Shen [Synlett, 2019, vol. 30, # 16, p. 1924 - 1928]

85
4-benzyloxy-1-<(4-methylphenyl)sulfonyl>indole [ No CAS ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
83%	With sodium hydride In N,N-dimethyl acetamide at 60℃; for 5h; Inert atmosphere;	General procedure for the detoyslation reaction. General procedure: To a suspension solution of NaH (0.4 mmol, 2.0 equiv) in dry DMA (1.0 mL) under N2 was added dropwise the solution of 4 or 5 (0.2 mmol, 1 equiv) in dry DMA (0.5 mL) by syringe. Then the mixture was heated at 60 °C until TLC showed the completion of the reaction. A saturated solution of NH4Cl was added to quench the reaction and extracted with EtOAc for one time. The organic layer was washed with water for three times, and the combined aqueous layers were extracted with EtOAc for one time. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography to give corresponding products 3 or 6.

Reference： [1]Sun, Wanwan; Chen, Xiaobei; Hu, Ying; Geng, Huihui; Jiang, Yuanrui; Zhou, Yuxin; Zhu, Wenjing; Hu, Min; Hu, Haohua; Wang, Xingyi; Wang, Xinli; Zhang, Shilei; Hu, Yanwei [Tetrahedron Letters, 2020, vol. 61, # 43]

86
C₁₇H₁₈N₂O₃ [ No CAS ]
[ 20289-26-3 ]

Yield	Reaction Conditions	Operation in experiment
46%	With iron(III) chloride; hydrazine hydrate at 100℃; for 12h;	1.4 (3) The reaction system was reduced to 25°C, FeCl3 (2.4g, 0.1eq) and NH2NH2·H2O (36.5g, 5eq) were added, and the reaction system was heated to 100°C for 12 hours.(4) TLC monitors the completion of the reaction;(5) 150ML of water was added to the reaction system, and the aqueous phase was extracted with ethyl acetate (200ML×3). Combine the organic phases, wash the organic phases with saturated brine (200ML×3), dry with anhydrous sodium sulfate, add 3 g of activated carbon for decolorization, and filter with 0.1 kg of silica gel;(6) Concentrate the organic phase to obtain a crude product. The crude product is purified by column chromatography to obtain 15 g of product with a yield of 46.0%.

Reference： [1]Current Patent Assignee: ASTATECH CHENGDU BIOPHARMACEUTICAL - CN112552224, 2021, A Location in patent: Page/Page column 0039; 0072-0076

87
[ 6138-90-5 ]
[ 20289-26-3 ]
C₂₅H₂₉NO [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 4-benzyloxy-1H-indole With potassium hydroxide In N,N-dimethyl-formamide at 20℃; Stage #2: trans-geranyl bromide	2.1.1. General procedure for the synthesis of N-geranylatedbenzyloxyindole (7) General procedure: Briefly, to 10 mL DMF taken in a 100 mL round bottomedflask, 25.6 mmol of KOH was added and stirred vigorously for15 min at room temperature. To this, 8.5 mmol of variousbenzyloxy substituted indoles (6) was added and the stirring was continued. After 30 min, a solution of geranyl bromide(8.5 mmol in 5mL DMF) was added dropwise for over 5 minto the reaction mixture, and the stirring was continued overnight.The reaction mixture was then transferred to ice-coldwater. The N-geranyl derivatives of various benzyloxy substitutedindoles, obtained as oily liquids, were extracted usingchloroform and purified through column chromatography.

Reference： [1]George, Ginson; P. S, Dileep; Palawat, Saksham; Paul, Atish T.; S. N. C, Sridhar; Sengupta, Pracheta [Journal of Biomolecular Structure and Dynamics, 2021]

88
[ 20289-26-3 ]
(±)-trans-(3-phenyloxiran-2-yl)methyl 4-methylbenzenesulfonate [ No CAS ]
rac-4-(benzyloxy)-1-(((2R*,3R*)-3-phenyloxiran-2-yl)methyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: 4-benzyloxy-1H-indole With potassium hydroxide In dimethyl sulfoxide at 20℃; for 0.75h; Inert atmosphere; Stage #2: (±)-trans-(3-phenyloxiran-2-yl)methyl 4-methylbenzenesulfonate In dimethyl sulfoxide at 20℃; for 0.75h; Inert atmosphere; Cooling;

Reference： [1]Das, Arup Jyoti; Chouhan, Raju; Das, Sajal Kumar [Journal of Organic Chemistry, 2021, vol. 86, # 12, p. 8274 - 8285]

89
[ 20289-26-3 ]
sodium difluoromethanesulfinate-d [ No CAS ]
4-(benzyloxy)-3-((difluoromethyl-d)thio)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With chloro-trimethyl-silane; phosphonic acid diethyl ester In toluene at 85℃; for 3h; Sealed tube;

Reference： [1]Dong, Lefeng; Li, Zhong; Liang, Junqing; Pang, Xiwen; Qin, Jiawei; Shao, Xusheng; Wang, Gangao; Xu, Xiaoyong [Organic Letters, 2021, vol. 23, # 14, p. 5545 - 5548]

90
[ 79-37-8 ]
[ 20289-26-3 ]
[ 53170-19-7 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-bis(methyl-d3)-2-oxoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
63.7%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether at 0 - 20℃; for 18h; Stage #2: d6-dimethylamine hydrochloride With potassium carbonate In tetrahydrofuran; diethyl ether at 20℃; for 4.08333h;	1 Synthesis of 2-(4-(benzyloxy)-1 H-indol-3-yl)-N,N-bis(methyl-c/₃)-2-oxoacetamide (41): A solution of 4-(benzyloxy)-1H-indole (2.27 g, 10.16 mmol) in dry ether (50 mL) was treated with oxalyl chloride (0.86 mL, 10.16 mmol) drop-wise at 0 °C. The reaction was brought to room temperature and stirred for over night (18 h). The reaction was cooled to 0 °C treated with bis(methyl-c/3)amine hydrochloride (2.22 g, 25.41 mmol, free based with K2CO3 in THF) over a period of 5 min. The reaction was brought to room temperature and stirred for 4 h. The reaction was quenched with water (100 mL) and product was extracted into ethyl acetate (2 x 100 mL). Combined ethyl acetate layer was washed with brine (50 mL) and dried (Na2S0 ). Solvent was evaporated and crude was purified by flash column chromatography (MeOH: CH2CI2, 5:95) on silica gel to obtain the title compound (2.13 g, 63.7%) as a light brown foam. 1H NMR (CDCb): 5 10.20 (s, 1H), 7.56-7.53 (m, 3H), 7.42- 7.30 (m, 3H), 7.05 (t, 1H, J = 6.0 Hz), 6.90 (d, 1H, J = 6.0 Hz), 6.65 (d, 1H, J = 6.0 Hz), 5.26 (s, 2H); ESI-MS (m/z, %): 351 (M+Na, 100), 329 (MH+).

Reference： [1]Current Patent Assignee: MINDSET PHARMA - WO2021/155470, 2021, A1 Location in patent: Paragraph 00253

91
[ 6850-57-3 ]
[ 79-37-8 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-N-(2-methoxybenzyl)ethan-1-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
27%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: 2-methoxybenzylamine In diethyl ether; dichloromethane at 20℃; Cooling with ice; Stage #3: With borane-THF In tetrahydrofuran at 70℃; Cooling with ice;	24.1 Step 1: 2-(4-(benzyloxy)-1H-indol-3-yl)-N-(2-methoxybenzyl)ethan-1-amine To a stirred solution of 4-(benzyloxy)-1H-indole (5.40 g, 24.2 mmol) in diethyl ether (120 ml_) under ice-salt bath cooling was dropwise added a solution of oxalyl chloride (6.15 g, 48.5 mmol) in ether. The resulting brown solution was stirred for 3 h, then dropwise added to a solution of (2-methoxyphenyl)methanamine (8.30 g, 60.6 mmol) in ether (110 ml_) under ice-salt bath cooling. The resulting mixture was diluted with DCM (20 ml_) and warmed up to room temperature. The mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The concentrate was dissolved in anhydrous THF (120 ml_) and 1M borane-THF complex (87 ml_, 87 mmol) was added dropwise under ice-water bath cooling. The resulting mixture was heated at 70°C overnight. The reaction was quenched slowly with 1N HCI under ice-water bath cooling. The mixture was stirred for 2 h at room temperature, then adjusted to basic pH with ammonia. The aqueous phase was extracted with DCM/MeOH (10/1). The combined organic phases were washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted by DCM with 3.0 M NH3 in MeOH in the volume ratio of 25:1 to 10:1) to afford the title product as a white solid (2.6 g, 27%).

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00275-00277

92
[ 20289-26-3 ]
[ 411235-57-9 ]
4-(benzyloxy)-1-cyclopropyl-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
39%	With dmap; copper diacetate; sodium hexamethyldisilazane In toluene at 95℃; for 72h; Inert atmosphere;	7.1 Step 1 : 4-(benzyloxy)-1-cyclopropyl-1H-indole To a stirred suspension of 4-(benzyloxy)-1H-indole (3.01 g, 13.4 mmol), cyclopropylboronic acid (3.52 g, 40.3 mmol), Cu(OAc)2 (2.50 g, 13.4 mmol) and DMAP (5.0 g, 40 mmol) in anhydrous toluene (72 ml_) under nitrogen atmosphere at room temperature was added NaHMDS (7.4 ml_, 2.0M, 14.8 mmol). The mixture was heated to 95°C under oxygen atmosphere, and stirred for 3d until the starting material was consumed. The mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was triturated several times with petroleum ether. The combined petroleum ether extracts were concentrated, and the residue purified by silca gel column chromatography (eluent: PE/EtOAc = 10/1) to afford the title product as a brown oil (1.40 g, 39%). NMR (400 MHz, CDC ) d 7.51-7.47 (m, 2H), 7.41-7.35 (m, 2H), 7.34-7.28 (m, 1 H), 7.20 (d, J = 8.4 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 3.2 Hz, 1 H), 6.61-6.56 (m, 2H), 5.22 (s, 2H), 3.36-3.29 (m, 1H), 1.06- 0.99 (m, 4H).

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00126-00128

93
[ 79-37-8 ]
[ 20289-26-3 ]
[ 124-40-3 ]
[ 52061-51-5 ]

Yield	Reaction Conditions	Operation in experiment
52%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Inert atmosphere; Stage #2: dimethyl amine In diethyl ether; water at 20℃; Cooling with ice; Inert atmosphere;	1; 19.1 Step 1: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide To a solution of 4-(benzyloxy)-1H-indole (5.0 g, 22.4 mmol) in ether (100 ml_) under ice- salt water bath cooling was added dropwise a solution of oxalyl chloride (5.80 g, 45.7 mmol) in ether (45 ml_) under nitrogen atmosphere. The resulting brown suspension was stirred for 3 h, then added dropwise into 40% aq. dimethylamine (50 ml_) under ice-salt water bath cooling. The resulting suspension was stirred overnight at room temperature. The suspension was filtered, and the filter cake was rinsed with water. The filter cake was dried under reduced pressure, and then slurried in hexane (50 ml_). After stirrring at room temperature for 1 h, the slurry was filtered to afford the title product as an orange solid (3.81 g, 52%).

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 0092-0093; 00234-00236

94
[ 79-37-8 ]
[ 624-78-2 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-N-ethyl-N-methyl-2-oxoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: N-Ethylmethylamine In diethyl ether; dichloromethane at 20℃; Cooling with ice;	12.1 Step 1 : 2-(4-(benzyloxy)-1 H-indol-3-yl)-N-ethyl-N-methyl-2-oxoacetamide To a stirred solution of 4-(benzyloxy)-1H-indole (3.0 g, 13 mmol) in diethyl ether (100 ml_) under ice-salt bath cooling was added a solution of oxalyl chloride (3.4 g, 27 mmol) in ether dropwise.Tthe resulting brown solution was stirred for 3 h, and then added dropwise into a solution of methylethyl amine (4.0 g, 67 mmol) in ether under ice-salt bath cooling. The resulting mixture was diluted with DCM (10 ml_) and then allowed to warmup to room temperature. After stirring overnight, the mixture was filtered. The filter cake was dissolved in DCM, washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 1/1) to afford the title compound as a brown solid (2.7 g, 60%) which was used without further purification in the next step.

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00157-00159

95
[ 79-37-8 ]
[ 20289-26-3 ]
[ 108-18-9 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-diisopropyl-2-oxoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: diisopropylamine In diethyl ether; dichloromethane at 20℃; Cooling with ice;	14.1 Step 1 : 2-(4-(benzyloxy)-1 H-indol-3-yl)-N,N-diisopropyl-2-oxoacetamide To a stirred solution of 4-(benzyloxy)-1H-indole (3.0 g, 13 mmol) in diethyl ether (65 ml_) under ice-salt bath cooling was added a solution of oxalyl chloride (3.4 g, 36 mmol) in ether dropwise. The resulting brown solution was stirred for 3 h, and then added into a solution of diisopropylamine (6.78 g, 67 mmol) in ether (65 ml_) under ice-salt bath cooling dropwise. The resulting mixture was diluted with DCM (10 ml_) and then allowed to warmeup to room terperature. After stirring overnight, the mixture was filtered. The filter cake was dissolved in DCM, washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: PE/EtOAc = 1/1) to afford the title product as a yellow green solid (3.1 g, 58%) and that was used without further purification in the next step.

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00181-00183

96
[ 79-37-8 ]
[ 753-90-2 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-2-oxo-N-(2,2,2-trifluoroethyl)acetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: trifluoroethylamine With N-ethyl-N,N-diisopropylamine In diethyl ether; dichloromethane at 20℃; Cooling with ice;	15.1 Step 1 : 2-(4-(benzyloxy)-1 H-indol-3-yl)-2-oxo-N-(2,2,2-trifluoroethyl)acetamide To a stirred solution of 4-(benzyloxy)-1H-indole (3.0 g, 13 mmol) in diethyl ether (65 ml_) under ice-salt bath cooling was added a solution of oxalyl chloride (3.4 g, 37 mmol) in ether dropwise.The resulting brown solution was stirred for 3h, and then added into a solution of trifluoroethylamine (4.0 g, 40 mmol) and DIPEA (11 ml_, 67 mmol) in ether (65 ml_) under ice- salt bath cooling dropwise. The resulting mixture was diluted with DCM (10 ml_) and then warmed up to room temperature. After stirring overnight, the mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The brown waxy solid crude product (5.1 g) was used directly in the next step.

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00192-00194

97
[ 79-37-8 ]
[ 430-67-1 ]
[ 20289-26-3 ]
2-(4-(benzyloxy)-1H-indol-3-yl)-N-(2,2-difluoroethyl)-2-oxoacetamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: 2,2-difluorethylamine With N-ethyl-N,N-diisopropylamine In diethyl ether; dichloromethane at 20℃; Cooling with ice;	17.1 Step 1 : 2-(4-(benzyloxy)-1 H-indol-3-yl)-N-(2,2-difluoroethyl)-2-oxoacetamide To a stirred solution of 4-(benzyloxy)-1H-indole (5.0 g, 22 mmol) in diethyl ether (170 ml_) under ice-salt bath cooling was added a solution of oxalyl chloride (5.67 g, 45 mmol) in ether dropwise. The resulting brown solution was stirred for 3 h, and then added into a solution of 2,2-difluoroethan-1-amine (9.0 g, 110 mmol) and DIPEA (18.5 ml_) in ether (110 ml_) under ice-salt bath cooling dropwise. The resulting mixture was diluted with DCM (20 ml_) and then allowed to warm up to room terperature. After stirring overnight, the mixture was partitioned between DCM and water. The organic phase was washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The crude brown wax-like solid product (8.5 g) was used directly in the next step.

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00212-00214

98
[ 79-37-8 ]
[ 20289-26-3 ]
[ 109-89-7 ]
[ 94862-21-2 ]

Yield	Reaction Conditions	Operation in experiment
34%	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether for 3h; Cooling with ice; Stage #2: diethylamine In diethyl ether; dichloromethane at 20℃; Cooling with ice;	18.1 Step 1 : 2-(4-(benzyloxy)-1 H-indol-3-yl)-N,N-diethyl-2-oxoacetamide To a stirred solution of 4-(benzyloxy)-1H-indole (5.0 g, 22 mmol) in diethyl ether (170 ml_) under ice-salt bath cooling was added a solution of oxalyl chloride (5.68 g, 44.8 mmol) in ether dropwise. The resulting brown solution was stirred for 3 h, and then added into a solution of diethylamine (8.2 g, 112 mmol) in ether (110 ml_) under ice-salt bath cooling dropwise. The resulting mixture was diluted with DCM (10 ml_) and then allowed to warm up to room terperature. After stirring overnight, the mixture was filtered. The filter cake was dissolved in DCM, washed with brine, dried over Na2SC>4, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluent: PE/EtOAc = 1/1) to afford the title compound as a light brown solid (2.7g, 34%) which was used directly in the next step.

Reference： [1]Current Patent Assignee: MEDICAL COLLEGE OF WISCONSIN; BRIGHT MINDS BIOSCIENCES, INC - WO2021/179091, 2021, A1 Location in patent: Paragraph 00225-00227

99
[ 20289-26-3 ]
[ 85-46-1 ]
4-(benzyloxy)-1-(naphthalen-1-ylsulfonyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	Stage #1: 4-benzyloxy-1H-indole With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.5h; Stage #2: 1-Naphthalenesulfonyl chloride In tetrahydrofuran at 20℃;	4.1.3 General procedure for the synthesis of compounds 2, 3 and 4 (GP1) General procedure: To an ice-bath solution of potassium tert-butoxide (1.2 equiv) and 18-crown-6 ether (0.2 equiv) in THF, 4-(benzyloxy)-1H-indole (1.0 equiv) dissolved in THF was added dropwise; after 30min, appropriate chloride or bromide (1.3-1.5 equiv) was added and the mixture was stirred at ambient temperature for 18h. After that time, the solvent was removed in vacuo, the residue was dissolved in DCM, washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by crystallization or flash chromatography according to methods described below.

Reference： [1]Wichur, Tomasz; Godyń, Justyna; Góral, Izabella; Latacz, Gniewomir; Bucki, Adam; Siwek, Agata; Głuch-Lutwin, Monika; Mordyl, Barbara; Śniecikowska, Joanna; Walczak, Maria; Knez, Damijan; Jukič, Marko; Sałat, Kinga; Gobec, Stanislav; Kołaczkowski, Marcin; Malawska, Barbara; Brazzolotto, Xavier; Więckowska, Anna [European Journal of Medicinal Chemistry, 2021, vol. 225]

100
[ 20289-26-3 ]
[ 352-34-1 ]
4-(benzyloxy)-1-(4-fluorophenyl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h; Inert atmosphere;	1.A.2 Step 2. Synthesis of 4-benzyloxy-l-(4-fluorophenyl)indole A mixture of 4-benzyloxy-lH-indole C59 (10 g, 44.8 mmol), l-fluoro-4-iodo-benzene (6.5 mL, 56.4 mmol), Cul (500 mg, 2.63 mmol) and cesium carbonate (25 g, 76.7 mmol) in DMF (50 mL) was bubbled with nitrogen and stirred at 120 °C for 48 hours. The reaction mixture was diluted with water (500 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x 100 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The resulting solid was triturated with ether (100 mL), filtered. The solid was washed with ether (25 mL) and dried under high vacuum to afford the product 4-benzyloxy-l-(4-fluorophenyl)indole (10.5 g, 71%) as grey colored solid. NMR (400 MHz, DMSO-d) d 7.66 - 7.58 (m, 2H), 7.55 - 7.50 (m, 4H), 7.45 - 7.37 (m, 5H), 7.36 - 7.27 (m, 1H), 7.09 (d, J = 6.0 Hz, 2H), 6.73 (q, J = 2.7, 2.2 Hz, 2H), 5.28 (s, 2H). LCMS m/z 318.12 [M+H]+.
71%	With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h; Inert atmosphere;	1.A.2 Step 2. Synthesis of 4-benzyloxy-l-(4-fluorophenyl)indole A mixture of 4-benzyloxy-lH-indole C59 (10 g, 44.8 mmol), l-fluoro-4-iodo-benzene (6.5 mL, 56.4 mmol), Cul (500 mg, 2.63 mmol) and cesium carbonate (25 g, 76.7 mmol) in DMF (50 mL) was bubbled with nitrogen and stirred at 120 °C for 48 hours. The reaction mixture was diluted with water (500 mL) and EtOAc (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x 100 mL). The combined organic layers were washed with brine, dried over Na2S04 and concentrated under reduced pressure. The resulting solid was triturated with ether (100 mL), filtered. The solid was washed with ether (25 mL) and dried under high vacuum to afford the product 4-benzyloxy-l-(4-fluorophenyl)indole (10.5 g, 71%) as grey colored solid. NMR (400 MHz, DMSO-d) d 7.66 - 7.58 (m, 2H), 7.55 - 7.50 (m, 4H), 7.45 - 7.37 (m, 5H), 7.36 - 7.27 (m, 1H), 7.09 (d, J = 6.0 Hz, 2H), 6.73 (q, J = 2.7, 2.2 Hz, 2H), 5.28 (s, 2H). LCMS m/z 318.12 [M+H]+.
64%	With copper(l) iodide; caesium carbonate In N,N-dimethyl-formamide at 120℃; for 48h; Inert atmosphere;	1.A.1 Step 1. Synthesis of 4-(Benzyloxy)-1-(4-fluorophenyl)-1H-indole (S10) Nitrogen was bubbled through a mixture of 4-benzyloxy-1H-indole C29 (20 g, 89.6 mmol), 1-fluoro-4-iodo-benzene (15 mL, 130 mmol), CuI (1 g, 5.25 mmol) and cesium carbonate (50 g, 154 mmol) in DMF (125 mL) and then stirred at 120 °C for 48 h. The reaction mixture was diluted with water (1 L) and EtOAc (500 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give a brown solid. The solid was triturated with ether and filtered to give the product S10 (19 g, 64%) as a grey colored solid. 1H NMR (400 MHz, DMSO-d6) δ 7.66 - 7.58 (m, 2H), 7.55 - 7.50 (m, 4H), 7.45 - 7.37 (m, 5H), 7.36 - 7.27 (m, 1H), 7.09 (d, J = 6.0 Hz, 2H), 6.73 (q, J = 2.7, 2.2 Hz, 2H), 5.28 (s, 2H). LCMS m/z 318.16 [M+H]+.

Reference： [1]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203023, 2021, A1 Location in patent: Paragraph 00234-00235; 00303-00304
[2]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203023, 2021, A1 Location in patent: Paragraph 00234-00235; 00303-00304
[3]Current Patent Assignee: VERTEX PHARMACEUTICALS (OLD) - WO2021/203014, 2021, A1 Location in patent: Paragraph 00128-00129; 00163

101
[ 20289-26-3 ]
[ 610-14-0 ]
(4-(benzyloxy)-1H-indol-1-yl)(2-nitrophenyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%	Stage #1: 4-benzyloxy-1H-indole With tetra(n-butyl)ammonium hydrogensulfate; sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.333333h; Stage #2: 2-nitrobenzyl chloride In N,N-dimethyl-formamide at 20℃; for 2h;

Reference： [1]Zhang, Jingyu; Xia, Wei; Qu, Meilin; Huda, Saskia; Ward, Jas S.; Rissanen, Kari; Albrecht, Markus [European Journal of Organic Chemistry, 2021, vol. 2021, # 45, p. 6097 - 6101]

102
[ 421-83-0 ]
[ 20289-26-3 ]
4-(benzyloxy)-3-((trifluoromethyl)thio)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With cetyltrimethylammonim bromide; squaric acid; sodium iodide In acetonitrile at 80℃; for 6h; Inert atmosphere; Schlenk technique;

Reference： [1]Xiang, Haonan; Liu, Jie; Wang, Jieping; Jiang, Lvqi; Yi, Wenbin [Organic Letters, 2022, vol. 24, # 1, p. 181 - 185]

103
[ 20289-26-3 ]
[ 2432-51-1 ]
1-(4-(benzyloxy)-1H-indol-1-yl)butan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With caesium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 12h; chemoselective reaction;	General procedure for indoleamide General procedure: A 25 mL tube was charged with 1 (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0 equiv),Cs2CO3 (0.6 mmol, 3.0 equiv) and xylene (2.0 mL) was added. The reaction was heatedunder 140 °C for 12 hours. Afterward, the reaction is cooled to room temperature. Afterremoval of the solvent under reduced pressure, the pure product 3 was obtained bycolumn chromatography on silica gel (eluent: pentane).

Reference： [1]Du, Tianri; Fang, Ruiru; Li, Yahui; Liang, Zhi; Wei, Xiangmu; Xu, Honghong; Yuan, Zheng; Zhang, Xin [Beilstein Journal of Organic Chemistry, 2022, vol. 18, p. 89 - 94]

104
[ 20289-26-3 ]
[ 35377-82-3 ]
(4-(benzyloxy)-1H-indol-1-yl)(cyclohexyl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With caesium carbonate In 5,5-dimethyl-1,3-cyclohexadiene at 140℃; for 12h; chemoselective reaction;	General procedure for indoleamide General procedure: A 25 mL tube was charged with 1 (0.2 mmol, 1.0 equiv), 2 (0.6 mmol, 3.0 equiv),Cs2CO3 (0.6 mmol, 3.0 equiv) and xylene (2.0 mL) was added. The reaction was heatedunder 140 °C for 12 hours. Afterward, the reaction is cooled to room temperature. Afterremoval of the solvent under reduced pressure, the pure product 3 was obtained bycolumn chromatography on silica gel (eluent: pentane).

Reference： [1]Du, Tianri; Fang, Ruiru; Li, Yahui; Liang, Zhi; Wei, Xiangmu; Xu, Honghong; Yuan, Zheng; Zhang, Xin [Beilstein Journal of Organic Chemistry, 2022, vol. 18, p. 89 - 94]

105
[ 20289-26-3 ]
4-methyl-N-(4-oxo-4-phenylbut-2-yn-1-yl)benzenesulfonamide [ No CAS ]
4-(benzyloxy)-3-(5-phenyl-1-tosyl-1H-pyrrol-3-yl)-1H-indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
93%	With Echavarren's catalyst In toluene at 80℃; for 1h; Inert atmosphere; Sealed tube;

Reference： [1]Pei, Miaomiao; Wang, Ali; Xie, Xin; Hu, Xiaoping; Liu, Yuanhong [Organic Letters, 2022, vol. 24, # 7, p. 1541 - 1545]

106
[ 20289-26-3 ]
1-dimethylamino-2-nitroethylene [ No CAS ]
C₁₇H₁₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
12%	With trifluoroacetic acid at 20℃; for 0.666667h;	1 Trifluoroacetic acid (1.34 mL) was added to a mixture of 4- benzoxylindole (9A-1 , 300 mg, 1.34 mmol) and dimethylamino-2-nitroethylene (170 mg, 1.46 mmol). The reaction mixture was stirred at room temperature for forty minutes before poured it into a mixture of EtOAc (7.8 mL) and 10% aqueous Na2COs (23.5 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (4 x 16 mL). The combined organic solutions were washed with brine (40 mL) and dried over anhydrous MgSO4. The organic solvent was concentrated in vacuo. The product was purified by flash chromatography on silica gel (eluted with a gradient of hexanes-DCM, 100:00 to 00:100) to afford compound 9A-2 as a red solid. Yield: 12%.

Reference： [1]Current Patent Assignee: MAGICMED IND - WO2022/47583, 2022, A1 Location in patent: Paragraph 00101; 00321

107
[ 79-37-8 ]
[ 20289-26-3 ]
[ 19961-27-4 ]
C₂₂H₂₄N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether at 0 - 5℃; for 3.5h; Inert atmosphere; Stage #2: N-ethyl-N-isopropyl-2-amine In diethyl ether for 1h; Inert atmosphere;	4 To a solution of 4-benzyloxyindole 1 (1.00 mmol, 1.00 eq) dissolved in anhydrous diethyl ether (10 mL)under argonsparging at 0 °C, was added oxalyl chloride (2.05 mmol, 2.05 eq) dropwise over the course of 30 minutes, and the reaction was continued at 0 - 5 °C for 3 hours. A solution of N- ethyl(isopropyl)amine (9.00 total eq, required for R group “D” in FIG. 11) in anhydrous diethyl ether (5 mL) was added dropwise over the course of 1 hour. The diethyl ether was removed in vacuo, and the residue was redissolved in dichloromethane (30 mL). The organic solution was washed with water (4 x 10 mL) and brine (10 mL), then dried with MgSO4 and concentrated under vacuo to yield 2, which was used without purification in the following step. A solution of lithium aluminum hydride in anhydrous THF (1 M, 5.20 eq) in dry 1 ,4-dioxane (2.0 mL) was brought to 60 °Cunder argon. A solution of 2 in a mixture of anhydrous THF (2.0 mL) and 1 ,4-dioxane (3.5 mL) was added dropwise over 30 minutes, and the reaction mixture was brought to 70 °C for 2 hours, then torefluxat 95 °C for 20 hours. After cooling to 0 °C, excess lithium aluminum hydride was quenched through the dropwise addition of a mixture of water (0.4 mL) - THF (2.0 mL), yielding a flocculant precipitate. Diethyl ether (10 mL) was added, and the reaction mixture was allowed to stir at room temperature for 30 minutes. The precipitate was removed via vacuum filtration, the filtrate was dried over MgSO4, and concentrated under vacuo to yield 3 which was used without purification. The above obtained 3 was dissolved in 95% EtOH (10 mL), and 10% palladium on activated charcoal (0.110 eq) was added. The reaction flask was evacuated then backfilled with hydrogen. After stirring at room temperature for 2 hours, the catalyst was removed through filtration and solvent removed in vacuo to yield 4, which was purified by liquid chromatography on C18 silica gel using a water - acetonitrile + 0.1 % formic acid eluent system.
	Stage #1: oxalyl dichloride; 4-benzyloxy-1H-indole In diethyl ether at 0 - 5℃; for 3.5h; Inert atmosphere; Stage #2: N-ethyl-N-isopropyl-2-amine In diethyl ether for 1h; Inert atmosphere;	4 To a solution of 4-benzyloxyindole 1 (1.00 mmol, 1.00 eq) dissolved in anhydrous diethyl ether (10 mL)under argonsparging at 0 °C, was added oxalyl chloride (2.05 mmol, 2.05 eq) dropwise over the course of 30 minutes, and the reaction was continued at 0 - 5 °C for 3 hours. A solution of N- ethyl(isopropyl)amine (9.00 total eq, required for R group “D” in FIG. 11) in anhydrous diethyl ether (5 mL) was added dropwise over the course of 1 hour. The diethyl ether was removed in vacuo, and the residue was redissolved in dichloromethane (30 mL). The organic solution was washed with water (4 x 10 mL) and brine (10 mL), then dried with MgSO4 and concentrated under vacuo to yield 2, which was used without purification in the following step. A solution of lithium aluminum hydride in anhydrous THF (1 M, 5.20 eq) in dry 1 ,4-dioxane (2.0 mL) was brought to 60 °Cunder argon. A solution of 2 in a mixture of anhydrous THF (2.0 mL) and 1 ,4-dioxane (3.5 mL) was added dropwise over 30 minutes, and the reaction mixture was brought to 70 °C for 2 hours, then torefluxat 95 °C for 20 hours. After cooling to 0 °C, excess lithium aluminum hydride was quenched through the dropwise addition of a mixture of water (0.4 mL) - THF (2.0 mL), yielding a flocculant precipitate. Diethyl ether (10 mL) was added, and the reaction mixture was allowed to stir at room temperature for 30 minutes. The precipitate was removed via vacuum filtration, the filtrate was dried over MgSO4, and concentrated under vacuo to yield 3 which was used without purification. The above obtained 3 was dissolved in 95% EtOH (10 mL), and 10% palladium on activated charcoal (0.110 eq) was added. The reaction flask was evacuated then backfilled with hydrogen. After stirring at room temperature for 2 hours, the catalyst was removed through filtration and solvent removed in vacuo to yield 4, which was purified by liquid chromatography on C18 silica gel using a water - acetonitrile + 0.1 % formic acid eluent system.

Reference： [1]Current Patent Assignee: MAGICMED IND - WO2022/47580, 2022, A1 Location in patent: Paragraph 00384-00385
[2]Current Patent Assignee: MAGICMED IND - WO2022/47580, 2022, A1 Location in patent: Paragraph 00384-00385

108
[ 20289-26-3 ]
[ 100-17-4 ]
C₂₂H₁₉NO₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With dicyclohexyl(2′,4′,6′-tri-isopropyl-3,6-dimethoxy-[1,1′-biphenyl]-2-yl)phosphane at 150℃; Schlenk technique; Inert atmosphere;	32 Example 32 Add 0.30.4mmol p-nitroanisole, 0.2mmol 4-benzyloxyindole, 0.02mmol to Schlenk tube Palladium acetylacetonate or tris(dibenzylideneacetone)dipalladium, 0.03 mmol BrettPhos, 0.4-0.6 mmol potassium carbonate, potassium phosphate or rubidium carbonate, 1.0-2.0 mL o-xylene, dioxane or m-xylene. After stirring and reacting at 150° C. under N2 conditions for 16-24 hours, heating and stirring were stopped, and the mixture was cooled to room temperature. Suction filtration, rotary evaporation under reduced pressure to remove the solvent, and separation and purification by column chromatography to obtain the target product. The volume ratio of the column chromatography eluent used was 200:1 petroleum ether:ethyl acetate mixed solvent.

Reference： [1]Current Patent Assignee: UNIV GUANGXI - CN114380730, 2022, A Location in patent: Paragraph 0193-0200

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• Acetal Formation • Esters Are Reduced by LiAlH4 to Give Alcohols • Esters Hydrolyze to Carboxylic Acids and Alcohols • Ether Synthesis by Oxymercuration-Demercuration • Ethers Synthesis from Alcohols with Strong Acids • Grignard Reagents Transform Esters into Alcohols • Nomenclature of Ethers • Preparation of Ethers • Primary Ether Cleavage with Strong Nucleophilic Acids • Reactions of Benzene and Substituted Benzenes • Reactions of Ethers • Ring Opening of Oxacyclopropane • Synthesis of Alcohols from Tertiary Ethers • The Nucleophilic Opening of Oxacyclopropanes

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P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere

[ CAS No. 20289-26-3 ] {[proInfo.proName]}

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[ 20289-26-3 ] Synthesis Path-Upstream 1~4

[ 20289-26-3 ] Synthesis Path-Downstream 1~108

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Aryls

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