[ CAS No. 5192-03-0 ] {[proInfo.proName]}

Name: 5192-03-0|1H-Indol-5-amine|98%
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Quality Control of [ 5192-03-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 5192-03-0 ]

Product Details of [ 5192-03-0 ]

CAS No. :	5192-03-0	MDL No. :	MFCD00005679
Formula :	C₈H₈N₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ZCBIFHNDZBSCEP-UHFFFAOYSA-N
M.W :	132.16	Pubchem ID :	78867
Synonyms :

Calculated chemistry of [ 5192-03-0 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	0.0
Num. H-bond donors :	2.0
Molar Refractivity :	42.7
TPSA :	41.81 Å²

Pharmacokinetics

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) :	-6.61 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.08
Log Po/w (XLOGP3) :	0.7
Log Po/w (WLOGP) :	1.76
Log Po/w (MLOGP) :	0.91
Log Po/w (SILICOS-IT) :	1.86
Consensus Log Po/w :	1.26

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.77
Solubility :	2.26 mg/ml ; 0.0171 mol/l
Class :	Very soluble
Log S (Ali) :	-1.16
Solubility :	9.24 mg/ml ; 0.0699 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.89
Solubility :	0.171 mg/ml ; 0.00129 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.12

Safety of [ 5192-03-0 ]

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

Application In Synthesis of [ 5192-03-0 ]

* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.

Upstream synthesis route of [ 5192-03-0 ]
Downstream synthetic route of [ 5192-03-0 ]

[ 5192-03-0 ] Synthesis Path-Upstream 1~21

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Yield	Reaction Conditions	Operation in experiment
98%	With silver tetrafluoroborate; 4,4'-Dimethoxy-2,2'-bipyridin; potassium <i>tert</i>-butylate; hydrogen In 1,4-dioxane at 80℃; for 24 h; Autoclave	In Example 1, the m-nitroacetophenone used was replaced with an equimolar 5-nitroindole, and at a hydrogen pressure of4.0 MPa for 24 hours at 80 ° C. The other procedure was the same as in Example 1 to give 5-aminoindole in a yield of 98percent, _: A solution of 16.44 mg (0.04 mmol) 4,4'-dimethoxy-2,2'-bipyridine silver 11.22 mg (0.1 mmol) of potassuim t-butoxide and 1 mL of 1,4-dioxane were charged into an autoclave. After stirring, 165.15 mg (1 mmol) of m-nitroacetophenone was added and the mixture was stirred at 80 °C. The reaction was carried out for 8 hours. After the reaction has finishedm the reaction solution was extracted with water and dichloromethane to collect the organic phase. Then, the organic phase was dried over anhydrous Na₂SO_4,suction filtered, rotary evaporated and chromatographed to give a yellow solid 3-acetanilide. Yield 96 percent.
96%	With hydrogen In ethanol; ethyl acetate	To reduce a given model compound (5-nitroindol) in accordance with the above reaction scheme (to 5-aminoindol), the reservoir 104 of the hydrogenation apparatus 100 was filled with, as a sample solution, a stock solution of a 1:1 mixture of EtOAc:EtOH containing 5-nitroindol in a concentration of 0.05 mol/dm³. At the same time, a catalyst of 10percent by weight bone black palladium (Pd) or Raney nickel was arranged within the reactor 110 as the catalyst packing. After this, a flow rate of 0.1 ml/s was set within the apparatus by means of the feed pump 102, while a pressure of 30 bar was generated in the flow path by means of the pressure-adjusting unit 112. During the operation of the apparatus these values were continuously maintained. The produced hydrogenate, i.e. the 5-aminoindol was collected in the product receptacle 114, and then was subjected to an analytical assay (HPLC UV, λ=254 nm). As a result of the analysis, we concluded that the collected hydrogenate was of the purity of 99.9percent, and the yield of the reaction was about 96percent.
94%	With sodium tetrahydroborate In methanol; water at 0 - 50℃; for 2 h;	General procedure: A mixture of nitroarene (1 mmol), SS-Pd (2 molpercent Pd) and sodium borohydride (3 mmol) were taken in a 25 ml round bottomed flask. 3 ml of MeOH:H₂O (3:7) was added to the mixture by a syringe at 0 ^oC in stirring condition. After 10 minutes the reaction mixture was heated to 50 ^oC. Progress of the reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Na₂SO₄. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.

92.5%	With hydrogen In ethanol for 3 h;	A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5percent; 1 g), dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. The reaction mixture was filtered and the excess of ethanol was evaporated under reduced pressure. Solid product was recrystallized from hexane to obtain the pure compound 5-aminoindole (55-1). Yield: 92.5percent. ¹H NMR (500 MHz, CDCI₃): δ 7.96 (br, 1 H), 7.20 (d, 1 H), 7.13 (s, 1 H), 6.95 (s, 1 H), 6.67 (dd, 1 H), 6.37 (s, 1 H), 3.50 (s, 2 H). MS (ESI) mJz 133.0 (M + H)⁺_.
90%	With sodium tetrahydroborate; PdCu/graphene (2 mol % Pd) In ethanol; water at 0 - 50℃;	General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H₂O (1:2 in volume ratio) was added by a syringe at 0°C. After 10 min the reaction mixture was placed in an oil bath at 50°C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Mg₂SO₄. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60–120 mesh) afforded desired corresponding amines.
81%	With hydrazine In ethanol for 2 h; Reflux	25 mL of hydrazine (98-100percent) are added slowly to a mixture of 25.0 g of 5-nitroindole, 1.2 g of 10percent palladium on carbon and 200 mL of absolute ethanol. After the addition, the resulting reaction mixture is then taken to reflux for 2 hours. The catalyst is eliminated by filtration and the filtrate is evaporated in order to produce a solid yellow residue. The crystals are washed with 200 ml of water and they are dried under vacuum in order to produce 16.5 g (81percent) of 5-aminoindole. Melting point: 131-134° C.
79%	With hydrazine hydrate In ethanol at 80℃; for 1 h; Inert atmosphere	General procedure: Hydrazine hydrate was chosen as the hydrogen donor for the low emission of pollutants. In a typical procedure, hydrazine hydrate (4 equiv) was added into the reactor which containing fresh prepared catalyst as described above. Then the reactor was put into a preheated oil bath with a stirring speed of 500 rpm, and the substrate (1 mmol)dissolved in 1 mL ethanol was added drop-wisely under argon. The reactions were monitored by TLC. After the reaction, the reaction mixture was vacuum filtered through a pad of silica on a glass-fritted funnel and an additional 15 mL of ethyl acetate (5 mL portions) was used to rinse the product from the silica, the filtrate was concentrated in vacuum and analyzed by GC. Products were purified by column chromatography and identified by 1H NMR and 13C NMR.
55%	With ammonium formate In tetrahydrofuran; methanol	REFERENCE EXAMPLE 1 Preparation of (1H-indole-5-yl)-amine 5-nitroindole (1.0 g, 6.17 mmol) was dissolved in methanol (10 ml) and anhydrous tetrahydrofuran (10 ml) at room temperature and then, palladium/carbon (10percent) of a catalystic amount and ammonium formate (2.0 g, 31.7 mmol) were added to be stirred slowly at room temperature for 30 minutes. After completing the reaction, the reacting solution was filtered through celite, washed with methanol, concentrated under reduced pressure and then, dropped a silica gel short column. Afterward, the residue was concentrated again under reduced pressure and triturated with isooctane. As a result, the present compound (0.45 g, productive yield 55percent) was obtained as a solid phase. ¹H-NMR (400 MHz, CDCl₃) δ2.55 (br s, 2H), 6.35 (s, 1H), 6.65 (d, J=8 Hz, 1H), 6.95 (s, 1H), 7.10-7.15 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.95 (br s, 1H) melting point: 126° C.
53%	With palladium 10% on activated carbon; hydrogen In ethanol for 2.5 h;	General procedure: General procedure (9): Nitroindole derivative (1 equiv) was dissolved in ethanol (30 ml_ for 20.40 mmol of starting material) and 10percent palladium on carbon (10 mmolpercent) was added. The reaction flask was shaken under hydrogen at 30 psi using the Parr Shaker Hydrogenation Apparatus for 2.5 h. The reaction was filtered over celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography to afford the aminoindole product. Intermediate 16 1/-/-indol-5-amine Intermediate 16 (2.7 g, 20.4 mmol) was prepared as a black solid from 5-nitro-1 /-/-indole (6.3 g, 38.9 mmol, 1 equiv) according to general procedure (9) using 1 :1 hexane/ethyl acetate as the eluent for flash silica gel column chromatography. Yield: 53percent. ¹H NMR (400 MHz, CDCI₃) δ: 7.96 (bs, 1 H), 7.22 - 7.17 (m, 1 H), 7.13 (t, J = 2.8 Hz, 1 H), 6.97 - 6.94 (m, 1 H), 6.67 (dd, J = 8.5, 2.2 Hz, 1 H), 6.39 - 6.37 (m, 1 H), 3.49 (s, 2H).
53%	With palladium 10% on activated carbon; hydrogen In ethanol for 2.5 h;	5-nitro-1H-indole (6.3 g, 38.9 mmol, 1 equiv) was dissolved in ethanol (30 mL). 10percent palladium on carbon (630 mg, 10 mmolpercent) was added. The reaction flask was shaken under hydrogen at 30 psi using the Parr Shaker Hydrogenation Apparatus for 2.5 h. The reaction was filtered over celite and washed with ethyl acetate. The filtrate was evaporated, concentrated in vacuo and purified by silica gel flash column chromatography (1:1 hexane/ethyl acetate) to afford intermediate 16 as a black solid (2.7 g, 20.4 mmol). Yield: 53percent. ¹H NMR (400 MHz, CDCl₃) δ: 7.96 (bs, 1H), 7.22-7.17 (m, 1H), 7.13 (t, J = 2.8 Hz, 1H), 6.97-6.94 (m, 1H), 6.67 (dd, J = 8.5, 2.2 Hz, 1H), 6.39-6.37 (m, 1H), 3.49 (s, 2H).
51%	Stage #1: With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron In water at 20℃; for 0.5 h; Stage #2: With sodium hydrogencarbonate In water	General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO₃(aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
152.2 mg	With sodium tetrahydroborate; PdCu/graphene (2 mol % Pd) In ethanol; water at 0℃; for 1.5 h; Heating	General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2 mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H₂O (1:2 in volume ratio) was added by a syringe at 0 °C. After 10 min the reaction mixture was placed in an oil bath at 50 C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried ove ranhydrous Mg₂SO₄. Evaporation of the combined organic layer andfollowed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.
80.6 %Chromat.	With ammonium formate; cetyltrimethylammonim bromide In water at 130℃; for 6 h; Inert atmosphere	General procedure: For the catalytic reactions, typically, 0.5 mmol nitroarene,2.5 mL solvent, 189 mg ammonium formate (3.0 mmol), and catalyst (20 mg) were added to a 15 mL pressure bottle reactor (maximum pressure 1.0 MPa, the typical reaction pressure wasless than 0.4 MPa) with magnetic stirring. The atmosphere in the reactor was then replaced with Ar gas three times and tightly sealed. The reactor was placed in an oil bath preheated to the desired temperature. After the set reaction time, the reactor was quenched with cold water and the reaction mixture was diluted with 7.5 mL ethanol. The ethanol solution was analyzed by GC and GC‐MS.

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[12] Patent: WO2011/109059, 2011, A1, . Location in patent: Paragraph 0047; 00396
[13] Journal of Medicinal Chemistry, 2014, vol. 57, # 17, p. 7355 - 7366
[14] Journal of the American Chemical Society, 2017, vol. 139, # 20, p. 7004 - 7011
[15] Advanced Synthesis and Catalysis, 2018, vol. 360, # 11, p. 2131 - 2137
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[36] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 105,109
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Reference： [1] Patent: US2003/232822, 2003, A1, . Location in patent: Page 7,8

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Yield	Reaction Conditions	Operation in experiment
82%	With ammonium hydroxide; copper(I) iodide; 1-ethylacetoacetate-3-methyl imidazolium hydroxide In acetonitrile at 80℃; for 12 h; Inert atmosphere	General procedure: An oven-dried flask was charged with aryl halide (1.0 mmol), aqueous NH₃ (28percent, 1.5 mmol), CuI nanoparticles (0.02 mmol), 4a (3.0 mmol) and acetonitrile (2 mL). The contents were stirred under argon atmosphere at rt for 12 h. After completion of the reaction as monitored by TLC, the product was extracted with diethyl ether (5×5 mL). The organic layer was washed with brine, dried over MgSO₄ and concentrated in vacuo. Purification was done on silica gel column, and elution with ethyl acetate–hexane mixture afforded the aminated products. All products obtained herein are known compounds, and were confirmed by ¹H NMR, ¹³C NMR and mass spectroscopic analysis, see Supplementary data for full details.

Reference： [1] Tetrahedron, 2013, vol. 69, # 25, p. 5092 - 5097

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Yield	Reaction Conditions	Operation in experiment
81%	at 150℃; for 0.25 h; Microwave irradiation	EXAMPLE 2; Following the procedure set forth in Example 1 (A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150° C. as set forth in Table 1 below.
81%	at 150℃; for 0.25 h; Microwave irradiation	Example 1; (A) A solution of the N-Boc protected amine (1 mmol) in TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) (5 mL) was placed in a sealed microwave vial. The reaction mixture was heated (100°C or 150°C) in a Biotage - Initiator^.(TM). Sixty microwave reactor with stirring until the disappearance of the starting material was observed. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash-column chromatography. ¹H NMR and ¹³C NMR were measured on Bruker Avance DPX-300 NMR or Bruker Avance-300 NMR spectrometers, operating at a proton (¹H) frequency of 300.13 MHz and carbon (¹³C) frequency of 75.43 MHz.Example 2 Following the procedure set forth in Example 1(A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150°C as set forth in Table 1 below.
70%	at 150℃; for 0.25 h; Microwave irradiation	Example 1; (A) A solution of the N-Boc protected amine (1 mmol) in TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) (5 mL) was placed in a sealed microwave vial. The reaction mixture was heated (100°C or 150°C) in a Biotage - Initiator^.(TM). Sixty microwave reactor with stirring until the disappearance of the starting material was observed. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash-column chromatography. ¹H NMR and ¹³C NMR were measured on Bruker Avance DPX-300 NMR or Bruker Avance-300 NMR spectrometers, operating at a proton (¹H) frequency of 300.13 MHz and carbon (¹³C) frequency of 75.43 MHz.Example 2 Following the procedure set forth in Example 1(A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150°C as set forth in Table 1 below.

Reference： [1] Synthetic Communications, 2006, vol. 36, # 14, p. 2069 - 2077
[2] Synthetic Communications, 2008, vol. 38, # 21, p. 3840 - 3853
[3] Patent: US2009/203910, 2009, A1, . Location in patent: Page/Page column 2-3
[4] Patent: EP2070899, 2009, A1, . Location in patent: Page/Page column 3; 4-5
[5] Patent: EP2070899, 2009, A1, . Location in patent: Page/Page column 3; 4-5

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Reference： [1] Phytochemistry (Elsevier), 1982, vol. 21, # 12, p. 2879 - 2886

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Yield	Reaction Conditions	Operation in experiment
48.9%	With potassium hydroxide In methanol	B. Via 5-amino-1H-indole To a solution of 1.29 gm (20 mMol) potassium hydroxide in 10 mL methanol were added 1.32 gm (10 mMol) 5-amino-lH-indole followed by 2.46 mL (20 mMol) 1-methyl-4-piperidone. The reaction mixture was then heated to reflux for 18 hours. The reaction mixture was cooled to ambient, diluted with 20 ml water and the precipitate collected by filtration. The solid was recrystallized from ethyl acetate:methanol to give 1.11 gm (48.9percent) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyr-idin-4-yl)-1H-indole as a tan solid (m.p.=200-203°C). The tan solid was subjected to flash chromatography, eluding with 100:20:0.5 dichloromethane:methanol:ammonium hydroxide, to give 0.99 gm 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole as a cream colored solid (m.p.=212-215°C (ethyl acetate:methanol)). MS(m/e): 227(M⁺) Calculated for C₁₄H₁₇N₃: Theory: C, 73.98; H, 7.54; N, 18.49. Found: C, 73.76; H, 7.48; N, 18.22.

Reference： [1] Patent: EP824917, 1998, A2,

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Reference： [1] Acta Chemica Scandinavica, 1999, vol. 53, # 10, p. 849 - 856

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[ 5192-03-0 ]

Reference： [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, p. 624 - 627[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 6, p. 766 - 769
[3] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 2541,2550; engl. Ausg. S. 2504, 2511

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Reference： [1] Phytochemistry (Elsevier), 1982, vol. 21, # 12, p. 2879 - 2886
[2] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 2541,2550; engl. Ausg. S. 2504, 2511

10
[ 87240-06-0 ]
[ 5192-03-0 ]

Reference： [1] Phytochemistry (Elsevier), 1982, vol. 21, # 12, p. 2879 - 2886

11
[ 166104-19-4 ]
[ 5192-03-0 ]

Reference： [1] Synthetic Communications, 2006, vol. 36, # 14, p. 2069 - 2077

12
[ 496-15-1 ]
[ 5192-03-0 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 12, p. 1092 - 1094
[2] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 2541,2550; engl. Ausg. S. 2504, 2511

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Reference： [1] Chemistry of Heterocyclic Compounds (New York, NY, United States), 1988, p. 624 - 627[2] Khimiya Geterotsiklicheskikh Soedinenii, 1988, vol. 24, # 6, p. 766 - 769

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Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 12, p. 1092 - 1094

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[ 5192-03-0 ]

Reference： [1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1995, vol. 34, # 12, p. 1092 - 1094

16
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[ 5192-03-0 ]

Reference： [1] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 105,109

17
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[ 5192-03-0 ]

Reference： [1] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 105,109

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[ 5192-03-0 ]

Reference： [1] Farmaco, Edizione Scientifica, 1958, vol. 13, p. 105,109

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[ 67-56-1 ]
[ 6146-52-7 ]
[ 5192-03-0 ]

Reference： [1] Acta Chemica Scandinavica, 1999, vol. 53, # 10, p. 849 - 856

20
[ 5192-03-0 ]
[ 75-36-5 ]
[ 7145-71-3 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine In dichloromethane at 20℃; for 3 h;	General procedure: General procedure (10): To a solution of aminoindole (1.0 equiv) and triethylamine (3.6 equiv) in dichloromethane (10 ml_ for 1.182 mmol of starting material), acetyl chloride (1.2 equiv) was added. The reaction was stirred at room temperature for 3 h. The mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. Purification by flash silica gel column chromatography afforded the indole-acetamide product. Intermediate 17 A/-(1/-/-indol-5-yl)acetamide Intermediate 17 (177 mg, 1.016 mmol) was prepared as a clear oil from Intermediate 16 (156 mg, 1.182 mmol) according to general procedure (10) using 7:3 hexane/ethyl acetate as the eluent for flash silica gel column chromatography. Yield: 85percent. ¹H NMR (400 MHz, CDCI₃) δ 8.27 (bs, 1 H), 7.80 (s, 1 H), 7.30 (d, J = 8.5 Hz, 2H), 7.20 (dd, J = 8.8, 2.0 Hz, 2H), 6.50 (s, 1 H), 2.18 (s, 3H).
85%	With triethylamine In dichloromethane at 20℃; for 3 h;	To a solution of intermediate 16 (156 mg, 1.182 mmol, 1.0 equiv) and triethylamine (591 μL, 429 mg, 4.240 mmol, 3.6 equiv) in DCM (10 mL), acetyl chloride (101 μL, 111 mg, 1.418 mmol, 1.2 equiv) was added. The reaction was stirred at room temperature for 3 h. The mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. Purification by flash silica gel column chromatography (7:3 hexane/ethyl acetate) afforded intermediate 7g as a clear oil (177 mg, 1.016 mmol). Yield: 85percent. ¹H NMR (400 MHz, CDCl₃) δ 8.27 (bs, 1H), 7.80 (s, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.20 (dd, J = 8.8, 2.0 Hz, 2H), 6.50 (s, 1H), 2.18 (s, 3H).

Reference： [1] Patent: WO2016/200339, 2016, A1, . Location in patent: Page/Page column 93-94
[2] European Journal of Medicinal Chemistry, 2018, vol. 156, p. 344 - 367

21
[ 5192-03-0 ]
[ 100846-24-0 ]

Reference： [1] Angewandte Chemie - International Edition, 2013, vol. 52, # 31, p. 7972 - 7975[2] Angew. Chem., 2013, vol. 125, # 31, p. 8130 - 8133

[ 5192-03-0 ] Synthesis Path-Downstream 1~77

1
[ 5192-03-0 ]
[ 98-88-4 ]
[ 6019-39-2 ]

Reference： [1]Journal of Medicinal Chemistry,1994,vol. 37,p. 2509 - 2512
[2]Zhurnal Obshchei Khimii,1959,vol. 29,p. 2541,2550; engl. Ausg. S. 2504, 2511

2
[ 6146-52-7 ]
[ 5192-03-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	With hydrazine monohydrate at 90℃; for 1.5h; chemoselective reaction;
99%	With C₂₀H₃₂Cl₄Cu₂N₄O₄ In lithium hydroxide monohydrate at 60℃; for 2h; Inert atmosphere; Schlenk technique;	2.4. General procedure for the reduction of nitro compounds withcopper complex catalyst General procedure: Copper complex (0.001 mmol, 1mol%), appropriate nitro compounds (0.1 mmol, 1.0 equiv) and NaBH4 (10.0 mmol, 10 equiv)in water (2.0 mL) were charged into a 15 mL pressure tube under air atmosphere. Subsequently, the resulting mixture was stirred atroom temperature in closed vessel. After completion of the reaction(monitored by TLC), the crude reaction mixturewas extraction with ether (3 2 mL), and analyzed by GC-MS chromatography using n-dodecaneas an internal standard.
99%	With borane-ammonia; N-hexadecyl-N,N,N-trimethylammonium bromide; [Ru(p-cymene)(2,6-bis(1-methylimidazole-2-thione)pyridine)](PF₆)₂ In lithium hydroxide monohydrate; acetonitrile at 79.84℃; for 24h; Inert atmosphere; Schlenk technique;

99%	With hydrogen at 130℃; for 6h; chemoselective reaction;
98%	With hydrogen In ethanol at 40℃; for 6h;
98%	With TPGS-750-M; ammonia hydrochloride; zinc In lithium hydroxide monohydrate at 20℃; for 6h; Green chemistry; chemoselective reaction;
98%	With hydrazine hydrate monohydrate In ethanol at 20℃; for 7h; chemoselective reaction;
98%	With anhydrous silver tetrafluoroborate; 4,4'-Dimethoxy-2,2'-bipyridin; potassium-t-butoxide; hydrogen In 1,4-dioxane at 80℃; for 24h; Autoclave;	5 Example 5 In Example 1, the m-nitroacetophenone used was replaced with an equimolar 5-nitroindole, and at a hydrogen pressure of4.0 MPa for 24 hours at 80 ° C. The other procedure was the same as in Example 1 to give 5-aminoindole in a yield of 98%, _: A solution of 16.44 mg (0.04 mmol) 4,4'-dimethoxy-2,2'-bipyridine silver 11.22 mg (0.1 mmol) of potassuim t-butoxide and 1 mL of 1,4-dioxane were charged into an autoclave. After stirring, 165.15 mg (1 mmol) of m-nitroacetophenone was added and the mixture was stirred at 80 °C. The reaction was carried out for 8 hours. After the reaction has finishedm the reaction solution was extracted with water and dichloromethane to collect the organic phase. Then, the organic phase was dried over anhydrous Na2SO4, suction filtered, rotary evaporated and chromatographed to give a yellow solid 3-acetanilide. Yield 96 %.
97%	With tris(2,4-pentanedionato)iron(III); hydrazine hydrate monohydrate In methanol at 150℃; Microwave irradiation; Green chemistry;
97%	With tris(2,4-pentanedionato)iron(III); hydrazine hydrate monohydrate In methanol at 150℃; for 0.133333h; Microwave irradiation; chemoselective reaction;
97%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 12h;
96%	With hydrogen In ethanol; ethyl acetate	1 To reduce a given model compound (5-nitroindol) in accordance with the above reaction scheme (to 5-aminoindol), the reservoir 104 of the hydrogenation apparatus 100 was filled with, as a sample solution, a stock solution of a 1:1 mixture of EtOAc:EtOH containing 5-nitroindol in a concentration of 0.05 mol/dm3. At the same time, a catalyst of 10% by weight bone black palladium (Pd) or Raney nickel was arranged within the reactor 110 as the catalyst packing. After this, a flow rate of 0.1 ml/s was set within the apparatus by means of the feed pump 102, while a pressure of 30 bar was generated in the flow path by means of the pressure-adjusting unit 112. During the operation of the apparatus these values were continuously maintained. The produced hydrogenate, i.e. the 5-aminoindol was collected in the product receptacle 114, and then was subjected to an analytical assay (HPLC UV, λ=254 nm). As a result of the analysis, we concluded that the collected hydrogenate was of the purity of 99.9%, and the yield of the reaction was about 96%.
95%	With hydrogen In tetrahydrofuran; lithium hydroxide monohydrate at 120℃; for 15h; chemoselective reaction;
95%	With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 0.583333h; Green chemistry;
95%	With hydrogen In methanol; ethyl acetate at 80℃; for 0.333333h; Flow reactor; Green chemistry; chemoselective reaction;
94%	With sodium tetrahydridoborate In methanol; lithium hydroxide monohydrate at 0 - 50℃; for 2h;	Reduction in presence of NaBH₄ (Method A) General procedure: A mixture of nitroarene (1 mmol), SS-Pd (2 mol% Pd) and sodium borohydride (3 mmol) were taken in a 25 ml round bottomed flask. 3 ml of MeOH:H2O (3:7) was added to the mixture by a syringe at 0 oC in stirring condition. After 10 minutes the reaction mixture was heated to 50 oC. Progress of the reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Na2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.
94%	With sodium tetrahydridoborate In lithium hydroxide monohydrate at 20℃; for 1h;
92.5%	With hydrogen In ethanol for 3h;	8; 15 A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd/C (5%; 1 g), dissolved in ethanol (50 mL), was hydrogenated for 3 h at 40 psi. The reaction mixture was filtered and the excess of ethanol was evaporated under reduced pressure. Solid product was recrystallized from hexane to obtain the pure compound 5-aminoindole (55-1). Yield: 92.5%. 1H NMR (500 MHz, CDCI3): δ 7.96 (br, 1 H), 7.20 (d, 1 H), 7.13 (s, 1 H), 6.95 (s, 1 H), 6.67 (dd, 1 H), 6.37 (s, 1 H), 3.50 (s, 2 H). MS (ESI) mJz 133.0 (M + H)+.
92.5%	With 5%-palladium/activated carbon; hydrogen In ethanol for 3h;
92%	With Zr₁₂(μ₃-O)₅[(μ₃-O)CoCl]₈[(μ₂-O)₂(μ₃-O)CoCl]₃Li₃(triphenyldicarboxylate)₉; hydrogen; sodium triethylborohydride In toluene at 110℃; for 42h; Inert atmosphere; Schlenk technique;
92%	With methanol; sodium tertiary butoxide In 1,4-dioxane at 80℃; for 8h;
91%	With copper phthalocyanine; hydrazine hydrate monohydrate In ethylene glycol at 90℃; for 2h; chemoselective reaction;
91.2%	With sodium tetrahydridoborate In tetrahydrofuran; lithium hydroxide monohydrate at 20℃; for 10h;
91%	With aluminum(III) oxide; ammsnium formate; potassium hydroxide In neat (no solvent) for 1.5h; Milling;
91%	With hydrogen In tetrahydrofuran; lithium hydroxide monohydrate at 120℃; for 20h; Autoclave;
90%	With sodium tetrahydridoborate; PdCu/graphene (2 mol % Pd) In ethanol; lithium hydroxide monohydrate at 0 - 50℃;	4.3 General procedure for reduction of aromatic nitro compound using PdCu/graphene¹⁶ General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H2O (1:2 in volume ratio) was added by a syringe at 0°C. After 10 min the reaction mixture was placed in an oil bath at 50°C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried over anhydrous Mg2SO4. Evaporation of the combined organic layer and followed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.
90%	With sodium tetrahydridoborate In lithium hydroxide monohydrate at 60℃; for 0.3h; Sonication;
90%	With borane-ammonia complex; copper(II) oxide In methanol at 50℃; for 0.333333h;
88%	With (phthalocyaninato)iron(II); diphenylsilane In ethanol at 100℃; for 24h;
88%	With C₂₀H₂₄ClNO₂Ru; isopropanol; potassium hydroxide at 89.84℃; for 3h; Sealed tube; Green chemistry;
88%	With hydrazine monohydrate In ethanol at 75℃; for 8h; Inert atmosphere;	2.4. The process for the hydrogenation of nitroarenes General procedure: To an 10 mL glass reactor was added 1 mmol of nitro compound, 0.1mmol of FeO(OH)/C nanoparticles, 2 mL of ethanol and 2 mmol of 80%N2H4.H2O at N2 atmosphere. Next, the reactant was stirred at 75 C forabout 2-12 h. After the reaction was finished, the catalyst was filteredoff and washed with dichloromethane or ethyl acetate, the solvents wereremoved in vacuo, and the target product was purified by columnchromatography or directly dried over in vacuo
87.1%	With 5%-palladium/activated carbon; hydrogen In ethanol at 25℃; for 18h;	4.1.8 Synthesis of 1H-indol-5-amine (9) A mixture of 5-nitro-1H-indole (2.00g, 12.33mmol) and Pd/C (5%; 0.20g) in ethanol (40mL) under 40 psi of hydrogen atmosphere, was stirred at 25°C for 18h. After the completion of the reaction, the insoluble solid was filtered out. The filtrate was evaporated under reduced pressure to give 1H-indol-5-amine 9 (1.42g yield 87.1%) as a light red solid. 1H NMR (600MHz, DMSO-d6) δ 10.56 (s, 1H), 7.13 (t, J=2.7Hz, 1H), 7.10 (d, J=8.5Hz, 1H), 6.70 (d, J=2.0Hz, 1H), 6.51 (dd, J=8.5, 2.1Hz, 1H), 6.14 (dd, J=3.4, 1.4Hz, 1H), 4.42 (s, 2H). 13C NMR (150MHz, DMSO-d6) δ 141.45, 130.26, 129.03, 125.20, 112.29, 111.86, 103.71, 100.09.
85%	With formic acid; tris(2-diphenylphosphinoethyl)phosphine In ethanol at 70℃; for 0.666667h;
85%	With sodium tetrahydridoborate; lithium hydroxide monohydrate at 20℃; for 0.5h; Green chemistry;
83%	With hydrogen; triethylamine In ethanol; lithium hydroxide monohydrate at 110℃; for 44h; Autoclave;
81%	With hydrazine In ethanol for 2h; Reflux;	25 mL of hydrazine (98-100%) are added slowly to a mixture of 25.0 g of 5-nitroindole, 1.2 g of 10% palladium on carbon and 200 mL of absolute ethanol. After the addition, the resulting reaction mixture is then taken to reflux for 2 hours. The catalyst is eliminated by filtration and the filtrate is evaporated in order to produce a solid yellow residue. The crystals are washed with 200 ml of water and they are dried under vacuum in order to produce 16.5 g (81%) of 5-aminoindole. Melting point: 131-134° C.
81%	With C₃₆H₅₆Cl₃CrN₂O; magnesium; 4,4,5,5-tetramethyl-1,3,2-dioxaborolane In tetrahydrofuran at 60℃; for 24h; Inert atmosphere; chemoselective reaction;
80%	With aluminium(III) chloride; lithium hydroxide monohydrate; zinc In tetrahydrofuran at 20℃; for 5h;
80%	With hydrazine hydrate monohydrate at 100℃; for 2.16667h;
80%	With sodium tetrahydridoborate; C₂₇H₂₅Cl₂NO₂Ru; N-hexadecyl-N,N,N-trimethylammonium bromide In lithium hydroxide monohydrate at 20℃; for 7h; Inert atmosphere; Schlenk technique;
80%	With tetrahydroxydiborane; isopropanol In ethanol at 20℃; for 12h; Schlenk technique; Inert atmosphere; Irradiation; Sealed tube; Green chemistry; chemoselective reaction;	General procedure for the deoxygenative hydrogenation of nitro compounds General procedure: An oven-dried 10 mL Schlenk tube containing a magnetic stirring bar was charged with substrates (0.2 mmol, 1.0 equiv.). Then the tube was evacuated and refilled with N2 (x 3 times). Isopropanol (3 mmol, 15 equiv.) and 0.6 mL degassed solvent (General procedure I: EtOH; General procedure II: THF with the addition of 5 equiv. of H2O) were sequentially added and the mixture was stirred at room temperature for 12 hours under the irradiation of 400 nm LED (10 W power). After reaction, the solvents were evaporated under reduced pressure. The residue was then subjected to flash column chromatography on silica gel or preparative layer chromatography using petroleum ether and dichloromethane as eluents to give products.
79%	With hydrazine hydrate monohydrate In ethanol at 80℃; for 1h; Inert atmosphere; chemoselective reaction;	2.2. Catalytic reduction of nitroarenes General procedure: Hydrazine hydrate was chosen as the hydrogen donor for the low emission of pollutants. In a typical procedure, hydrazine hydrate (4 equiv) was added into the reactor which containing fresh prepared catalyst as described above. Then the reactor was put into a preheated oil bath with a stirring speed of 500 rpm, and the substrate (1 mmol)dissolved in 1 mL ethanol was added drop-wisely under argon. The reactions were monitored by TLC. After the reaction, the reaction mixture was vacuum filtered through a pad of silica on a glass-fritted funnel and an additional 15 mL of ethyl acetate (5 mL portions) was used to rinse the product from the silica, the filtrate was concentrated in vacuum and analyzed by GC. Products were purified by column chromatography and identified by 1H NMR and 13C NMR.
67%	With chlorobis(cyclooctene)rhodium(I) dimer In N,N-dimethyl-formamide at 120℃; for 24h; Inert atmosphere;
66%	With 2-aminoquinazolin-4(3H)-one; potassium carbonate; hydrazine hydrate monohydrate In methanol at 100℃; for 12h;
62%	With hydrogenchloride; gallium⁽⁰⁾ In ethanol at 20℃; for 0.5h; Sonication;	1H-Indol-5-amine (6) To a 25 mL RBF containing molten Ga (280 mg, 4.02 mmol, 4.0 equiv) was added 5-nitro-1H-indol (163 mg, 1.00 mmol, 5), EtOH (10 mL), and 12 N HCl (1250 µL). The flask was sonicated for 30 min at rt. The rxn mixture was transferred to a 125 mL separatory funnel, basified with 3N NaOH (aq), 4 mL of Rochelles’s salt (aq) added and extracted with DCM (3 x 10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated by rotary evaporation. The residue (oily yellow solid) was purified by silica column chromatography to afford the product as a light brown solid (82 mg, 62%). 1H NMR (300 MHz, CDCl3) δ 7.96 (br s, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 2.4, 2.4 Hz, 1H), 6.95 (d, J = 1.8 Hz, 1H), 6.67 (dd, J = 8.9, 2.4 Hz, 1H), 6.38 (m, 1H), 3.49 (br s, 2H) ppm. MP = 131 - 133 oC. ESI-MS (m/z): 133.2 [M+H]+.
60%	With palladium 10% on activated carbon; hydrogen In methanol at 20℃; for 24h;
55%	With anhydrous ammonium formate In tetrahydrofuran; methanol	R.1 Preparation of (1H-indole-5-yl)-amine REFERENCE EXAMPLE 1 Preparation of (1H-indole-5-yl)-amine 5-nitroindole (1.0 g, 6.17 mmol) was dissolved in methanol (10 ml) and anhydrous tetrahydrofuran (10 ml) at room temperature and then, palladium/carbon (10%) of a catalystic amount and ammonium formate (2.0 g, 31.7 mmol) were added to be stirred slowly at room temperature for 30 minutes. After completing the reaction, the reacting solution was filtered through celite, washed with methanol, concentrated under reduced pressure and then, dropped a silica gel short column. Afterward, the residue was concentrated again under reduced pressure and triturated with isooctane. As a result, the present compound (0.45 g, productive yield 55%) was obtained as a solid phase. 1H-NMR (400 MHz, CDCl3) δ2.55 (br s, 2H), 6.35 (s, 1H), 6.65 (d, J=8 Hz, 1H), 6.95 (s, 1H), 7.10-7.15 (m, 1H), 7.20 (d, J=8 Hz, 1H), 7.95 (br s, 1H) melting point: 126° C.
53%	With palladium 10% on activated carbon; hydrogen In ethanol for 2.5h;	14 Intermediate 16 1H-indol-5-amine General procedure: General procedure (9): Nitroindole derivative (1 equiv) was dissolved in ethanol (30 ml_ for 20.40 mmol of starting material) and 10% palladium on carbon (10 mmol%) was added. The reaction flask was shaken under hydrogen at 30 psi using the Parr Shaker Hydrogenation Apparatus for 2.5 h. The reaction was filtered over celite and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by silica gel flash column chromatography to afford the aminoindole product. Intermediate 16 1/-/-indol-5-amine Intermediate 16 (2.7 g, 20.4 mmol) was prepared as a black solid from 5-nitro-1 /-/-indole (6.3 g, 38.9 mmol, 1 equiv) according to general procedure (9) using 1 :1 hexane/ethyl acetate as the eluent for flash silica gel column chromatography. Yield: 53%. 1H NMR (400 MHz, CDCI3) δ: 7.96 (bs, 1 H), 7.22 - 7.17 (m, 1 H), 7.13 (t, J = 2.8 Hz, 1 H), 6.97 - 6.94 (m, 1 H), 6.67 (dd, J = 8.5, 2.2 Hz, 1 H), 6.39 - 6.37 (m, 1 H), 3.49 (s, 2H).
53%	With palladium 10% on activated carbon; hydrogen In ethanol for 2.5h;	24.1 Step 1: 1H-indol-5-amine (16) 5-nitro-1H-indole (6.3 g, 38.9 mmol, 1 equiv) was dissolved in ethanol (30 mL). 10% palladium on carbon (630 mg, 10 mmol%) was added. The reaction flask was shaken under hydrogen at 30 psi using the Parr Shaker Hydrogenation Apparatus for 2.5 h. The reaction was filtered over celite and washed with ethyl acetate. The filtrate was evaporated, concentrated in vacuo and purified by silica gel flash column chromatography (1:1 hexane/ethyl acetate) to afford intermediate 16 as a black solid (2.7 g, 20.4 mmol). Yield: 53%. 1H NMR (400 MHz, CDCl3) δ: 7.96 (bs, 1H), 7.22-7.17 (m, 1H), 7.13 (t, J = 2.8 Hz, 1H), 6.97-6.94 (m, 1H), 6.67 (dd, J = 8.5, 2.2 Hz, 1H), 6.39-6.37 (m, 1H), 3.49 (s, 2H).
51%	Stage #1: 5-Nitro-1H-indole With hydrogenchloride; 1,1,1,3',3',3'-hexafluoro-propanol; iron⁽⁰⁾ In lithium hydroxide monohydrate at 20℃; for 0.5h; Stage #2: With Sodium hydrogenocarbonate In lithium hydroxide monohydrate chemoselective reaction;	2. General Procedure for the Reduction of Nitro Compounds General procedure: The nitro compound (1 equiv), HFIP (10 equiv), Fe powder (5 equiv) were mixed in a tube. Then 2 N HCl aqueous solutions was added to the reaction mixture. After stirring at room temperature for 30 min, the reaction mixture was neutralized with sat. NaHCO3 (aq.) and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was then purified by column chromatography on silica gel to furnish the desired amine product.
29%	With iron(III) chloride; N,N-Dimethylhydrazine In methanol at 85℃; for 44h;
	With ethanol; nickel; hydrazine hydrate monohydrate
	With ethanol; platinum Hydrogenation;
	With hydrogen In ethyl acetate at 20℃; for 3h;	5-(Piperazin-1-yl)-1H-indole; A mixture of 5-nitro-1H-indole (34 g), palladium (5 wt %, dry basis) on activated carbon (2.5 g) and ethyl acetate was shaken at room temperature for 1.5 h under 3 atmospheres of hydrogen. The mixture was filtered, and the solvent was removed in vacuo to yield a solid (28 g), which was dissolved in tetrahydrofuran (400 mL). This solution was added to a boiling mixture of N-benzyliminodiacetic acid (54.4 g) and 1,1'-carbonyldiimidazole (82.4 g) in tetrahydrofuran (1100 mL), and the resulting mixture was boiled under reflux for 3 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/triethylamine 100:4) to give a solid (57.5 g), which subsequently was suspended in tetrahydrofuran (300 mL) and added to alane in tetrahydrofuran (500 mL) at 5-16° C. The alane was prepared from lithium aluminium hydride (25 g) and 96% sulphuric acid (32.3 g). The mixture was stirred at 5° C. for 45 min and subsequently quenched by addition of water (50 mL), 15% aqueous sodium hydroxide solution (25 mL) and water (125 mL). The mixture was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate) to give a brown oily compound (44.9 g), which subsequently was dissolved in methanol (1000 mL). Ammonium formate (150 g) and palladium (5 wt %, dry basis) on activated carbon (12 g) was added, and the mixture was boiled under reflux for 45 min, cooled, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran/ethyl acetate and poured onto brine. Concentrated aqueous ammonia solution was added to the mixture under cooling to give an alkaline reaction mixture. The two phases were separated, and the aqueous phase was extracted twice with tetrahydrofuran/ethyl acetate. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was precipitated from tetrahydrofuran/heptane to give the title compound (17.3 g).
	With iron⁽⁰⁾; ammonia hydrochloride In ethanol; lithium hydroxide monohydrate for 2h; Reflux; Inert atmosphere;	42.1 A mixture of 5-nitroindole (5 g, 30.9 mrnol), Fe (8.6 g, 154 mmol), NH4Cl (16.5 g, 309 mmol), EtOH (80 mJL) and water (20 mL) was refluxed under N2 protection for 2 hours.The mixture was cooled to RTand filtered. The filtrate was concentrated and dissolved in water.The mixture was basified with Na2CO3 and extracted with CH2Cl2 two times. The combined organic phases were combined, dried over Na2SO4 and filtered. The filtrate was concentrated to yield the product (3.6 g). MS (ESI) IWe (M+^): 133. 1H NMR (DMSO) O: 10.55 (s, 1H), 7.12-7.06 (m, 2H), 6.68 (d, J=2.0 Hz, 1H), 6.48 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.12 (t, J=2.0 Hz, 1H),4.39 (s, 2H).
	With hydrogen In ethyl acetate at 20℃; for 1.5h;	A A mixture of 5-nitro-lH-indole (34 g), palladium (5 wt%, dry basis) on activated carbon (2.5 g) and ethyl acetate was shaken at room temperature for 1.5 h under 3 atmospheres of hydrogen. The mixture was filtered, and the solvent was removed in vacuo to yield a solid (28 g), which was dissolved in tetrahydrofuran (400 mL). This solution was added to a boiling mixture of iV-benzyliminodiacetic acid (54.4 g) and l,l'-carbonyldiimidazole (82.4 EPO g) in tetrahydrofuran (1100 mL), and the resulting mixture was boiled under reflux for 3 h. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate/triethylamine 100:4) to give a solid (57.5 g), which subsequently was suspended in tetrahydrofuran (300 mL) and added to alane in tetrahydrofuran (500 mL) at 5-16 0C. The alane was prepared from lithium aluminium hydride (25 g) and 96% sulphuric acid (32.3 g). The mixture was stirred at 5 0C for 45 min and subsequently quenched by addition of water (50 mL), 15 % aqueous sodium hydroxide solution (25 mL) and water (125 mL). The mixture was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silicagel (eluent: ethyl acetate) to give a brown oily compound (44.9 g), which subsequently was dissolved in methanol (1000 mL). Ammonium formate (150 g) and palladium (5 wt%, dry basis) on activated carbon (12 g) was added, and the mixture was boiled under reflux for 45 min, cooled, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran/ethyl acetate and poured onto brine. Concentrated aqueous ammonia solution was added to the mixture under cooling to give an alkaline reaction mixture. The two phases were separated, and the aqueous phase was extracted twice with tetrahydroiuran/ethyl acetate. The combined organic phases were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was precipitated from tetrahydroiuran/heptane to give the title compound (17.3 g).
99 %Chromat.	With (phthalocyaninato)iron(II); hydrazine hydrate monohydrate In H₂₀; ethanol at 120℃; chemoselective reaction;
95 %Chromat.	With hydrazine hydrate monohydrate In tetrahydrofuran at 100℃; for 10h; chemoselective reaction;
95 %Chromat.	With hydrogen at 150℃; for 6h; Autoclave; chemoselective reaction;
	With palladium 10% on activated carbon; hydrogen at 30 - 40℃;
60 %Chromat.	With zinc(II) phthalocyanine; hydrazine monohydrate In PEG-400 at 100℃; for 8h;
95 %Chromat.	With formic acid; [Mo₃S₄H₃(dmpe)3](BPh₄); triethylamine In tetrahydrofuran at 70℃; for 18h; Inert atmosphere; chemoselective reaction;
	With methanol at 70℃; for 1h; Inert atmosphere; chemoselective reaction;
152.2 mg	With sodium tetrahydridoborate; PdCu/graphene (2 mol % Pd) In ethanol; lithium hydroxide monohydrate at 0℃; for 1.5h; Heating;	4.3. General procedure for reduction of aromatic nitro compoundusing PdCu/graphene¹⁶ General procedure: A mixture of nitroarene (1 mmol), PdCu/graphene (6 mg) and sodium borohydride (2 mmol) were taken in a 25 mL reaction tube. 3 mL of EtOH:H2O (1:2 in volume ratio) was added by a syringe at 0 °C. After 10 min the reaction mixture was placed in an oil bath at 50 C. The reaction was monitored by TLC. On completion, the reaction mixture was extracted with ethylacetate and dried ove ranhydrous Mg2SO4. Evaporation of the combined organic layer andfollowed by column chromatography over silica gel (60-120 mesh) afforded desired corresponding amines.
	With iron⁽⁰⁾; ammonia hydrochloride In ethanol; lithium hydroxide monohydrate for 4h; Reflux; Inert atmosphere;
57 %Chromat.	With di-μ-chlorobis[(1,2,5,6-η)-1,5-cyclooctadiene]diiridium; 1,10-Phenanthroline; isopropanol; potassium hydroxide at 100℃; for 8h; Inert atmosphere; Schlenk technique;
95 %Chromat.	With Et₄N[Co(N₂,N₆-di-(pyridin-2-yl)pyridine-2,6-dicarboxamide)2(CoCl₂)2]*4H₂O; hydrazine hydrate monohydrate In ethanol at 60℃; for 6h; Schlenk technique; Inert atmosphere;
	With sodium tetrahydridoborate In tetrahydrofuran; lithium hydroxide monohydrate at 25℃; for 1h; Sealed tube; Sonication;
92 %Chromat.	With molybdenum dioxide; hydrazine hydrate monohydrate In ethanol at 50℃; for 1.5h;
	With hydrazine hydrate monohydrate In ethanol at 50℃; for 1.5h;	2.4. Catalytic reactions and product analyses General procedure: Nitrobenzene 0.5 mmol, solvent 2.0 mL and 50 L p-xylene asan internal standard were added into a 15 mL pressure bottle withmagnetic stirring. Then the hydrazine hydrate and catalyst wereadded into the reactor, and the reaction time was set as zero. Thesamples were obtained by hot filtration and analyzed by GC-MS(GC: Agilent 7890A, MS: Agilent 5975C) and GC (Agilent 7890A).
	With hydrogen In ethanol for 5h; Heating;
80.6 %Chromat.	With ammsnium formate; N-hexadecyl-N,N,N-trimethylammonium bromide In lithium hydroxide monohydrate at 130℃; for 6h; Inert atmosphere;	2.4. Catalytic reactions and product analyses General procedure: For the catalytic reactions, typically, 0.5 mmol nitroarene,2.5 mL solvent, 189 mg ammonium formate (3.0 mmol), and catalyst (20 mg) were added to a 15 mL pressure bottle reactor (maximum pressure 1.0 MPa, the typical reaction pressure wasless than 0.4 MPa) with magnetic stirring. The atmosphere in the reactor was then replaced with Ar gas three times and tightly sealed. The reactor was placed in an oil bath preheated to the desired temperature. After the set reaction time, the reactor was quenched with cold water and the reaction mixture was diluted with 7.5 mL ethanol. The ethanol solution was analyzed by GC and GC-MS.
	With ammsnium formate; N-hexadecyl-N,N,N-trimethylammonium bromide In lithium hydroxide monohydrate at 130℃; for 6h; Inert atmosphere; Sealed tube;	30 Example 30 20 mL of water, 0.15 g of cetyltrimethylammonium bromide, 5 mmol of 5-nitroindole, 20 mmol of ammonium formate and 0.2 g of O-MoS2 (30-180-12h) were charged into a reactor with magnetic stirring, nitrogen gas protection, sealed. The reaction was carried out at 130 ° C for 6 h and centrifuged. The resulting sample was analyzed qualitatively and quantitatively by GC-MS and GC. Nitrobenzene conversion of 90%, 5-aminoindole selectivity of 100%.
	With palladium 10% on activated carbon; hydrazine hydrate monohydrate In ethanol for 0.166667h; Reflux;	2.2.1. Synthesis of 2a-2b General procedure: To a solution of 1a-1b (4.5 mmol) in 4 mL ethanol was added80% hydrazine hydrate (2 mL) and 10% palladium charcoal (0.08g). The reaction was refluxed for 10 min and filtered by Celite.The filtrate was dried by sodium sulfate, and concentrated in vacuoto afford compounds 2a-2b, which were used without furtherpurification.
	With hydrogen In 1,4-dioxane; dodecane at 149.84℃; for 10h; Autoclave; chemoselective reaction;
	With sodium tetrahydridoborate In methanol at 30℃; for 0.5h;
81 %Spectr.	With hydrazine hydrate monohydrate; copper(II) oxide/zinc oxide composite In acetonitrile at 20℃; for 12h; Irradiation; Inert atmosphere;
60 %Spectr.	With 6Zr⁽⁴⁺⁾C₂₀H₁₂O₄^(2-)14O^(2-)*3Co⁽²⁺⁾; hydrogen; sodium triethylborohydride In toluene at 115℃; for 42h; Glovebox; Inert atmosphere;	19 Example 19 Zr₁₂-TPDC-Co Catalyzed Hydrogenation of Nitroarenes General procedure: Scheme 23 shows the hydrogenation of nitroarenes catalyzed by Zr12-TPDC-Co. In a nitrogen-filled glove box, Zr12-TPDC-CoH (0.50 mg) in 1.0 mL THF was charged into a glass vial. NaBEt3H (10 μL, 1.0 M in THF) was then added to the vial and the mixture was stirred for 1 h. The solid was then centrifuged, washed with THF twice, and transferred to a glass vial in 1.0 mL toluene. The nitroarene substrate was added to the vial, which was placed in a Parr reactor, sealed under nitrogen, and charged with hydrogen to 40 bar. After stirring at 115° C. for 1-2 d, the pressure was released and the MOF catalyst was removed from the reaction mixture via centrifugation. Mesitylene (internal standard) was added to the organic extracts and the yield of the product was determined by integrations of the product and mesitylene peaks in the 1H NMR spectra in CDCl3. Table 20, below summarizes the optimization of conditions for the MOF-CoH catalyzed hydrogenation of nitroarenes using nitrobenzene as an exemplary nitroarene. Table 21 summarizes results of the hydrogenation of various nitroarenes using Zr12-TDPC-CoH.
3.6 g	With lithium hydroxide monohydrate; iron⁽⁰⁾; ammonia hydrochloride In ethanol for 2h; Reflux; Inert atmosphere;	42.1 STEP 1 A mixture of 5-nitroindole (5 g, 30.9 mmol), Fe (8.6 g, 154 mmol), NH4Cl (16.5 g, 309 mmol), EtOH (80 mL) and water (20 mL) was refluxed under N2 protection for 2 hours. The mixture was cooled to RT and filtered. The filtrate was concentrated and dissolved in water. The mixture was basified with Na2CO3 and extracted with CH2Cl2 two times. The combined organic phases were combined, dried over Na2SO4 and filtered. The filtrate was concentrated to yield the product (3.6 g). MS (ESI) m/e (M+H+): 133. 1H NMR (DMSO) δ: 10.55 (s, 1H), 7.12-7.06 (m, 2H), 6.68 (d, J=2.0 Hz, 1H), 6.48 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.12 (t, J=2.0 Hz, 1H), 4.39 (s, 2H).
	With sodium tetrahydridoborate; bis(4,4,4',4'-tetramethyl-2,2'-bisoxazoline)(2,2'-bipyridine)ruthenium(II) hexafluorophosphate In ethanol; acetonitrile at 20℃; for 3h; Irradiation;
76 %Chromat.	With nickel(II) tetrafluoroborate hexahydrate; ammonia; hydrogen; bis(2-diphenylphosphinoethyl)phenylphosphine In 2,2,2-trifluoroethanol at 120℃; for 24h; chemoselective reaction;
	With hydrogen In lithium hydroxide monohydrate at 35℃; for 15h;
	With palladium 10% on activated carbon In ethanol at 20℃; for 16h;	1H-indol-5-amine (31). The commercial 5-nitroindole (1.00 g, 6.17 mmol) washydrogenated in absolute EtOH in the presence of 10% Pd-C (250 mg) for 16h atrt. Then the catalyst was filtered off through Celite and the Celite rinsedwith additional EtOH. The resulting solution was evaporated, to give 31 as a brown solid (799mg, 6.05 mmol, 98% yield). 1H-NMR(DMSO-d6): δ 4.38 (br s, 2H, NH2); 6.11-6.12 (m, 1H,Ar); 6.47 (dd, 1H, J=2.2, 8.4 Hz, Ar); 6.67 (d, 1H, J= 2.2 Hz, Ar); 7.06 (d,1H, J=8.4 Hz Ar); 7.11 (m, 1H, Ar); 10.54 (br s, 1H, NH) ppm.
	With hydrazine monohydrate; FeMo_1.1S_3.2 In ethanol at 30℃; for 1.5h; Inert atmosphere; chemoselective reaction;
	With iron⁽⁰⁾; ammonia hydrochloride In tetrahydrofuran; ethanol; lithium hydroxide monohydrate at 80℃; for 6h;	5.3. Synthesis of intermediate 11a-11f General procedure: Compounds 10a-10f (1.0 mmol, 1.0 eq), Fe (0.5 mmol, 0.5 eq) andNH4Cl (1.0 mmol, 1.0 eq) were added into 10 mL of EtOH/H2O/THF(1:1:1) and stirred at 80 C for 6 h. Then, the mixtures were concentratedunder reduced pressure to give crude products, which were then purified by silica gel column chromatography using PE/EA (2/1, v/v) as eluentsto get intermediate 11a-11f.

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3
[ 87240-07-1 ]
[ 5192-03-0 ]

Reference： [1]Phytochemistry,1982,vol. 21,p. 2879 - 2886

4
[ 5192-03-0 ]
[ 63558-65-6 ]
(1<i>H</i>-indol-5-yl)-(5-iodo-pyrimidin-4-yl)-amine [ No CAS ]

Reference： [1]Tetrahedron Letters,2002,vol. 43,p. 8235 - 8239

5
[ 5192-03-0 ]
[ 24424-99-5 ]
[ 184031-16-1 ]

Yield	Reaction Conditions	Operation in experiment
> 100%	In ethyl acetate; at 20℃; for 24h;	To a solution 5-aminoindole (1.0 g, 7.6 mmol) in 100 mL of EtOAc was added di- tert-butyldicarbonate (4.1 g. 19 mmol). The mixture was stirred at ambient temperature for 24 hours and then was quenched with 20 mL H2O. The layers were separated and the aqueous layer was extracted 3 X 10 mL of EtOAc. The combined organic extracts were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via flash column chromatography (SiO2, 50% hexanes in EtOAc) to provide the title compound (1.8 g, 7.7 mmol, ->100% yield). MS (DCI/NH3) m/z 233 (M+H)+.
94%	With triethylamine; In methanol; at 20℃; for 6h;	Example 16 (1-{4-[3-(4-Chloro-3-(trifluoromethyl)phenyl)ureido]-2-fluorophenyl}-1H-indol-5-yl)carbamic acid tert-butyl ester (Table 1, Compound No. 16) Step A Preparation of (1H-indole-5-yl)carbamic acid tert-Butyl ester [Show Image] In 100 mL of methanol, 2.64 g (20 mmol) of 5-aminoindole was dissolved, and 4.15 mL (30 mmol) of triethylamine and 5.23 g (24 mmol) of Boc2O were added thereto and the mixture solution was stirred at room temperature for six hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned with ethyl acetate (200 mL) and water (100 mL), and the organic layer was washed with a saturated sodium chloride solution. The organic layer was dried and then concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (200 mL) and water (100 mL) and the organic layer was washed with a saturated sodium chloride solution. The organic layer was dried and then concentrated under reduced pressure, and the residue was purified by a silica gel column (Wako Gel C200: 300 g, n-hexane:ethyl acetate=4:1) to obtain 4.38 g (94%) of (1H-indol-5-yl)carbamic acid tert-butyl ester as a white solid. 1H-NMR (270 MHz, CDCl3) δ (ppm): 1.43(9H,s), 6.38 (1H, br.s), 6.29-6.33 (1H, m), 7.04 (1H, dd, J=2.3, 8.9 Hz), 7.19 (1H, s), 7.23 (1H, d, J=8.9 Hz), 7.61 (1H, br.s)
43%	With triethylamine; In dichloromethane; at 0 - 20℃; for 4h;	Intermediate-69: tert-Butyl lH-indol-5-ylcarbamate To a stirred solution lH-indol-5 -amine (0.5 g, 3.78 mmol) in dichloromethane (10 mL), triethylamine (0.95g, 9.4 mmol) and di-tert-butyl dicarbonate (0.908 g, 4.166 mmol) were added at 0C. The reaction contents were stirred at room temperature for 4 h. The reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography to give tert-butyl lH-indol-5-ylcarbamate (0.380 g, 43%); MS: 233.5 (M+l).

In dichloromethane; at 20℃;

A solution of 5-amino indole (2 g, 15.2 mmol) and di-tert-butyl dicarbonate (3.49 g. 15.2 mmol) in dichloromethane (20 ml) was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure to yield crude (1H-indol-5-yl)-carbamic acid tert-butyl ester (3.47 g) which was used in the next step without further purification. MS: 250.3 (M+NH4)+.

Reference： [1]Patent: WO2006/69196,2006,A1 .Location in patent: Page/Page column 117
[2]Journal of the American Chemical Society,2005,vol. 127,p. 4996 - 4997
[3]Patent: EP1724258,2006,A1 .Location in patent: Page/Page column 69-70
[4]Synlett,2004,p. 1794 - 1798
[5]Journal of Medicinal Chemistry,2012,vol. 55,p. 10532 - 10539
[6]Patent: WO2012/69917,2012,A1 .Location in patent: Page/Page column 46-47
[7]Patent: US2005/96353,2005,A1 .Location in patent: Page/Page column 23
[8]Journal of Medicinal Chemistry,2008,vol. 51,p. 1904 - 1912

6
[ 166104-20-7 ]
[ 5192-03-0 ]

Yield	Reaction Conditions	Operation in experiment
81%	With 2,2,2-trifluoroethanol; at 150℃; for 0.25h;Microwave irradiation;Product distribution / selectivity;	EXAMPLE 2; Following the procedure set forth in Example 1 (A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150° C. as set forth in Table 1 below.
81%	With 2,2,2-trifluoroethanol; at 150℃; for 0.25h;Microwave irradiation;Product distribution / selectivity;	Example 1; (A) A solution of the N-Boc protected amine (1 mmol) in TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) (5 mL) was placed in a sealed microwave vial. The reaction mixture was heated (100°C or 150°C) in a Biotage - Initiator.(TM). Sixty microwave reactor with stirring until the disappearance of the starting material was observed. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash-column chromatography. 1H NMR and 13C NMR were measured on Bruker Avance DPX-300 NMR or Bruker Avance-300 NMR spectrometers, operating at a proton (1H) frequency of 300.13 MHz and carbon (13C) frequency of 75.43 MHz.Example 2 Following the procedure set forth in Example 1(A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150°C as set forth in Table 1 below.
70%	With 1,1,1,3',3',3'-hexafluoro-propanol; at 150℃; for 0.25h;Microwave irradiation;Product distribution / selectivity;	Example 1; (A) A solution of the N-Boc protected amine (1 mmol) in TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) (5 mL) was placed in a sealed microwave vial. The reaction mixture was heated (100°C or 150°C) in a Biotage - Initiator.(TM). Sixty microwave reactor with stirring until the disappearance of the starting material was observed. After cooling to room temperature, the mixture was evaporated to dryness under reduced pressure. The crude product was purified by flash-column chromatography. 1H NMR and 13C NMR were measured on Bruker Avance DPX-300 NMR or Bruker Avance-300 NMR spectrometers, operating at a proton (1H) frequency of 300.13 MHz and carbon (13C) frequency of 75.43 MHz.Example 2 Following the procedure set forth in Example 1(A) above, indole derivatives were deprotected using TFE or HFIP in a microwave reactor at 150°C as set forth in Table 1 below.

Reference： [1]Synthetic Communications,2006,vol. 36,p. 2069 - 2077
[2]Synthetic Communications,2008,vol. 38,p. 3840 - 3853
[3]Patent: US2009/203910,2009,A1 .Location in patent: Page/Page column 2-3
[4]Patent: EP2070899,2009,A1 .Location in patent: Page/Page column 3; 4-5
[5]Patent: EP2070899,2009,A1 .Location in patent: Page/Page column 3; 4-5

7
[ 5192-03-0 ]
[ 62088-13-5 ]
ethyl 3-(m-cyano-phenyl)-3-(indol-5-ylamino)-acrylate [ No CAS ]