Name: 3770-50-1|Ethyl indole-2-carboxylate|98%
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SKU: A362351
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1
[ 3770-50-1 ]
[ 560-95-2 ]
[ 91348-45-7 ]

Reference： [1]Chemische Berichte,1923,vol. 56,p. 1024
[2]Chemische Berichte,1923,vol. 56,p. 1024

2
[ 3770-50-1 ]
[ 93-61-8 ]
[ 18450-27-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trichlorophosphate In 1,2-dichloro-ethane for 1.5h; Heating / reflux;	I.a; 1.a To a mixture of N-methyl formanilide (4.2 g, 31 mmol) and phosphorus oxychloride (POCl3; 2.9 mL, 30.7 mmol) under argon was added ethylene dichloride (16 mL) and ethyl indole-2-carboxylate (1) (5.0 g, 26.4 mmol), and refluxed for 1.5 h. The reaction mixture was cooled to room temperature, poured into saturated aqueous sodium acetate (CH3CO2Na), and the precipitate collected by filtration, washed with H2O, ether and dried under vacuum overnight to give the desired product 2 as a solid in quantitative yield (6.0 g): 1H NMR (300 MHz, CDCl3) δ 1.48 (t, J=7.1 Hz, 3, CO2CH2C3), 4.54 (q, J=7.1 Hz, 2, CO2C2CH3), 7.36 (m, 1, ArH), 7.45 (m, 2, ArH), 8.49 (d, J=8.2 Hz, 1, ArH), 9.33 (br.s, 1, NH), 10.77 (s, 1, CO).
86%	With trichlorophosphate In 1,2-dichloro-ethane Heating;
66%	Stage #1: N-methyl-N-phenylformamide With chlorophosphonic acid at 20℃; for 0.25h; Stage #2: 2-carbethoxyindole In 1,2-dichloro-ethane for 1.5h; Heating / reflux;	14 Preparation 14; Ethyl 3-formylindole-2-carboxylate A mixture of N-methylformanilide (2.25 ml) and phosphoryl chloride (1.70 ml) was stirred at ambient temperature for 15 minutes. 1,2-dichloroethane (30 ml) was then added, followed by ethyl indole-2-carboxylate (3 g) and the reaction was heated at reflux for 90 minutes. The reaction mixture was then poured into a mixture of ice/water (200 ml) and sodium acetate (10 g) and extracted with ethyl acetate (2?200 ml). Combined organic phases were evaporated and the crude residue purified by column chromatography using dichloromethane as eluent to give the product as a white solid (2.27 g, 66%); NMR d (CD3SOCD3) 1.40 (t, 3H), 4.42 (q, 2H), 7.25 (m, 1H), 7.40 (m, 1H), 7.55 (m, 1H), 8.20 (m, 1H), 12.77 (s, 1H); M/z (+) 218.3 (MH+).

With 1,2-dichloro-ethane; trichlorophosphate Behandeln des Reaktionsgemisches mit wss. Natriumacetat;

Reference： [1]Current Patent Assignee: SRI INTERNATIONAL INC - US2004/43965, 2004, A1 Location in patent: Page/Page column 17
[2]Hickman; Sturino; Lachance [Tetrahedron Letters, 2000, vol. 41, # 43, p. 8217 - 8220]
[3]Current Patent Assignee: ASTRAZENECA PLC - US6833387, 2004, B1 Location in patent: Page column 32
[4]Shabica et al. [Journal of the American Chemical Society, 1946, vol. 68, p. 1156]

3
[ 3770-50-1 ]
[ 24621-70-3 ]

Yield	Reaction Conditions	Operation in experiment
100%		Compound 17: (1H-indol-2-yl)methanolTo ethyl 1H-indole-2-carboxylate 16 (6.5 g, 34.35 mmol) in THF at 0 C. was added lithium aluminum hydride solution (1M, in THF 1.43 g, 37.78 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at 0 C. The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed with THF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 5.37 g (100% yield) of the crude (1H-indol-2-yl)methanol 17 which was used directly in the next step.
99%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	Lithium aluminum hydride (0.82 g, 22 mmol) was stirred in THF (0.4 mL) at 0 C. A solution of ethyl indole-2-carboxylate (2.0 g, 10 mmol) in THF (13 mL) was added dropwise. The reaction mixture was slowly warmed up to rt and was stirred for 30 min. It was then cooled to 0 C. Water (2 mL), NaOH (1 N, aq., 5 mL), and water (6 mL) were added successively. The mixture was stirred at rt for 15 min, then filtered through Celite and washed with 10:1 CH2Cl2-MeOH (150 mL). The filtrate was washed with brine. The organic layer was dried over Na2SO4 and concentrated to give 1.55 g (99%) of Compound 59.
99%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 2h;	A solution of ethyl 1H-indole-2-carboxylate (501.7 mg, 2.65 mmol, 1 eq) in anhydrous THF (10 mL) was added dropwise to a cooled (0 C) suspension of lithium aluminium hydride (139.1 mg, 3.98 mmol, 1.5 eq) in anhydrous THF (10 mL) and the mixture stirred for 2 h. The reaction was quenched by dropwise addition of MeOH (5 mL) and washed with water (20 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 40% EtOAc/cyclohexane) to give the alcohol 6h as a white powder (386.7 mg, 99%).

99%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 2h;	EXAMPLE 6 (E)-2-cyano-3-(1H-indol-2-yl)acrylic Acid Sulfuric acid (248 pL) was added to a solution of indole-2-carboxylic acid (2.48 mmol) in absolute ethanol (8 mL). The reaction mixture was refluxed for 15 h, and sulfuric acid (248 pL) was added. The reaction mixture was heated for a further 3 h. After cooling to room temperature, the solvent was evaporated under reduced pressure, the residue was dissolved in 10 mL of DCM, and the resulting solution was washed with a saturated sodium carbonate aqueous solution (320 mL), water (10 mL) and brine (10 mL). The organic phase is dried with magnesium sulfate, filtered, evaporated under reduced pressure in order to obtain a white powder (365.8 mg, 77%). 1H NMR (400 MHz, CDCl3): delta 8.93 (s, 1H), 7.70 and 7.43 (2d, J=8.1 Hz, 2H), 7.36-7.24 (m, 2H), 7.16 (t, J=7.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.42 (t, J=7.1 Hz, 3H). A solution of ethyl 1H-indole-2-carboxylate (2.65 mmol) in anhydrous tetrahydrofurane (10 mL) was added dropwise to a cooled solution (0 C.), a lithium aluminium hydride (3.98 mmol) suspension in anhydrous tetrahydrofurane (10 mL) and the mixture was stirred for 2 h. The reaction was stopped by dropwise addition of (5 mL) and washed with water (20 mL). The organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 40% ethyl acetate cyclohexane) in order to obtain a white powder (386.7 mg, 99%). 1H NMR (400 MHz, CDCl3): delta 8.38 (se, 1H), 7.61 and 7.37 (2*d, J=8.0 Hz, 2H), 7.21 and 7.13 (m, 2H), 6.43 (t, J=7.3 Hz, 1H), 4.84 (se, 2H), 1.93 (se, 1H).
98%	With lithium aluminium tetrahydride; In diethyl ether; at 0 - 20℃; for 1h;	(a) Indole-2-carbinol (31). To a solution of ester 30 (7.5 g, 39.64 mmol) in ether (100 mL) was added LiAIH4 (2.3 g, 60.6 mmol) slowly at 0 C. under argon and warmed to room temperature for 1 h. The suspension was quenched with water and white precipitate was removed by filtration. The filtrate was dried (MgSO4) and concentrated to afford 31 as a solid (5.75 g, 98%): 1H NMR (300 MHz, CDCl3) delta 4.82 (s, 2, CH2OH), 6.41 (s,1, PyH), 7.11 (m, 1, ArH), 7.20 (m, 1, ArH), 7.35 (d, J=7.8 Hz, 1, ArH), 7.59 (d, J=7.7 Hz, 1, ArH), 8.35 (br.s, 1, NH).
98%		To a solution of ethyl 1H-indole-2-carboxylate (7.5 g, 39.64 mmol) in ether (100 mL) was added LiAlH4 (2.3 g, 60.6 mmol) slowly at 0 C. under argon and warmed to room temperature for 1 h. The suspension was quenched slowly with water and white precipitate was removed by filtration. The filtrate was dried (MgSO4) and concentrated to afford Indole-2-carbinol as a solid (5.75 g, 98%): 1H NMR (300 MHz, CDCl3) delta 4.82 (s, 2, C2OH), 6.41 (s, 1, PyH), 7.11 (m, 1, ArH), 7.20 (m, 1, ArH), 7.35 (d, J=7.8 Hz, 1, ArH), 7.59 (d, J=7.7 Hz, 1, ArH), 8.35 (br. s, 1, NH).
98%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 0.5h;	For the synthesis of 6, lithium aluminium hydride (2mmol) was stirred in dry THF at 0C. Then 1 (1mmol) was dissolved in THF and added drop wise to the solution of lithium aluminium hydride at 0C. Then, the mixture was slowly warmed to room temperature till the completion (0.5h) of reaction as monitored by TLC. It was then cooled to 0C, 10% aqueous sodium hydroxide (20mL) and 40mL of water was added successively. Then reaction mixture was allowed to stir for 0.5h, filtered through celite and washed with dry ethyl acetate, dried over anhydrous sodium sulfate, concentrated and purified by isocratic flash column chromatography (petroleum ether: ethyl acetate=8: 2, v/v) on silica gel (200-400) to get pure compound 6 with 98% yield.
98%	With C30H34Cl2N2P2Ru; potassium methanolate; hydrogen; In tetrahydrofuran; at 100℃; under 38002.6 - 76005.1 Torr; for 10h;Glovebox; Autoclave;	General procedure: In a glove box, add a ruthenium complex Ia (0.3 to 0.7 mg, 0.0002 to 0.001 mmol) to a 300 mL autoclave,Potassium methoxide (35-700 mg, 0.5-10 mmol), tetrahydrofuran (4-60 mL), and ester compounds (10-200 mmol).After sealing the autoclave, take it out of the glove box and fill it with 50 100atm of hydrogen.The reaction kettle was heated and stirred in an oil bath at 100 C for 10 to 336 hours.After the reaction kettle was cooled in an ice-water bath for 1.5 hours, the excess hydrogen was slowly released.The solvent was removed from the reaction solution under reduced pressure, and the residue was purified with a short silica gel column to obtain an alcohol compound. The results are shown in Table 5.
96%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 3.5h;	General procedure: To ethyl 1H-indole-2-carboxylate (1.3 g, 6.89 mmol) in THF at 0 .was added lithium aluminumhydride solution (1M, in THF 0.29 g, 1.54 mmol) dropwise and the reaction mixture was stirred for 3.5 hours at0 . The reaction mixture was quenched with H2O, 15% NaOH, and H2O before it was filtered and rinsed withTHF. Reaction mixture was dried (anhydrous Na2SO4) and evaporation of the solvent gave 1.1 g (96% yield) of thecrude (1H-indol-2-yl)methanol which was used directly in the next step.
92%	With lithium aluminium tetrahydride; In tetrahydrofuran;	General procedure: In round-bottom flask94 containing the correspondent indole ester (1 eq.) in THF, LiAlH4 (4 eq.) was added in an95 ice bath under stirring. The ice bath was removed and the reaction was kept under96 magnetic stirring until the completion of the reaction was detected by TLC (1 hour). Then, in an ice bath, the reaction was quenched with distilled water diluted in THF, followed 97 by 4 eq. of 1 M NaOH solution and finally three times this volume of distilled water. The 98 suspension was stirred for 10 min, when the white precipitate was filtered off and washed 99 with THF. The filtrate was partially evaporated under reduced pressure and the remaining 100 solution was extracted with 2 x 20 mL AcOEt. The organic layer was collected, dried 101 with Na2SO4, filtered and the solvent evaporated under reduced pressure. 102(1H-Indol-2-yl)methanol (12) (2). Obtained from the general procedure as a yellow 103 solid, 92% yield; mp 71.9 - 73.3 C; IR (neat, cm-1) 3393, 3373, 3236, 1453, 1415, 1054; 104 1H NMR (200 MHz, CDCl3) delta 8.41 (broad s, 1H), 7.61 (d, 1H, J = 7.3), 7.62-7.10 (m, 105 3H), 6.39 (s, 1H), 4.72 (s, 2H), 2.55 (broad s, 1H); 13C NMR (50 MHz, CDCl3) delta 137.5, 106 136.3, 127.9, 122.1, 120.6, 119.9, 111.0, 100.5, 58.5.
92%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2.5h;Inert atmosphere;	The solution of ethyl indole-2-carboxylate (4.73 g; 25 mmol) dissolved in dry THF (25 mL) was added dropwise to a stirredsuspension of LiAlH4 (1.23 g; 32.3 mmol) in dry THF (40 mL). The mixture was stirred 2.5 h at room temperature and cautiously quenched by adding dropwise: water (1.2 mL), 15% NaOH (1.2 mL) and again water (3.7 mL). The solution was stirred for 1 h andthe white precipitate was filtered out. The filter cake was washed with Et2O (4 × 25 mL). The combined organic phases were driedover Na2SO4 and the solvents were evaporated in vacuo. The crude product was crystallized from EtOAc-hexane 1:2 and washedwith EtOAc-hexane 1:20. The product that remained in the filtrate was separated by column chromatography (silica gel, EtOAchexane1:4, then 1:2).White solid, overall yield 3.39 g (92%); mp 74-75.5 C (EtOAc-hexane).1H NMR (Bruker 500 MHz, CDCl3) delta 2.16 (s 1H), 4.73 (s, 2H), 6.37 (s, 1H), 7.10 (t, J = 7.4 Hz; 1H), 7.17 (t, J = 7.6 Hz; 1H), 7.27 (d, J= 8.1 Hz; 1H), 7.57 (t, J = 7.7 Hz; 1H), 8.32 (s, 1H).13C NMR (Bruker 125 MHz, CDCl3) delta = 58.62, 100.54, 110.96, 119.92, 120.60, 122.17, 128.05, 136.36, 137.50.MS (EI): m/z (%) = 148 (15), 147 (98), 146 (25), 131 (26), 130 (98), 129 (100), 128 (25), 119 (11), 118 (35), 117 (23), 103 (15), 102(20), 91 (24), 90 (16), 89 (26), 84 (24), 77 (19), 73 (10), 69 (10), 66 (28), 65 (11), 63 (16), 57 (15), 51 (12), 43 (26), 39 (11).HRMS (EI) m/z calcd for C9H9NO*+: 147.0684; found: 147.0678.
83%		[1185] To a suspension of lithium aluminum hydride (10.6 g, 264 mmol) in THF (200 mL) is added dropwise a solution of ethyl indole-2-carboxylate (50.0 g, 256 mmol) in THF (250 mL) over 25 minutes. After 3 h, water (10.6 mL) is carefully added, followed by 15% NaOH (10.6 mL), followed by additional portion of water (31.8 mL). The resulting suspension is dried (Na2SO4) and filtered through celite. After concentration under reduced pressure, the white solid (34.0 g) is crystallized from EtOAc/hexanes to give white needles for 1H-indol-2-ylmethanol. Yield 83%. HRMS (FAB) calcd for C9H9NO+H 148.0762, found 148.0771.
75%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 1.5h;	Compound 1a (100.00 g, 528.51 mmol) was dissolved in tetrahydrofuran (1000 mL), and lithium aluminum hydride (24.07 g, 634.21 mmol) was slowly added in batch at 0 C. The reaction mixture was stirred at this temperature for 1.5 hr, and then water (24 mL), 10% sodium hydroxide solution (24 mL), and water (72 mL) were successively added dropwise. The resulting mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to dryness to obtain an oil crude product. The oil crude product was then slurried in a mixed solvent of ethyl acetate and petroleum ether (300 mL, v/v=50/1) to give Compound 1b (59.00 g, yield: 75%). 1H NMR (400 MHz, CDCl3) delta8.37 (br. s., 1H), 7.59 (d, J=7.6 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.22-7.16 (m, 1H), 7.15-7.07 (m, 1H), 6.41-6.40 (m, 1H), 4.81 (s, 2H), 1.97 (br. s., 1H). MS-ESI calculated value [M+ H]+ 148, measured value 148.
1.76 g (99%)	With hydrogenchloride; diisobutylaluminium hydride; In tetrahydrofuran;	2-Indolemethanol: In a 50-mL round-bottom flask, a total of 2.28 g (12 mmol) of ethyl 2-indolecarboxylate was dissolved in 15 mL of dry THF under N2. The solution was cooled to -78 C. (acetone-dry ice bath) and 24 mL (24 mmol) of 1.0M DIBAL in THF was added over a period of 1 h. The mixture was stirred for 2 h at -78 C., quenched with 10 mL of 1N HCl, then allowed to warm to room temperature. The reaction mixture was then extracted with ether (4100 mL) and the ether layer was washed with 1N HCL (2100 mL), dried over MgSO4, filtered, and evaporated in vacuo. The product was purified by flash chromatography (1:1 ethyl acetate:petroleum ether). Yield: 1.76 g (99%). 1 H NMR (CDCl3): delta1.86 (t, 1H, J=6, OH), 4.82 (d, 2H, J=6), 6.40 (s, 1H), 7.0-7.3 (m, 2H), 7.34 (d, 1H, J=7.8), 7.58 (d, 1H, J=7.8), 8.36 (br s, 1H) MS (EI): m/z 147 (M+).
		To a solution of ethyl indole-2-carboxylate (20 g) in 200 mL of TEtaF cooled at -78 0C was added 1 10 mL of 1 M solution LiAlEta4 in THF. The reaction mixture was stirred between -78 0C and 0 0C for 1 h, and then quenched by slow addition of 125 mL of 4N HCl followed by 150 mL of water. The reaction mixture was extracted with 1 L of 1 : 1 EtOAc/hexane and the extract was dried over Na2Stheta4. Filtration and concentration provided the crude alcohol, which was dissoled in 1.2 L of CH2CI2 and treated with 100 g of Mntheta2- After stirring for 2 h, the mixture was filtered through celite and the filtrate was used for the next step without further purification.
		Stepl : 1 //-indole-2-carbaldehyde; To a -780C solution of ethyl indole-2-carboxylate in THF (0.5 M) was added 1.04 equiv. LiAlH4 as a IM solution in THF. The reaction was stirred for Ih with warming to O0C and then quenched by the slow addition of 5 equiv. HCl as a 4 N aqueous solution followed by an equal volume of water. The reaction mixture was extracted twice with excess EtO Ac/Hex (1 :1) and the combined organic layers were dried over Na2SO4. Filtration and evaporation of the volatiles provided the crude alcohol, which was dissolved in CH2Cl2 (0.1 M) and treated with 11 equiv. OfMnO2. After stirring for 2h, the mixture was filtered through Celite and the filtrate was used for the next step without further purification.
		Description 1; 2-HydroxymethyI-lH-Indole (Dl); lH-Indole-2-carboxylic acid ethyl ester (20 gm, 0.105 M) in THF (50 mL) was treated with cooled and stirred suspension of Lithium Aluminum Hydride (6.21 gm, 0.163 M) in THF (15 mL) slowly over the period of lhour. The reaction mixture was heated at reflux for 3 hours. After the completion of reaction, the reaction mixture was cooled to room temperature, added ethyl acetate (20 mL) drop-wise, stirred for 30 minutes and poured on to the ice water and compound was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure to afford the compound, which was identified by IR, NMR Mass Spectral analyses as the title compound.Mass: 148 (M+H)+; NMR : 4.82 (2H, s), 6.40 - 6.40 (IH, d), 7.08 - 7.12 (IH, m), 7.16 - 7.25 (IH, m), 7.33 - 7.35 (IH, m), 7. 57 - 7.59 (IH, m), 8.35 (IH, bs).
1.5 g	With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃;	To a slurry of lithium aluminum hydride (1.00 g, 26.3 mmol) in anhydrous tetrahydrofuran (50 mL) which was cooled to 0 C was added a solution of ethyl 1H-indole-2-carboxylate (3.80 g, 20.0 mmol) in tetrahydrofuran (50 mL) dropwise at 0 C while stirring. The temperature of the mixture was then warmed naturally to room temperature and the mixture was stirred at room temperature overnight. The resulting mixture was quenched with methanol, and then filtered through a celite pad. The filtrate was concentrated in vacuo to afford 1.5 g of 1H-indol-2- ylmethanol.
2.3 g	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 2h;Cooling with ice;	In a 100 ml reaction flask, lithium aluminumhydride (902.63 mg, 23.78 mmol) and THF (30 ml) were added successively, stirred at room temperature for 5 min, then ice-cooled and slowly added. indole-2-carboxylic acid ethyl ester (3 g, 15.86 mmol) was added and the mixture was warmed to room temperature for 2 h.After completion of the reaction, the system was cooled to 0 C, then 20 ml of THF and 1.7 ml of 20% KOH were added thereto, stirred for 10 min, filtered, and the filter cake was washed with 20 ml of THF.The filtrate was washed once with saturated NaCl (10 ml), dried over anhydrous sodium sulfate and filtered.It was concentrated to dryness to give the title compound (2.3 g).

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4
[ 3770-50-1 ]
[ 1477-50-5 ]

Yield	Reaction Conditions	Operation in experiment
99.9%	With potassium hydroxide In water at 120℃; for 0.5h;	1.a Preparation of 1H-indole-2-carboxylic acid 1a Ethyl ethyl-1H-indole-2-carboxylate (1.0 g, 5.3 mmol) was added to 10 ml of water.Further potassium hydroxide (2.0 g, 31.8 mmol) was added and refluxed at 120 ° C for 0.5 hours.After cooling to room temperature, a large amount of white solid was precipitated from pH 10 to 4 with 10M hydrochloric acid, filtered, and dried to give 853 mg (99.9%) of white solid.
97%	With sodium hydroxide In ethanol; water at 70℃; for 2h;
94%	With sodium hydroxide at 200℃; for 0.0166667h; Irradiation; microwave;

94%	Stage #1: 2-carbethoxyindole With lithium hydroxide In tetrahydrofuran; water Stage #2: With hydrogenchloride In water
93%	Stage #1: 2-carbethoxyindole With sodium hydroxide In methanol; water for 0.5h; Reflux; Green chemistry; Stage #2: With hydrogenchloride In methanol; water at 40℃; Green chemistry;	1.3 Synthesis of indole-2-carboxylic acid A mixture of 94.6 g of indole-2-carboxylate,In a mixed solution of 31.25 g of 96% sodium hydroxide, 183 ml of methanol and 183 ml of water,Heated to reflux for 0.5 hours,Cooled to 40 ° C, 10% hydrochloric acid was added dropwise to a pH of 3 to 4,The product was filtered to yield 75 g of an off-white indole-2-carboxylic acid in a yield of 93% and an HPLC content of ≥96%
90%	With sodium hydroxide for 1h; Heating;
76%	With potassium fluoride; tetrabutyl ammonium fluoride In tetrahydrofuran; water at 70℃; for 7h;	General procedure for ester and acetate hydrolysis General procedure: To a solution of ester or acetate (1 mmol) in THF (5 mL) was added alkali metal fluoride (2 mmol) followed by quaternary ammonium salt (1 M in THF, 2 mL) and the resultant solution was stirred for 7 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (2 × 20 mL) followed by brine solution (20 mL). The organic layer was dried over MgSO4 and concentrated under reduced pressure to get a crude compound, which was triturated with hexane to get the corresponding product in 60-95 % yield.
	With sodium hydroxide
	With potassium hydroxide In ethanol for 0.5h; Heating;
	With lithium hydroxide In tetrahydrofuran at 60℃; for 2h;
	With sodium hydroxide In methanol; water
	Stage #1: 2-carbethoxyindole With water In tetrahydrofuran Stage #2: With hydrogenchloride In water	2 Ethyl 1H-indole-2-carboxylate (3.0 g, 15.86 mmol) and lithium hydroxide, H2O (3.33 g, 79 mmol) were dissolved in THF (Ratio: 1.000, Volume: 10 ml) and Water (Ratio: 2, Volume: 20.00 ml). The reaction was stirred overnight. The reaction was diluted with water and diethyl ether. The water layer was washed with diethyl ether twice. The aqueous layer was acidified to pH 2 using 2N HCl. The suspension was extracted using ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to obtain product. (Yield: 2.39 g, white solid) 1H-NMR (400 MHz, DMSO-d6) 12.90, 11.70, 7.60, 7.40, 7.24-7.14, 7.07-6.98
	With water; potassium hydroxide In acetone for 1h; Reflux;	Method b General procedure: a solution of the appropriate ester 2-4 and KOH (6.0 mmol in 1.0 mL H2O) and acetone (10 mL) was refluxed for one hour, then the above purification process was followed.
	Multi-step reaction with 2 steps 1: sodium methylate / methanol / 1 h 2: potassium hydroxide; water / acetone / 1 h / Reflux
	With lithium hydroxide monohydrate In tetrahydrofuran; methanol; water at 20℃; for 18h;
	With sodium hydroxide In ethanol for 3h; Reflux;
	With sodium hydroxide In water for 1h; Reflux;
200 kg	With water; sodium hydroxide at 75℃; Large scale;	3.3 3. Preparation of Compound IV: Add 344 kg of water and 234.9 kg of compound 3 to a 2000 L reactor and stir.Slowly add 644kg of sodium hydroxide solution(158.9kg sodium hydroxide is dissolved in 485kg water),Control the temperature in the kettle to not exceed 75 ° C, stir the reaction for 2-4 hours,The reaction solution was dark red. Add 4.6kg of activated carbon and stir for 1-2 hours.After suction filtration, the filter cake was rinsed with 200 kg of water, and the filtrate was combined.The filtrate was heated to 60-75 ° C, 332.3 kg of 30% hydrochloric acid was added dropwise, and stirred.There are a large number of white solids, and the pH is adjusted between 2 and 3.Stirring was continued for 30 min. Cool down to 40 ~ 50 ° C, centrifuge,The filter cake is rinsed with 216k water until the pH of the aqueous phase is between 5-6.A light yellow to off-white solid wet material, dried at 60-75 ° C,200kg of pale yellow to off-white solid compound IV,Content (HPLC) ≥ 97.0%, moisture ≤ 0.5%.
	With sodium hydroxide In ethanol for 3h; Reflux;

Reference： [1]Current Patent Assignee: EAST CHINA NORMAL UNIVERSITY; Shanghai Institute of Materia Medica (in: CAS); CHINESE ACADEMY OF SCIENCES - CN108794379, 2018, A Location in patent: Paragraph 0125; 0126
[2]Jiang, Xiaojian; Zhang, Feng; Yang, Junjie; Yu, Pei; Yi, Peng; Sun, Yewei; Wang, Yuqiang [Advanced Synthesis and Catalysis, 2016, vol. 358, # 24, p. 3938 - 3942]
[3]Strauss, Christopher R.; Trainor, Robert W. [Australian Journal of Chemistry, 1998, vol. 51, # 8, p. 703 - 705]
[4]Sindac, Janice A.; Barraza, Scott J.; Dobry, Craig J.; Xiang, Jianming; Blakely, Pennelope K.; Irani, David N.; Keep, Richard F.; Miller, David J.; Larsen, Scott D. [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9222 - 9241]
[5]Current Patent Assignee: CHINA AGRICULTURAL UNIVERSITY - CN104402795, 2017, B Location in patent: Paragraph 0035; 0038; 0058
[6]Pierini, Adriana B.; Cardozo, Mario G.; Montiel, Aida A.; Albonico, Sem M.; Pizzorno, Maria T. [Journal of Heterocyclic Chemistry, 1989, vol. 26, p. 1003 - 1008]
[7]Vijayalakshmi; Balakrishna; Mustafa, Shaik [Asian Journal of Chemistry, 2018, vol. 30, # 2, p. 309 - 311]
[8]Brehm [Journal of the American Chemical Society, 1949, vol. 71, p. 3541]
[9]Font, M.; Monge, A.; Cuartero, A.; Ellorriaga, A.; Martinez-Irujo, J.J.; et al. [European Journal of Medicinal Chemistry, 1995, vol. 30, # 12, p. 963 - 972]
[10]Nazare, Marc; Essrich, Melanie; Will, David W.; Matter, Hans; Ritter, Kurt; Urmann, Matthias; Bauer, Armin; Schreuder, Herman; Dudda, Angela; Czech, Joerg; Lorenz, Martin; Laux, Volker; Wehner, Volkmar [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 16, p. 4191 - 4195]
[11]Kuuloja, Noora; Vaismaa, Matti; Franzén, Robert [Tetrahedron, 2012, vol. 68, # 10, p. 2313 - 2318]
[12]Current Patent Assignee: UNIVERSITY OF MICHIGAN - US2012/252807, 2012, A1 Location in patent: Page/Page column 57-58
[13]Boraei, Ahmed T. A.; El Ashry, El Sayed H.; Barakat, Assem; Ghabbour, Hazem A. [Molecules, 2016, vol. 21, # 3]
[14]Boraei, Ahmed T. A.; El Ashry, El Sayed H.; Barakat, Assem; Ghabbour, Hazem A. [Molecules, 2016, vol. 21, # 3]
[15]Pieroni, Marco; Azzali, Elisa; Basilico, Nicoletta; Parapini, Silvia; Zolkiewski, Michal; Beato, Claudia; Annunziato, Giannamaria; Bruno, Agostino; Vacondio, Federica; Costantino, Gabriele [Journal of Medicinal Chemistry, 2017, vol. 60, # 5, p. 1959 - 1970]
[16]Franz, Nicholas D.; Belardinelli, Juan Manuel; Kaminski, Michael A.; Dunn, Louis C.; Calado Nogueira de Moura, Vinicius; Blaha, Michael A.; Truong, Dan D.; Li, Wei; Jackson, Mary; North, E. Jeffrey [Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 14, p. 3746 - 3755]
[17]Shi, Ying; Duan, Yan-Hui; Ji, Yue-Yang; Wang, Zhi-Long; Wu, Yan-Ran; Gunosewoyo, Hendra; Xie, Xiao-Yu; Chen, Jian-Zhong; Yang, Fan; Li, Jing; Tang, Jie; Xie, Xin; Yu, Li-Fang [Journal of Medicinal Chemistry, 2017, vol. 60, # 16, p. 7067 - 7083]
[18]Current Patent Assignee: NANJING F S PHARMATECH - CN108752259, 2018, A Location in patent: Paragraph 0038; 0045-0047
[19]Shen, Qing-Kun; Deng, Hao; Wang, Shi-Ben; Tian, Yu-Shun; Quan, Zhen-Shan [European Journal of Medicinal Chemistry, 2019, vol. 173, p. 15 - 31]

5
[ 3770-50-1 ]
[ 5055-39-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With hydrazine hydrate monohydrate Heating;
98.5%	With hydrazine hydrate monohydrate In ethanol for 4h; Heating;
87%	With hydrazine monohydrate In ethanol at 75℃; for 20h;	Synthesis of 1 H-indole-2-carbohydrazide 1A. Hydrazine hydrate [7803-57-8] (13,66 mL, 0.28 mol) was added to a stirred solution of ethyl indole-2-carboxylate [3770-50-1] (5,2 g, 0,027 mol) in EtOH (40 mL) in a 100 ml round bottom flask. The mixture was stirred at 75°C for 20 h. After that, the reaction mixture was cooled to 0°C and the solids were filtered, washed with cold water and cold EtOH and then dried under vacuo at 50°C overnight to yield lH-indole-2- carbohydrazide 1A (4.20 g, 87%) as a white crystalline solid.

87%	With hydrazine monohydrate In ethanol at 75℃; for 20h;	Synthesis of 1 H-indole-2-carbohydrazide 1A. Hydrazine hydrate [7803-57-8] (13,66 mL, 0.28 mol) was added to a stirred solution of ethyl indole-2-carboxylate [3770-50-1] (5,2 g, 0,027 mol) in EtOH (40 mL) in a 100 ml round bottom flask. The mixture was stirred at 75°C for 20 h. After that, the reaction mixture was cooled to 0°C and the solids were filtered, washed with cold water and cold EtOH and then dried under vacuo at 50°C overnight to yield lH-indole-2- carbohydrazide 1A (4.20 g, 87%) as a white crystalline solid.
84%	With hydrazine hydrate monohydrate In ethanol Reflux;
84%	With hydrazine hydrate monohydrate In ethanol Reflux;	General method for the preparation of hydrazides 19a-e General procedure: The appropriate aryl-ester 18a-e (1 eq), was added of EtOH (2.22 ml*mmol/eq) followed by hydrazine monohydrate (3 eq). The solution was refluxed overnight, then cooled to room temperature. The precipitate obtained was filtered and washed with cold EtOH and n-hexane to give the pure product.
84%	With hydrazine hydrate monohydrate In ethanol for 2h; Reflux;	3.1.2. Preparation of Key Intermediate 1H-Indole-2-Carbohydrazide 4 An excess of 99% hydrazine monohydrate (3.7 mL, 75 mmol) was added to a hot solution of ethyl indole-2-carboxylate 3 (2.84 g, 15 mmol) in ethyl alcohol (25 mL). The resulting reaction mixture was heated under reflux for two hours. Thereafter, it was cooled to r.t. and then poured over crushed ice. The formed solid was filtered-off, washed with water (3 x 5 mL), and recrystallized from isopropyl alcohol to produce the key intermediate 1H-indole-2-carbohydrazide 4.
77%	With hydrazine monohydrate In ethanol for 6h; Reflux;	1 To a round bottom flask add 0.005 moles of ethyl indole-2-carboxylate with 20 mE ethanol. Add 0.5 mE hydrazine hydrate (50-60%). Reflux solution for 6 hours.Allow solution to cool to room temperature and allow product to precipitate out by placing round bottom flask in an ice bath. Filter product and recrystallize in ethanol. Yield77%.
71%	With hydrazine hydrate monohydrate In ethanol Reflux;
60%	With hydrazine In ethanol for 168h; Reflux;
44%	With hydrazine hydrate monohydrate In ethanol for 6h; Reflux;
	With hydrazine hydrate monohydrate
	With hydrazine hydrate monohydrate In ethanol for 5h; Heating;
	With hydrazine In ethanol for 16h; Reflux; Inert atmosphere;
	With hydrazine In water monomer
	With hydrazine monohydrate In ethanol at 140℃; for 0.25h; Microwave irradiation;
	With hydrazine hydrate monohydrate In ethanol for 3h; Reflux;
	In ethanol for 3h; Reflux; Inert atmosphere;
	With hydrazine hydrate monohydrate In ethanol for 4h; Reflux;	3.6. Hydrazide Formation General procedure: Either ethyl indol-2-carboxylate 1 or methyl indol-2-carboxylate 8 was refluxed with hydrazine hydrate in ethanol (4 h), the formed ppt was collected and crystalized from 95% ethanol.
	Multi-step reaction with 2 steps 1: sodium methoxide / methanol / 1 h 2: hydrazine hydrate monohydrate / ethanol / 4 h / Reflux
	With hydrazine hydrate monohydrate In neat (no solvent) at 120℃; Sealed tube;
	With hydrazine monohydrate In ethanol for 12h; Reflux;
	With hydrazine hydrate monohydrate for 6h; Reflux;
	With hydrazine hydrate monohydrate In ethanol Reflux;
	With hydrazine monohydrate In neat (no solvent) at 120℃; Sealed tube;	- Route B (R1 = aryl) General procedure: Note: hydrazine and carbon disulphide used during this procedure have to be handled withcaution.The carboxylic compound was first converted into its ethyl ester by refluxing in absoluteethanol in the presence of a few drops of H2SO4. The ester was then treated overnight withhydrazine hydrate (2 to 4 equiv.) without solvent at 120 °C. Evaporation of excess hydrazineyielded the corresponding hydrazide compound. The hydrazide, solubilized in absolute ethanol,was treated with CS2 (5 equiv.) in the presence of KOH (1.7 equiv.) at 85 °C for 3 h. Water wasadded and pH was adjusted to 2-3 with 1N HCl. The formed precipitate was collected byfiltration and washed with water, yielding the 1,3,4-oxadiazol-thione, which was used withoutfurther purification. Finally, the preceding compound was treated with hydrazine hydrate (10equiv.) in absolute ethanol at 100 °C overnight in a sealed tube. After evaporation of excesshydrazine, the residue was purified on a silica gel column to yield the final compound.
	With hydrazine hydrate monohydrate In ethanol for 6h; Reflux;	3.2.2. Synthesis of 1H-Indole-2-Carbohydrazide (3) Compound 2 (0.875 g, 5 mmol) was suspended in absolute ethanol (10 mL), andhydrazine hydrate (2.5 mL, 50 mmol) was added. The reaction mixture was subjected toreflux for six hours under stirring. The reaction mixture was cooled to ambient temperature.The precipitated solid was filtered and dried to afford the carbohydrazide 3 [34,36].
	With hydrazine hydrate monohydrate In ethanol at 100℃; Sealed tube;	General procedure: The ester was then solubilized in EtOH and treated with hydrazine, hydrate (5 equiv.). The mixture was refluxed overnight and solvents were evaporated. Diethyl ether was added and the formed precipitate was filtered and washed with the same solvent to yield the expected hydrazide compound as a powder.
	With hydrazine hydrate monohydrate In ethanol at 20℃;

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[2]Sarhan [Monatshefte fur Chemie, 2001, vol. 132, # 6, p. 753 - 763]
[3]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/219784, 2021, A1 Location in patent: Page/Page column 60
[4]Current Patent Assignee: JOHNSON & JOHNSON INC - WO2021/219784, 2021, A1 Location in patent: Page/Page column 60
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[8]Current Patent Assignee: NORTHERN ILLINOIS UNIVERSITY - US2018/271098, 2018, A1 Location in patent: Paragraph 0184; 0185
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6
[ 3770-50-1 ]
[ 38343-91-8 ]

Yield	Reaction Conditions	Operation in experiment
99%	With 2-chloro-1,3-bis(methoxycarbonyl)guanidine In chloroform; acetonitrile at 20℃; for 12h; regioselective reaction;
98%	With N-chloro-succinimide; 2,4,6-trimethylaniline In dichloromethane at 20℃; for 17h; Inert atmosphere;
98%	With ammonium peroxydisulfate; N-chloro-succinimide; oxygen; methylene green In acetonitrile at 20℃; for 24h; Irradiation; regioselective reaction;	4.2. General procedure for the chlorination of arenes and heteroarenes General procedure: To an oven-dried flask was added a magnetic stir bar, methylene green (9.1 mg, 0.05 equiv, 0.025 mmol), ammonium peroxodisulfate (11.4 mg, 0.1 equiv, 0.05 mmol), arene/heteroarene (1 equiv, 0.5 mmol), acetonitrile (2.5 mL), and then N-chlorosuccinimide (73.4 mg, 1.1 equiv, 0.55 mmol). The reaction mixture was stirred open to air at room temperature (20 C) in a white LED chamber for 24 h. For substrates that produced a mixture of mono- and dibrominated products upon full conversion, 2.2 equivalents (1.1 mmol) of N-chlorosuccinimide was employed. Upon completion of the reaction, the crude mixture was evaporated under pressure and the chlorinated product was isolated via column chromatography on silica gel.

98%	With N-chloro-succinimide; silver hexafluoroantimonate; 1-methylthiotriptycene In 1,2-dichloro-ethane at 20℃; for 2h; Inert atmosphere; Schlenk technique;
98%	With dichlorohydantoin; dimethyl sulfoxide In chloroform at 25℃; for 2h; Schlenk technique;	1.a-1.ao ab) Take a 25 mL Schlenk reaction tube, add 94.6 mg of ethyl indole-2-carboxylate, 118.2 mg of dichlorohydantoin, 7 μL of dimethyl sulfoxide, and 2 mL of chloroform, and stir for 2 hours at 25°C.After the reaction, the solvent was removed by rotary evaporation and column chromatography was separated to obtain 109.3 mg of ethyl 3-chloro-indole-2-carboxylate with a yield of 98%.
96%	With 1-chloro-1λ³-benzo[d][1,2]iodaoxol-3(1H)-one In N,N-dimethyl-formamide at 20℃; for 12h; regioselective reaction;
95%	With N-chloro-succinimide In N,N-dimethyl-formamide at 20℃; for 2h;
91.8%	With N-chloro-succinimide In N,N-dimethyl-formamide at 0 - 20℃; for 18h;	To a stirred solution of I (1 eq.) in dimethylformamide (10vol) was added a solution ofN-chlorosuccinimide (1.1 eq.) in dimethylformamide (10 vol) at 00 C. The reaction was stirred for 18 hours at room temperature. On completion of reaction (HPLC-MS and TLC) the reaction mixture was poured into ice water and the resulting precipitate was collected by filtration, washed with water (20 vol) and dried in vacuo to get thechloro ester as a white solid (Yield 91.8%). A solution of comp of the chloro ester (1 eq) in methanol (10 vol) and aqueous 4N NaOH (4 eq.) was refluxed for 4 hours. On completion of reaction (HPLC-MS, TLC), the solvent was removed in vacuo and the reaction was acidified with aceticacid (pH.-5), The aqueous layer was extracted with ethyl acetate (2x 15 vol), dried over anhydrous sodium sulphate and concentrated in vacuo to get II as a white solid (Yield 8 6%).
87%	With 1,4-diaza-bicyclo[2.2.2]octane; N-chloro-succinimide In dichloromethane at 20℃;
87%	With 1,4-diaza-bicyclo[2.2.2]octane; N-chloro-succinimide In dichloromethane at 25℃; for 2h;	11 Synthesis of compound 2k In a 25mL reaction tube,ethyl 2-indolecarboxylate indole (0.5 mmol) was added,N-chlorosuccinimide (0.55 mmol),Triethylenediamine (0.025 mmol) and dichloromethane (2 mL),Stir at 25°C for 2 hours,After the reaction is completed,concentrate,The product 2k was isolated by column chromatography (87%).
85%	With sulfuryl dichloride In benzene for 3.5h; Inert atmosphere; Reflux;	3.1.31 Ethyl 3-chloro-1H-indole-2-carboxylate 20 To a solution of ethyl 1H-indole-2-carboxylate (1.00 g, 5.29 mmol, 1.0 equiv) in benzene (50 ml) was added slowly sulfuryl chloride (1.78 g, 1.07 ml, 13.2 mmol, 2.5 equiv) and the solution was heated to reflux for 3.5 h. After removal of the solvent under reduced pressure, the crude product was purified by column chromatography (n-hexane/EtOAc 4:1, v/v) to give 20 as a white solid (1.01 g, 85%); mp: 158 °C; IR (KBr): ν˜ ν˜ = 3294, 2982, 1683, 1522, 1335, 1257, 744 cm-1; 1H NMR (400 MHz, CDCl3): δ = 1.47 (t, J = 7.2 Hz, 3H), 4.49 (q, J = 7.2 Hz, 2H), 7.22 (ddd, J = 8.0, 6.2, 1.7 Hz, 1H), 7.35-7.41 (m, 2H), 7.72 (dd, J = 8.2, 1.0 Hz, 1H), 9.24 (br, 1H); 13C NMR (100 MHz, CDCl3): δ = 14.5, 61.6, 112.2, 112.5, 120.3, 121.4, 122.5, 126.3, 126.7, 135.0, 161.3; ESI-HRMS m/z calcd for C11H10ClNO2: 246.02923 [M+Na]+, 469.06923 [2M+Na]+, found: 246.02913, 469.06860.
81%	With N-chloro-N-fluorobenzenesulfonamide In acetonitrile at 20℃; regioselective reaction;
76%	With N-chloro-succinimide In propan-2-one at 20℃; for 16h;
73%	With N-chloro-succinimide In Carbon tetrachloride for 16h; Reflux;	4.1 Ethyl 1H-indole-2-carboxylate (26.45 mmol, 1.0 equiv.) was dissolved in CCl4 (26 ml); NCS (29.10 mmol, 1.1 equiv.) was added and the mixture was heated for 16 h at boiling temperature. The resulting solid was filtered out, and the filtrate was washed with water (2×50 ml) and sat. NaCl solution (50 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (10% ethyl acetate in hexane). Yield: 73%
67%	With N-chloro-succinimide In acetonitrile at 20℃; Reflux;	34.a To a stirred suspension of 3 g (15.86 mmol) of lH-indole-2-carboxylic acid ethyl ester in 30 mL of acetonitrile 2.33 g (17.44 mmol) of N-chlorosuccinimide was added. The reaction mixture was refluxed for 6 h and allowed to stand at room temperature overnight. The separated crystalline solid was filtered off, washed with acetonitrile and dried to give 2.4 g (67 %) of the title compound as a yellowish crystalline solid. MS (EI) 224.1 (MH+).
67%	With N-chloro-succinimide In acetonitrile at 20℃; Reflux;	34.a a) 3-Chloro-1H-indole-2-carboxylic acid ethyl ester a) 3-Chloro-1H-indole-2-carboxylic acid ethyl ester To a stirred suspension of 3 g (15.86 mmol) of 1H-indole-2-carboxylic acid ethyl ester in 30 mL of acetonitrile 2.33 g (17.44 mmol) of N-chlorosuccinimide was added. The reaction mixture was refluxed for 6 h and allowed to stand at room temperature overnight. The separated crystalline solid was filtered off, washed with acetonitrile and dried to give 2.4 g (67%) of the title compound as a yellowish crystalline solid. MS (EI) 224.1 (MH+).
63%	With trichloroisocyanuric acid; brilliant green In acetonitrile at 20℃; for 1h; Irradiation; regioselective reaction;
	With phosphorus(V) chloride

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[2]Samanta, Ramesh C.; Yamamoto, Hisashi [Chemistry - A European Journal, 2015, vol. 21, # 34, p. 11976 - 11979]
[3]Rogers, David A.; Gallegos, Jillian M.; Hopkins, Megan D.; Lignieres, Austin A.; Pitzel, Amy K.; Lamar, Angus A. [Tetrahedron, 2019, vol. 75, # 36]
[4]Nishii, Yuji; Ikeda, Mitsuhiro; Hayashi, Yoshihiro; Kawauchi, Susumu; Miura, Masahiro [Journal of the American Chemical Society, 2020, vol. 142, # 3, p. 1621 - 1629]
[5]Current Patent Assignee: PEKING UNIVERSITY - CN112573978, 2021, A Location in patent: Paragraph 0036-0079
[6]Wang, Mengzhou; Zhang, Yanyan; Wang, Tao; Wang, Chao; Xue, Dong; Xiao, Jianliang [Organic Letters, 2016, vol. 18, # 9, p. 1976 - 1979]
[7]Wang, Zhengqiang; Vince, Robert [Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 7, p. 3587 - 3595]
[8]Current Patent Assignee: NO NO - US9334256, 2016, B2 Location in patent: Page/Page column 98; 99
[9]Hu, Lanping; Huang, Weichun; Wang, Yang; Wu, Zheng-Guang; Xu, Haiyan; Zhu, Guanghua; Zhu, Yueping; Zi, You [RSC Advances, 2022, vol. 12, # 12, p. 7115 - 7119]
[10]Current Patent Assignee: UNIV NANTONG - CN114292153, 2022, A Location in patent: Paragraph 0067-0070
[11]Seifert, Katrin; Buettner, Anita; Rigol, Stephan; Eilert, Nicole; Giannis, Athanassios; Wandel, Elke [Bioorganic and medicinal chemistry, 2012, vol. 20, # 21, p. 6465 - 6481,17]
[12]Lu, Zehai; Li, Qingwei; Tang, Minghua; Jiang, Panpan; Zheng, Hao; Yang, Xianjin [Chemical Communications, 2015, vol. 51, # 80, p. 14852 - 14855]
[13]Laufer, Stefan; Lehmann, Frank [Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 5, p. 1461 - 1464]
[14]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US2010/222324, 2010, A1 Location in patent: Page/Page column 46-47
[15]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - WO2012/59776, 2012, A1 Location in patent: Page/Page column 75
[16]Current Patent Assignee: angolul : Chemical Works of Gedeon Richter Plc. Gedeon Richter Plc. - US2013/217702, 2013, A1 Location in patent: Paragraph 0254
[17]Rogers, David A.; Bensalah, Adam T.; Espinosa, Alvaro Tomas; Hoerr, John L.; Refai, Fares H.; Pitzel, Amy K.; Alvarado, Juan J.; Lamar, Angus A. [Organic Letters, 2019, vol. 21, # 11, p. 4229 - 4233]
[18]Gabriel; Gerhard; Wolter [Chemische Berichte, 1923, vol. 56, p. 1024]

7
[ 3770-50-1 ]
[ 91348-45-7 ]

Yield	Reaction Conditions	Operation in experiment
90%	With pyridinium hydrobromide perbromide; In pyridine; (2S)-N-methyl-1-phenylpropan-2-amine hydrate; water;	EXAMPLE 119A Ethyl 3-bromo-1H-indole-2-carboxylate A solution of ethyl indole-2-carboxylate (1.0 g, 5.29 mmol) in pyridine (23 mL) and water (2 mL) at 0 C. was treated with a solution of pyridinium bromide perbromide (1.7 8 g, 5.55 mmol) in pyridine (30 mL), treated with ice water, and extracted three times with diethyl ether. The combined extracts were washed with 1N HCl, dried (Na2SO4), filtered, and concentrated to provide the desired product (1.28 g, 90%). MS (ESI), m/e 266, 268 (M-H)-.
90%	With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 20℃; for 12h;Inert atmosphere;	To a solution of ethyl 1H-indole-2-carboxylate (2 mmol) in dry DMF (10 mL) was added NBS (2 mmol). The resulting mixture was stirred at room temperature under nitrogen gas for 12 h. Crushed ice was added into the reaction mixture. White precipitate appeared was collected under vacuum suction, washed with cold water, dried, and re-crystallized from ethanol to get pure product (1) (0.49 g, 90%); mp146-148 C; FTIR (KBr, cm-1) numax: 3377, 3297, 1686,1573, 1515, 740, 642; 1H NMR (400 MHz, CDCl3): delta =9.28 (s, 1H, NH), 7.67 (m, 1H, Ar-H), 7.40 (m, 2H, Ar-H),7.25 (m, 1H, Ar-H), 4.49 (q, J = 7.12 Hz, 2H,COOCH2CH3), 1.47 (t, J = 7.08 Hz, 3H, COOCH2CH3); 13C NMR (100MHz, CDCl3): delta = 161.16 (C,COOCH2CH3), 135.41 (C, C-2), 128.01 (C, C-7a), 126.57(CH, C-4), 121.47 (CH, C-5), 121.33 (CH, C-6), 112.06 (CH, C-7), 98.31 (C-Br, C-3), 61.54 (CH2, COOCH2CH3),14.36 (CH3, COOCH2CH3); ESI-MS (m/z): [M+Na]+Calcd for C11H10BrNO2: 266.98; Found: 289.98.
85%	With bromine; In N,N-dimethyl-formamide;	a) Ethyl 3-bromoindole-2-carboxylate. To a solution of ethyl indole-2-carboxylate (25.0 g, 132 mmol) in DMF (50 mL), stirred at room temperature under an argon atmosphere, was added dropwise a solution of Br2 (23.3 g, 145 mmol) in DMF (80 mL). Upon completion of the addition, the reaction mixture was stirred an additional 5 min then poured into ice water. The resulting solid was collected by filtration then crystallized from EtOAc/hexanes to afford the title compound (29.9 g, 85%); m.p. 149-150 C.

84%	With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; for 3h;	Ethyl 1H-indole-2-carboxylate (500 mg, 2.65 mmol) and N-bromosuccinimide (494 mg,2.78 mmol) were dissolved in THF (10 mL). The reaction mixture was stirred at roomtemperature for 3 hours. THF was then removed under reduced pressure and replaced by dichloromethane. The resulting residue was suspended in dichloromethane. The suspension was filtered to give a product as a white solid (597 mg, 84%). ?H NMR (300 IVIFIz, CDC13) 9.16 (br, 1H), 7.69-7.66 (d, 1H), 7.40-7.35 (m, 2H), 7.24-7.21 (m, 1H), 4.50 (q, 2H), 1.43-1.48 (t,3H).
81%	With N-Bromosuccinimide; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 1.5h;	Example 11: Synthesis of 3-PHENYL-1-{4-[(PHENYLSULFONYL) amino] benzyl}-1H- indole-2-carboxylic acid. [0120] Step 1: A solution of N-bromosuccinimide (4.94 g, 27.7 mmol) in DMF (20 mL) was added dropwise to a stirred solution of ethyl LH-INDOLE-2-CARBOXYLATE (5.0 g, 26.4 mmol) in DMF (15 mL) at 0-5C. After the addition was completed, the reaction was warmed to room temperature and stirring was continued for an additional 1.5 h. The reaction mixture was poured over ice water and the resulting precipitate was collected and dried to give 3-bromo-1H- indolecarboxylic acid ethyl ester (6.68 g, 81%) as a white solid
80%		EXAMPLE V This example demonstrates the preparation of 3-Bromo-2-carbethoxyindole The above compound was prepared from 2-carbethoxyindole (1.16 g, 11.4 mmol)using the procedure described at Example II. Recrystallization from ethyl acetate/hexane afforded 3-Bromo-2-carbethoxyindole as colorless needles (2.6 g, 80%): mp 150-152 C.; NMR (CDCl3) delta9.15 (broad multiplet, 1H), 7.67 (m, 1H), 7.38 (m, 2H), 7.22 (m, 1H), 4.48 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H). Anal. calcd for C11 H10 BrNO2: C, 49.28; H, 3.76; N, 5.22. Found: C, 49.39; H, 3.79; N, 5.08.
72%	With bromine; In N,N-dimethyl-formamide;	Method C Ethyl 3-bromoindole-2-carboxylate Asolution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151; NMR delta(CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 1H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (bs, 1H); M/z (-) 268 (M+), 266, 196, 194.
72%	With bromine; In N,N-dimethyl-formamide;	Method B Ethyl 3-bromoindole-2-carboxylate A solution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151; NMR delta (CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 1 H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (bs, 1H); M/z(-) 268 (M+), 266, 196, 194.
72%	With bromine; In DMF (N,N-dimethyl-formamide); for 0.666667h;	A solution of bromine (2.72 ml) in DMF was added dropwise over 10 mins to a solution of ethyl indole-2-carboxylate in DMF. The reaction was stirred for 30 mins, then poured into water to precipitate a pale yellow solid which was filtered off and recrystallized from ethyl acetate to give the desired starting material as white needles (10.2 g, 72%), mp 150-151; NMR d (CDCl3) 1.44 (t, 3H), 4.45 (q, 2H), 7.22 (m, 1H), 7.38 (m, 2H), 7.66 (d, 1H), 9.27 (brs, 1H); M/z (?) 268 (M+), 266, 196, 194.
		a ethyl 3-bromoindole-2-carboxylate Following the procedure of Example 1(a), except substituting ethyl indole-2-carboxylate for ethyl 5-benzyloxyindole-2-carboxylate, the title compound was prepared (94%). 1 H NMR (400 MHz, CDCl3) delta 9.07 (br s, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.43-7.37 (m, 2H), 7.26-7.23 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H).
	With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; for 1h;	EXAMPLE 3 IB ethyl 3-bromo- 1 H-indole-2-carboxylateA mixture of ethyl-2-indole carboxylate (1.89 g) and N-bromosuccinimide (1.77 g) in THF (30 mL) was stirred at room temperature for 1 hour. The mixture was poured into water (150 mL) and filtered. The filtrant was washed with THF, dried under vacuum at 60 C, and recrystallized from ethyl acetate/hexanes.
	With N-Bromosuccinimide; In tetrahydrofuran; at 20℃; for 1h;	EXAMPLE 101 A ethyl 3-bromo- 1 H-indole-2-carboxylateTo a stirred solution of ethyl 1 H-indole-2-carboxylate (9.45 g) in tetrahydrofuran (100 mL) was added N-bromosuccinimide (8.89 g, 50 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and the residue was dissolved with water (100 ml) and diethyl ether (300 ml). The organic layer was washed with water brine and dried over Na2SC>4. After filtration, concentration of solvent afforded the title compound.
	With pyridine; pyridinium hydrobromide perbromide; at 0 - 50℃; for 0.5h;	Method a Ethyl 3-bromo-1H-indole-2-carboxylate 67 g of pyridinium tribromide in 300 ml of pyridine are added slowly, at 0 C. under argon, to a solution of 37.8 g of ethyl indole-2-carboxylate in 900 ml of pyridine. The solution is then heated at 50 C. for 30 minutes and then poured onto 4 l of ice-cold water. The solid formed is filtered off, washed with water and filter-dried. After drying under vacuum, 48.4 g of ethyl 3-bromo-1H-indole-2-carboxylate are obtained, the characteristics of which are as follows: MS (ES+) spectrum: m/z=269 [MH]+ Melting point=148-150 C. (Koefler bench). 1H NMR spectrum (300 MHz, DMSO-d6, delta in ppm): 1.38 (t, J=7.0 Hz, 3H); 4.38 (q, J=7.0 Hz, 2H); 7.20 (broad t, J=8.0 Hz, 1H); 7.37 (broad t, J=8.0 Hz, 1H); 7.50 (broad d, J=8.0 Hz, 1H); 7.54 (broad d, J=8.0 Hz, 1H); 12.2 (broad m, 1H) IR spectrum (KBr): 3454; 3319; 3297; 1701; 1681; 1517; 1331; 1240 and 644 cm-1

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5659 - 5663
[2]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 4708 - 4713
[3]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 3587 - 3595
[4]Organic Letters,2015,vol. 17,p. 2886 - 2889
[5]Tetrahedron Letters,2004,vol. 45,p. 4887 - 4890
[6]Tetrahedron,2008,vol. 64,p. 11625 - 11631
[7]Patent: US2002/91148,2002,A1
[8]Medicinal Chemistry Research,2017,vol. 26,p. 745 - 759
[9]RSC Advances,2016,vol. 6,p. 90031 - 90034
[10]Patent: US5686481,1997,A
[11]Patent: WO2018/218192,2018,A1 .Location in patent: Page/Page column 75; 77
[12]Patent: WO2005/30717,2005,A1 .Location in patent: Page/Page column 38
[13]Journal of Medicinal Chemistry,1992,vol. 35,p. 1791 - 1799
[14]Patent: US5051442,1991,A
[15]Patent: US6441004,2002,B1
[16]Patent: US6288103,2001,B1
[17]Patent: US6833387,2004,B1 .Location in patent: Page column 29
[18]Nippon Kagaku Zasshi,1957,vol. 78,p. 1798
Chem.Abstr.,1960,p. 1487
[19]Patent: US5684032,1997,A
[20]Patent: WO2008/130970,2008,A1 .Location in patent: Page/Page column 74
[21]Patent: WO2008/130970,2008,A1 .Location in patent: Page/Page column 100
[22]Medicinal Chemistry Research,2018,vol. 27,p. 903 - 914
[23]Patent: US2007/259910,2007,A1 .Location in patent: Page/Page column 9

8
[ 3770-50-1 ]
[ 18450-27-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	With trichlorophosphate In water; N,N-dimethyl-formamide	105.A Ethyl 3-formyl-1H-indole-2-carboxylate EXAMPLE 105A Ethyl 3-formyl-1H-indole-2-carboxylate A solution of POCl3 (5.52 mL, 59.2 mmol) in DMF (18 mL, 232.5 mmol) at 0° C. was stirred for 40 minutes, treated dropwise with a solution of ethyl indole-2-carboxylate (10 g, 52.8 mmol) in DMF (15 mL), warmed to room temperature, stirred for 30 minutes, heated to 60° C. for 4 hours, cooled to room temperature, treated with water (60 mL), and adjusted to pH 7 with 2M NaOH. The precipitate was filtered, washed with water, dried under vacuum, and recrystallized from ethyl acetate to provide the desired product (10.9 g, 95%).
76%		97 Ethyl 3-Formylindole-2-carboxylate EXAMPLE 97 Ethyl 3-Formylindole-2-carboxylate Using the procedure of Example 53 but replacing benzyl indole-2-carboxylate with ethyl indole-2-carboxylate gave the desired compound in 76% yield as a light pink crystalline solid after recrystallization from ethanol. 1 H NMR (CDCl3) δ 1.49 (t,J=7 Hz,3H), 4.53 (q,J=7 Hz,2H), 7.3-7.6 (m,4H), 8.49 (d,J=9 Hz,1H), 9.33 (br s,1H). Mass spectrum: (M+H)+ =218.
35%	With trichlorophosphate In N,N-dimethyl-formamide at 60℃; for 8h; Inert atmosphere;	3.2 Synthesis of 3 In nitrogen atmosphere, 2 ml dry DMF was taken andthen freshly distilled 2 ml phosphorus oxychloride(POCl3) was added dropwise under ice-cold condition.The mixture was stirred until a red colouration arise.Then, indole-2-ethyl carboxylate (2) (500 mg, 2.65mmol) dissolved in least amount of dry DMF wasadded to the previous mixture. Then, the whole mixturewas heated to 50-60°C for 8 h. After completionof the reaction (evaluated by TLC monitoring), themixture was cooled and poured into ice with stirringand then work up with ethyl acetate. The organic layerwas dehydrated over sodium sulphate, and the solventswere evaporated under reduced pressure. Thecrude product was purified by column chromatographyusing (8% v/v) ethyl acetate-hexane to give purealdehyde. White solid (200 mg, 35%). 1H-NMR (CDCl3,300 MHz): δ (ppm) 10.67 (s, 1H), 8.34 (d, 1H, J = 8.1 Hz),7.54 (d, 1H, J = 8.1 Hz), 7.32 (m, 2H),4.48 (q, 2H, J = 7.2Hz), 3.06 (s, 1H), 1.46 (t, 3H, J = 7.2 Hz).

	With hydrogenchloride; diethyl ether; dicyanozinc Erwaermen des Reaktionsprodukts mit H₂O;
	Multi-step reaction with 2 steps 1: trifluoroacetic acid / 0 - 20 °C 2: iron(III) chloride; iron; hydrogenchloride / water; toluene / 60 °C

Reference： [1]Current Patent Assignee: ABBOTT LABORATORIES INC - US2002/91148, 2002, A1
[2]Current Patent Assignee: ABBOTT LABORATORIES INC - US4994477, 1991, A
[3]Samanta, Sandip Kumar; Ali, Syed Samim; Gangopadhyay, Ankita; Maiti, Kalipada; Pramanik, Ajoy Kumar; Guria, Uday Narayan; Ghosh, Aritri; Datta, Pallab; Mahapatra, Ajit Kumar [Supramolecular Chemistry, 2019, vol. 31, # 5, p. 349 - 360]
[4]Boyd; Robson [Biochemical Journal, 1935, vol. 29, p. 546,549]
[5]Current Patent Assignee: COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK - WO2013/28999, 2013, A1

9
[ 784-98-5 ]
[ 3770-50-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With sodium dithionite In 1,4-dioxane; water for 3h; Reflux;	General procedure for synthesis of indole-2-carboxylic acid and its derivatives A solution of Na2S2O4 (0.78 g, 4.5 mmol) in water (50 mL) was added to a solution of corresponding pyruvate derivative 4 (1.5 mmol) in dioxane (50 mL) and resulting mixture was stirred at reflux for 3 h. After allowing the reaction mixture to cool to room temperature was poured into water (200 mL). The precipitates formed were filtered off, washed with water (3×30 mL), and dried in air to afford pure 5a-e.
62%	With palladium 10% on activated carbon; hydrogen In methanol at 25℃; for 5h;
62%	With palladium on activated charcoal; hydrogen In methanol at 25℃; for 5h;	1.3 Step 3: Preparation of a compound (Ethyl 1H-indole-2-carboxylate)represented by the following formula A suspension containing the compound represented by Chemical Formula 2 (0.16 g, 0.67 mmol) and Pd/C (70 mg, 0.067 mmol) in methanol (5 mL)was stirred at 25° C. for 5 hours under positiveH2pressure.The reaction mixture was filtered using a short pad of celite.The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel flash column chromatography to obtain a white solid type compound represented by Chemical Formula 4 (78 mg, 0.41 mmol) (62% yield).

	With acetic acid; nickel(II) nitrate; zinc at 10 - 15℃; dann bei 60-70grad;
	With acetic acid; cobalt(II) nitrate; zinc at 10 - 15℃; dann bei 60-70grad;
	With acetic acid; platinum Hydrogenation;
	With palladium/alumina; hydrogen; Cinchonidin In methanol at 20℃; for 3h; Autoclave;

Reference： [1]Mamedov, Vakhid A.; Mamedova, Vera L.; Syakaev, Victor V.; Khikmatova, Gul'naz Z.; Korshin, Dmitry E.; Kushatov, Temur A.; Latypov, Shamil K. [Tetrahedron Letters, 2018, vol. 59, # 44, p. 3923 - 3925]
[2]Ju, Yeming; Miao, Di; Yu, Ruiyang; Koo, Sangho [Organic and Biomolecular Chemistry, 2015, vol. 13, # 9, p. 2588 - 2599]
[3]Current Patent Assignee: MYONGJI UNIVERSITY - KR101599969, 2016, B1 Location in patent: Paragraph 0028; 0052; 0072-0076
[4]Maurer; Moser [Hoppe-Seyler's Zeitschrift fur Physiologische Chemie, 1926, vol. 161, p. 136]
[5]Maurer; Moser [Hoppe-Seyler's Zeitschrift fur Physiologische Chemie, 1926, vol. 161, p. 136]
[6]Brehm [Journal of the American Chemical Society, 1949, vol. 71, p. 3541] Noland; Baude [Organic Syntheses, Collective, 1973, vol. Vol. V, p. 567,568]
[7]Szollosi, Gyoergy; Makra, Zsolt; Kovacs, Lenke; Fueloep, Ferenc; Bartok, Mihaly [Advanced Synthesis and Catalysis, 2013, vol. 355, # 8, p. 1623 - 1629]

10
[ 4792-54-5 ]
[ 3770-50-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With phosphoric acid at 50 - 90℃; for 0.833333h; Green chemistry;	1.2 500 grams of polyphosphoric acid and 250 grams of phosphoric acid mixed,Stirring under heating to 50 ° C under the conditions of batch into the raw material phenylhydrazine pyruvate phenyl hydrazone 75 grams,Control the temperature range of 70 ~ 90 , 0.5 hours to complete the raw materials, continue to temperature control reaction for 20 minutes,The reaction was complete, poured into 1500 g of ice-water mixture, cooled, filtered and dried to give a pale yellow solid product,Dried to give 63 g of ethyl indole-2-carboxylate in 92% yield.
55%	With boron trifluoride diethyl etherate In acetic acid for 3h; Heating;
	With sulfuric acid; acetic acid

	With PPA at 150℃;
	With boron trifluoride at 120℃;
	With toluene-4-sulfonic acid In toluene
	With polyphosphoric acid In toluene at 100℃; for 5h;
	With polyphosphoric acid In toluene at 100℃; for 5h;
	With PPA In toluene at 100℃; for 5h;
	With polyphosphoric acid In ethanol at 85℃;
	With polyphosphoric acid In ethanol at 45 - 120℃; Large scale;	1; 3.2 2. Preparation of Compound III: Add 546.36kg polyphosphoric acid to the 1000L reactor.Advance preheated to 45-55 deg.] C, the control temperature between 45 and 110 degrees in the kettle,189 kg of ethanol was added dropwise, and the mixture was diluted for about 1 to 2 hours. Control the internal temperature of the kettle at 80 ~ 120 ° C,256.5 kg of compound 2 solid was added in portions, and the addition was completed in 2 to 4 hours; the incubation reaction was carried out for 1 to 2 hours. Cool down to 60-80 ° C, add 513.00 kg of water, stir,It was precipitated as a pale yellow solid, suction filtered, and the filter cake was rinsed with 100 kg of water.Compound III was obtained in an amount (HPLC) >95%.

Reference： [1]Current Patent Assignee: CHINA AGRICULTURAL UNIVERSITY - CN104402795, 2017, B Location in patent: Paragraph 0035; 0037; 0057
[2]Bailey, A. Sydney; Scott, Peter W.; Vandrevala, Marazban H. [Journal of the Chemical Society. Perkin transactions I, 1980, p. 97 - 101]
[3]Andrisano; Vitali [Gazzetta Chimica Italiana, 1957, vol. 87, p. 949,953, 958] Elks et al. [Journal of the Chemical Society, 1944, p. 629,631]
[4]Andrisano; Vitali [Gazzetta Chimica Italiana, 1957, vol. 87, p. 949,953, 958]
[5]Snyder; Smith [Journal of the American Chemical Society, 1943, vol. 65, p. 2452]
[6]El Ashry, El Sayed H.; El Tamany, El Sayed H.; Abd El Fattah, Mohy El Din; Boraei, Ahmed T. A.; Abd El-Nabi, Heba M. [European Journal of Medicinal Chemistry, 2013, vol. 66, p. 106 - 113]
[7]Panathur, Naveen; Dalimba, Udayakumar; Koushik, Pulla Venkat; Alvala, Mallika; Yogeeswari, Perumal; Sriram, Dharmarajan; Kumar, Vijith [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 125 - 138]
[8]Gokhale, Nikhila; Panathur, Naveen; Dalimba, Udayakumar; Kumsi, Manjunatha [Australian Journal of Chemistry, 2015, vol. 68, # 10, p. 1603 - 1613]
[9]Panathur, Naveen; Gokhale, Nikhila; Dalimba, Udayakumar; Koushik, Pulla Venkat; Yogeeswari, Perumal; Sriram, Dharmarajan [Medicinal Chemistry Research, 2016, vol. 25, # 1, p. 135 - 148]
[10]Xie, Hui; Yang, Jian-Xin; Bora, Pranjal Protim; Kang, Qiang [Tetrahedron, 2016, vol. 72, # 22, p. 3014 - 3021]
[11]Current Patent Assignee: NANJING F S PHARMATECH - CN108752259, 2018, A Location in patent: Paragraph 0011; 0024; 0025; 0027; 0038; 0042-0044

11
[ 3770-50-1 ]
[ 6414-69-3 ]
[ 63158-53-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In acetonitrile;	EXAMPLE VI Ethyl 2-Carboethoxy-3-indolepropanoate Ethyl 2-indolecarboxylate (3 gm), <strong>[6414-69-3]ethyl 3-iodopropanoate</strong> (5.4 gm), potassium carbonate (5 gm), and acetonitrile (50 ml) were combined and the mixture heated to reflux for 48 hours. The mixture was cooled and poured into water (50 ml). The mixture was extracted with ether (375 ml) and the combined ether extracts were washed with water (330 ml). The organic layer was dried over sodium sulfate and the solvent removed on a rotary evaporator. The diester product was obtained as a colorless oil.

Reference： [1]Journal of Medicinal Chemistry,1991,vol. 34,p. 1283 - 1292
[2]Patent: US5137910,1992,A

12
[ 3770-50-1 ]
[ 2969-81-5 ]
[ 131848-99-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; Inert atmosphere; Stage #2: Ethyl 4-bromobutyrate In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;
88%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: Ethyl 4-bromobutyrate In N,N-dimethyl-formamide; mineral oil at 20℃; for 30h; Inert atmosphere;	Procedures for synthesis of compounds 5a and 5b General procedure: A solution of 1 (10.0g, 1 eq) in anhydrous DMF (175 mL) was added dropwise to a stirred suspension of NaH (2.33 g of a 60% dispersion in mineral oil, 1.1 eq) in dry DMF (20 mL) under N2. After l h a solution of ethyl 4-bromobutyrate (11.4 g, 1.1 eq) or ethyl 5- bromopentanoate (12.2 g, 1.1 eq) was added dropwise to the mixture and stirred at rt for 30 h. The reaction was quenched by the addition of water (50 mL), followed by 1 N HCI (25 mL), and the solution was extracted with DCM (4 x 75 mL). The combined organic extracts were washed with water (5 x 100 mL) and concentrated under vacuum. The resulting brown oil was dissolved in EtOAc (75 mL) and the solution was washed with water (3 x 100 mL) and concentrated under vacuum. Purification by column chromatography gave compounds 5a and 5b.
87%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h; Inert atmosphere;

With sodium hydride 1.) DMF 2.) rt, 18 h; Yield given. Multistep reaction;

Reference： [1]Glaisyer, Elizabeth L.; Watt, Michael S.; Booker-Milburn, Kevin I. [Organic Letters, 2018, vol. 20, # 18, p. 5877 - 5880]
[2]Noland, Wayland E.; Herzig, Ryan J.; Kumar, Honnaiah Vijay; Narina, Venkata Srinivasarao; Elkin, Pavel K.; Valverde, Karen I.; Kim, Briana L. [Tetrahedron, 2017, vol. 73, # 44, p. 6341 - 6346]
[3]Location in patent: experimental part Derudas, Marco; Pala, Nicolino; Sanna, Vanna; Dallocchio, Roberto; Dessi, Alessandro; Roggio, Anna Maria; Sechi, Mario [Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1161 - 1168]
[4]Bit; Davis; Hill; Keech; Vesey [Tetrahedron, 1991, vol. 47, # 26, p. 4645 - 4664]

13
[ 3770-50-1 ]
[ 14660-52-7 ]
[ 131849-47-3 ]

Yield	Reaction Conditions	Operation in experiment
89%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 1h; Inert atmosphere; Stage #2: ethyl 5-bromovalerate In N,N-dimethyl-formamide; mineral oil at 20℃; for 30h; Inert atmosphere;	Procedures for synthesis of compounds 5a and 5b General procedure: A solution of 1 (10.0g, 1 eq) in anhydrous DMF (175 mL) was added dropwise to a stirred suspension of NaH (2.33 g of a 60% dispersion in mineral oil, 1.1 eq) in dry DMF (20 mL) under N2. After l h a solution of ethyl 4-bromobutyrate (11.4 g, 1.1 eq) or ethyl 5- bromopentanoate (12.2 g, 1.1 eq) was added dropwise to the mixture and stirred at rt for 30 h. The reaction was quenched by the addition of water (50 mL), followed by 1 N HCI (25 mL), and the solution was extracted with DCM (4 x 75 mL). The combined organic extracts were washed with water (5 x 100 mL) and concentrated under vacuum. The resulting brown oil was dissolved in EtOAc (75 mL) and the solution was washed with water (3 x 100 mL) and concentrated under vacuum. Purification by column chromatography gave compounds 5a and 5b.
	With sodium hydride 1.) DMF, 1 h 2.) rt, 48 h; Yield given. Multistep reaction;
	In <i>N</i>-methyl-acetamide	49.a EXAMPLE 49 a) A solution of 18.9 g of ethyl indole-2-carboxylate in 100 ml of dimethylformamide was added to a suspension of 2.64 g of sodium hydride in 50 ml of dimethylformamide. After 1 hour, a solution of 20.9 g of ethyl 5-bromovalerate in 100 ml of dimethylformamide was added dropwise. After 48 hours, the mixture was poured into water, extracted with dichloromethane and the combined dichloromethane extracts were washed with water, dried and concentrated to give 26.2 g of ethyl 1-(4-ethoxycarbonylbutyl)indole-2-carboxylate.

Reference： [1]Noland, Wayland E.; Herzig, Ryan J.; Kumar, Honnaiah Vijay; Narina, Venkata Srinivasarao; Elkin, Pavel K.; Valverde, Karen I.; Kim, Briana L. [Tetrahedron, 2017, vol. 73, # 44, p. 6341 - 6346]
[2]Bit; Davis; Hill; Keech; Vesey [Tetrahedron, 1991, vol. 47, # 26, p. 4645 - 4664]
[3]Current Patent Assignee: ROCHE HOLDING AG; JAMES ANDREW MARCELIN - US5721245, 1998, A

14
[ 3770-50-1 ]
[ 16932-45-9 ]
[ 131157-33-0 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1990,vol. 38,p. 2118 - 2126

15
[ 3770-50-1 ]
[ 75-03-6 ]
[ 40913-41-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: ethyl iodide In N,N-dimethyl-formamide at 100℃; for 1h;	Compound 155a:; Ethyl 1-ethyl-1H-indole-2-carboxylate 155aSodium hydride (60%, 0.12g, 2.93 mmol) was placed in the flask, washed with hexane, and dried. Dimethylformamide (9.0 ml.) was added, and the flask placed in an ice bath. Ethyl indole-2- carboxylate (0.5Og, 2.66 mmol) dissolved in DMF (6.0 ml_) was added, and the reaction stirred at room temperature for 30 minutes, lodoethane (0.30 ml_, 3.73 mmol) dissolved in DMF (1.0 mL) was added, and the reaction heated to 100°C for one hour. The reaction was poured into ice water, and the product was extracted with diethyl ether. The organic phase was separated, washed with water and brine, dried (MgSO4), and concentrated to give 0.53g (92%) of a clear oil: Rf = 0.31 (10% EtOAc/hexane); 1H NMR (CDCI3): 7.67 (1 H, d, J = 8.1 Hz), 7.40 (1 H, d, J = 7.6 Hz), 7.35-7.31 (1 H, m), 7.30 (1 H, s), 7.15-7.11 (1 H, m), 4.62 (2H, q, J = 7.0 Hz), 4.37 (2H, q, J = 7.0 Hz), 1.42-1.37 (6H, m). See J. Med. Chem. 31 , 944 (1988).
44%	With potassium carbonate In N,N-dimethyl-formamide at 80 - 90℃; for 10h;
	With sodium hydride 1.) DMF, RT, 20 min, 2.) DMF, reflux, 1 h; Yield given. Multistep reaction;

	With sodium hydride In dimethyl sulfoxide
	With sodium hydride	Materials. General procedure: The 1-methyl- (4d) and 1-ethylindole-2-carboxylic acids (4e) were prepared byalkylation of ethyl 2-indolecarboxylate with alkyl iodides in the presence of sodium hydride followed byhydrolysis.

Reference： [1]Current Patent Assignee: PFIZER INC - WO2006/40646, 2006, A1 Location in patent: Page/Page column 93
[2]Javed, Tariq; Shattat, Ghassan F. [Journal of Heterocyclic Chemistry, 2005, vol. 42, # 2, p. 217 - 220]
[3]Hlasta; Luttinger; Perrone; Silbernagel; Ward; Haubrich [Journal of medicinal chemistry, 1987, vol. 30, # 9, p. 1555 - 1562]
[4]Fagan, Gay P.; Chapleo, Christopher B.; Lane, Anthony C.; Myers, Malcolm; Roach, Alan G.; et al [Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 944 - 948]
[5]Inoue, Takeshi; Nishino, Hiroshi [Heterocycles, 2018, vol. 97, # 1, p. 431 - 450]

16
[ 3770-50-1 ]
[ 106-95-6 ]
[ 108797-23-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 100℃; for 1.5h; Inert atmosphere;
95%	With sodium hydride In tetrahydrofuran at 25℃;
94%	With potassium carbonate In acetonitrile for 60h; Heating;

94%	With potassium carbonate In acetonitrile for 60h; Reflux;	4.1.2 General procedure for preparation of compounds 2a-g General procedure: To a solution of methyl or ethyl indole-2-carboxylate 1 (5.34mmol) and allylbromide (1.24mL, 14.41mmol) in anhydrous MeCN (15mL) was added K2CO3 (1.70g, 12.28mmol). The reaction mixture was refluxed 2.5 days then concentrated in vacuo. The crude residue was diluted with water (20mL) and extracted with EtOAc (3×15mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (PE/EtOAc) to give 2.
85%	Stage #1: 2-carbethoxyindole With potassium hydroxide In water; acetone at 20℃; for 0.5h; Stage #2: allyl bromide In water; acetone at 20℃; for 2h;	3.2. General Procedure for the Alkylation of Ethyl Indol-2-carboxylate (1) General procedure: A solution of ethyl indol-2-carboxylate (1, 1.0 mmol) and aq. KOH (3.0 mmol) in acetone (10 mL) was stirred at 20 °C for half hour, then the appropriate alkylating agent (1.1 mmol) was added and stirring was continued for 2 h to give 2 and 3 and for eight hours to give 4. The solvent was removed, water was added and organic layer was extracted using ethyl acetate. The products were purified using column chromatography (ethyl acetate/hexane 1:9).
77%	With potassium <i>tert</i>-butylate In tetrahydrofuran for 18h; Heating;
	With sodium hydride 1.) DMF, RT, 20 min, 2.) DMF, reflux, 1 h; Yield given. Multistep reaction;
	Stage #1: 2-carbethoxyindole With sodium hydride In tetrahydrofuran; N,N-dimethyl-formamide for 1h; Stage #2: allyl bromide In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 25℃; for 17h;	85.1 Example 85(3/g.55.85)-λ/'-αi/?.2-Sl-l-(r(Cvclopropylsulfonyl)amino1carbonyl}-2-vinylcvclopropylV8- isopropyl-l,7,10-trioxo-4,5,7,8,9,l 0,12,13 ,14,17-decahydro-lH,3H-3,6- methanofl,. 0,3,6,131dioxatriazacvclononadecinori3,12-αlindole-5-carboxamideStep 1 : Ethyl l-allyl-lH-indole-2-carboxylateTo a suspension of NaH (254 mg, 60 wt%, 10.57 mmol) in THF (5 mL), a solution of ethyl lH-indole-2-carboxylate (1 g, 5.29 mmol) in DMF (10 mL) was added. After 1 hour, the mixture was cooled to 0°C and allyl bromide (0.55 mL, 6.34 mmol) was added. After stirring for 2 hours at 0°C, the mixture was slowly warmed to RT and stirred a further 15 hours. The reaction was quenched with H2O and extracted with EtOAc. The organic layer was dried over MgSO4, and the solvent was removed in vacuo. The crude product was purified on SiO2 (gradient elution, 15-40% EtOAc/hexanes) to yield the title compound as a clear oil. LRMS ESf (M+H)+ 230.2.
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 23℃; for 1.25h; Inert atmosphere; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 100℃; for 2h; Inert atmosphere;
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 25℃; for 2h; Inert atmosphere;
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: allyl bromide In N,N-dimethyl-formamide at 50℃; Inert atmosphere;
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: allyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃;
	With sodium hydride In N,N-dimethyl-formamide at 25℃;

Reference： [1]Nicolai, Stefano; Piemontesi, Cyril; Waser, Jerome [Angewandte Chemie - International Edition, 2011, vol. 50, # 20, p. 4680 - 4683]
[2]Current Patent Assignee: JINAN UNIVERSITY (GUANGZHOU) - CN106928121, 2017, A Location in patent: Page/Page column 27
[3]Putey, Aurélien; Fournet, Guy; Joseph, Benoît [Synlett, 2006, # 17, p. 2755 - 2758]
[4]Putey, Aurélien; Fournet, Guy; Lozach, Olivier; Perrin, Lionel; Meijer, Laurent; Joseph, Benoît [European Journal of Medicinal Chemistry, 2014, vol. 83, p. 617 - 629]
[5]Boraei, Ahmed T. A.; El Ashry, El Sayed H.; Barakat, Assem; Ghabbour, Hazem A. [Molecules, 2016, vol. 21, # 3]
[6]Padwa, Albert; Hertzog, Donald L.; Nadler, William R.; Osterhout, Martin H.; Price, Alan T. [Journal of Organic Chemistry, 1994, vol. 59, # 6, p. 1418 - 1427]
[7]Hlasta; Luttinger; Perrone; Silbernagel; Ward; Haubrich [Journal of medicinal chemistry, 1987, vol. 30, # 9, p. 1555 - 1562]
[8]Current Patent Assignee: MERCK & CO INC - WO2008/57209, 2008, A1 Location in patent: Page/Page column 128
[9]Miles, Kelsey C.; Le, Chi; Stambuli, James P. [Chemistry - A European Journal, 2014, vol. 20, # 36, p. 11336 - 11339]
[10]Cheng, Yi An; Yu, Wesley Zongrong; Yeung, Ying-Yeung [Angewandte Chemie - International Edition, 2015, vol. 54, # 41, p. 12102 - 12106][Angew. Chem., 2015, vol. 54, p. 12102 - 12106,5]
[11]Boothe, Jordan R.; Shen, Yifan; Wolfe, John P. [Journal of Organic Chemistry, 2017, vol. 82, # 5, p. 2777 - 2786]
[12]Zhang, Kaifan; Xu, Xiaoying; Zheng, Jiuan; Yao, Hequan; Huang, Yue; Lin, Aijun [Organic Letters, 2017, vol. 19, # 10, p. 2596 - 2599]
[13]Mayooufi; Romdhani-Younes; Carcenac; Thibonnet [Synthetic Communications, 2019, vol. 49, # 17, p. 2168 - 2179]

17
[ 3770-50-1 ]
[ 77-78-1 ]
[ 18450-24-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate In acetonitrile at 90℃; for 6h;	6.1 6. Preparation of Selected AcidsSynthesis of 2-(1-methyl-1H-indol-3-yl)propanoic acid (Examples 1, 2, 3, 15)Step 1: To a stirred suspension of ethyl 1H-indole-2-carboxylate (10 g, 52.85 mmol), K2CO3 (21.9 g, 158.5 mmol) in acetonitrile (100 mL), dimethyl sulfate (7.54 mL, 79.27 mmol) was added at room temperature and the mixture was stirred at 90° C. for 6 h until complete consumption of the starting material. The reaction mixture was cooled to room temperature, filtered through celite pad to remove K2CO3, washed with ethyl acetate (2×25 mL). The filtrate was concentrated. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (2×50 mL), brine solution (30 mL), dried over anhydrous Na2SO4, filtered and concentrated. The obtained crude compound was purified by column chromatography (100-200 mesh silica gel) using 6% EtOAc in petroleum ether as eluent to afford ethyl 1-methyl-1H-indole-2-carboxylate as a pale brown solid (10.6 g, 98% yield).
98%	With potassium carbonate In acetonitrile at 90℃; for 6h;	6.1 To a stirred suspension of ethyl 1 H-indole-2-carboxylate (10 g, 52.85 mmol), K2C03 (21.9 g, 158.5 mmol) in acetonitrile (100 mL), dimethyl sulfate (7.54 mL, 79.27 mmol) was added at room temperature and the mixture was stirred at 90°C for 6 h until complete consumption of the starting material. The reaction mixture was cooled to room temperature, filtered through celite pad to remove K2C03, washed with ethyl acetate (2x25 mL). The filtrate was concentrated. The obtained residue was diluted with ethyl acetate (300 mL), washed with water (2x50 mL), brine solution (30 mL), dried over anhydrous Na2S04, filtered and concentrated. The obtained crude compound was purified by column chromatography (100-200 mesh silica gel) using 6% EtOAc in petroleum ether as eluent to afford ethyl 1- methyl-1 H-indole-2-carboxylate as a pale brown solid (10.6 g, 98% yield).
90%	With potassium carbonate In acetone for 18h; Heating;

With potassium sulfate

Reference： [1]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - US2012/115903, 2012, A1 Location in patent: Page/Page column 35
[2]Current Patent Assignee: Gruenenthal Pharma GmbH & Co. Kommanditgesellschaft - WO2012/62462, 2012, A1 Location in patent: Page/Page column 77
[3]Monge Vega; Martinez; Palop; et al. [Journal of Heterocyclic Chemistry, 1981, vol. 18, # 5, p. 889 - 892]
[4]Fagan, Gay P.; Chapleo, Christopher B.; Lane, Anthony C.; Myers, Malcolm; Roach, Alan G.; et al [Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 944 - 948]

18
[ 3770-50-1 ]
[ 140-88-5 ]
[ 1421-18-7 ]

Yield	Reaction Conditions	Operation in experiment
84%	Stage #1: 2-carbethoxyindole With sodium hydride In toluene; mineral oil at 20℃; Stage #2: ethyl acrylate In toluene; mineral oil at 20℃; Reflux;	Synthesis of Ethyl 2,3-dihydro-1-oxo-1H-pyrrolo[1,2-a]indole-2-carboxylate (2) A solution of 1 (5.32 g, 28.1 mmol) in anhydrous toluene (150 mL) was added dropwise to a well-stirred suspension of NaH (1.41 g of 60% dispersion in mineral oil, 35.3 mmol) in anhydrous toluene (50 mL) under N2. The resulting mixture was stirred at rt for 1 h and ethyl acrylate (3.4 mL, 31.9 mmol) was added dropwise. The mixture was stirred for 15 min at rt and then refluxed for 1 h. Then a mixture of additional NaH (1.24 g of 60% dispersion in mineral oil, 31.0 mmol) in anhydrous toluene (20 mL) was added dropwise. Then ethyl acrylate (0.9 mL, 8.5 mmol) was added dropwise. The mixture was refluxed for an additional 5 h and then allowed to cool to rt. Then the reaction was quenched by adding EtOH (25 mL), followed by saturated aqueous NH4Cl (25 mL). The acidity was adjusted to pH 4 by adding 1 N HCl, and the solution was extracted with DCM (4 x 75 mL), and concentrated under vacuum. The viscous orange oil crystallized upon the addition of MeOH, giving 2 as a white solid (5.75 g, 84%)
75%	With sodium hydride In toluene; mineral oil for 5h; Inert atmosphere; Reflux;
30%	With sodium tetrahydroborate In 1,4-dioxane 1.) reflux, 8 h, 2.) room temperature, 16 h;

With hydrogenchloride In dichloromethane; water; toluene

3 2,3-dihydro-1-oxo-1H-pyrrolo[1.2-a]indole EXAMPLE 3 2,3-dihydro-1-oxo-1H-pyrrolo[1.2-a]indole A stirred solution of ethyl indole-2-carboxylate (5.67 g, 30 mmol) in 400 ml of toluene under N was treated with sodium hydride (1.44 g, 36 mmol). Ethyl acrylate (3.6 ml, 33 mol) was added and the mixture was heated at reflux. Additional portions of ethyl acrylate (6 mmol) and sodium hydride (16 mmol) were added after 3 hr. After a total time of 6 hr, t.l.c. indicated that all starting material are consumed. The mixture was quenched with ethanol and treated with water, dilute HCl, and methylene chloride. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2,3-dihydro-1-oxo-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole, which was used directly in the next step.

Reference： [1]Noland, Wayland E.; Herzig, Ryan J.; Kumar, Honnaiah Vijay; Narina, Venkata Srinivasarao; Elkin, Pavel K.; Valverde, Karen I.; Kim, Briana L. [Tetrahedron, 2017, vol. 73, # 44, p. 6341 - 6346]
[2]Location in patent: experimental part Derudas, Marco; Pala, Nicolino; Sanna, Vanna; Dallocchio, Roberto; Dessi, Alessandro; Roggio, Anna Maria; Sechi, Mario [Journal of Heterocyclic Chemistry, 2011, vol. 48, # 5, p. 1161 - 1168]
[3]Bailey, A. Sydney; Scott, Peter W.; Vandrevala, Marazban H. [Journal of the Chemical Society. Perkin transactions I, 1980, p. 97 - 101]
[4]Current Patent Assignee: PFIZER INC - US5428043, 1995, A

19
[ 3770-50-1 ]
[ 74-88-4 ]
[ 18450-24-3 ]

Yield	Reaction Conditions	Operation in experiment
100%	Stage #1: 2-carbethoxyindole With sodium hydride In DMF (N,N-dimethyl-formamide) for 0.333333 - 0.416667h; Stage #2: methyl iodide In DMF (N,N-dimethyl-formamide) at 40 - 45℃; for 1h;	1.a Preparation 1; Preparation of 1-Methyl-2-(methylaminomethyl)indole; a) Ethyl 1-Methylindole-2-carboxylate NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washed with hexanes, then was suspended in dry DMF (530 mL). Solid ethyl indole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over 5-10 min. allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40-45° C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O(500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL), dried (MgSO4), and concentrated to leave the title compound (27.10 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf=0.39.
100%	Stage #1: 2-carbethoxyindole With sodium hydride In DMF (N,N-dimethyl-formamide) for 0.25h; Stage #2: methyl iodide In N,N-dimethyl-formamide for 1h;	1.a NaH (60% dispersion in mineral oil, 8.0 g, 200.5 mmole) was washed with hexanes, then was suspended in dry DMF (530 mL). Solid ethyl indole-2-carboxylate (25.3 g, 133.7 mmole) was added portionwise over 5-10 min, allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40-45 C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O (500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL). dried (MgSO4), and concentrated to leave the title compound (27.1 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf=0.39.
100%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h;

98%	Stage #1: 2-carbethoxyindole With sodium hydride In tetrahydrofuran; dimethyl sulfoxide at 0℃; for 1.25h; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; dimethyl sulfoxide at 0 - 20℃; Inert atmosphere;
97%	With sodium hydride In N,N-dimethyl-formamide at 20℃; Inert atmosphere;
88%	With potassium hydroxide In dimethyl sulfoxide at 20℃; for 1h;
88%	Stage #1: 2-carbethoxyindole With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 12h;
80%	With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate In water; toluene for 1h; Heating;
76.4%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; for 1h;
75%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 2 - 30℃; for 0.5h; Stage #2: methyl iodide In N,N-dimethyl-formamide at 30℃; for 28h;
50%	In tetrahydrofuran	26.a a a Ethyl 1-methylindole-2-carboxylate Iodomethane (4.98 mL, 80 mmol) was added dropwise to a mixture containing ethyl indole-2-carboxylate (1.89 g, 10 mmol) and sodium hydride (1.2 g, 60% dispersion, prewashed by hexane) in anhydrous THF (60 mL) in a flame dried flask under argon at 0° C. After 4 h at RT the reaction was concentrated on the rotavap. The residue was taken into EtOAc and washed sequentially with H2 O and saturated NaCl. Drying (MgSO4) and concentration gave the title compound (1.01 g, 50%) as a pale yellow solid.
	With potassium carbonate In acetone Heating;
	With sodium hydride In N,N-dimethyl-formamide
	With potassium carbonate
	With NaH; ammonium chloride In N,N-dimethyl-formamide; mineral oil	1.a Preparation of 1-methyl-2-(methylaminomethyl)-1 H -indole a) Ethyl 1-methyl-1H-indole-2-carboxylate NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washed with hexanes, then was suspended in dry DMF (530 mL). Solid ethyl indole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over 5 - 10 min, allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40 - 45°C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O(500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL), dried (MgSO4), and concentrated to leave the title compound (27.10 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf = 0.39.
	With NaH; ammonium chloride In N,N-dimethyl-formamide; mineral oil	1.a a a Ethyl 1-methyl-1H-indole-2-carboxylate NaH (60% dispersion in mineral oil, 8.02 g, 200.49 mmole) was washed with hexanes, then was suspended in dry DMF (530 mL). Solid ethyl indole-2-carboxylate (25.29 g, 133.66 mmole) was added portionwise over 5-10 min, allowing gas evolution to subside between additions. When the addition was complete, the yellow mixture was stirred for 15 min, then methyl iodide (42 mL, 668.3 mmole) was added all at once. The reaction was exothermic, and the internal temperature rose to 40-45° C. After 1 hr, the reaction was quenched with 10% NH4Cl (100 mL) and concentrated on the rotavap (high vacuum). The residue was partitioned between Et2O(500 mL) and H2O (100 mL), and the layers were separated. The Et2O layer was washed with H2O (100 mL), dried (MgSO4), and concentrated to leave the title compound (27.10 g, quantitative) as a light yellow solid. This was used without further purification: TLC (10% EtOAc/hexanes) Rf=0.39.
	With sodium hydride In N,N-dimethyl-formamide
	With sodium hydride In tetrahydrofuran at 0℃; for 0.666667h;
	With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 20℃; for 12h;
	With potassium carbonate In N,N-dimethyl-formamide at 60℃; Inert atmosphere;
	With sodium amide In tetrahydrofuran at 20℃;
	With sodium hydride	Materials. General procedure: The 1-methyl- (4d) and 1-ethylindole-2-carboxylic acids (4e) were prepared byalkylation of ethyl 2-indolecarboxylate with alkyl iodides in the presence of sodium hydride followed byhydrolysis.

Reference： [1]Current Patent Assignee: DEBIOPHARM INTERNATIONAL SA - US6730684, 2004, B1 Location in patent: Page column 16; 17
[2]Current Patent Assignee: DEBIOPHARM INTERNATIONAL SA - US6762201, 2004, B1 Location in patent: Page/Page column 12
[3]Wang, Fangyuan; Yang, Tilong; Wu, Ting; Zheng, Long-Sheng; Yin, Congcong; Shi, Yongjie; Ye, Xiang-Yu; Chen, Gen-Qiang; Zhang, Xumu [Journal of the American Chemical Society, 2021, vol. 143, # 6, p. 2477 - 2483]
[4]Hendrick, Charles E.; Bitting, Katie J.; Cho, Seoyoung; Wang, Qiu [Journal of the American Chemical Society, 2017, vol. 139, # 33, p. 11622 - 11628]
[5]Chen, Wenyong; Sana, Kasinath; Jiang, Yi; Meyer, Esmerelda V. S.; Lapp, Stacey; Galinski, Mary R.; Liebeskind, Lanny S. [Organometallics, 2013, vol. 32, # 24, p. 7594 - 7611]
[6]Dhar, Arghya K.; Mahesh, Radhakrishnan; Jindal, Ankur; Bhatt, Shvetank [Archiv der Pharmazie, 2015, vol. 348, # 1, p. 34 - 45]
[7]Gokhale, Nikhila; Panathur, Naveen; Dalimba, Udayakumar; Nayak, Pawan G.; Pai, K. Sreedhar Ranganath [Journal of Heterocyclic Chemistry, 2016, vol. 53, # 2, p. 513 - 524]
[8]Eggers, Mary E.; Jog, Parag V.; Bates, Dallas K. [Tetrahedron, 2007, vol. 63, # 49, p. 12185 - 12194]
[9]Baytas, Sultan; Kapcak, Evin; Coban, Tuelay; Oezbilge, Hatice [Turkish Journal of Chemistry, 2012, vol. 36, # 6, p. 867 - 884]
[10]Verma, Raman K.; Ghosh, Prithwish; Kumar, Vijay; Wadhwa, Lalit K. [Journal of Chemical Sciences, 2013, vol. 125, # 6, p. 1555 - 1571]
[11]Current Patent Assignee: GLAXOSMITHKLINE PLC - US5977101, 1999, A
[12]Sukari, Mohamed A.; Vernon, John M. [Journal of the Chemical Society. Perkin transactions I, 1983, p. 2219 - 2224]
[13]Faul, Margaret M.; Winneroski, Leonard L. [Tetrahedron Letters, 1997, vol. 38, # 27, p. 4749 - 4752]
[14]Malapel-Andrieu, Beatrice; Merour, Jean-Yves [Tetrahedron, 1998, vol. 54, # 37, p. 11079 - 11094]
[15]Current Patent Assignee: DEBIOPHARM INTERNATIONAL SA - EP1226138, 2004, B1
[16]Current Patent Assignee: DEBIOPHARM INTERNATIONAL SA - US2004/53814, 2004, A1
[17]Verma, Raman K.; Kumar, Vijay; Ghosh, Prithwish; Wadhwa, Lalit K. [Journal of Chemical Sciences, 2012, vol. 124, # 5, p. 1063 - 1069]
[18]Panathur, Naveen; Dalimba, Udayakumar; Koushik, Pulla Venkat; Alvala, Mallika; Yogeeswari, Perumal; Sriram, Dharmarajan; Kumar, Vijith [European Journal of Medicinal Chemistry, 2013, vol. 69, p. 125 - 138]
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[22]Inoue, Takeshi; Nishino, Hiroshi [Heterocycles, 2018, vol. 97, # 1, p. 431 - 450]

20
[ 3770-50-1 ]
[ 117637-79-3 ]

Yield	Reaction Conditions	Operation in experiment
99%	With potassium hydroxide; iodine In lithium hydroxide monohydrate; N,N-dimethyl-formamide for 0.5h; Ambient temperature;
96%	With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃; for 1h;	1.1 3-iodo-1H-indole-2-ethyl carboxylate (2) A solution of 1H-indole 2-ethyl carboxylate (1.89 g, 10 mmol) in DMF (15 ml) is slowly added to a solution containing NIS (2.25 g, 12 mmol) in DMF (20 ml) at 0° C. The mixture is stirred at room temperature for 1 hour. Next, a solution of sodium thiosulfate at 10% (5 ml) and water (10 ml) are added. stirring at room temperature for another hour. During that time, a precipitate appears that is collected by filtration. 2.9 g (96%) of a white solid are obtained. MS (ES, positive mode): m/z 315 (96%) (M+1)+. 1H NMR (DMSO-d6) δ 12.25 (s, 1H), 7.78-6.88 (m, 4H), 4.38 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).
95%	With N-chloro-succinimide; sodium iodide In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere;

95%	With N-chloro-succinimide; sodium iodide In N,N-dimethyl-formamide at 20℃; for 1h;
94%	With 1,4-diaza-bicyclo[2.2.2]octane; N-iodo-succinimide In dichloromethane at 20℃;
94%	With 1,4-diaza-bicyclo[2.2.2]octane; N-iodo-succinimide In dichloromethane at 25℃; for 2h;	20 Synthesis of compound 2v In a 25mL reaction tube,ethyl 2-indolecarboxylate (0.5 mmol) was added,N-iodosuccinimide (0.55 mmol),triethylenediamine (0.025 mmol) and dichloromethane (2 mL),Stir at 25°C for 2 hours,After the reaction is completed,concentrate,The product 2v was isolated by column chromatography (94%).
93%	Stage #1: ethyl 2-indolecarboxylate With N-iodo-succinimide In N,N-dimethyl-formamide at 0 - 20℃; Stage #2: With Na₂S₂O₃ In lithium hydroxide monohydrate; N,N-dimethyl-formamide for 1h; Further stages.;
90%	With potassium hydroxide; iodine In lithium hydroxide monohydrate; N,N-dimethyl-formamide at 70℃; for 3h;	2 Compound 60: Ethyl 3-iodoindole-2-carboxylate Compound 60: Ethyl 3-iodoindole-2-carboxylate A 1L round-bottom flask containing a magnetic stirring bar equipped with a reflux condenser was charged with 10g (0.053mol) of ethyl indole-2-carboxylate (A), 100mL DMF, 50mL of water, 30g (0.106mol) of iodine and 6.6g (0.106mol) of potassium hydroxide. The resulting mixture was heating at 70°C for 3 hours. 500mL of ice was poured into this flask, and the mixture was agitating for an hour. After filtration and drying, we obtained 15g (315,1g.mol-1) of expected compound 60. Yield: 90%. 1H NMR (400 MHz, CDC13) δ 1.45 (3H, t) 4.48 (2H, q) 7.22 (1H, q) 7.38 (2H, m) 7.57 (1H, q) 9.23 (1H, bs).
88%	With N-chloro-succinimide; sodium iodide In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere;
86%	With N-iodo-succinimide In dichloromethane at 0 - 20℃; for 24h;
84%	With ammonium iodide; lithium hydroxide monohydrate; sodium bisulfate hydrate In acetonitrile for 144h; Irradiation;	27 Synthesis of Compound 3e In a 25 mL reaction tube, add 1H-indole-2-carboxylic acid ethyl ester (33.0 mg, 0.2 mmol), ammonium iodide (58.0 mg, 0.4 mmol), sodium bisulfate hydrate (55.2 mg, 0.4 mmol) , Water (72mg, 4mmol) and acetonitrile (2mL), stirred under the irradiation of three 2-watt LED lamps for 144 hours, after the reaction was completed, extracted, dried, filtered, concentrated, and separated by column chromatography to obtain a white solid 3e (54mg, 84%);
84%	With ammonium iodide; sodium hydrogen sulphate monohydrate; lithium hydroxide monohydrate In acetonitrile at 20℃; for 144h; Schlenk technique; Irradiation; Green chemistry;
81%	With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 1.5h;	6.3. General procedures for iodination General procedure: Method A: to a DMF solution (5 mL) of crushed pellets of KOH (4.0 eq.) and indole (1.0 eq.) at room temperature was dropwise added a solution of iodine (1eq) in DMF (3 mL). After 1.5 h, the mixture was poured onto a saturated aqueous solution (15 mL) of NaHSO3, NH4OH (30%, 2 mL) and water (15 mL). The solid was filtered, dried under reduced pressure and used without further purification.
80%	With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃; for 3h;	Ethyl 3-iodo-1H-indole-2-carboxylate (23) [24]. To indole-2-carboxylate (1.0 g,5.29 mmol) in dry dimethylformamide (20 mL) powdered potassium hydroxide (0.89 g,15.86 mmol) and iodine (1.48 g, 5.53 mmol) in dry dimethylformamide (1 mL) were added.Then, the reaction mixture was stirred at room temperature for 3 h. After completion ofthe reaction as indicated by TLC, the reaction mixture was quenched with 10% sodiumbisulfite solution and extracted with ethyl acetate (3 × 50 mL). The ethyl acetate extractwas repeatedly washed with 10% sodium thiosulfate and water. The combined organicphases were dried and concentrated under reduced pressure to afford the pure product.Yield: 1.33 g, 80%. 1H NMR (500 MHz, CDCl3), δ, ppm: 9.30 (s, 1H, NH), 7.57 (dd, J =8.1, 0.8 Hz, 1H, HAr), 7.39 (d, J = 0.6 Hz, 2H, HAr), 7.23 (ddd, J = 8.0, 6.1, 1.8 Hz, 1H,HAr), 1.65 (s, 2H, CH2CH3), 1.47 (t, J = 7.1 Hz, 3H, CH2CH3). Preparation of compound23 by a different method was described in the literature; NMR data was reported inCDCl3.[25]
	With iodine
	With potassium hydroxide; ammonia; iodine; sodium hydrogen sulphite In lithium hydroxide monohydrate; N,N-dimethyl-formamide	193.A Ethyl 3-iodo-1H-indole-2-carboxylate EXAMPLE 193A Ethyl 3-iodo-1H-indole-2-carboxylate A solution of potassium hydroxide (8.82 g, 0.16 mol) in N,N-dimethylformamide (100 mL) at room temperature was stirred for 15 minutes, treated with ethyl 1H-indole-2-carboxylate (8.50 g, 0.045 mol), stirred for 5 minutes, treated dropwise with a solution of iodine (11.44 g, 0.045 mol) in N,N-dimethylformamide (50 mL), stirred for 40 minutes, poured into a mixture of sodium bisulfite (10.0 g), ammonia (100 mL), and water (1500 mL), and filtered. The filter cake was dried to provide the desired product (14.0 g). MS (ESI(+)) m/e 316 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 1.39 (t, 3H), 4.38 (q, 2H), 7.18 (t, 1H), 7.34 (t, 1H), 7.44 (dd, 2H), 12.24 (br s, 1H).
	With potassium hydroxide; iodine In N,N-dimethyl-formamide at 20℃; for 0.75h;
	With potassium hydroxide; iodine In N,N-dimethyl-formamide at 20℃; for 0.75h;
172.7 mg	With 1,3-Diiodo-5,5-dimethyl-2,4-imidazolidinedione; 4,4'-dimethoxyphenyl disulfide In acetonitrile at 20℃; for 0.75h;
	With N-iodo-succinimide In N,N-dimethyl-formamide at 20℃; for 3h; Inert atmosphere;
	With N-iodo-succinimide In N,N-dimethyl-formamide at 0℃; for 1h;

Reference： [1]Sakamoto, Takao; Nagano, Tatsuo; Kondo, Yoshinori; Yamanaka, Hiroshi [Chemical and pharmaceutical bulletin, 1988, vol. 36, p. 2248 - 2252]
[2]Current Patent Assignee: GOVERNMENT OF SPAIN - US2017/283378, 2017, A1 Location in patent: Paragraph 0133
[3]Inack Ngi, Samuel; Guilloteau, Vincent; Abarbri, Mohamed; Thibonnet, Jerome [Journal of Organic Chemistry, 2011, vol. 76, # 20, p. 8347 - 8354]
[4]Deng, Shuang; Jiao, Yinchun; Li, Tian-Zhen; Liu, Si-Jia; Shi, Feng; Wang, Cong-Shuai; Zhang, Yu-Chen [Chinese Journal of Chemistry, 2020, vol. 38, # 6, p. 543 - 552]
[5]Hu, Lanping; Huang, Weichun; Wang, Yang; Wu, Zheng-Guang; Xu, Haiyan; Zhu, Guanghua; Zhu, Yueping; Zi, You [RSC Advances, 2022, vol. 12, # 12, p. 7115 - 7119]
[6]Current Patent Assignee: UNIV NANTONG - CN114292153, 2022, A Location in patent: Paragraph 0111-0114
[7]Poriel, Cyril; Lachia, Mathilde; Wilson, Claire; Davies, James R.; Moody, Christopher J. [Journal of Organic Chemistry, 2007, vol. 72, # 8, p. 2978 - 2987]
[8]Current Patent Assignee: TEVA PHARMACEUTICAL INDUSTRIES LTD. - EP1589016, 2005, A1 Location in patent: Page/Page column 33
[9]Hammoud, Sokaina; Anselmi, Elsa; Cherry, Khalil; Kizirian, Jean-Claude; Thibonnet, Jérôme [European Journal of Organic Chemistry, 2018, vol. 2018, # 45, p. 6314 - 6327]
[10]Santra, Subhankar; Hota, Pradip Kumar; Bhattacharyya, Rangeet; Bera, Parthasarathi; Ghosh, Prasenjit; Mandal, Swadhin K. [ACS Catalysis, 2013, vol. 3, # 12, p. 2776 - 2789]
[11]Current Patent Assignee: EAST CHINA NORMAL UNIVERSITY - CN111138307, 2020, A Location in patent: Paragraph 0133-0135
[12]Jiang, Xuefeng; Li, Yiming; Lu, Lingling [Green Chemistry, 2020, vol. 22, # 18, p. 5989 - 5994]
[13]Location in patent: experimental part Neagoie, Cleopatra; Vedrenne, Emeline; Buron, Frédéric; Mérour, Jean-Yves; Rosca, Sorin; Bourg, Stéphane; Lozach, Olivier; Meijer, Laurent; Baldeyrou, Brigitte; Lansiaux, Amelie; Routier, Sylvain [European Journal of Medicinal Chemistry, 2012, vol. 49, p. 379 - 396]
[14]Arion, Vladimir B.; Bacher, Felix; Chuang, Hsiang-Yu; Kuznetcova, Irina; Vegh, Daniel [Beilstein Journal of Organic Chemistry, 2022, vol. 18, p. 143 - 151]
[15]Kasahara, Takahiro; Kondo, Yoshinori [Chemical Communications, 2006, # 8, p. 891 - 893]
[16]Current Patent Assignee: ABBOTT LABORATORIES INC - US2002/91148, 2002, A1
[17]Location in patent: experimental part Keller, Laurent; Beaumont, Stéphane; Liu, Jian-Miao; Thoret, Sylviane; Bignon, Jérôme S.; Wdzieczak-Bakala, Joanna; Dauban, Philippe; Dodd, Robert H. [Journal of Medicinal Chemistry, 2008, vol. 51, # 12, p. 3414 - 3421]
[18]Location in patent: scheme or table Beaumont, Stephane; Retailleau, Pascal; Dauban, Philippe; Dodd, Robert H. [European Journal of Organic Chemistry, 2008, # 30, p. 5162 - 5175]
[19]Iida, Keisuke; Ishida, Shunsuke; Watanabe, Takamichi; Arai, Takayoshi [Journal of Organic Chemistry, 2019] Iida, Keisuke; Ishida, Shunsuke; Watanabe, Takamichi; Arai, Takayoshi [Journal of Organic Chemistry, 2019, vol. 84, # 11, p. 7411 - 7417]
[20]Fu, Jian; Hammoud, Sokaina; Kremer, Laurent; Maaliki, Carine; Raynaud, Clément; Thibonnet, Jérôme; Thiery, Emilie; Viljoen, Albertus; Villaume, Sydney; Vincent, Stéphane P. [Bioorganic and medicinal chemistry, 2020, vol. 28, # 13]
[21]Bono-Yagüe, José; Campos, Angela; Castro, Ana; Cumella, José; García-Gimeno, María Adelaida; Lagartera, Laura; Pérez, Concepción; Priego, Eva-María; Sanchis, Ana; Sanz, Pascual; Vázquez-Manrique, Rafael P.; Vela, Marta [ACS Chemical Neuroscience, 2022, vol. 13, # 2, p. 275 - 287]

21
[ 4966-38-5 ]
[ 3770-50-1 ]
[ 70761-93-2 ]
[ 16732-80-2 ]

Reference： [1]Chemical and Pharmaceutical Bulletin,1993,vol. 41,p. 1910 - 1919
[2]Chemical and Pharmaceutical Bulletin,1993,vol. 41,p. 1910 - 1919

22
[ 3770-50-1 ]
[ 33513-42-7 ]
[ 18450-27-6 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.166667h; Stage #2: indole-2-carboxylate ethyl ester at 0 - 60℃; for 3.5h;	Synthesis 1-(Carboxymethyl)-3-cyano-1H-indole-2-carboxylic acid (12b) DMF (3.5 equiv., 1.46 g, 20 mmol) was added to ice-cooled POCl3 (1.05 equiv., 0.92 g, 6 mmol), and the mixture was stirred for 10 min at 0 °C. A solution of ethyl 1H-indole-2-carboxylate (1 equiv., 1.08 g, 5.7 mmol) in DMF (2.5 mL) was added and the mixture was stirred for 30 minutes at 0 °C. The reaction mixture was then heated and stirred at 60 °C for 3 hours, then it was cooled and poured into crushed ice. The resulting mixture was diluted with 2M NaOH to adjust pH 10-11. The suspension was stirred at 3 °C, precipitate was filtered and air-dried. Ethyl 3-formyl-1H-indole-2-carboxylate was obtained as a yellow powder (1.18 g, 95%) which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 10.77 (s, 1H), 9.35 (br.s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.47 (dt, J = 8.3, 1.1Hz, 1H), 7.44 - 7.40 (m, 1H), 7.35 (ddd, J = 8.1, 6.8, 1.4 Hz, 1H), 4.53 (q, J = 7.1Hz, 2H), 1.48 (t, J = 7.1Hz, 3H).[1] To a solution of ethyl 3-formyl-1H-indole-2-carboxylate from previous step (1.0 equiv., 1.15 g, 5.3 mmol) in EtOH (50 mL), pyridine (3.0 equiv., 15.8 mmol, 1.25 g) and NH2OH*HCl (2.5 equiv., 0.92 g, 13.3 mmol) were added and the mixture was refluxed for 15 hours. The solvent was evaporated under reduced pressure, the residue was extracted with Et2O (225 mL), organic phase was washed with 1M HCl (20 mL), H2O (20 mL) and brine, and the solvent was evaporated under reduced pressure. Ethyl 3-((hydroxyimino)methyl)-1Hindole-2-carboxylate was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 12.05 (br.s, 1H), 11.13 (s, 1H), 8.86 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.33 (ddd, J = 8.2, 7.0, 1.1Hz, 1H), 7.18 - 7.14 (m, 1H), 4.39 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.1Hz, 3H). To a solution of ethyl 3-((hydroxyimino)methyl)-1H-indole-2-carboxylate from previous step and pyridine (20 equiv., 6.99 g, 88.5 mmol) in 1,4-dioxane (25 mL) MsCl (4.0 equiv., 2.03 g, 17.7 mmol) was added and the mixture was heated at 60 °C for 5 hours. The solvent was evaporated, the residue was extracted with DCM (220 mL), washed with H2O and brine. The solvent was evaporated in vacuo. Ethyl 3-cyano-1Hindole-2-carboxylate was obtained as a beige powder (0.94 g, 83% for 2 steps) and was introduced into the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 9.46 (br.s, 1H), 7.85 (dt, J = 8.1, 1.0 Hz, 1H), 7.51 (dt, J = 8.3, 1.0 Hz, 1H), 7.45 (ddd, J = 8.4, 6.9, 1.2 Hz, 1H), 7.36 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 4.54 (q, J = 7.1Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). S4 NaH (60% suspension in mineral oil, 1.1 equiv., 0.19 g, 4.84 mmol) was slowly added to a solution of ethyl 3-cyano-1H-indole-2-carboxylate (0.94 g, 4.4 mmol) in dry DMF (10 mL). Upon cooling to room temperature methyl bromoacetate (1.5 equiv., 1.01 g, 6.6 mmol) was added. The reaction mixture was heated at 80 °C for 3 hours, then cooled and poured into H2O (20 mL). Product was extracted with EtOAc (220 mL), organic phase was washed with brine and the solvent was evaporated in vacuo. Methyl 3-cyano-1-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate was obtained as viscous brown oil contaminated with mineral oil. It was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.0 Hz, 1H), 7.49 (m, 1H), 7.38 (t, J = 8.3 Hz, 2H), 5.38 (s, 2H), 4.49 (q, J = 7.1Hz, 2H), 3.53 (s, 3H), 1.49 (t, J = 7.1Hz, 3H). To a solution of obtained methyl 3-cyano-1-(2-methoxy-2-oxoethyl)-1H-indole-2-carboxylate in THF (5 mL) was added a solution of NaOH (4.0 equiv., 0.37 g, 9.1 mmol) in H2O (20 mL) and the mixture was stirred for 24 hours at room temperature. The reaction mixture was washed with DCM (10 mL), the aqueous solution was then acidified with HClconc to pH ~ 2. The separated oil was extracted with EtOAc (220 mL), the organic phase was washed with brine and the solvent was evaporated under reduced pressure. 1-(Carboxymethyl)-3-cyano-1H-indole-2-carboxylic acid (12b) was obtained as a beige powder (445 mg, 80% for 2 steps);
91%	With trichlorophosphate at 20℃; for 1h;
87%	With trichlorophosphate

86%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; Stage #2: indole-2-carboxylate ethyl ester In N,N-dimethyl-formamide at 20 - 70℃; for 7h; Stage #3: With sodium hydroxide In lithium hydroxide monohydrate; N,N-dimethyl-formamide Cooling;	4.2.2. Ethyl-3-formyl-1H-indole-2-carboxylate¹¹ 10 At first, POCl3 (9.8 ml, 0.11 mol) was added dropwise to DMF (30 ml) at 0 °C to obtain the chloroiminium ion. A solution of ethyl-1H-indole-2-carboxylate 9 (19 g, 0.10 mol) in DMF (30 ml) was added to the vessel containing the formylating agent and the resulting mixture was stirred at room temperature for 1 h and at 70 °C for 6 h. The reaction mixture was poured into cold water (400 ml) and neutralized with 2 M NaOH. The yellow precipitate was collected by filtration to give product 10 as a yellow powder (18 g, 86%). Mp 187-188 °C; 1H NMR (300 MHz, DMSO-d6) δ: 12.84 (s, 1H), 10.62 (s, 1H), 8.26 (d, 1H, J = 8.07 Hz), 7.58 (dt, 1H, J = 8.23, 0.94 Hz), 7.41 (ddd, 1H, J = 9.0, 6.0, 1.3 Hz), 7.31 (ddd, 1H, J = 8.0, 7.0, 1.1 Hz), 4.46 (q, 2H, J = 7.1 Hz), 1.41 (t, 3H, J = 7.1 Hz); 13C NMR (75 MHz, DMSO-d6) δ: 187.6, 160.2, 135.8, 132.8, 126.0, 124.8, 123.6, 122.4, 118.4, 113.2, 61.8, 14.1. HRMS-ESI (m/z) for C12H11NO3Na, (M+Na) found 240.0636, calcd 240.0637.
78%	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.166667h; Inert atmosphere; Stage #2: indole-2-carboxylate ethyl ester at 0 - 60℃; for 4.66667h; Inert atmosphere; Stage #3: With lithium hydroxide monohydrate; anhydrous sodium carbonate Cooling; Inert atmosphere;
	With trichlorophosphate 2) 40-60 deg C, 4 h; Yield given. Multistep reaction;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: indole-2-carboxylate ethyl ester at 20 - 60℃; for 4.5h; Inert atmosphere;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0 - 20℃; for 0.25h; Inert atmosphere; Stage #2: indole-2-carboxylate ethyl ester In 1,2-dichloro-ethane for 7h; Reflux; Inert atmosphere;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: indole-2-carboxylate ethyl ester at 20 - 60℃; for 4.5h; Inert atmosphere;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.0833333h; Inert atmosphere; Stage #2: indole-2-carboxylate ethyl ester at 0 - 60℃; for 4.5h; Inert atmosphere; Stage #3: With lithium hydroxide monohydrate; sodium hydroxide In lithium hydroxide monohydrate at 0℃; for 0.0833333h; Inert atmosphere;
	Stage #1: N,N-dimethyl-formamide With trichlorophosphate at 0℃; for 0.25h; Stage #2: indole-2-carboxylate ethyl ester at 0 - 60℃;	1.2 General synthetic procedures of step 2 General procedure: Taking the synthesis of C10c as an example. To a solution of DMF (5 mL) was addedphosphorus oxychloride (11 mmol), which was stirred at 0°C for 15 min. After that, to a solutionof DMF (5 mL) was added compound C10b (10 mmol), and this solution was dropped into thecooled DMF solution of phosphorus oxychloride. This mixture was stirred 0°C for 30 min. Then itwas heated to 60°C and stirred for 8-12 h to accomplish the reaction. After it cooled to roomtemperature, the mixture was poured into ice water and pH value was raised to 10 with 1 M NaOH,and the compound was precipitated as light-yellow solid. The precipitate was filtered and dried in50°C oven to afford the purified C10c without further purification, yield 97.5%.

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[2]Jakše, Renata; Bevk, David; Golobič, Amalija; Svete, Jurij; Stanovnik, Branko [Zeitschrift fur Naturforschung, B: Chemical Sciences, 2006, vol. 61, # 4, p. 413 - 419]
[3]Location in patent: experimental part Ramesh, Neelamegam; Rajeshwaran, Ganesan Gobi; Mohanakrishnan, Arasambattu K. [Tetrahedron, 2009, vol. 65, # 18, p. 3592 - 3602]
[4]Location in patent: experimental part Kuuloja, Noora; Tois, Jan; Franzen, Robert [Tetrahedron Asymmetry, 2011, vol. 22, # 4, p. 468 - 475]
[5]Preti, Delia; Romagnoli, Romeo; Rondanin, Riccardo; Cacciari, Barbara; Hamel, Ernest; Balzarini, Jan; Liekens, Sandra; Schols, Dominique; Estévez-Sarmiento, Francisco; Quintana, José; Estévez, Francisco [Journal of Enzyme Inhibition and Medicinal Chemistry, 2018, vol. 33, # 1, p. 1225 - 1238]
[6]Font, M.; Monge, A.; Cuartero, A.; Ellorriaga, A.; Martinez-Irujo, J.J.; et al. [European Journal of Medicinal Chemistry, 1995, vol. 30, # 12, p. 963 - 972]
[7]Tan, Wei; Li, Xin; Gong, Yu-Xin; Ge, Meng-Di; Shi, Feng [Chemical Communications, 2014, vol. 50, # 100, p. 15901 - 15904]
[8]Chen, Huayan; Yang, Hui; Wang, Zhilong; Xie, Xin; Nan, Fajun [ACS Medicinal Chemistry Letters, 2016, vol. 7, # 3, p. 335 - 339]
[9]Wang, Cong-Shuai; Wu, Jia-Le; Li, Can; Li, Lin-Zhi; Mei, Guang-Jian; Shi, Feng [Advanced Synthesis and Catalysis, 2018, vol. 360, # 5, p. 846 - 851]
[10]Devi, Manju; Jadhav, Amol P.; Singh, Ravi P. [New Journal of Chemistry, 2021, vol. 45, # 19, p. 8445 - 8448]
[11]Chen, Dawei; Chen, Linbo; Fan, Tingting; Gao, Zhenxiong; Jiang, Yuyang; Li, Yuan; Liu, Zijian; Qiu, Zixuan; Wai Wong, Vincent Kam; Wu, Weibin; Yang, Mengchu; Zhang, Cunlong; Zhou, Yaoyao [European Journal of Medicinal Chemistry, 2022, vol. 238]

23
[ 187753-58-8 ]
[ 3770-50-1 ]
[ 776-41-0 ]

Reference： [1]Australian Journal of Chemistry,1996,vol. 49,p. 1315 - 1323

24
[ 3770-50-1 ]
[ 28598-81-4 ]
[ 1026947-18-1 ]

Reference： [1]Journal of Medicinal Chemistry,1997,vol. 40,p. 2694 - 2705

25
[ 3770-50-1 ]
[ 105-36-2 ]
[ 256931-80-3 ]

Yield	Reaction Conditions	Operation in experiment
98.8%	With potassium carbonate In acetonitrile at 80℃; for 20h;	36A Embodiment 36A Ethyl 1-(2-ethoxy-2-oxoethyl)-1H-indole-2-carboxylate Ethyl indole-2-carboxylate (32.00 g, 169.12 mmol), ethyl bromoacetate (70.61 g, 422.80 mmol) and potassium carbonate (70.12 g, 507.36 mmol) were mixed in acetonitrile (400 mL) and stirred at 80 °C for 20 hours. LCMS showed the the reaction was complete. The reaction mixture was diluted with ethyl acetate (500 mL) and water (500 mL) and separated. The organic phase was concentrated and purified by column chromatography (PE: EA = 20: 1) to deliver the title compound (46.00 g, 98.80% yield) as a colorless oil. 1H NMR (400MHz, CDCl3): δ 7.72 (d, J=8.1 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.34 - 7.29 (m, 1H), 7.20 (t, J=7.5 Hz, 1H), 5.34 (s, 2H), 4.38 (q, J=7.2 Hz, 2H), 4.24 (q, 2H), 1.42 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H). LCMS (ESI) (5-95AB): m/z: 276.2 [M+1].
80%	With potassium carbonate In acetonitrile for 48h; Heating;
	With potassium <i>tert</i>-butylate 1.) DMSO, from 110 to 120 deg C, 15 min, 2.) DMSO, from 110 to 120 deg C, 15 min; Multistep reaction;

Reference： [1]Current Patent Assignee: NANJING SANHOME INVESTMENT GROUP CO LTD - EP3290419, 2018, A1 Location in patent: Paragraph 0510; 0511; 0512
[2]Collot, Valerie; Schmitt, Martine; Marwah, Padma; Bourguignon, Jean-Jacques [Heterocycles, 1999, vol. 51, # 12, p. 2823 - 2847]
[3]Lehr, Matthias [Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2694 - 2705]

26
[ 79-37-8 ]
[ 3770-50-1 ]
[ 64-17-5 ]
[ 127221-02-7 ]
[ 128942-88-1 ]

Reference： [1]Heterocycles,1999,vol. 51,p. 2823 - 2847

27
[ 26340-49-8 ]
[ 105-58-8 ]
[ 3770-50-1 ]

Reference： [1]Synthetic Communications,2001,vol. 31,p. 947 - 951

28
[ 3770-50-1 ]
[ 26226-72-2 ]
[ 386213-04-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2001,vol. 11,p. 2569 - 2572

29
[ 3770-50-1 ]
[ 98-09-9 ]
[ 40899-92-1 ]

Yield	Reaction Conditions	Operation in experiment
96%	Stage #1: 2-carbethoxyindole With 18-crown-6 ether; potassium <i>tert</i>-butylate In tetrahydrofuran at 0℃; for 0.25h; Stage #2: benzenesulfonyl chloride In tetrahydrofuran at 20℃; for 3.5h;
84%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: benzenesulfonyl chloride In N,N-dimethyl-formamide for 1.5h;	3.1 Preparation of ethyl 1-(phenylsulfonyl)-1H-indole-2-carboxylate 100 mg (0.53 mmol) of ethyl 1H-indole-2-carboxylate and 32 mg (0.79 mmol) of sodium hydride were dissolved in 2 ml of DMF, stirred at 0 ° C for 10 minutes,136 ul (1.06 mmol) of van gentyl sulfonyl chloride was added and stirred for 1 hour and 30 minutes. After completion of the reaction, the mixture was extracted with 75 ml of ethyl acetate, washed with saturated sodium chloride solution and water, and dried over anhydrous sodium sulfate.The filtrate concentrated under reduced pressure was purified by column chromatography (normal nucleic acid: ethyl acetate = 15: 1, v / v) to obtain 148 mg (0.44 mmol) of the target compound as a white solid in 84% yield.

Reference： [1]Silvestri, Romano; De Martino, Gabriella; La Regina, Giuseppe; Artico, Marino; Massa, Silvio; Vargiu, Laura; Mura, Massimo; Loi, Anna Giulia; Marceddu, Tiziana; La Colla, Paolo [Journal of Medicinal Chemistry, 2003, vol. 46, # 12, p. 2482 - 2493]
[2]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - KR101725451, 2017, B1 Location in patent: Paragraph 0319-0321

30
[ 3770-50-1 ]
[ 590-17-0 ]
[ 126718-04-5 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: cyanomethyl bromide In N,N-dimethyl-formamide at 60 - 65℃; for 0.5h;
90%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Stage #2: cyanomethyl bromide In N,N-dimethyl-formamide; mineral oil at 20 - 65℃;	1 Ethyl 1-(cyanomethyl)-1H-indol-2-carboxylate (13). A mixture of sodium hydride (60% dispersion in mineral oil, 190.0 mg, 7.94 mmol) and ethyl indole-2-carboxylate 12 (1.0 g, 5.29 mmol) in dry DMF (4.6 mL), was stirred at room temperature for 30 min and to this bromoacetonitrile (0.74 mL, 10.60 mmol) in dry DMF (1.0 mL) was added. The reaction mixture was then maintained at 65° C. for 30 min, and stirred for further 6 h at room temperature, left overnight and decomposed with ice. The separated solid was re-crystallized from ethanol to give 13 (90% yield) as white solid: mp (ethanol) 83-84° C.; 1H NMR (CDCl3) δ 1.42 (t, 3H; J=7.3 Hz), 4.41 (q, 2H; J=14.2, 7.2 Hz), 5.60 (s, 2H), 7.37 (m, 4H), 7.71 (d, 1H; J=7.9 Hz); GC-MS m/z 228 [M]+ (100), 199, 182, 154, 128, 115, 101, 89, 77. Anal. (C13H12N2O2) C, H, N.
78%	With sodium hydride In N,N-dimethyl-formamide at 65℃; for 17h;	68.1 Step 1: ethyl-l-(cyanomethyl)-lH-indole-2-carboxylate To a solution of ethyl- lH-indole-2-carboxylate (1.89 g, 10 mmol) in DMF (20 mL) was added NaH(0.46g,20 mmol) and 2-bromoacetonitrile (1.18 g, 10 mmol) and the solution was stirred for 17 hrs at 65 °C, then concentrated to give the crude. The crude was purified by chromatography (silica, EtOAc/PE = 1/5) to afford ethyl- l-(cyanom ethyl)- lH-indole-2- carboxylate (1.8 g, 7.8 mmol, 78%) as a yellow solid. MS (EI+, m/z): 229 [M+H]+.

78%	With sodium hydride In N,N-dimethyl-formamide at 65℃; for 17h;	68.1 Step 1: Step 1: ethyl-1-(cyanomethyl)-1H-indole-2-carboxylate To a solution of ethyl-1H-indole-2-carboxylate (1.89 g, 10 mmol) in DMF (20 mL) was added NaH (0.46 g, 20 mmol) and 2-bromoacetonitrile (1.18 g, 10 mmol) and the solution was stirred for 17 hrs at 65° C., then concentrated to give the crude. The crude was purified by chromatography (silica, EtOAc/PE=1/5) to afford ethyl-1-(cyanomethyl)-1H-indole-2-carboxylate (1.8 g, 7.8 mmol, 78%) as a yellow solid. MS (EI+, m/z): 229 [M+H]+.
66%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Inert atmosphere; Stage #2: cyanomethyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 14h;	102.102a A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and nitrogen inlet was purged with nitrogen and charged with ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) and DMF (100 mL). The solution was cooled to 0 °C using an ice bath. NaH (60% dispersion in mineral oil, 2.54 g, 63.5 mmol) was added. The resulting mixture was stirred at room temperature for 1 h. After that time, bromoacetonitrile (7.62 g, 63.5 mmol) was added. The mixture was stirred at room temperature for 14 h. After that time, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (300 mL) and water (900 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3 x 300 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to afford a 66% yield (8.00 g) of 102a as an off-white solid: mp 65-67 °C; ]H NMR (300 MHz, CDC13) δ 7.72 (d, 1H, J =8.1), 7.44 (m, 3H), 7.25 (m, 1H), 5.62 (s, 2H), 4.42 (q, 2H, / = 7.2 Hz), 1.43 (t, 3H, / = 7.2 Hz); MS (ESI+) m/z 229.1 (M+H).
	In <i>N</i>-methyl-acetamide; water	290 EXAMPLE 290 EXAMPLE 290 Ethyl indole-2-carboxylate (6.0 g) was dissolved in dimethylformamide (60 ml) and sodium hydride (60% in oil, 1.4 g) was added under ice-cooling. After stirring for 30 minutes, bromoacetonitrile (2.3 ml) was added and the mixture was stirred. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 6.6 g of ethyl 1-cyanomethylindole-2-carboxylate. m.p. 92°-94° C. Ethyl 1-cyanomethylindole-2-carboxylate (5.35 g) obtained was dissolved in dimethylformamide (55 ml).
1.87 g	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.5h; Inert atmosphere; Stage #2: cyanomethyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 65℃; for 20h; Inert atmosphere;	12.a Step a To a suspension of sodium hydride (CAS no. 7646-69-7, available from Spectrochem; as 60% dispersion in mineral oil) (0.38 g, 1 .585 mmol) in DMF (8.2 ml) was added ethyl 1H -indole-2-carboxylate (CAS no. 3770-50-1 , available from Avra synthesis) (2.0 g, 10.57 mmol) was stirred at room temperature for 30 min under nitrogen atmosphere. A solution of bromoacetonitrile (CAS No. 590-17-0, available from TCI chemicals) (2.53 g, 21 .14 mmol) in DMF (3 ml) was added drop wise into the reaction mixture at 0 C under nitrogen atmosphere and the resulting reaction mixture was heated to 65 C for 30 min; followed by stirring at room temperature for 20 h. The reaction mixture was diluted with cold water (200 ml) and extracted with ethyl acetate (4x50 ml). The combined organic layer was brine washed, dried over anhydrous Na2S04and concentrated under reduced pressure. The resulting crude material was purified by flash chromatography (6.0% ethyl acetate in hexane) yielding ethyl 1 - (cyanomethyl)-1 H-indole-2-carboxylate (1 .87 g, 8.199 mmol). LCMS: Method A, 2.742 min, MS: ES+ 229.1 (M+1 );1H NMR (400 MHz, CDCI3) δ ppm: 7.755-7.734 (d, J = 8.4 Hz, 1 H), 7.512-7.428 (m, 3H), 7.301 -7.261 (m, 1 H), 5.642 (s, 2H), 4.471 -4.417 (q, J = 7.2 Hz, 2H), 1 .474-1 .439 (t, J = 6.8 Hz, 3H).
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: cyanomethyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 12h;

Reference： [1]Campiani, Giuseppe; Butini, Stefania; Trotta, Francesco; Fattorusso, Caterina; Catalanotti, Bruno; Aiello, Francesca; Gemma, Sandra; Nacci, Vito; Novellino, Ettore; Stark, Jennifer Ann; Cagnotto, Alfredo; Fumagalli, Elena; Carnovali, Francesco; Cervo, Luigi; Mennini, Tiziana [Journal of Medicinal Chemistry, 2003, vol. 46, # 18, p. 3822 - 3839]
[2]Current Patent Assignee: UNIVERSITA DEGLI STUDI DI SIENA - US2009/238761, 2009, A1 Location in patent: Page/Page column 26; 20
[3]Current Patent Assignee: NAVITOR PHARMACEUTICALS - WO2018/89493, 2018, A1 Location in patent: Paragraph 00413
[4]Current Patent Assignee: NAVITOR PHARMACEUTICALS - US2019/389843, 2019, A1 Location in patent: Paragraph 0752
[5]Current Patent Assignee: ROCHE HOLDING AG; GILEAD SCIENCES INC - WO2011/140488, 2011, A1 Location in patent: Page/Page column 122; 123
[6]Current Patent Assignee: MITSUBISHI CHEMICAL HOLDINGS CORPORATION - US5760032, 1998, A
[7]Current Patent Assignee: ARGONAUT THERAPEUTICS LIMITED - WO2018/167276, 2018, A1 Location in patent: Paragraph 00184; 00185
[8]Wang, Lei; Fang, Kun; Cheng, Junfei; Li, Yu; Huang, Yahui; Chen, Shuqiang; Dong, Guoqiang; Wu, Shanchao; Sheng, Chunquan [Journal of Medicinal Chemistry, 2020, vol. 63, # 2, p. 696 - 713]

31
[ 3770-50-1 ]
[ 1996-44-7 ]
3-(2,4-difluoro-phenylsulfanyl)-1<i>H</i>-indole-2-carboxylic acid ethyl ester [ No CAS ]

Reference： [1]Tetrahedron Letters,2004,vol. 45,p. 4073 - 4075

32
[ 3770-50-1 ]
[ 932-87-6 ]
ethyl 1-(2-phenylethynyl)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	With potassium phosphate; 1,10-Phenanthroline; copper (II) sulfite In toluene at 85℃;
56%	With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In tetrahydrofuran at 80℃; Inert atmosphere;	ethyl 1-(phenylethynyl)-1H-indole-2-carboxylate, 7c General procedure: The flask charged with CuSO4·5H2O (164.8 mg, 0.66 mmol) and 1,10-phenanthroline (237 mg, 1.32 mmol) was evacuated and backfilled with argon three times, and THF (13.2 mmol) was added. The mixture was stirred at 80 ºC for 10 min, and then charged with K2CO3 (1.82 g, 13.2 mmol), 3-acetylindole (1.05 g, 6 mmol), and bromoethynylbenzene (1.2 mL, 9.9 mmol). After stirring at 80 ºC for 17 h, the reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate (10 mL), and filtered through a pad of celite and florisil. To the mixture was added toluene (30 mL) and water (20 mL), and organic phase was extracted with toluene (10 mL x 3). Combined organic phases were washed with brine (20 mL), and then dried over Na2SO4, and concentrated to give the crude. The crude was purified by silica gel column chromatography (eluent, toluene only) to afford 1-(1-(phenylethynyl)-1H-indol-3-yl)ethanone
	With 1,10-Phenanthroline; copper(ll) sulfate pentahydrate; potassium carbonate In toluene at 85℃; for 24h; Inert atmosphere; Sealed tube;

Reference： [1]Zhang, Yanshi; Hsung, Richard P.; Tracey, Michael R.; Kurtz, Kimberly C. M.; Vera, Eymi L. [Organic Letters, 2004, vol. 6, # 7, p. 1151 - 1154]
[2]Sato, Akihiro H.; Ohashi, Kazuhiro; Ito, Kouhei; Iwasawa, Tetsuo [Tetrahedron Letters, 2013, vol. 54, # 22, p. 2878 - 2881]
[3]Alcaide, Benito; Almendros, Pedro; Lázaro-Milla, Carlos [Advanced Synthesis and Catalysis, 2017, vol. 359, # 15, p. 2630 - 2639]

33
[ 3770-50-1 ]
[ 622-95-7 ]
[ 199604-34-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With caesium carbonate In acetonitrile at 60℃;	4.2.2 N-alkylation of indole derivatives General procedure: Ethyl indole-2-carboxylate (3) (5.0mmol) was first dissolved in acetonitrile (40mL); cesium carbonate (7.5mmol) was then added and the mixture stirred for 15min at room temperature. Subsequently, the corresponding alkyl bromide (5.5mmol) was added to the reaction mixture which was heated overnight at reflux. Upon completion of the reaction, which was monitored by TLC, the mixture was concentrated in vacuo and the residue dissolved in dichloromethane (80mL). The organic phase was washed with water (2×30mL), dried with anhydrous Na2SO4 and then concentrated in vacuo to afford sufficiently pure N-alkylated products
	With sodium hydride In N,N-dimethyl-formamide at 80℃; for 1h;

Reference： [1]Keček Plešec, Kaja; Urbančič, Dunja; Gobec, Martina; Pekošak, Aleksandra; Tomašič, Tihomir; Anderluh, Marko; Mlinarič-Raščan, Irena; Jakopin, Žiga [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5221 - 5234]
[2]Nazare, Marc; Essrich, Melanie; Will, David W.; Matter, Hans; Ritter, Kurt; Urmann, Matthias; Bauer, Armin; Schreuder, Herman; Dudda, Angela; Czech, Joerg; Lorenz, Martin; Laux, Volker; Wehner, Volkmar [Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 16, p. 4191 - 4195]

34
[ 74-96-4 ]
[ 3770-50-1 ]
[ 40913-41-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With sodium hydride In tetrahydrofuran at 25℃;
87%	Stage #1: 2-carbethoxyindole With potassium hydroxide In dimethyl sulfoxide at 20℃; Stage #2: ethyl bromide In dimethyl sulfoxide at 20℃;
56%	With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 19h;	2.1 Step 1: Preparation of ethyl 1-ethyl-1H-indole-2-carboxylate After dissolving 200 mg (1.06 mmol) of ethyl 1H-indole-2-carboxylate and 730 mg (5.29 mmol) of potassium carbonate in 2 ml of DMF, 197 μl (2.64 mmol) of bromoethane was added and stirred at 50 ° C. for 19 hours . After completion of the reaction, the reaction mixture was extracted with ethyl acetate, washed with saturated sodium chloride and water, and dried over anhydrous sodium sulfate.The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (normal hexane: ethyl acetate = 10: 1, v / v) to obtain 130 mg (0.60 mmol) of the desired compound as a colorless liquid in 56% yield.

	With potassium carbonate In N,N-dimethyl-formamide
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: ethyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃;

Reference： [1]Current Patent Assignee: JINAN UNIVERSITY (GUANGZHOU) - CN106928121, 2017, A Location in patent: Page/Page column 22
[2]Sechi, Mario; Derudas, Massimiliano; Dallocchio, Roberto; Dessì, Alessandro; Bacchi, Alessia; Sannia, Luciano; Carta, Fabrizio; Palomba, Michele; Ragab, Omar; Chan, Carney; Shoemaker, Robert; Sei, Shizuko; Dayam, Raveendra; Neamati, Nouri [Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5298 - 5310]
[3]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - KR101725451, 2017, B1 Location in patent: Paragraph 0307-0309
[4]Hopkins, Corey R.; O'Neil, Steven V.; Laufersweiler, Michael C.; Wang, Yili; Pokross, Matthew; Mekel, Marlene; Evdokimov, Artem; Walter, Richard; Kontoyianni, Maria; Petrey, Maria E.; Sabatakos, Georgios; Roesgen, Jeff T.; Richardson, Eloise; Demuth Jr., Thomas P. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5659 - 5663]
[5]Zhang, Kaifan; Xu, Xiaoying; Zheng, Jiuan; Yao, Hequan; Huang, Yue; Lin, Aijun [Organic Letters, 2017, vol. 19, # 10, p. 2596 - 2599]

35
[ 3770-50-1 ]
[ 100-39-0 ]
[ 17017-66-2 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate In acetonitrile for 16h; Reflux;
96%	With potassium hydroxide In dimethyl sulfoxide for 2h;	Potassium hydroxide (4mmol) was stirred in dried dimethyl sulfoxide (25mL) for 10min in a round-bottom flask. Ethyl 1H-indole-2-carboxylate 1 (1mmol) was added to the solution and the mixture was stirred for 0.5h. Benzyl bromide (1.3mmol) was added to the stirring mixture. After the completion of the reaction (1.5h) as monitored by TLC the reaction mixture was cooled to 0°C. Product was extracted with ethyl acetate, the organic layer was washed using brine solution (40mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and was purified by isocratic flash column chromatography (petroleum ether: ethyl acetate=9: 1, v/v) on silica gel (200-400) to get pure compound 2 with 95% yield.
95%	Stage #1: 2-carbethoxyindole With potassium hydroxide In dimethyl sulfoxide for 1.5h; Stage #2: benzyl bromide In dimethyl sulfoxide for 1.5h;	4 General procedure for the synthesis of intermediates 2,3,4 and 5 General procedure: Potassium hydroxide (4 mmol) was stirred in dried dimethylsulfoxide (25 mL) for 10 min in a round-bottom flask. Ethyl 1H-indole-2-carboxylate 1 (1 mmol) was added to the solution and the mixture was stirred for 0.5 h. Benzyl bromide (1.3 mmol) was added to the stirring mixture. After the completion of the reaction(1.5 h) as monitored by TLC the reaction mixture was cooled to 0°C. Product was extracted with ethyl acetate, the organic layer was washed using brine solution (40 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and was purified by isocratic flash column chromatography (petroleum ether: ethyl acetate = 9:1, v/v) on silica gel (200-400) to get pure compound 2 with 95% yield.

95%	Stage #1: 2-carbethoxyindole With potassium hydroxide In dimethyl sulfoxide for 0.5h; Stage #2: benzyl bromide In dimethyl sulfoxide for 1.5h;	4.3.2. General procedure for the synthesis of intermediates 2, 3 and 4 Potassium hydroxide (4 mmol) was stirred in dried dimethylsulfoxide (25 mL) for 10 min in a round-bottom flask. Ethyl 1Hindole-2-carboxylate 1 (1 mmol) was added to the solution, andthe mixture was stirred for 0.5 h. Benzyl bromide (1.3 mmol) wasadded to the stirring mixture. After the completion of the reaction(1.5 h) as monitored by TLC, the reaction mixture was cooled to 0C. The product was extracted with ethyl acetate; the organic layerwas washed using brine solution (40 mL). The combined organiclayer was dried over anhydrous sodium sulfate, filtered, concentratedand was purified by flash column chromatography (petroleumether: ethyl acetate = 9: 1, v/v) on silica gel (200-400) toget pure compound 2 with 95% yield.
94%	Stage #1: 2-carbethoxyindole With potassium hydroxide In water monomer; acetone at 20℃; for 0.5h; Stage #2: benzyl bromide In water monomer; acetone at 20℃; for 2h;	3.2. General Procedure for the Alkylation of Ethyl Indol-2-carboxylate (1) General procedure: A solution of ethyl indol-2-carboxylate (1, 1.0 mmol) and aq. KOH (3.0 mmol) in acetone (10 mL) was stirred at 20 °C for half hour, then the appropriate alkylating agent (1.1 mmol) was added and stirring was continued for 2 h to give 2 and 3 and for eight hours to give 4. The solvent was removed, water was added and organic layer was extracted using ethyl acetate. The products were purified using column chromatography (ethyl acetate/hexane 1:9).
91%	Stage #1: 2-carbethoxyindole With potassium hydroxide In dimethyl sulfoxide at 20℃; Stage #2: benzyl bromide In dimethyl sulfoxide at 20℃;
88%	Stage #1: 2-carbethoxyindole With sodium hydride In acetonitrile; mineral oil at 0℃; for 0.166667h; Stage #2: benzyl bromide In acetonitrile; mineral oil at 0 - 20℃;	Ethyl 1-benzyl-1H-indole-2-carboxylate (19). A suspension of ethyl 1H-indole-2-carboxylate (6.00 g, 31.7 mmol) in dry acetonitrile was cooled to 0 °C and sodium hydride(60% dispersion in mineral oil, 1.77 g, 44.4 mmol) was added in small portions. Theresulting mixture was stirred at 0 °C for 10 min and a solution of benzyl bromide (4.52 mL,38.0 mmol) in dry acetonitrile (50 mL) was added dropwise. Afterwards, the reactionmixture was allowed to slowly reach room temperature and stirred overnight. On the nextday, the reaction was quenched with saturated aqueous ammonium chloride solution(100 mL) and extracted with dichloromethane (3 × 150 mL). The combined organic layers were dried over magnesium sulfate and evaporated. The residue was purified on a silicacolumn by using a mixture of hexane/ethyl acetate 9:1 as eluent. Yield: 7.80 g, 88%. 1HNMR (500 MHz, DMSO-d6), δ, ppm: 7.72 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H),7.38 (d, J = 0.4 Hz, 1H), 7.33 - 7.29 (m, 1H, HAr), 7.26 (t, J = 7.4 Hz, 2H, HAr), 7.19 (t, J= 7.3 Hz, 1H, HAr), 7.14 (t, J = 7.4 Hz, 1H, HAr), 7.02 (d, J = 7.2 Hz, 2H, HAr), 5.87 (s, 2H,CH2C6H5), 4.31 - 4.25 (m, 2H, CH2CH3), 1.28 (t, J = 7.1 Hz, 3H, CH2CH3). Preparation ofcompound 19 by slightly different methods has been described in the literature; however,NMR data in DMSO-d6 was not reported.[8],[16],[17],[18],[19],[20]
80%	Stage #1: 2-carbethoxyindole With potassium carbonate In acetonitrile at 20℃; for 0.166667h; Stage #2: benzyl bromide In acetonitrile for 23h; Reflux;	5.1 Preparation of ethyl 1-benzyl-1H-indole-2-carboxylate 100 mg (0.53 mmol) of ethyl 1H-indole-2-carboxylate and 184 mg (1.33 mmol) of potassium carbonate were dissolved in 10 ml of acetonitrile, stirred at room temperature for 10 minutes, 82 [mu] l (0.66 mmol) of benzyl bromide were added and the mixture was refluxed for 23 hours.After completion of the reaction, the mixture was extracted with 75 ml of ethyl acetate, washed with saturated sodium chloride solution and water, and dried over anhydrous sodium sulfate.The filtrate was concentrated under reduced pressure and purified by column chromatography (normal nucleic acid: ethyl acetate = 15: 1, v / v) to obtain 119 mg (0.43 mmol) of the target compound as a white solid in 80% yield.
76%	With Cs₂CO₃ In acetonitrile at 60℃;	4.2.2 N-alkylation of indole derivatives General procedure: Ethyl indole-2-carboxylate (3) (5.0mmol) was first dissolved in acetonitrile (40mL); cesium carbonate (7.5mmol) was then added and the mixture stirred for 15min at room temperature. Subsequently, the corresponding alkyl bromide (5.5mmol) was added to the reaction mixture which was heated overnight at reflux. Upon completion of the reaction, which was monitored by TLC, the mixture was concentrated in vacuo and the residue dissolved in dichloromethane (80mL). The organic phase was washed with water (2×30mL), dried with anhydrous Na2SO4 and then concentrated in vacuo to afford sufficiently pure N-alkylated products
27%	Stage #1: 2-carbethoxyindole With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 0.333333h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide at 60℃; Inert atmosphere;
	With potassium carbonate In N,N-dimethyl-formamide
	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.333333h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃;
2.3 g	Stage #1: 2-carbethoxyindole With potassium hydroxide In dimethyl sulfoxide for 0.5h; Stage #2: benzyl bromide In dimethyl sulfoxide for 1h;

Reference： [1]González Cabrera, Diego; Douelle, Frederic; Feng, Tzu-Shean; Nchinda, Aloysius T.; Younis, Yassir; White, Karen L.; Wu, Quoc; Ryan, Eileen; Burrows, Jeremy N.; Waterson, David; Witty, Michael J.; Wittlin, Sergio; Charman, Susan A.; Chibale, Kelly [Journal of Medicinal Chemistry, 2011, vol. 54, # 21, p. 7713 - 7719]
[2]Singla, Ramit; Gupta, Kunj Bihari; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas [European Journal of Medicinal Chemistry, 2018, vol. 146, p. 206 - 219]
[3]Singla, Ramit; Gupta, Kunj Bihari; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas [Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 1, p. 266 - 277]
[4]Singla, Ramit; Prakash, Kunal; Bihari Gupta, Kunj; Upadhyay, Shishir; Dhiman, Monisha; Jaitak, Vikas [Bioorganic Chemistry, 2018, vol. 79, p. 72 - 88]
[5]Boraei, Ahmed T. A.; El Ashry, El Sayed H.; Barakat, Assem; Ghabbour, Hazem A. [Molecules, 2016, vol. 21, # 3]
[6]Sechi, Mario; Derudas, Massimiliano; Dallocchio, Roberto; Dessì, Alessandro; Bacchi, Alessia; Sannia, Luciano; Carta, Fabrizio; Palomba, Michele; Ragab, Omar; Chan, Carney; Shoemaker, Robert; Sei, Shizuko; Dayam, Raveendra; Neamati, Nouri [Journal of Medicinal Chemistry, 2004, vol. 47, # 21, p. 5298 - 5310]
[7]Arion, Vladimir B.; Bacher, Felix; Chuang, Hsiang-Yu; Kuznetcova, Irina; Vegh, Daniel [Beilstein Journal of Organic Chemistry, 2022, vol. 18, p. 143 - 151]
[8]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - KR101725451, 2017, B1 Location in patent: Paragraph 0343-0345
[9]Keček Plešec, Kaja; Urbančič, Dunja; Gobec, Martina; Pekošak, Aleksandra; Tomašič, Tihomir; Anderluh, Marko; Mlinarič-Raščan, Irena; Jakopin, Žiga [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5221 - 5234]
[10]Sindac, Janice A.; Barraza, Scott J.; Dobry, Craig J.; Xiang, Jianming; Blakely, Pennelope K.; Irani, David N.; Keep, Richard F.; Miller, David J.; Larsen, Scott D. [Journal of Medicinal Chemistry, 2013, vol. 56, # 22, p. 9222 - 9241]
[11]Hopkins, Corey R.; O'Neil, Steven V.; Laufersweiler, Michael C.; Wang, Yili; Pokross, Matthew; Mekel, Marlene; Evdokimov, Artem; Walter, Richard; Kontoyianni, Maria; Petrey, Maria E.; Sabatakos, Georgios; Roesgen, Jeff T.; Richardson, Eloise; Demuth Jr., Thomas P. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5659 - 5663]
[12]Zhang, Kaifan; Xu, Xiaoying; Zheng, Jiuan; Yao, Hequan; Huang, Yue; Lin, Aijun [Organic Letters, 2017, vol. 19, # 10, p. 2596 - 2599]
[13]Mo, Fanyang; Li, Fei; Qiu, Di; Zhang, Yan; Wang, Jianbo [Chinese Journal of Chemistry, 2012, vol. 30, # 10, p. 2297 - 2302,6]

36
[ 3770-50-1 ]
[ 14204-27-4 ]
[ 106184-17-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With magnesium bromide In N,N-dimethyl acetamide at 120℃; for 24h;

Reference： [1]Tudge, Matthew; Tamiya, Minoru; Savarin, Cecile; Humphrey, Guy R. [Organic Letters, 2006, vol. 8, # 4, p. 565 - 568]

37
[ 3770-50-1 ]
[ 1700-31-8 ]
[ 915700-93-5 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5659 - 5663

38
[ 3770-50-1 ]
[ 85482-13-9 ]
[ 915700-96-8 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5659 - 5663

39
[ 3770-50-1 ]
[ 402-49-3 ]
[ 866236-21-7 ]

Yield	Reaction Conditions	Operation in experiment
66%	With caesium carbonate In acetonitrile at 60℃;	4.2.2 N-alkylation of indole derivatives General procedure: Ethyl indole-2-carboxylate (3) (5.0mmol) was first dissolved in acetonitrile (40mL); cesium carbonate (7.5mmol) was then added and the mixture stirred for 15min at room temperature. Subsequently, the corresponding alkyl bromide (5.5mmol) was added to the reaction mixture which was heated overnight at reflux. Upon completion of the reaction, which was monitored by TLC, the mixture was concentrated in vacuo and the residue dissolved in dichloromethane (80mL). The organic phase was washed with water (2×30mL), dried with anhydrous Na2SO4 and then concentrated in vacuo to afford sufficiently pure N-alkylated products
	With potassium carbonate In N,N-dimethyl-formamide

Reference： [1]Keček Plešec, Kaja; Urbančič, Dunja; Gobec, Martina; Pekošak, Aleksandra; Tomašič, Tihomir; Anderluh, Marko; Mlinarič-Raščan, Irena; Jakopin, Žiga [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5221 - 5234]
[2]Hopkins, Corey R.; O'Neil, Steven V.; Laufersweiler, Michael C.; Wang, Yili; Pokross, Matthew; Mekel, Marlene; Evdokimov, Artem; Walter, Richard; Kontoyianni, Maria; Petrey, Maria E.; Sabatakos, Georgios; Roesgen, Jeff T.; Richardson, Eloise; Demuth Jr., Thomas P. [Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5659 - 5663]

40
[ 1189-71-5 ]
[ 5734-64-5 ]
[ 3770-50-1 ]
C₁₇H₁₆ClN₅O₆S [ No CAS ]

Reference： [1]Organic Preparations and Procedures International,2006,vol. 38,p. 469 - 473

41
[ 3770-50-1 ]
[ 13920-91-7 ]
[ 1000069-56-6 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 12185 - 12194

42
[ 3770-50-1 ]
[ 21109-25-1 ]

Reference： [1]Tetrahedron,2007,vol. 63,p. 4983 - 4989
[2]Journal of Agricultural and Food Chemistry,2012,vol. 60,p. 7792 - 7798
[3]Journal of Medicinal Chemistry,2015,vol. 58,p. 9480 - 9497
[4]Patent: US5977101,1999,A

43
[ 3770-50-1 ]
[ 28737-29-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5659 - 5663
[2]Journal of Medicinal Chemistry,2004,vol. 47,p. 5298 - 5310
[3]RSC Advances,2016,vol. 6,p. 21165 - 21186
[4]Patent: KR101725451,2017,B1

44
[ 3770-50-1 ]
[ 144069-67-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1: DBU / 3 h / Heating 2: 99 percent / 4-dimethylaminopyridine / tetrahydrofuran / 1 h / 20 °C 3: 92 percent / magnesium; methanol / 4 h / 0 °C 4: 49 percent / Chirazyme L-2 / aq. phosphate buffer / 30 h / 60 °C / pH 7.0

Reference： [1]Kurokawa, Masayuki; Sugai, Takeshi [Bulletin of the Chemical Society of Japan, 2004, vol. 77, # 5, p. 1021 - 1025]

45
[ 3770-50-1 ]
[ 163229-48-9 ]

Reference： [1]Bulletin of the Chemical Society of Japan,2004,vol. 77,p. 1021 - 1025

46
[ 3770-50-1 ]
[ 36193-65-4 ]

Reference： [1]Journal of Organic Chemistry,2002,vol. 67,p. 9276 - 9287
[2]Patent: US5977101,1999,A

47
[ 3770-50-1 ]
[ 1485-22-9 ]

Reference： [1]Tetrahedron Letters,1997,vol. 38,p. 4749 - 4752
[2]Journal of Chemical Sciences,2012,vol. 124,p. 1063 - 1069
[3]Journal of Chemical Sciences,2013,vol. 125,p. 1555 - 1571
[4]Organometallics,2013,vol. 32,p. 7594 - 7611
[5]Organic Letters,2017,vol. 19,p. 2596 - 2599

48
[ 3770-50-1 ]
[ 80875-98-5 ]

Reference： [1]Journal of Medicinal Chemistry,1987,vol. 30,p. 992 - 998

49
[ 3770-50-1 ]
[ 89607-68-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	Stage #1: 2-carbethoxyindole With acetic acid; sodium nitrite In dichloromethane at 20℃; for 48h; Stage #2: With acetic acid; sodium nitrite In dichloromethane for 24h;	8 Preparation 8; Ethyl 3-diazoindole-2-carboxylate Acetic acid (77 ml) was added dropwise to a suspension of sodium nitrite (82 g) and ethyl indole-2-carboxylate (25 g) in dichloromethane (1000 ml), and stirred at ambient temperature under inert atmosphere. After 2 days, further sodium nitrite (20 g) was added, and acetic acid (19 ml) was added dropwise, and the reaction left stirring for a further day. The reaction was poured into water (300 ml), extracted with dichloromethane (2?200 ml), and neutralised with saturated sodium hydrogen carbonate solution (300 ml). Combined organic extracts were dried (MgSO4), and concentrated in vacuo to afford the product as a yellow solid (26.96 g, 95%), NMR d (CD3SOCD3) 1.34 (t, 3H), 4.37 (q, 2H), 7.38 (m, 2H), 7.84 (m, 2H); M/z (+) 216.2 (MH30).
	Multi-step reaction with 3 steps 1: 1.) 20percent aq. HCl, NaNO₂, 2.) 15percent aq. Na₂CO₃ / 1.) 3-5 deg C, 2.) DMF, 5 deg C, 1 h 2: 58 percent / Sn, aq. HCl / propan-2-ol / 2 h / Heating 3: 73 percent / aq. HCl, NaNO₂ / 0.5 h / 5 - 10 °C
	With acetic acid; sodium nitrite In dichloromethane at 20℃; for 72h;	Intermediate 30: Ethyl 3-(1λ5-diazynylidene)-3H-indole-2-carboxylateA solution of 5.00 g of ethyl indole-2-carboxylate in 500 ml of DCM sparged with nitrogen and maintained under a nitrogen atmosphere was treated with 18.23 g of NaNO2 followed by 15 ml of glacial acetic acid added dropwise. The mixture was stirred at ambient temperature for 2 days then treated with 3.66 g of NaNO2 and 3 ml of acetic acid and allowed to stir for one day. Approximately 300 ml of water was added to the mixture, and the organic phase was separated. The aqueous phase was made alkaline with sat. NaHCO3, and extracted once with DCM. The combined organic phases were washed with sat. NaHCO3, dried with Na2SO4 and concentrated in vacuo to give 5.59 g of yellow crystalline solid. The crude product was purified by chromatography on ~150g of silica gel eluting with 0-4% ethyl acetate/hexane to give 4.8Og of ethyl 3-(1λ5-diazynylidene)-3H-indole-2-carboxylate as a yellow crystalline solid. 1 H NMR (DMSO-d6) δ 7.88 (m, 2H), 7.39 (m, 2H), 4.40 (q, 2H, J = 7Hz), 1.36 (t, 3H, J = 7Hz). MS ES+ m/z 216 [M+H]+, 238 [M+Na]+. HPLC [Waters X-terra C-18; 10-100% CH3CN/H2O(0.1 % TFA)/5 min; UV det.] RT=3.09 min (98%).

Reference： [1]Current Patent Assignee: ASTRAZENECA PLC - US6833387, 2004, B1 Location in patent: Page column 30
[2]Simakov, S. V.; Velezheva, V. S.; Kozik, T. A.; Ershova, Yu. A.; Chernov, V. A.; Suvorov, N. N. [Pharmaceutical Chemistry Journal, 1983, vol. 17, # 10, p. 707 - 712][Khimiko-Farmatsevticheskii Zhurnal, 1983, vol. 17, # 10, p. 1183 - 1188]
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/28118, 2008, A1 Location in patent: Page/Page column 84

50
[ 3770-50-1 ]
[ 28737-33-9 ]

Reference： [1]Chemische Berichte,1923,vol. 56,p. 1024
[2]Nippon Kagaku Zasshi,1957,vol. 78,p. 1798
Chem.Abstr.,1960,p. 1487

51
[ 3770-50-1 ]
[ 885-77-8 ]
[ 187535-49-5 ]

Yield	Reaction Conditions	Operation in experiment
97%		R.9 Ethyl 3-[bis(4-methylphenyl)methyl]indole-2-carboxylate REFERENCE EXAMPLE 9 Ethyl 3-[bis(4-methylphenyl)methyl]indole-2-carboxylate Substantially the same procedure as in Reference Example 4 was repeated using 4,4'-dimethylbenzhydrol (11.8 g, 55.5 mmol) and ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) to give 19.8 g (yield: 97%) of the title compound. 1 H-NMR(CDCl3) δ(ppm): 1.39 (3H, t, J=7.1 Hz), 2.31 (6H, s), 4.38 (2H, q, J=7.1 Hz), 6.60 (1H, s), 6.85-6.95 (1H, m), 7.0-7.15 (9H, m), 7.2-7.3 (1H, m), 7.35 (1H, d, J=8.6 Hz), 8.82 (1H, s).
97%		R.6 Ethyl 3-[bis(4-methylphenyl)methyl]indole-2-carboxylate Reference Example 6 Ethyl 3-[bis(4-methylphenyl)methyl]indole-2-carboxylate Substantially the same procedure as in Reference Example 1 was repeated using 4,4'-dimethylbenzhydrol (11.8 g, 55.5 mmol) and ethyl indole-2-carboxylate (10.0 g, 52.9 mmol) to give 19.8 g (yield: 97%) of the title compound. 1H-NMR(CDCl3) δ(ppm): 1.39 (3H, t, J=7.1Hz), 2.31 (6H, s), 4.38 (2H, q, J=7.1Hz), 6.60 (1H, s), 6.85-6.95 (1H, m), 7.0-7.15 (9H, m), 7.2-7.3 (1H, m), 7.35 (1H, d, J=8.6Hz), 8.82 (1H, s).

Reference： [1]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - US5891902, 1999, A
[2]Current Patent Assignee: KIRIN HOLDINGS CO., LTD.; Kyowa Kirin (in: Kirin Holdings) - EP782989, 1997, A1

52
[ 3770-50-1 ]
[ 2859-78-1 ]
[ 7787-70-4 ]
1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
92%	With pyridine; potassium carbonate; In nitrobenzene;	(a) Preparation of 1-(3,4-dimethoxyphenyl)indole-2-carboxylic acid ethyl ester 4-Bromoveratrole (8.8 g, 40 mmol), indole-2-carboxylic acid ethyl ester (1.9 g, 10 mmol), potassium carbonate (1.9 g), copper- (I) bromide (o.2 g), pyridine (2 ml) and nitrobenzene (10 ml) were stirred at 140 C. for 14 hours. After cooling to room temperature, the reaction mixture was applied onto a silica gel flash chromatography column (silica gel: 140 g). The column was subsequently eluted with toluene (500 ml), toluene/acetone (95:5, 500 ml) and toluene/acetone (90:10, 500 ml). 1-(3,4-Dimethoxyphenyl)indole-2-carboxylic acid ethyl ester was eluted with toluene/acetone (90:10) and gave colorless crystals upon evaporation of the solvent. The crystals were triturated with diisopropyl ether, collected by vacuum filtration and dried in the air. Yield: 3.0 g. (92% of theoretical yield) M.pt.: 126-128 C. Rf (toluene/acetone, 9:1)=0.53.

Reference： [1]Patent: US5399559,1995,A

53
[ 3770-50-1 ]
[ 98-59-9 ]
[ 132819-92-2 ]

Yield	Reaction Conditions	Operation in experiment
74%	With potassium tert-butylate; In tetrahydrofuran;Reflux;	General procedure: Ethyl indole-2-carboxylate (3) (5mmol) was dissolved in THF (15mL); potassium tert-butoxide (7.5mmol) was then added and the mixture stirred for 15min at room temperature. Subsequently, the corresponding sulfonyl chloride (5.5mmol) was added to the reaction mixture which was heated overnight at reflux. Upon completion of the reaction, which was monitored by TLC, the mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (80mL). The organic phase was washed with water (2×30mL), dried with anhydrous Na2SO4 then concentrated in vacuo. The residue was purified by flash silica gel column chromatography (gradient elution; starting eluent: hexane/ethyl acetate 6:1 v/v) to afford pure N-sulfonylated compounds.
61%		Step 1)1-(Toluene-4-sulfonyl)-1H-indole-2-carboxylic acid ethyl ester To a stirred solution 1H-Indole-2-carboxylic acid ethyl ester (ig, 5.29 mmol) in dry THF at 0Cwas added sodium hydride in 60% oil dispersion (0.423g, 10.58 mmol) and stirred for 30 mm.To this mixture was added p-toluene sulfonyl chloride (2g, 10.58mmol) and stuffed for 12h. It was quenched with saturated ammonium chloride, extracted with ethyl acetate, dried over anhydrous sodium sulfate, evaporated under reduced pressure and the crude material was purified by column chromatography (silica gel, 5% EtOAc/Hexanes) to provide 1 -(toluene-4-sulfonyl)- 1 H-indole-2-carboxylic acid ethyl ester as white solid (1.1 g, 61%). MS calcd. for C18H17N045 [(M+H)i 344, obsd. 344.1.
	In tetrahydrofuran; paraffin oil;	Step 1 1-(4-Methylphenyl)sulfonyl-1H-indole-2-carboxylic acid ethyl ester To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30 C. The reaction mixture was stirred for 30 min. and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After two hours stirring at room temperature and one hour at 45 C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8 g, 78%), m.p. 92-95 C.

	In tetrahydrofuran; paraffin oil;	Step 1 1-(4-Methylphenyl)sulfonyl-1H-indole-2-carboxylic acid ethyl ester To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30 C. The reaction mixture was stirred for 30 min. and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After two hours stirring at room temperature and one hour at 45 C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8g, 78%), m.p. 92-95 C.
	In tetrahydrofuran; paraffin oil;	1-(4-Methylphenyl)sulfonyl-1H-indol-2-carboxylic acid ethyl ester To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30 C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After 2 hours stirring at room temperature and 1 hour at 45 C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8 g, 78%), mp 92-95 C.
	In tetrahydrofuran; paraffin oil;	1-(4-Methylphenyl)sulfonyl-1H-indol-2-carboxylic acid ethyl ester To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 ml), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30 C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After 2 hours stirring at room temperature and 1 hour at 45 C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8 g, 78%), mp 92-95 C.
		General procedure: Into a flask was added ethyl indole-2-carboxylate (1.0 g, 1.0 equiv), DMA (10 ml) was added to the flask under an inert atmosphere. NaH (0.32 g, 1.5 equiv) was added to the flask at -40. The reaction mixture was stirred for 1 h at -40. 4-methylbenzenesulfonyl chloride (2.01 g, 2.0 equiv) was added to the flask slowly. The reaction mixture was stirred overnight at rt. The reaction was diluted with water and extracted with ethyl acetate (3×100ml). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, filtered, concentrated and purified by column chromatography (EtOAc/PE = 1/2) to give ethyl 1-tosl-1H-indole-2-carboxylate b (1.4 g, 77% yield)

Reference： [1]Chemical Communications,2014,vol. 50,p. 8904 - 8907
[2]Organic and Biomolecular Chemistry,2015,vol. 13,p. 10015 - 10024
[3]Bioorganic and Medicinal Chemistry,2016,vol. 24,p. 5221 - 5234
[4]Journal of Medicinal Chemistry,2016,vol. 59,p. 10586 - 10600
[5]Patent: WO2015/86636,2015,A1 .Location in patent: Page/Page column 42
[6]Patent: US5278316,1994,A
[7]Patent: US5631281,1997,A
[8]Patent: US5631281,1997,A
[9]Patent: US5278316,1994,A
[10]Synthesis,2018,vol. 50,p. 4915 - 4921

54
[ 3770-50-1 ]
[ 124-63-0 ]
[ 213599-07-6 ]

Yield	Reaction Conditions	Operation in experiment
79%	With sodium hydrogencarbonate In tetrahydrofuran	5.a a a Ethyl 1-(methylsulfonyl)-2-indolecarboxylate A solution of ethyl-2-indolecarboxylate (500 mg, 2.64 mmol) in dry THF (5 mL) under an argon atmosphere was cooled to 0° C. and treated with sodium hydride (116 mg, 2.90 mmol). After stirring at room temperature for 5 minutes, the reaction was cooled to 0° C. and treated with methanesulfonyl chloride (0.23 mL, 2.90 mmol). The resulting mixture was gradually warmed to room temperature and stirred for 20 h. The reaction was quenched with saturated NaHCO3 and diluted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo. The resulting golden yellow oil was chromatographed over silica gel eluding with 5%, 10%, and 15% ethyl acetate/hexane to provide the title compound (79%, 556.6 mg) as a cream solid. 1H NMR (400 MHz, CDCl3) δ8.05 (d, 1H), 7.65 (d, 1H), 744 (t, 1H), 7.31 (m, 2H), 4.42 (q, 2H), 3.71 (s, 3H), 1.42 (t, 3H).
77%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: methanesulfonyl chloride In N,N-dimethyl-formamide for 1h;	4.1 Preparation of ethyl 1-(methanesulfonyl)-1H-indole-2-carboxylate 100 mg (0.53 mmol) of ethyl 1H-indole-2-carboxylate and 32 mg (0.79 mmol) of sodium hydride were dissolved in 2 ml of DMF, stirred at 0 ° C for 10 minutes,82 ul (1.06 mmol) of methylsulfonyl chloride was added and stirred for 1 hour. After completion of the reaction, the mixture was extracted with 75 ml of ethyl acetate, washed with saturated sodium chloride solution and water, and dried over anhydrous sodium sulfate.The filtrate was concentrated under reduced pressure and purified by column chromatography (normal nucleic acid: ethyl acetate = 15: 1, v / v) to obtain 109 mg (0.41 mmol) of the target compound as a white solid in 77% yield.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC; TEVA PHARMACEUTICAL INDUSTRIES LTD. - US6214856, 2001, B1
[2]Current Patent Assignee: KOREA RESEARCH INSTITUTE OF CHEMICAL TECHNOLOGY - KR101725451, 2017, B1 Location in patent: Paragraph 0331-0333

55
[ 3770-50-1 ]
[ 536-74-3 ]
ethyl 1-(2-phenylethynyl)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With pyridine; oxygen; sodium carbonate In toluene at 70℃; for 4h;

Reference： [1]Hamada, Tetsuya; Ye, Xuan; Stahl, Shannon S. [Journal of the American Chemical Society, 2008, vol. 130, # 3, p. 833 - 835]

56
[ 3770-50-1 ]
[ 768-60-5 ]
C₂₀H₁₇NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
51%	With pyridine; oxygen; sodium carbonate In toluene at 70℃; for 4h;

Reference： [1]Hamada, Tetsuya; Ye, Xuan; Stahl, Shannon S. [Journal of the American Chemical Society, 2008, vol. 130, # 3, p. 833 - 835]

57
[ 3770-50-1 ]
[ 2632-14-6 ]
[ 1049318-37-7 ]

Reference： [1]Journal of Heterocyclic Chemistry,2008,vol. 45,p. 1083 - 1087

58
[ 3770-50-1 ]
[ 78667-04-6 ]
[ 1119282-69-7 ]

Yield	Reaction Conditions	Operation in experiment
		60% NaH (527 mg, 0.0132 mol) is added to a mixture of ethyl lH-indole-2- carboxylate (1.13 g, 0.0059 mol) in DMF (20 mL) at rt and stirred for 10 mins. 2- Chloromethyl-1-methylimidazole hydrochloride is then added to the mixture and stirred for 20 h. The mixture is diluted with ice water (100 mL) and the white solid is filtered to afford the title compound.
		EXAMPLE 4; N l-((l-methyl-lH-imidazol-2-yl)methyl)-N-((l-(pyridin-3-yl)cyclohexyl)methyl)-lH-indole-2- carboxamide; Step 1. Ethyl; 60% NaH (527 mg, 0.0132 mol) is added to a mixture of ethyl lH-indole-2- carboxylate (1.13 g, 0.0059 mol) in DMF (20 mL) at rt and stirred for 10 mins. 2-Chloromethyl- 1-methylimidazole hydrochloride is then added to the mixture and stirred for 20 h. The mixture is diluted with ice water (100 mL) and the white solid is filtered to afford the title compound.

Reference： [1]Patent: WO2009/23623,2009,A1 .Location in patent: Page/Page column 67
[2]Patent: WO2009/108551,2009,A2 .Location in patent: Page/Page column 57

59
[ 3770-50-1 ]
[ 106-96-7 ]
[ 1062323-82-3 ]

Yield	Reaction Conditions	Operation in experiment
98%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Stage #2: propargyl bromide In N,N-dimethyl-formamide; mineral oil at 20℃; for 48h;	General procedure for propargylation of pyrrole and indole derivatives. General procedure: To a stirred solution of substituted methyl 1H-pyrrole-2-carboxylate (5 mmol) in DMF (10 mL) was added solid NaH (8 mmol) portionwise at 0 °C over 30 min. The reaction mixture was stirred at room temperature for 30 min. followed by dropwise addition of propargyl bromide or 1-bromobut-2-yne (6 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 2 d. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (4 × 25 mL) and dried over MgSO4. Evaporation of solvent gave propargyl esters.
97%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: propargyl bromide In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere;
94%	With sodium hydride In N,N-dimethyl-formamide; toluene; mineral oil at 20℃; for 4h;

92%	With sodium hydride In tetrahydrofuran at 25℃;
88%	Stage #1: 2-carbethoxyindole With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 0.25h; Stage #2: propargyl bromide With tetrabutylammomium bromide In N,N-dimethyl-formamide; toluene at 20℃; for 6h;	General procedure for the synthesis of ethyl 1-(prop-2-ynyl)-1H-indole-2-carboxylates (4a and 4b) General procedure: To a solutionof ethyl-1H-indole-2-carboxylate intermediate (3a/3b)in DMF, K2CO3 was added and the reaction mass was keptfor stirring at RT for 15 min. Propargyl bromide (80 %solution in toluene) was then charged into the reactionmass followed by catalytic amount of n-tetrabutyl ammoniumbromide, and the reaction mass was stirred at roomtemperature (RT) for 6 h. The reaction was monitoredusing TLC, and after the completion of the reaction, thereaction mass was added to cold water with stirring. The product was extracted with ethyl acetate, and the organiclayer was given thorough water wash followed by brinewash. The organic layer was then dried using Na2SO4 andconcentrated to get the crude product. The crude productwas then purified using column chromatography usingethylacetate/pet ether (1:1) as the eluent to get the pureproduct (4a/4b). Ethyl 1-(prop-2-ynyl)-1H-indole-2-carboxylate (4a) Theabove-mentioned procedure was followed for compound3a (7 g, 37.04 mmol) in DMF (35 mL) using K2CO3(12.8 g, 92.6 mmol) and propargyl bromide (44.44 mmol)to get the intermediate (4a) as red viscous liquid. Yield:7.4 g (88 %); 1H NMR (300 MHz, CDCl3): δ 7.01-7.71(5H, m, Ar-H), 5.79 (2H, s, N-CH2), 4.42 (2H, q,J = 7.4 Hz, CO2CH2), 2.64 (1H, s, -C:CH), 1.44 (3H, t,J = 7.4 Hz, CO2CH2CH3); 13C NMR (100 MHz, CDCl3):δ 164.2 (C, C=O), 149.5 (C, C-8), 145.3 (C, C-9), 138.4 (C,C-2), 125.6 (CH, C-5), 123.1 (CH, C-6), 120.5 (CH, C-4),120.2 (CH, C-7), 110.9 (CH, C-3), 75.1 (C, C:CH), 69.3(CH, C:CH), 61.2 (CH2, OCH2), 38.7 (CH2, NCH2), 10.9(CH3). Anal. calculated for C14H13NO2; C, 73.99; H, 5.77;N, 6.16. Found: C, 74.28; H, 5.00; N, 6.22.
81%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.5h; Stage #2: propargyl bromide In N,N-dimethyl-formamide; mineral oil at 0℃; for 4h;
80.7%	With sodium hydride In N,N-dimethyl-formamide at 0℃; Inert atmosphere;
	With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere;

Reference： [1]Taskaya, Sultan; Menges, Nurettin; Balci, Metin [Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 897 - 905]
[2]Hammoud, Sokaina; Anselmi, Elsa; Cherry, Khalil; Kizirian, Jean-Claude; Thibonnet, Jérôme [European Journal of Organic Chemistry, 2018, vol. 2018, # 45, p. 6314 - 6327]
[3]Basceken, Sinan; Kaya, Serdal; Balci, Metin [Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12552 - 12561]
[4]Current Patent Assignee: JINAN UNIVERSITY (GUANGZHOU) - CN106928121, 2017, A Location in patent: Page/Page column 26
[5]Panathur, Naveen; Gokhale, Nikhila; Dalimba, Udayakumar; Koushik, Pulla Venkat; Yogeeswari, Perumal; Sriram, Dharmarajan [Medicinal Chemistry Research, 2016, vol. 25, # 1, p. 135 - 148]
[6]Verniest, Guido; Padwa, Albert [Organic Letters, 2008, vol. 10, # 19, p. 4379 - 4382]
[7]Al-Qawasmeh, Raed A.; Al-Nazer, Louy A.; Dawlat-Kari, Sarah A.; Abu-Qatouseh, Luay; Sabri, Salim S.; Aldamen, Murad A.; Sinnokrot, Mutasem [Open Chemistry, 2020, vol. 18, # 1, p. 138 - 148]
[8]Fu, Jian; Hammoud, Sokaina; Kremer, Laurent; Maaliki, Carine; Raynaud, Clément; Thibonnet, Jérôme; Thiery, Emilie; Viljoen, Albertus; Villaume, Sydney; Vincent, Stéphane P. [Bioorganic and medicinal chemistry, 2020, vol. 28, # 13]

60
[ 79-37-8 ]
[ 3770-50-1 ]
[ 138731-14-3 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of 31 g AlCl3 in 400 ml DCM, 20 ml oxalyl dichloride was added dropwise. Then, after 30 min 20 g 1 H-Indole-2-carboxylic acid ethyl ester in 200 ml DCM were added and the reaction mixture was stirred for 2 h. The reaction mixture was poured on to crushed ice and extracted twice with 500 ml DCM. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The residue was taken-up in 500 ml Propan-2-ol and stirred for 4 h at room temperature. After concentration of the reaction mixture under reduced pressure the residue was purified by chromatography on silica gel eluting with an ethyl acetate/heptane 1:10 -> 4:1 gradient. Yield: 5.24 g.

Reference： [1]Patent: EP1479677,2004,A1 .Location in patent: Page 51

61
[ 1906-82-7 ]
[ 26260-02-6 ]
[ 3770-50-1 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 6549 - 6551

62
[ 1906-82-7 ]
[ 89-98-5 ]
[ 3770-50-1 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 6549 - 6551
[2]RSC Advances,2017,vol. 7,p. 13754 - 13759

63
[ 1906-82-7 ]
[ 6630-33-7 ]
[ 3770-50-1 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 6549 - 6551
[2]RSC Advances,2017,vol. 7,p. 13754 - 13759

64
[ 109-06-8 ]
[ 3770-50-1 ]
[ 1278518-06-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: α-picoline With lithium diisopropyl amide In tetrahydrofuran; hexane at -60 - 0℃; for 1.5h; Inert atmosphere; Stage #2: 2-carbethoxyindole In tetrahydrofuran; hexane at 0 - 20℃; for 18h; Inert atmosphere;	5.1.3. General synthetic procedure for 1-(1H-indol-2-yl)-2-arylketones (7-10, 12)⁴³ General procedure: An oven-dried flask was purged with argon while hot, then allowed to cool down to room temperature under argon and charged with dry THF (2 mL/mmol of starting indole 3/6) and diisopropylamine (4.0 equiv). The solution was cooled to -78 °C in a dry ice/isopropanol bath and n-butyl lithium, 1.6 M solution in hexanes (4.0 equiv), was added to give a bright yellow solution. The mixture was stirred for 30 min below -60 °C whereupon a solution of picoline or another appropriate reagent with an ionizable methyl(ene) group (4.0 equiv) in THF (2 mL/mmol of starting indole 3 or 6) was added to give a yellow to red colored mixture. During a further 30 min, the bath temperature was allowed to rise to approx. 0 °C during which time the reaction mixture became a yellow to red suspension. The temperature was then kept at 0 °C (using an ice/water bath) for an additional 30 min. At this point, a solution of the indole-2-carbonyl compound 3/6 (1.0 equiv) in THF (4 mL/mmol) was added dropwise over the flask wall. The reaction mixture darkened (dark purple to dark brown color in most cases) and was then allowed to attain room temperature overnight. At 18 h (unless otherwise stated) after the addition of the indole component, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL/mmol of starting compound 3/6) and stirred for several minutes. Upon partition between ethyl acetate and water, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were dried over MgSO4. The title products were purified by chromatography (the products typically eluted with 70-80% of ethyl acetate). The products were then precipitated by concentration of the pooled column fractions combined with the addition of cyclohexane. The precipitates formed were filtered off, washed twice with cyclohexane and dried at 40 °C in vacuo to yield analytically pure samples. The following compounds were prepared in this way:

Reference： [1]Location in patent: experimental part Dolusic, Eduard; Larrieu, Pierre; Blanc, Sebastien; Sapunaric, Frederic; Norberg, Bernadette; Moineaux, Laurence; Colette, Delphine; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Ferain, Thierry; Fraser, Graeme; Galeni, Moreno; Frre, Jean-Marie; Masereel, Bernard; Van Den Eynde, Benoit; Wouters, Johan; Frederick, Raphael [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 4, p. 1550 - 1561]

65
[ 108-89-4 ]
[ 3770-50-1 ]
[ 54852-14-1 ]

Yield	Reaction Conditions	Operation in experiment
90%	Stage #1: picoline With lithium diisopropyl amide In tetrahydrofuran; hexane at -60 - 0℃; for 1.5h; Inert atmosphere; Stage #2: 2-carbethoxyindole In tetrahydrofuran; hexane at 0 - 20℃; for 18h; Inert atmosphere;	5.1.3. General synthetic procedure for 1-(1H-indol-2-yl)-2-arylketones (7-10, 12)⁴³ General procedure: An oven-dried flask was purged with argon while hot, then allowed to cool down to room temperature under argon and charged with dry THF (2 mL/mmol of starting indole 3/6) and diisopropylamine (4.0 equiv). The solution was cooled to -78 °C in a dry ice/isopropanol bath and n-butyl lithium, 1.6 M solution in hexanes (4.0 equiv), was added to give a bright yellow solution. The mixture was stirred for 30 min below -60 °C whereupon a solution of picoline or another appropriate reagent with an ionizable methyl(ene) group (4.0 equiv) in THF (2 mL/mmol of starting indole 3 or 6) was added to give a yellow to red colored mixture. During a further 30 min, the bath temperature was allowed to rise to approx. 0 °C during which time the reaction mixture became a yellow to red suspension. The temperature was then kept at 0 °C (using an ice/water bath) for an additional 30 min. At this point, a solution of the indole-2-carbonyl compound 3/6 (1.0 equiv) in THF (4 mL/mmol) was added dropwise over the flask wall. The reaction mixture darkened (dark purple to dark brown color in most cases) and was then allowed to attain room temperature overnight. At 18 h (unless otherwise stated) after the addition of the indole component, the reaction was quenched with saturated aqueous ammonium chloride solution (10 mL/mmol of starting compound 3/6) and stirred for several minutes. Upon partition between ethyl acetate and water, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were dried over MgSO4. The title products were purified by chromatography (the products typically eluted with 70-80% of ethyl acetate). The products were then precipitated by concentration of the pooled column fractions combined with the addition of cyclohexane. The precipitates formed were filtered off, washed twice with cyclohexane and dried at 40 °C in vacuo to yield analytically pure samples. The following compounds were prepared in this way:

Reference： [1]Location in patent: experimental part Dolusic, Eduard; Larrieu, Pierre; Blanc, Sebastien; Sapunaric, Frederic; Norberg, Bernadette; Moineaux, Laurence; Colette, Delphine; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Ferain, Thierry; Fraser, Graeme; Galeni, Moreno; Frre, Jean-Marie; Masereel, Bernard; Van Den Eynde, Benoit; Wouters, Johan; Frederick, Raphael [Bioorganic and Medicinal Chemistry, 2011, vol. 19, # 4, p. 1550 - 1561]

66
[ 40114-49-6 ]
[ 3770-50-1 ]
[ 1268716-42-2 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1-benzyl-3-piperidone; 2-carbethoxyindole With sulfuric acid In water; acetic acid at 120℃; Stage #2: With hydrogen In methanol for 8h; Inert atmosphere;	3 General Procedure for the Synthesis of 2-Substituted indole-piperidine esters Example 3 General Procedure for the Synthesis of 2-Substituted indole-piperidine esters A solution of 1H-indole-2-carboxylic acid ethyl ester (5 g, 26.2 mmol), 1-benzyl-piperidin-3-one (12.9 g, 51.9 mmol) and concentrated sulfuric acid (1.45 mL, 26.2 mmol) in acetic acid (20 mL) is heated at 120° C. The reaction is monitored by thin layer chromatography. The mixture is diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture is purified on a silica gel column chromatography to give a mixture of 3-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-indole-2-carboxylic acid ethyl ester and 3-(1-benzyl-1,4,5,6-tetrahydro-pyridin-3-yl)-1H-indole-2-carboxylic acid ethyl ester (8.6 g, 91.2%). MS (m/z): 360.93 (M+1). A mixture of 3-(1-benzyl-1,2,5,6-tetrahydro-pyridin-3-yl)-1H-indole-2-carboxylic acid ethyl ester, 3-(1-benzyl-1,4,5,6-tetrahydro-pyridin-3-yl)-1H-indole-2-carboxylic acid ethyl ester (8.6 g, 23.5 mmol) and Pd(OH)2/C (6 g, 10% wt) in methanol (200 mL) is purged with nitrogen and filled with hydrogen at 60 PSI and the reaction mixture is agitated in a Parr shaker for 8 h. The mixture is filtered through a Celite pad, which is washed with methanol. The combined filtrates are concentrated and used for the next reaction without purification (5.9 g, 92.2%).MS (m/z): 272.95 (M+1).
	Stage #1: 1-benzyl-3-piperidone; 2-carbethoxyindole With sulfuric acid In acetic acid at 120℃; Stage #2: With hydrogen In methanol for 8h; Inert atmosphere;	3 A solution of IH-indole-2-carboxylic acid ethyl ester (5 g, 26.2 mmol), l-benzyl-piperidin-3-one (12.9 g, 51.9 mmol) and concentrated sulfuric acid (1.45 mL, 26.2 mmol) in acetic acid (20 mL) is heated at 120°C. The reaction is monitored by thin layer chromatography. The mixture is diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture is purified on a silica gel column chromatography to give a mixture of 3-(l -benzyl- 1 ,2,5,6-tetrahydro-pyridin-3-yl)-l H-indoie-2-carboxylic acid ethyl ester and 3-(l-benzyl-l,4,5,6-tetrahydro-pyridin-3-yl)-lH-indole-2-carboxylic acid ethyl ester (8.6 g, 1.2%). MS (m/z): 360.93 (M+l). A mixtureof 3-(l-benzy.-l,2,5,6-tetrahydro-pyridin-3-yl)-lH-indole-2-carboxylic acid ethyl ester, 3-(l-benzyl-l,4,5,6-tetrahydro-pyridin-3-yl)-IH-indole-2-carboxylic acid ethyl ester (8.6 g, 23.5 mmol) and Pd(OH)2/C (6 g, 10% wt) in methanol (200 mL) is purged with nitrogen and filled with hydrogen at 60 PSI and the reaction mixture is agitated in a Parr shaker for 8 h. The mixture is filtered through a Celite pad, which is washed with methanol. The combined filtrates are concentrated and used for the next reaction without purification (5.9 g, 92.2%).MS (m/z): 272.95 (M+l).

Reference： [1]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - US2011/53925, 2011, A1 Location in patent: Page/Page column 21-22
[2]Current Patent Assignee: NOVARTIS AG; Novartis (w/o Sandoz) - WO2012/25155, 2012, A1 Location in patent: Page/Page column 38

67
[ 3770-50-1 ]
[ 882-33-7 ]
[ 106184-17-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With potassium carbonate In dimethyl sulfoxide at 100℃; for 9h; Green chemistry;
67%	With copper(l) iodide; oxygen In dimethyl sulfoxide at 110℃; regioselective reaction;	4.2. General procedure for chalcogenylation of azaheterocycles with dichalcogenides General procedure: A mixture of azaheterocycles 1 or 4 (0.20 mmol), dichalcogenides 2 (0.10 mmol), and CuI (0.020 mmol, 10 mol %) in DMSO (2.0 mL) was stirred at 110 °C under air atmosphere for 10-18 h until complete consumption of staring material as monitored by TLC. The solution was then cooled to room temperature, diluted with ethyl acetate (10 mL), washed with H2O (3×10 mL), dried over Na2SO4, filtered, and evaporated under vacuum. The crude product was purified by column chromatography on silica gel (eluting with PE/EA=25/1 to 4/1) to afford the desired products 3 or 5.

Reference： [1]Sang, Peng; Chen, Zhengkai; Zou, Jianwei; Zhang, Yuhong [Green Chemistry, 2013, vol. 15, # 8, p. 2096 - 2100]
[2]Li, Zhen; Hong, Jianquan; Zhou, Xigeng [Tetrahedron, 2011, vol. 67, # 20, p. 3690 - 3697]

68
[ 24393-59-7 ]
[ 3770-50-1 ]

Yield	Reaction Conditions	Operation in experiment
92%	With dichloro bis(acetonitrile) palladium(II); 1,10-Phenanthroline; phenyl formate; triethylamine In acetonitrile at 140℃; for 3h; Inert atmosphere;
92%	With dichloro bis(acetonitrile) palladium(II); 1,10-Phenanthroline; phenyl formate; triethylamine In acetonitrile at 140℃; for 3h; Inert atmosphere; Schlenk technique; Sealed tube;
86%	With triethyl phosphate for 3h; Reflux;

Reference： [1]Formenti, Dario; Ferretti, Francesco; Ragaini, Fabio [ChemCatChem, 2018, vol. 10, # 1, p. 148 - 152]
[2]Ahmed Fouad, Manar; Ferretti, Francesco; Formenti, Dario; Milani, Fabio; Ragaini, Fabio [European Journal of Organic Chemistry, 2021, vol. 2021, # 34, p. 4876 - 4894]
[3]Location in patent: experimental part Le, Thanh Nguyen; Yang, Su Hui; Khadka, Daulat Bikram; Cho, Suk Hee; Zhao, Chao; Cho, Won-Jea [Bulletin of the Korean Chemical Society, 2011, vol. 32, # 12, p. 4309 - 4315]

69
[ 3770-50-1 ]
[ 84978-69-8 ]

Reference： [1]Patent: US2012/302578,2012,A1

70
[ 3770-50-1 ]
[ 100-52-7 ]
3,3'-benzylidene-bis-indole-2-carboxylic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With bromine In acetonitrile at 50℃; for 2h;	2.1 General procedure in CH₃CN (taking 3a as an example) General procedure: A 25-mL flask, equipped with a magnetic stirring bar, was charged with 1H-indole 1a (117mg, 1.0mmol), CH3CN (4.0mL), and benzaldehyde 2a (0.056mL, 0.55mmol), followed by addition of a solution of Br2 (0.0010mL) in CH3CN (1.0mL). The reaction mixture was stirred at 50°C for 1min. After 1a was consumed, as indicated by thin-layer chromatography (TLC), the reaction mixture was quenched with aqueous Na2S2O3, cooled to room temperature, poured into 30mL water under stirring, and extracted with CH2Cl2 three times. The extract was dried over anhydrous MgSO4. After removal of solvents, the residue was purified by column chromatography on silica gel (petroleum ether-ethyl acetate=9/1, V/V) to afford the product 3a as a pink solid (158mg, 98% yield).
90%	With hydrogenchloride In ethanol; water for 2h; Inert atmosphere; Reflux;	1 Compound 2. Compound 2. Ethyl indole-2-carboxylate (18.9g, 100mmol) was dissolved in 200ml ethanol under nitrogen atmosphere; benzaldehyde (5.3g, 50mmol) was added and the mixture was heated to reflux temperature. Concentrated HCI (3.7ml) was added and the reaction was left for 2 hour. After cooling the white product was filtered off and washed thoroughly with cold ethanol. The reaction can be followed by TLC (CHCI3 : Hexane = 1 : 1 ). Yield was 90%.
89%	With hydrogenchloride In ethanol; water for 2h; Inert atmosphere; Reflux;	Compound 2. To a solution of ethyl 1H-indole-2-carboxylate (1) (1.89g, 10mmol) in ethanol (20mL), benzaldehyde (0.53g, 5mmol) and 37% HCl (0.4mL) were added under nitrogen atmosphere. The reaction mixture was heated to reflux and stirred for 2h followed by cooling to room temperature (rt). The precipitate from the cooled solution was filtered, washed with cold ethanol and dried over MgSO4. Yield: 2.076g (4.49mmol; 89%). 1H NMR (400-MHz, DMSO-d6) δ 11.72 (s, 2H, NH indole), 7.44 (d, 2H, Ph), 7.37 (s, 1H, Ph-CH), 7.24 (m, 3H, Ph), 7.06-7.14 (m, 4 H, Ph), 6.45-6.66 (m, 4H, Ph), 4.19 (q, 4 H, CH2), 1.17 (t, 6H, CH3). ESI-MS for C29H26N2O4 [M+Na]+: found 489.18Da, calculated 489.17Da. Compound 3: compound 2 (0.5g, 1.07mmol) and hydrazine monohydrate (1mL, 20.6mmol) were dissolved in a mixture of pyridine (6mL) and methanol (3mL) and the resulting mixture was heated to reflux and stirred for 48h. After removal of solvents and excess hydrazine azeotropically with water under reduced pressure, the residue was dissolved in dichloromethane and the hydrazide was precipitated by addition of acetonitrile to the solution. The white precipitate was collected by filtration and dried over MgSO4. Yield: 0.34g (0.78mmol; 73%). 1H NMR (400-MHz, DMSO-d6) δ 11.38 (s, 2H, NH indole), 9.57 (s, 2H, CONH), 7.39 (d, 2H, Ph), 7.25 (s, 1H, Ph-CH), 7.21 (m, 3H, Ph), 6.99-7.09 (m, 4H, Ph), 6.58-6.66 (m, 4H, Ph), 4.5 (s, 4H, NH2). ESI-MS for C25H22N6O2 [M+Na]+: found 461.17Da, calculated 461.17Da. Compound 4: compound 3 (17.5mg, 0.04mmol), DOTA-NHS (50mg, 0.1mmol) and DIEA (77.5μL, 0.45mmol) were dissolved in dry DMF (2mL) and the resulting mixture was stirred for 24h at rt. After addition of water the solvents were removed under reduced pressure and the resulting white powder was dissolved in a mixture of acetonitrile/H2O (1:1, v/v) and purified by preparative RP-HPLC using an XTerra Prep RP18 column (10μm, 10mm×250mm; Waters) eluted with gradient mixtures of 0.1% TFA in H2O/0.1% TFA in acetonitrile (0-25min: 80/20 to 35/65 v/v, linear gradient) at a flow rate of 3.0mL/min. Yield: 34mg (0.028mmol; 70%). 1H NMR (600-MHz, DMSO-d6) δ 11.79 (br s, 6H, COOH), 10.21 (br s, 2H, NH indole), 7.42 (m, 2H, Ph), 7.21 (m, 3H, Ph), 7.16 (m, 1H, Ph-CH), 7.14 (m, 2H, Ph), 6.98 (m, 2H, Ph), 6.65 (m, 2H, Ph), 6.58 (m, 2H, Ph), 3.84-3.70 (m, 4H, COCH2N), 3.48-3.29 (m, 12H, NCH2COOH), 3.03 (m, 32H, CH2N). 13C NMR (125-MHz, DMSO-d6) δ 162.19, 160.15-159.50, 144.23, 136.13, 128.97, 128.37, 127.18, 126.75, 124.87, 124.53, 122.75, 121.97, 120.18, 112.93, 55.68, 50.49 and 46.33. ESI-MS for C57H74N14O16 [M+H]+: found 1211.45Da, calculated 1211.54Da.

Reference： [1]Liang, Deqiang; Huang, Wenzhong; Yuan, Lin; Ma, Yinhai; Ma, Jingmei; Ning, Deman [Catalysis Communications, 2014, vol. 55, p. 11 - 14]
[2]Current Patent Assignee: RF THERAPEUTICS - WO2016/90491, 2016, A1 Location in patent: Paragraph 0096
[3]Prinsen, Kristof; Cona, Marlein Miranda; Cleynhens, Jan; Vanbilloen, Hubert; Li, Junjie; Dyubankova, Natalia; Lescrinier, Eveline; Bormans, Guy; Ni, Yicheng; Verbruggen, Alfons [Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 11, p. 3216 - 3220]

71
[ 1464963-64-1 ]
[ 3770-50-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With potassium hydroxide In acetonitrile at 20℃; for 20h; Schlenk technique;	4) Synthesis of Indole from indoline General procedure: A Schlenk tube was charged with indoline (0.2mmol) and KOH (0.5 mmol). Then 2 mL acetonitrile was added. The reactionmixture was stirred at room temperature for 20 h then filtered and concentratedin vacuo. The residue was purified by column chromatography on silica gel(eluting with 5:1 petroleum ether/ethyl acetate) to provide the desiredproduct.

Reference： [1]Huang, Hui; Yang, Yuan; Zhang, Xiaoyun; Zeng, Weilan; Liang, Yun [Tetrahedron Letters, 2013, vol. 54, # 45, p. 6049 - 6052]

72
[ 3770-50-1 ]
[ 901309-71-5 ]
[ 1603834-02-1 ]

Yield	Reaction Conditions	Operation in experiment
88%	Stage #1: 1-benzylpyrrolidine-3-carbonyl chloride With aluminum (III) chloride In 1,2-dichloro-ethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-carbethoxyindole In 1,2-dichloro-ethane at 0 - 20℃; for 18h; Stage #3: With aluminum (III) chloride In 1,2-dichloro-ethane at 70℃; for 3h;	91.a a) Ethyl 5-(l-benzylpyrrolidine-3-carbonyl)-lH-indole-2-carboxylate Example 91 5-(l-(l-Benzylpyrrolidin -yl)vinyl)-N-(3,5-difluorophenyl)-lH-indole-2-carboxamide a) Ethyl 5-(l-benzylpyrrolidine-3-carbonyl)-lH-indole-2-carboxylate To a solution of l-benzylpyrrolidine-3-carbonyl chloride (3.65 g, 16.3 mmol) in 1,2- dichloroethane (23 mL) was added under an atmosphere of nitrogen at 0°C aluminum chloride (3.26 g, 24.5 mmol). After stirring for 30 minutes at 0°C ethyl lH-indole-2-carboxylate (3.09 g, 16.3 mmol) was added and stirred for 18 hours at room temperature. After the addition of aluminum chloride (3.26 g, 24.5 mmol) the reaction was stirred for 3 hours at 70°C. After cooling to 0°C the reaction was diluted with ethyl acetate (100 mL) and basified by drop wise addition of a 1 M aqueous solution of sodium carbonate (200 mL). After stirring for 30 minutes the suspension was filtered over Hyflo and was washed well with ethyl acetate. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers were washed with a 1 M aqueous solution of sodium carbonate (100 mL). The combined organic layers were dried over sodium sulfate, filtered and purified by flash chromatography on silica gel using heptane / (ethyl acetate: NEt3 95:5) (50.50 to 30:70) to yield the title compound as a light brown foam (5.38 g, 88 %). MS ISP (m/e): 377.4 (100) [(M+H)+].
88%	Stage #1: 1-benzylpyrrolidine-3-carbonyl chloride With aluminum (III) chloride In 1,2-dichloro-ethane at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-carbethoxyindole In 1,2-dichloro-ethane at 70℃; for 3h; Inert atmosphere;	91.a Ethyl 5-(1-benzylpyrrolidine-3-carbonyl)-1H-indole-2-carboxylate To a solution of 1-benzylpyrrolidine-3-carbonyl chloride (3.65 g, 16.3 mmol) in 1,2-dichloroethane (23 mL) was added under an atmosphere of nitrogen at 0°C aluminum chloride (3.26 g, 24.5 mmol). After stirring for 30 minutes at 0°C ethyl 1H-indole-2-carboxylate (3.09 g, 16.3 mmol) was added and stirred for 18 hours at room temperature. After the addition of aluminum chloride (3.26 g, 24.5 mmol) the reaction was stirred for 3 hours at 70°C. After cooling to 0°C the reaction was diluted with ethyl acetate (100 mL) and basified by drop wise addition of a 1 M aqueous solution of sodium carbonate (200 mL). After stirring for 30 minutes the suspension was filtered over Hyflo and was washed well with ethyl acetate. The aqueous layer was extracted with ethyl acetate (150 mL). The organic layers were washed with a 1 M aqueous solution of sodium carbonate (100 mL). The combined organic layers were dried over sodium sulfate, filtered and purified by flash chromatography on silica gel using heptane / (ethyl acetate: NEt3 95:5) (50.50 to 30:70) to yield the title compound as a light brown foam (5.38 g, 88 %). MS ISP (m/e): 377.4 (100) [(M+H)+].

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2014/60386, 2014, A1 Location in patent: Page/Page column 86
[2]Current Patent Assignee: ROCHE HOLDING AG - EP2722329, 2014, A1 Location in patent: Paragraph 0278

73
[ 60032-57-7 ]
[ 3770-50-1 ]
[ 1531589-66-8 ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 736 - 741

74
[ 60032-57-7 ]
[ 3770-50-1 ]
[ 1531589-67-9 ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 736 - 741

75
[ 60032-57-7 ]
[ 3770-50-1 ]
[ 1531589-68-0 ]

Reference： [1]Journal of Organic Chemistry,2014,vol. 79,p. 736 - 741

76
[ 3770-50-1 ]
[ 5257-24-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / 0.08 h / 0 °C / Inert atmosphere 1.2: 4.5 h / 20 - 60 °C / Inert atmosphere 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 5.17 h / 0 - 80 °C / Inert atmosphere 3.1: manganese(IV) oxide / acetonitrile / 15 h / 20 °C
	Multi-step reaction with 3 steps 1.1: trichlorophosphate / 0.08 h / 0 °C / Inert atmosphere 1.2: 4.5 h / 0 - 60 °C / Inert atmosphere 1.3: 0.08 h / 0 °C / pH 7 / Inert atmosphere 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 5.17 h / 0 - 80 °C / Inert atmosphere 3.1: manganese(IV) oxide / acetonitrile / 15 h / 20 °C / Inert atmosphere

Reference： [1]Tan, Wei; Li, Xin; Gong, Yu-Xin; Ge, Meng-Di; Shi, Feng [Chemical Communications, 2014, vol. 50, # 100, p. 15901 - 15904]
[2]Devi, Manju; Jadhav, Amol P.; Singh, Ravi P. [New Journal of Chemistry, 2021, vol. 45, # 19, p. 8445 - 8448]

77
[ 31577-25-0 ]
[ 3770-50-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2015,vol. 13,p. 2588 - 2599

78
[ 3770-50-1 ]
[ 2945-03-1 ]
C₂₀H₂₀N₂O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62%	Stage #1: 2-carbethoxyindole With potassium carbonate In acetonitrile at 85℃; for 0.0833333h; Stage #2: N-benzyl-2-bromoacetamide In acetonitrile at 85℃; for 2h;

Reference： [1]Rodriguez, Veronica; Valente, Sergio; Rovida, Stefano; Rotili, Dante; Stazi, Giulia; Lucidi, Alessia; Ciossani, Giuseppe; Mattevi, Andrea; Botrugno, Oronza A.; Dessanti, Paola; Mercurio, Ciro; Vianello, Paola; Minucci, Saverio; Varasi, Mario; Mai, Antonello [MedChemComm, 2015, vol. 6, # 4, p. 665 - 670]

79
[ 3770-50-1 ]
[ 3355-28-0 ]
ethyl 1-(but-2-yn-1-yl)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With sodium hydride In N,N-dimethyl-formamide; mineral oil at 20℃; for 2h;
80%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide at 0 - 20℃; for 0.5h; Inert atmosphere; Stage #2: 1-Bromo-2-butyne In N,N-dimethyl-formamide at 0 - 20℃; for 4h; Inert atmosphere;
70%	Stage #1: 2-carbethoxyindole With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 1h; Stage #2: 1-Bromo-2-butyne In N,N-dimethyl-formamide; mineral oil at 20℃; for 48h;	General procedure for propargylation of pyrrole and indole derivatives. General procedure: To a stirred solution of substituted methyl 1H-pyrrole-2-carboxylate (5 mmol) in DMF (10 mL) was added solid NaH (8 mmol) portionwise at 0 °C over 30 min. The reaction mixture was stirred at room temperature for 30 min. followed by dropwise addition of propargyl bromide or 1-bromobut-2-yne (6 mmol) in DMF (5 mL). The resulting mixture was stirred at room temperature for 2 d. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (4 × 25 mL) and dried over MgSO4. Evaporation of solvent gave propargyl esters.

Reference： [1]Basceken, Sinan; Kaya, Serdal; Balci, Metin [Journal of Organic Chemistry, 2015, vol. 80, # 24, p. 12552 - 12561]
[2]Hammoud, Sokaina; Anselmi, Elsa; Cherry, Khalil; Kizirian, Jean-Claude; Thibonnet, Jérôme [European Journal of Organic Chemistry, 2018, vol. 2018, # 45, p. 6314 - 6327]
[3]Taskaya, Sultan; Menges, Nurettin; Balci, Metin [Beilstein Journal of Organic Chemistry, 2015, vol. 11, p. 897 - 905]

80
[ 3770-50-1 ]
[ 108-98-5 ]
[ 106184-17-2 ]

Yield	Reaction Conditions	Operation in experiment
87%	With tert.-butylhydroperoxide; iodine In acetonitrile at 60℃; regioselective reaction;	4.2 Experimental procedure for mono- and bis-sulfenylation of indoles General procedure: A mixture of indole 1 (0.5mmol), thiol 2 (0.505mmol) and TBHP (0.51mmol) were dissolved in MeCN (2.0mL) at 60°C in a flask, then iodine (0.10mmol, 10mol%) was added. The reaction proceeded under an air atmosphere for 0.5-1.0 h until complete consumption of starting material as monitored by TLC. The reaction mixture was quenched by the addition of saturated aq Na2S2O3 (5mL) and then extracted with EtOAc (2×10mL). The combined organic layer was separated, dried (MgSO4), filtered and concentrated under vacuum and the crude product was purified by column chromatography using petroleum ether/ethyl acetate as eluent to provide the product 3.
75%	With tetrabutylammomium bromide; iodine; oxygen; bovine serum albumin In water at 50℃; for 12h; Green chemistry; regioselective reaction;
67%	With iodine; dimethyl sulfoxide In 1,2-dichloro-ethane at 60℃; for 44h; regioselective reaction;

Reference： [1]Zhang, Hailei; Bao, Xiaoze; Song, Yuming; Qu, Jingping; Wang, Baomin [Tetrahedron, 2015, vol. 71, # 47, p. 8885 - 8891]
[2]Saima; Equbal, Danish; Lavekar, Aditya G.; Sinha, Arun K. [Organic and Biomolecular Chemistry, 2016, vol. 14, # 25, p. 6111 - 6118]
[3]Yi, Shanli; Li, Meichao; Mo, Weimin; Hu, Xinquan; Hu, Baoxiang; Sun, Nan; Jin, Liqun; Shen, Zhenlu [Tetrahedron Letters, 2016, vol. 57, # 17, p. 1912 - 1916]

81
[ 67-56-1 ]
[ 3770-50-1 ]
[ 558-13-4 ]
[ 54781-93-0 ]

Reference： [1]Chemistry - A European Journal,2015,vol. 21,p. 18052 - 18056

82
[ 3770-50-1 ]
[ 441800-93-7 ]

Reference： [1]ACS Medicinal Chemistry Letters,2016,vol. 7,p. 335 - 339

83
[ 3770-50-1 ]
ethyl 3-fluoro-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
70%	With water; Selectfluor In acetonitrile at 20℃;
47%	With Selectfluor In acetonitrile at 20℃; for 0.75h;	1.1 Step 1: Ethyl 3-fluoro-1H-indol-2-carboxylate To a solution of ethyl 1H-indol-2-carboxylate (35.0 g, 185 mmol) in acetonitrile (1.75 L) was added 1-chloromethyl-4-fluoro-1, 4-diazobicyclo [2.2.2] octanedi (tetrafluoroboric acid) salt (65.5 g, 1185 mmol) , and stirred at room temperature for 45 minutes. The reaction was quenched by adding saturated brine, the organic phase was collected, and concentrated in vacuum under reduced pressure, and the resulting residue was purified with silica gel column chromatography (petroleum ether/ethyl acetate) to give the target product (18.0 g, yield 47%) .
22.71%	With 1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octane bis(tetrafluoroborate) In acetonitrile at 20 - 30℃; for 2h; Inert atmosphere;	4.1.1 (1.1) Synthesis of intermediate 18a 1H-indole-2-carboxylic acid ethyl ester (1.89g, 9.99mmol)Soluble in acetonitrile (200 mL),1-chloromethyl-4-fluoro-1,4-diazobicyclo-2.2.2 octane bis(tetrafluoroborate) salt (4.24 g, 12.0 mmol) was added, and the reaction was stirred at room temperature for 24 hours.After evaporating the solvent under reduced pressure,Purified intermediate by column chromatography18a (470 mg, 2.27 mmol, yield 22.71%).

Reference： [1]Jiang, Xiaojian; Yang, Junjie; Zhang, Feng; Yu, Pei; Yi, Peng; Sun, Yewei; Wang, Yuqiang [Organic Letters, 2016, vol. 18, # 13, p. 3154 - 3157]
[2]Current Patent Assignee: HUTCHISON CHINA MEDITECH LTD. - WO2021/164735, 2021, A1 Location in patent: Page/Page column 130
[3]Current Patent Assignee: CHENGDU PIONEER PHARMACEUTICAL DEVELOPMENT CO LTD - CN109705071, 2019, A Location in patent: Paragraph 0255-0260

84
[ 3770-50-1 ]
[ 85953-39-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: sodium hydroxide / ethanol / 40 °C 1.2: 0.42 h / 250 °C / Microwave irradiation 2.1: sodium hydride 3.1: n-butyllithium / tetrahydrofuran / 0.5 h / -70 °C / Inert atmosphere 3.2: 2.25 h / -70 - 20 °C / Inert atmosphere 4.1: N-chloro-succinimide / dichloromethane / 2 h / 5 °C

Reference： [1]Greig, Iain R.; Baillie, Gemma L.; Abdelrahman, Mostafa; Trembleau, Laurent; Ross, Ruth A. [Bioorganic and Medicinal Chemistry Letters, 2016, vol. 26, # 18, p. 4403 - 4407]

85
[ 3770-50-1 ]
[ 589-15-1 ]
ethyl 1-(4-bromobenzyl)-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
87%	With caesium carbonate In acetonitrile at 60℃;	4.2.2 N-alkylation of indole derivatives General procedure: Ethyl indole-2-carboxylate (3) (5.0mmol) was first dissolved in acetonitrile (40mL); cesium carbonate (7.5mmol) was then added and the mixture stirred for 15min at room temperature. Subsequently, the corresponding alkyl bromide (5.5mmol) was added to the reaction mixture which was heated overnight at reflux. Upon completion of the reaction, which was monitored by TLC, the mixture was concentrated in vacuo and the residue dissolved in dichloromethane (80mL). The organic phase was washed with water (2×30mL), dried with anhydrous Na2SO4 and then concentrated in vacuo to afford sufficiently pure N-alkylated products

Reference： [1]Keček Plešec, Kaja; Urbančič, Dunja; Gobec, Martina; Pekošak, Aleksandra; Tomašič, Tihomir; Anderluh, Marko; Mlinarič-Raščan, Irena; Jakopin, Žiga [Bioorganic and Medicinal Chemistry, 2016, vol. 24, # 21, p. 5221 - 5234]

86
[ 50501-07-0 ]
[ 3770-50-1 ]

Yield	Reaction Conditions	Operation in experiment
99%	With H₈O₂₀P₈Pt₂^(4-)*4C₃₄H₇₂N⁽¹⁺⁾ In methanol Inert atmosphere; Irradiation;
92%	With rose bengal; oxygen In N,N-dimethyl acetamide at 20℃; for 24h; Irradiation;
91%	With tetrasodium cobalt(II) 4,4',4'',4'''-tetrasulphophthalocyanine In water; ethyl acetate at 20℃; for 36h; Irradiation; Green chemistry;

90%	With oxygen In ethanol at 60℃; for 24h; Green chemistry;
88%	With potassium <i>tert</i>-butylate In decane at 150℃; for 36h; Inert atmosphere; Schlenk technique;
83%	With trimethylamine-N-oxide In toluene at 100℃; for 20h; Inert atmosphere; Schlenk technique;	Oxidative dehydrogenation of indoline: General procedure: In a 2-neck RBF, 1 (20 mg, 0.0005 mmol) and TMNO (45 mg, 0.6 mmol) were suspended in toluene (4 mL) and to this solution indoline (60 mg, 0.5 mmol) was added. The reaction mixture was then heated to 100 oC for 20 h and it was filtered and solvent evaporated. The crude product obtained was purified by column chromatography using hexane/ethylacetate (7:1) as eluent to give pure indole (47 mg, 79%). A similar procedure was used for the other indolines and N-heterocycles.
69%	With tris(bipyridine)ruthenium(II) dichloride hexahydrate; Co(dmgH)<SUB>2</SUB>(4-MeCO<SUB>2</SUB>Py)Cl In water at 28℃; for 12h; Schlenk technique; Inert atmosphere; Irradiation;

Reference： [1]Zhong, Jian-Ji; To, Wai-Pong; Liu, Yungen; Lu, Wei; Che, Chi-Ming [Chemical Science, 2019, vol. 10, # 18, p. 4883 - 4889]
[2]Sahoo, Manoj K.; Jaiswal, Garima; Rana, Jagannath; Balaraman, Ekambaram [Chemistry - A European Journal, 2017, vol. 23, # 57, p. 14167 - 14172]
[3]Abinaya, R.; Baskar, B.; Mariappan, M.; Prasanth, Arun; Sridhar, R.; Srinath, S. [Green Chemistry, 2020, vol. 22, # 8, p. 2575 - 2587]
[4]Cui, Fu-Jun; Guo, Fu-Hu; Liu, Jing-Jiang; Liu, Xiao-Yu; Quan, Zheng-Jun; Ullah, Arif; Wang, Xi-Cun; Zhu, Ji-Hua [New Journal of Chemistry, 2022, vol. 46, # 4, p. 1791 - 1799]
[5]Jaiswal, Garima; Subaramanian, Murugan; Sahoo, Manoj K.; Balaraman, Ekambaram [ChemCatChem, 2019, vol. 11, # 10, p. 2449 - 2457]
[6]Kumaran, Elumalai; Leong, Weng Kee [Tetrahedron Letters, 2018, vol. 59, # 44, p. 3958 - 3960]
[7]Sahoo, Manoj K.; Balaraman, Ekambaram [Green Chemistry, 2019, vol. 21, # 8, p. 2119 - 2128]

87
[ 3770-50-1 ]
[ 108797-25-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrabutylammomium bromide; potassium carbonate In N,N-dimethyl-formamide at 20 - 50℃; for 43h; Inert atmosphere;	Ethyl 1-butylindole-2-carboxylate To a solution of ethyl indole-2-carboxylate (7.51 g; 39.7 mmol) and Bu4NBr (0.38 g; 1.2 mmol) dissolved in dry DMF (20 mL), solidK2CO3 (21.94 g; 158.7 mmol) was poured and BuI (6.8 mL; 10.95 g; 59.5 mmol) was added dropwise. The mixture was vigorouslystirred for 42 h at room temperature and then heated for 1 h at 50 °C. Solid was filtered out, washed with Et2O (2 × 50 mL). Theorganic phases were combined and washed with water (150 mL). The aqueous phase was washed with Et2O (4 × 50 mL). Theorganic phases again were combined, washed with water (2 × 25 mL), brine (1 × 100 mL), dried over Na2SO4 and the solvent wasevaporated in vacuo. The product was pure enough to use it in the next step without further purification.Dark yellow oil, yield 10.00 g (~100%).IR (CH2Cl2) 3059, 2958, 2932, 2872, 1712, 1614, 1518, 1480, 1465, 1413, 1368, 1354, 1320, 1297, 1248, 1235 cm-1.1H NMR (Bruker 500 MHz, CDCl3) δ = 0.94 (t, J = 7.4 Hz, 3H), 1.37 (sex, J = 7.6 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.78 (sex, J = 7.6Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.56 (t, J = 7.5 Hz, 2H), 7.13 (t, J = 7.3 Hz, 2H), 7.31 - 7.34 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.67(d, J = 8.0 Hz, 1H).13C NMR (Bruker 125 MHz, CDCl3) δ = 13.84, 14.35, 20.20, 32.73, 44.53, 69.44, 110.37, 110.47, 120.38, 122.59, 124.74, 125.97,127.52, 139.06, 162.02.HRMS (ESI) m/z calcd for C15H20NO2+: 246.1494; found: 246.1487

Reference： [1]Nowacki, Michał; Wojciechowski, Krzysztof [Beilstein Journal of Organic Chemistry, 2018, vol. 14, p. 194 - 202]

88
[ 3770-50-1 ]
[ 25554-84-1 ]
[ 63158-54-3 ]

Reference： [1]Organic Letters,2018,vol. 20,p. 1413 - 1416

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CAS No. :	3770-50-1	MDL No. :	MFCD00005609
Formula :	C₁₁H₁₁NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	QQXQAEWRSVZPJM-UHFFFAOYSA-N
M.W :	189.21	Pubchem ID :	73125
Synonyms :	2-Carbethoxyindole;2-Ethoxycarbonylindole

Num. heavy atoms :	14
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.18
Num. rotatable bonds :	3
Num. H-bond acceptors :	2.0
Num. H-bond donors :	1.0
Molar Refractivity :	54.39
TPSA :	42.09 Å²

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.32 cm/s

Log Po/w (iLOGP) :	2.15
Log Po/w (XLOGP3) :	3.0
Log Po/w (WLOGP) :	2.34
Log Po/w (MLOGP) :	1.67
Log Po/w (SILICOS-IT) :	2.7
Consensus Log Po/w :	2.37

[ CAS No. 3770-50-1 ] {[proInfo.proName]}

Quality Control of [ 3770-50-1 ]

Related Doc. of [ 3770-50-1 ]

Product Details of [ 3770-50-1 ]

Calculated chemistry of [ 3770-50-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 3770-50-1 ]

Application In Synthesis of [ 3770-50-1 ]

[ 3770-50-1 ] Synthesis Path-Upstream 1~7

[ 3770-50-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of
[ 3770-50-1 ]

Esters

Related Parent Nucleus of
[ 3770-50-1 ]

Indoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

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

Log S (ESOL) :	-3.18
Solubility :	0.125 mg/ml ; 0.000659 mol/l
Class :	Soluble
Log S (Ali) :	-3.55
Solubility :	0.0535 mg/ml ; 0.000283 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.77
Solubility :	0.0324 mg/ml ; 0.000171 mol/l
Class :	Soluble

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.74

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
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

[ CAS No. 3770-50-1 ] {[proInfo.proName]}

Quality Control of [ 3770-50-1 ]

Related Doc. of [ 3770-50-1 ]

Product Details of [ 3770-50-1 ]

Calculated chemistry of [ 3770-50-1 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 3770-50-1 ]

Application In Synthesis of [ 3770-50-1 ]

[ 3770-50-1 ] Synthesis Path-Upstream 1~7

[ 3770-50-1 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 3770-50-1 ]

Esters

Related Parent Nucleus of [ 3770-50-1 ]

Indoles

Precautionary Statements-General

Prevention

Response

Storage

Disposal

Physical hazards

Health hazards

Environmental hazards

Inquiry

Related Functional Groups of
[ 3770-50-1 ]

Related Parent Nucleus of
[ 3770-50-1 ]