[ CAS No. 10517-21-2 ] {[proInfo.proName]}

Name: 10517-21-2|5-Chloro-1H-indole-2-carboxylic acid|97%
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Quality Control of [ 10517-21-2 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 10517-21-2 ]

CAS No. :	10517-21-2	MDL No. :	MFCD00005613
Formula :	C₉H₆ClNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	FUQOTYRCMBZFOL-UHFFFAOYSA-N
M.W :	195.60	Pubchem ID :	82693
Synonyms :

Calculated chemistry of [ 10517-21-2 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	9
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	2.0
Molar Refractivity :	50.27
TPSA :	53.09 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) :	-5.41 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.4
Log Po/w (XLOGP3) :	2.94
Log Po/w (WLOGP) :	2.52
Log Po/w (MLOGP) :	1.65
Log Po/w (SILICOS-IT) :	2.5
Consensus Log Po/w :	2.2

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-3.35
Solubility :	0.0871 mg/ml ; 0.000445 mol/l
Class :	Soluble
Log S (Ali) :	-3.72
Solubility :	0.0375 mg/ml ; 0.000192 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.28
Solubility :	0.103 mg/ml ; 0.000528 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.38

Safety of [ 10517-21-2 ]

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 [ 10517-21-2 ]

* 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 [ 10517-21-2 ]
Downstream synthetic route of [ 10517-21-2 ]

[ 10517-21-2 ] Synthesis Path-Upstream 1~16

1
[ 10517-21-2 ]
[ 827-01-0 ]

Reference： [1] Journal of the Chemical Society, 1958, p. 3493,3494

2
[ 4792-67-0 ]
[ 10517-21-2 ]

Yield	Reaction Conditions	Operation in experiment
92.5%	Stage #1: With sodium hydroxide In methanol; water for 1 h; Reflux; Green chemistry Stage #2: With hydrogenchloride In methanol; water at 40℃; Green chemistry	A mixture of 111.5 g of 5-chloroindole-2-carboxylate in 31.25 g of 96percent sodium hydroxide,183 ml of methanol and 183 ml of water was heated under reflux for 1 hour, cooled to 40 ° C,Dropping 10percent hydrochloric acid to pH 3 to 4, fully cooled,The product was filtered to give 90.1 g of an off-white indole-2-carboxylic acid in a yield of 92.5percent and an HPLC content of ≥96percent
90%	Stage #1: With sodium hydroxide In ethanol for 3 h; Reflux Stage #2: With acetic acid In ethanol; waterCooling with ice	A mixture of compound 3a (33.5 g, 0.15 mol), 4percent NaOH solution (335 mL) and ethanol (335 mL) was heated to reflux for 3 h. Upon cooling to room temperature, the mixture was poured into ice-water, adjusted to pH 5 with glacial acetic acid, and then the precipitate was collected by filtration. 4a was obtained as a white solid (26.4 g, 90percent). m.p. 295-298 °C. ESI-MS m/z: 193.4 (Cl = 35), 195.4 (Cl = 37) [M - H]^-. ¹H NMR (300 MHz, DMSO-d₆) δ: 7.06 (s, 1H), 7.24 (s, 1H), 7.43 (s, 1H), 7.70 (s, 1H), 11.95 (s, 1H), 13.10 (s, 1H).

Reference： [1] Chemical Biology and Drug Design, 2017, vol. 90, # 1, p. 64 - 82
[2] Patent: CN104402795, 2017, B, . Location in patent: Paragraph 0045; 0048
[3] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3149 - 3157
[4] Advanced Synthesis and Catalysis, 2016, vol. 358, # 24, p. 3938 - 3942
[5] Journal of the Chemical Society, 1955, p. 3499,3502
[6] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2486 - 2493

3
[ 63069-48-7 ]
[ 127-17-3 ]
[ 10517-21-2 ]

Reference： [1] ChemMedChem, 2018, vol. 13, # 12, p. 1181 - 1192

4
[ 106-47-8 ]
[ 10517-21-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3149 - 3157
[2] ChemMedChem, 2018, vol. 13, # 12, p. 1181 - 1192

5
[ 1073-70-7 ]
[ 10517-21-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3149 - 3157

6
[ 91473-66-4 ]
[ 10517-21-2 ]

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3149 - 3157

7
[ 36255-90-0 ]
[ 10517-21-2 ]

Reference： [1] Journal of the Chemical Society, 1958, p. 3493,3494

8
[ 17333-85-6 ]
[ 10517-21-2 ]

Reference： [1] Journal of the Chemical Society, 1955, p. 3499,3502

9
[ 5296-86-6 ]
[ 10517-21-2 ]

Reference： [1] Journal of the Chemical Society, 1955, p. 3499,3502

10
[ 10517-21-2 ]
[ 64-17-5 ]
[ 4792-67-0 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5251 - 5256
[2] ChemMedChem, 2018, vol. 13, # 12, p. 1181 - 1192

11
[ 10517-21-2 ]
[ 21109-01-3 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2005, vol. 15, # 24, p. 5439 - 5441

12
[ 10517-21-2 ]
[ 74-88-4 ]
[ 59908-47-3 ]

Reference： [1] Patent: WO2006/66879, 2006, A2, . Location in patent: Page/Page column 48-49; 53

13
[ 10517-21-2 ]
[ 59908-47-3 ]

Reference： [1] Patent: WO2016/40449, 2016, A1,
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 21, p. 5664 - 5671

14
[ 10517-21-2 ]
[ 53590-49-1 ]

Reference： [1] Synlett, 2007, # 11, p. 1707 - 1710
[2] Chemical Communications, 2013, vol. 49, # 28, p. 2894 - 2896
[3] Journal of Medicinal Chemistry, 2013, vol. 56, # 9, p. 3725 - 3732
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 2, p. 364 - 377
[5] Journal of Organic Chemistry, 2018, vol. 83, # 4, p. 2486 - 2493

15
[ 10517-21-2 ]
[ 51843-24-4 ]

Reference： [1] European Journal of Medicinal Chemistry, 2011, vol. 46, # 7, p. 3149 - 3157

16
[ 109-01-3 ]
[ 10517-21-2 ]
[ 459168-41-3 ]

Yield	Reaction Conditions	Operation in experiment
0.18 g	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 48 h;	A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N, N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with N-methylpiperazine (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10percent 2 M ammonia in methanol/ dichloromethane) to give the title compound (0.18 g). ¹H NMR (400 MHz, CDCl₃): δ 9.60 (br s, 1 H), 7.65 (d, J = 1.5 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.26 (d, 1.8 Hz, 1 H), 6.76 (d, J = 1.5 Hz, 1 H), 4.0 (br m, 4H), 2.56 (t, J = 5.1 Hz, 4H), 2.41 (s, 3H). Analysis: Calc'd for C₁₄H₁₆ClN₃O; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87.

Reference： [1] Heterocyclic Communications, 2011, vol. 17, # 5-6, p. 207 - 210
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 19, p. 3957 - 3960
[3] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 21, p. 5251 - 5256
[4] Patent: US2003/207893, 2003, A1,
[5] Patent: WO2004/22061, 2004, A1, . Location in patent: Page/Page column 42
[6] European Journal of Medicinal Chemistry, 2012, vol. 54, p. 660 - 668
[7] Patent: EP1373204, 2016, B1, . Location in patent: Paragraph 0113

[ 10517-21-2 ] Synthesis Path-Downstream 1~88

1
[ 10517-21-2 ]
[ 17422-32-1 ]

Yield	Reaction Conditions	Operation in experiment
53%	With quinoline; copper; for 3h;Neat (no solvent); Reflux;	A mixture of compound 4a (23.5 g, 0.12 mol), copper powder (5.4 g, 0.084 mol) and quinoline (235 mL) was heated to reflux for 3 h. Upon cooling to room temperature, the filtrate was collected by filtration, diluted with ice-water and adjusted to pH 4 with concentrated hydrochloric acid, extracted with CH2Cl2 (3 × 100 mL), washed with 2 N hydrochloric acid (3 × 50 mL), saturated NaHCO3 solution (3 × 50 mL) and brine (2 × 50 mL), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography. 5a was obtained as a white solid (9.6 g, 53%). m.p. 71-72 C. ESI-MS m/z: 151.6 (Cl = 35), 153.6 (Cl = 37) [M + H]+. 1H NMR (300 MHz, DMSO-d6) δ: 6.42-6.40 (m, 1H), 7.06 (dd, J1 = 8.7 Hz, J2 = 2.1 Hz, 1H), 7.42-7.38 (m, 2H), 7.57 (d, J = 2.1 Hz, 1H), 11.27 (d, J = 1.8 Hz, 1H).

Reference： [1]Organic Process Research and Development,2012,vol. 16,p. 1449 - 1454
[2]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157
[3]Journal of the Chemical Society,1958,p. 3493,3494
[4]Journal of the Chemical Society,1955,p. 3499,3502

2
[ 4792-67-0 ]
[ 10517-21-2 ]

Yield	Reaction Conditions	Operation in experiment
92.5%		A mixture of 111.5 g of 5-chloroindole-2-carboxylate in 31.25 g of 96% sodium hydroxide,183 ml of methanol and 183 ml of water was heated under reflux for 1 hour, cooled to 40 C,Dropping 10% hydrochloric acid to pH 3 to 4, fully cooled,The product was filtered to give 90.1 g of an off-white indole-2-carboxylic acid in a yield of 92.5% and an HPLC content of ?96%
90%		A mixture of compound 3a (33.5 g, 0.15 mol), 4% NaOH solution (335 mL) and ethanol (335 mL) was heated to reflux for 3 h. Upon cooling to room temperature, the mixture was poured into ice-water, adjusted to pH 5 with glacial acetic acid, and then the precipitate was collected by filtration. 4a was obtained as a white solid (26.4 g, 90%). m.p. 295-298 C. ESI-MS m/z: 193.4 (Cl = 35), 195.4 (Cl = 37) [M - H]-. 1H NMR (300 MHz, DMSO-d6) delta: 7.06 (s, 1H), 7.24 (s, 1H), 7.43 (s, 1H), 7.70 (s, 1H), 11.95 (s, 1H), 13.10 (s, 1H).
	With water;Alkaline conditions;	General procedure: Indole-2-carboxylic acid (4a) was purchased from Tokyo Kasei Co., Ltd., and indole and ethylindole-2-carboxylate were from Wako Pure Chemical Ind., Ltd., and used as received. The 5-chloro- (4b)and 5-fluoro-indole-2-carboxylic acids (4c) were synthesized by saponification of the corresponding ethyl esters which were prepared by [3,3]sigmatropic rearrangement of the arylhydrazones in the presence ofpolyphosphoric acid.

Reference： [1]Chemical Biology and Drug Design,2017,vol. 90,p. 64 - 82
[2]Patent: CN104402795,2017,B .Location in patent: Paragraph 0045; 0048
[3]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157
[4]Advanced Synthesis and Catalysis,2016,vol. 358,p. 3938 - 3942
[5]Journal of the Chemical Society,1955,p. 3499,3502
[6]Journal of Organic Chemistry,2018,vol. 83,p. 2486 - 2493
[7]European Journal of Medicinal Chemistry,2019,vol. 173,p. 15 - 31
[8]Heterocycles,2018,vol. 97,p. 431 - 450

3
[ 10517-21-2 ]
[ 882-33-7 ]
[ 118427-38-6 ]

Yield	Reaction Conditions	Operation in experiment
	In N-methyl-acetamide; hexane;	Step A 5-Chloro-3-phenylthioindole-2-carboxylic acid To a suspension of sodium hydride (3.0 g, 60% dispersion in oil, 0.076 mol) in dimethylformamide (125 mL) was added 5-chloroindole-2-carboxylic acid (5.0 g, 0.0255 mol) and phenyldisulfide (6.1 g, 0.028 mol). The reaction was heated under nitrogen at 50 C. overnight. The reaction was cooled, and additional sodium hydride (1.8 g) and phenyldisulfide (3.6 g) were added and heating continued for 1 h. The reaction was cooled and the dimethylformamide distilled in vacuo. The residue was partitioned between ethyl acetate and water. The aqueous layer was separated and the pH adjusted to pH1 with 10% aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the ethyl acetate extract was washed with water and saturated brine, and dried over magnesium sulfate. The crude product was recrystallized from ethyl acetate in hexane to afford the title compound as an off-white solid.

Reference： [1]Journal of Medicinal Chemistry,1993,vol. 36,p. 1291 - 1294
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 2482 - 2493
[3]Patent: US5527819,1996,A

4
[ 59719-62-9 ]
[ 10517-21-2 ]
[ 874889-02-8 ]

Yield	Reaction Conditions	Operation in experiment
68%		Sodium triacetoxyborohydride (11.0 mmol, 2.33 g) was added to a mixture of 4-nitro-benzaldehyde Compound 4a (10.0 mmol, 1.51 g), cyclohexylamine Compound lOa (10.5mmol, 1.2 mL) and glacial acetic acid (5 drops) in CH2C12 (40 mL) and the resulting suspensionwas allowed to stir at room temperature for 12 hrs. An aliquot of the reaction mixture showedthe formation of product (MS m/e 235, 100%). The reaction mixture was basified with 2NNaOH solution and was extracted with CH2Cl2. The organic layer was washed with brine,separated and dried over Na2S(X<. The drying agent was filtered and the solvent was removedin vacua to yield cyclohexyl-(4-nitro-benzyl)-amine Compound 14a (1.56 g, 67%) as a yellowoil, which was used in the next step without further purification.; An aqueous solution of formaldehyde (37% solution, 9:6 mmol, 0.8 mL) was added toa solution of Compound 14a (3.41 mmol, 0.8 g) in CH2C12; followed by sodiumtriacetoxyborohydride (7.0 mmol, 1.5 g). The mixture was allowed to stir at r.t. for 2 hrs. Thereaction mixture was basified with 2N NaOH solution and was extracted with CH2C12. Theorganic layer was washed with brine, separated and dried over Na2SO4. The drying agent wasfiltered and the solvent was removed in vacuo. The resulting gummy residue was purified bycolumn chromatography (9:1 EtOAc/MeOH) to yield cyclohexyl-methyl-(4-nitro-benzyl)-amine Compound 14b (0.8 g, 94%) as a yellow oil. MS m/e 249 (M+H, 100%).; SnCl2.2H2O (16.0 mmol, 3.6 g) was added to a solution of Compound 14b (3.2 mmol,0.8 g) in EtOH (40 mL) at r.t.. The resulting yellow solution was stirred overnight and thesolvent was removed in vacua. The resulting residue was basified with 2N NaOH solution andthe aqueous layer was extracted with CH2C12 (2 X 30 mL). The combined organic layers weredried over Na2SO4, filtered and the solvent was removed in vacno to obtain 4-[(cyclohexyl-methyl-amino)-methyl]-phenylamine Compound 14c (0.69 g, 98%) as a thick yellow oil, whichwas used in the next step without further purification. MS m/e 219 (M+H, 100%).; EDCI (0.33 mmol> 0.07 g) was added in one portion to a suspension of Compound 14c(0.25 mmol, 0.05 g), 5-chloro-lH-indole-2-carboxylic acid Compound 14d (0.22 mmol, 0.04 g)and HOBt (0.22 mmol, 0.03 g) in DMF (5.0 mL) at 0C. The resulting suspension was warmedto r.t. and then a crystal of DMAP and Et3N (0.65 mmol, 0.1 mL) was added and the reactionmixture was stirred overnight. The resulting orange-yellow suspension was poured in waterand was extracted with EtOAc (25 mL). The organic layer was washed with water (2 X 20 mL)followed by 5% NaOH solution (10 mL) and brine. The organic layer was separated, driedover Na2SO4 and filtered. The solvent was removed in vacua and the resulting residue waspurified by preparative TLC (15:1 CtLC^/MeOH) to yield 5-chloro-lH-indole-2-carboxylicacid {4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}-amide Compound 14e (0.06 g, 68%) as apale yellow solid. MS m/e 396 (M+H, 100%).; lodomethane (0.5 mL) was added to a solution of Compound 14e (0.08 mmol, 0.03 g)in CH2C12 (1.0 mL) at r.t. The resulting solution was allowed to stand overnight and a yellowprecipitate was observed. The solvent was removed in vacuo and the resulting yellow solidwas washed with Et2O to obtain Compound 167 as a yellow solid (0.04 g, 72%). MS m/e 410(M+H, 100%).
68%	With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃;	EDCI (0.33 mmol, 0.07 g) was added in one portion to a suspension of Compound 14c (0.25 mmol, 0.05 g), 5-chloro-1H-indole-2-carboxylic acid Compound 14d (0.22 mmol, 0.04 g) and HOBt (0.22 mmol, 0.03 g) in DMF (5.0 mL) at 0 C. The resulting suspension was warmed to r.t. and then a crystal of DMAP and Et3N (0.65 mmol, 0.1 mL) was added and the reaction mixture was stirred overnight. The resulting orange-yellow suspension was poured in water and was extracted with EtOAc (25 mL). The organic layer was washed with water (2×20 mL) followed by 5% NaOH solution (10 mL) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The solvent was removed in vacuo and the resulting residue was purified by preparative TLC (15:1 CH2Cl2/MeOH) to yield 5-chloro-1H-indole-2-carboxylic acid {4-[(cyclohexyl-methyl-amino)-methyl]-phenyl}-amide Compound 14e (0.06 g, 68%) as a pale yellow solid. MS m/e 396 (M+H, 100%).

Reference： [1]Patent: WO2006/12135,2006,A1 .Location in patent: Page/Page column 72-74
[2]Patent: US2006/293379,2006,A1 .Location in patent: Page/Page column 81

5
[ 109-01-3 ]
[ 10517-21-2 ]
[ 459168-41-3 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonia; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In methanol; dichloromethane; ethyl acetate; N,N-dimethyl-formamide;	Example 1 (5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N,N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with N-methylpiperazine (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.18 g). 1H NMR (400 MHz, CDCl3): delta 9.60 (br s, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=2.0 Hz, 1H), 7.26 (d, 1.8 Hz, 1H), 6.76 (d, J=1.5 Hz, 1H), 4.0 (br m, 4H), 2.56 (t, J=5.1 Hz, 4H), 2.41 (s, 3H). Analysis: Calc'd for C14H16ClN3O; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87.
	With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h;	A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N, N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with [N-METHYLPIPERAZINE] (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10% 2 M ammonia [IN RNETHANOL/DICHLOROMETHANE)] to give the title compound (0.18 [G).'H] NMR (400 MHz, [CDCI3)] : [No. ] 9.60 (br s, 1 H), 7.65 (d, J = 1.5 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.26 (d, 1.8 Hz, 1 H), 6.76 (d, J = 1.5 Hz, 1 H), 4.0 (br m, 4H), 2. [56] (t, J = 5.1 Hz, 4H), 2.41 (s, 3H). Analysis: [CALC'D FORC14H16CIN3O] ; C, 60.54 ; H, 5.81 ; N, 15.13 ; Found: C, 59.99 ; H, 5.94 ; N, 18.87.
		General procedure: (5-Chloro-7-fluoro-1H-indole-2-yl)-carboxylic acid (5a) (50 mg, 0.23 mmol), N,N-diisopropylethylamine (82 mul, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) were dissolved in 550 mul N,N-dimethylformamide. After stirring for 10 min 4-methyl-piperazin 6a (26 mul, 0.23 mmol) was added and the reaction mixture was stirred for 16 h at 20 C. The solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P1, yielding 37 mg (53%) of the title compound.

0.18 g

With 1-hydroxy-7-aza-benzotriazole; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 48h;

A mixture of 5-chloroindole-2-carboxylic acid (0.234 g), HATU (0.569 g), HOAT (0.203 g) and N, N-diisopropylethylamine (0.191 mL) in DMF (0.6 mL) was treated with N-methylpiperazine (0.1 mL) stirred at ambient temperature for 48 h then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (3-10% 2 M ammonia in methanol/ dichloromethane) to give the title compound (0.18 g). 1H NMR (400 MHz, CDCl3): delta 9.60 (br s, 1 H), 7.65 (d, J = 1.5 Hz, 1 H), 7.40 (d, J = 8.6 Hz, 1 H), 7.29 (d, J = 2.0 Hz, 1 H), 7.26 (d, 1.8 Hz, 1 H), 6.76 (d, J = 1.5 Hz, 1 H), 4.0 (br m, 4H), 2.56 (t, J = 5.1 Hz, 4H), 2.41 (s, 3H). Analysis: Calc'd for C14H16ClN3O; C, 60.54; H, 5.81; N, 15.13; Found: C, 59.99; H, 5.94; N, 18.87.

Reference： [1]Heterocyclic Communications,2011,vol. 17,p. 207 - 210
[2]Journal of Medicinal Chemistry,2003,vol. 46,p. 3957 - 3960
[3]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5251 - 5256
[4]Patent: US2003/207893,2003,A1
[5]Patent: WO2004/22061,2004,A1 .Location in patent: Page/Page column 42
[6]European Journal of Medicinal Chemistry,2012,vol. 54,p. 660 - 668
[7]Patent: EP1373204,2016,B1 .Location in patent: Paragraph 0113

6
[ 10517-21-2 ]
[ 86499-35-6 ]
3-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	EXAMPLE 19 3-(5-chloroindole-2-carbonylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one The title compound was prepared according to the Carbodiimide Mediated Amide Bond Formation Procedure from <strong>[86499-35-6]3-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one</strong> (amine prepared in Schoen, et al., J. Med. Chem. 1994, 37, 897-906). HPLC/MS [M+H]+, 354. Carbodiimide Mediated Amide Bond Formation Procedure [0286] A mixture of amine (0.04-0.23 mmol), N,N-dimethylformamide (0.8 mL), 5-chloroindole-2-carboxylic acid (1-2 equiv), 1-hydroxy-7-azabenzotriazole (1-2 equiv), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.5-2.0 equiv) was stirred at room temperature. The starting amines were free bases unless otherwise noted. In cases where an amine salt was used, a scavenger base, generally triethylamine (1-2 equiv), was also present. After 16 h, 1.0 M aqueous sodium bicarbonate (0.5 mL) was added to hydrolyze any remaining activated ester. Water (2 mL) was added 1 day later, and the resulting precipitated mixture was centrifuged. The supernatant was removed, and the precipitate was washed by resuspension in water, centrifugation, and supernatant removal. In cases where an additional chemical step was required, such as ester hydrolysis, this crude amide product was used without further purification. In cases where the amide was the final product, further purification was performed as follows. A. The crude amide was stirred at room temperature in N,N-dimethylformamide (0.5 mL), then diluted with methanol (1 mL) and water (0.1 mL). B. The supernatant was injected onto reverse phase preparative HPLC using trifluoroacetic acid containing solvents to isolate pure amide product. Steps A and B were repeated with any remaining precipitate until either the precipitate contained no amide product or the precipitate was pure amide product.

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2003,vol. 13,p. 4385 - 4388
[2]Patent: US2004/2495,2004,A1 .Location in patent: Page/Page column 32; 36

7
[ 10517-21-2 ]
[ 64507-05-7 ]

Yield	Reaction Conditions	Operation in experiment
100%	With thionyl chloride;N,N-dimethyl-formamide; In toluene; for 4h;Heating / reflux;Product distribution / selectivity;	5-Chloro-1 H-indole-2-carboxylic acid [4'-fluoro-3-(1H-tetrazol-5-yl)-biphenyl-4-yl]amide (23)To a solution of commercial 5-chloroindole-2-carboxylic-acid (0.5 g, 1 eq) in dry TOL (10 ml), thionyl chloride (1.86 ml, 10 eq) is carefully added, followed by 1 -2 drops of dry DMF. The resulting yellow solution is refluxed for 4 hours and then evaporated to dryness, to get the 5-chloro-1 H-indole-2-carbonyl chloride as a yellow <n="33"/>residue (yield 100%). To a solution of 4'-fluoro-3-(1 H-tetrazol-5-yl)-biphenyl-4-ylamine prepared as described in WO 2006064015 (0.65 g, 1 eq) in dry TOL (20 ml) and Py (3 ml), a solution of the above acid chloride in dry TOL (5 ml) is added drop wise and the mixture is heated (600C) overnight. The day after the suspension is evaporated to dryness (0.79 g, yield -72%) and the resulting solid residue is purified by crystallization from EtOH. LC-ESI-HRMS of [M-H]- shows 431.084 Da. CaIc. 431.08234 Da, dev. 3.9 ppm.
100%	With oxalyl dichloride;N,N-dimethyl-formamide; In toluene; at 60℃; for 3h;Product distribution / selectivity;	5-Chloro-1 H-indole-2-carboxylic acid [5-chloro-2-(1H-tetrazol-5-yl)-phenyl]-amide (25) To a solution of commercial 5-chloroindole-2-carboxylic-acid (0.50 g, 1 eq) in dry TOL (20 ml), an excess of oxalyl chloride (0.9 ml) is added, followed by 1 -2 drops of dry DMF. The resulting yellow solution is heated (600C) for 3 hours and evaporated to dryness, to get the correspondent 5-chloro-1 H-indole-2-carbonyl chloride (yield 100%). To a solution of 5-chloro-2-(1 H-tetrazol-5-yl)-phenylamine prepared as described by Valgeirsson et al. in Journal of Medicinal Chemistry 2004 47 (27) 6948-6957 in dry TOL (20 ml) and Py (2 ml), a solution of the above acid chloride derivative in dry TOL (10 ml) is added drop wise and stirred at room temperature overnight. The day after the suspension is evaporated to dryness (-0.73 g, -100% yield) and the yellow residue is suspended in HCI 1 N, stirred for 20 min and filtered. The residue on the filter is repeatedly washed with water and finally dried (0.74 g, 78%). The crude compound is easily purified by crystallization from a mixture of DMSO and water. LC-ESI-HRMS of [M+H]+ shows 373.0389 Da. CaIc. 373.03714 Da, dev. 4.7 ppm.
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃;Heating / reflux;	5-Chloroindole-2-carboxylic acid (20 g) was suspended in methylene chloride (1500 mL), and N,N-dimethylformamide (2 mL) was added thereto, followed by dropwise addition of thionyl chloride (11 mL) at room temperature. The reaction mixture was heated under reflux overnight, and the resultant mixture was concentrated under reduced pressure. The residue was dissolved in methylene chloride (1000 mL). Triethylamine (84.7 mL) was added to the solution under ice cooling, and p-nitrophenol (14.2 g) was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and 0.2N hydrochloric acid. The organic layer was sequentially washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, to thereby give the title compound (29.9 g).1H-NMR(CDCl3) delta:7.35(1H, dd, J=9.0, 1.7Hz), 7.39-7.42(2H, m), 7.45(2H, dd, J=7.3, 1.7Hz), 7.73(1H, d, J=1.0Hz), 8.35(2H, dd, J=7.3, 1.7Hz), 9.09(1H, br.s). MS(FD)m/z:316(M+).

	With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 25℃; for 1h;	Example 1C[00155] 5-chloro-lH-indole-2-carbonyl chloride[00156] 5-Chloroindole-2-carboxylic acid (59 ing, 0.30 mmol) was suspended in dichloromethane (10 mL). Oxalyl chloride (41 muL, 0.45 mmol) and NN-dimethylformamide (5 muL) were added, and the reaction mixture was stirred at 25 0C for 1 hour. The mixture was concentrated, and the residue was dried under high vacuum to provide the crude product which was used without additional purification.
	With thionyl chloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃;	[Referential Example 52] 4-Nitrophenyl 5-chloroindole-2-carboxylate: After 5-chloroindole-2-carboxylic acid (20 g) was suspended in methylene chloride (1500 ml), and N,N-dimethylformamide (2 ml) was added, thionyl chloride (11 ml) was added dropwise at room temperature.. The reaction mixture was heated overnight under reflux and then concentrated under reduced pressure.. The residue was dissolved in methylene chloride (1000 ml), and triethylamine (84.7 ml) and p-nitrophenol (14.2 g) were added to the mixture under ice cooling.. After stirring for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure, and ethyl acetate and 0.2N hydrochloric acid were added to the residue to separate an organic layer.. The organic layer was successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate.. The solvent was distilled off under reduced pressure to obtain the title compound (29.9 g).1H-NMR (CDCl3) delta: 7.35(1H,dd,J=9.0,1.7Hz), 7.39-7.42(2H,m), 7.45(2H,dd,J=7.3,1.7Hz), 7.73(1H,d, J=1.0Hz), 8.35 (2H,dd,J=7.3,1.7Hz), 9.09(1H,br.s). MS (FD) m/z: 316(M+).
	With thionyl chloride; at 80℃; for 1h;	Example IV; Diethyl [[1 -(5-chloro-1 H-indole-2-carbonyl)-2,3-dihvdro-1 H-indol-5-yll-(3,5- dichloro-phenylsulphonyl)-amino1-methyl)-phosphonate 50 mg 5-chloro-1 H-indole-2-carboxylic acid are dissolved in 2 ml of thionyl chloride and heated to 800C for 1 hour. The solvent is eliminated in vacuo and the residue is twice combined with dichloromethane and this is again eliminated in vacuo. The residue is taken up in 5 ml dichloromethane and the solution is added dropwise to a mixture of 100 mg diethyl [(3,5-dichloro- phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)-amino]-methyl}-phosphonate and 60 mg potassium carbonate in 2 ml dimethylformamide. The mixture is stirred for 2 hours at ambient temperature, diluted with ethyl acetate and washed with 1 N HCI and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/ methanol 95:5 to 70:30). Yield: 65 mg (48 % of theory) Mass spectrum (ESI+): m/z = 670 [M+H]+
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; dichloromethane; at 20℃; for 1 - 1.5h;Product distribution / selectivity;	To a stirred solution of 5-chloroindole-2-carboxylic acid (86 mg, 0.44 mmol) in tetrahydrofuran (2 mL) at room temperature under nitrogen was added oxalyl chloride (2.0 M in dichloromethane solution, 0.45 mL, 0.90 mmol) and N,N-dimethylformamide (0.010 mL). After 1 h, the reaction mixture was concentrated under vacuum to provide the acid chloride, which was taken up in tetrahydrofuran (3 mL). To the resulting solution stirring under nitrogen at room temperature was added 3-amino-2-naphthol (70 mg, 0.44 mmol) followed by triethylamine (0.3 mL, 2.2 mmol). After 1 h, the reaction mixture was quenched by addition of 1.0 M aqueous hydrochloric acid solution and diluted with ethyl acetate. The reaction mixture was filtered to remove insoluble materials. The filtrate was washed sequentially with 1.0 M aqueous hydrochloric acid solution and brine, dried over anhydrous magnesium sulfate, and concentration under vacuum to yield a residue. The residue was suspended in methanol and the methanol solution phase was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain Example 1 (16 mg, 11%) as a light yellow solid. 1H NMR (400 MHz, d8-tetrahydrofuran) delta 9.61 (s, 1H), 9.13 (s, 1H), 8.79 (s, 1H), 7.74 (d, J=7.0 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.2 Hz, 1H), 7.19 (m, 4H), 7.17 (s, 1H), 7.13 (s, 1H). MS [M+H]+, 337; [M-H]-, 335.; To a stirred solution of 5-chloroindole-2-carboxylic acid (300 mg, 1.53 mmol) in tetrahydrofuran (10 mL) at room temperature under nitrogen was added oxalyl chloride (2.0 M in dichloromethane solution, 1.53 mL, 3.06 mmol) and N,N-dimethylformamide (0.010 mL). After 1.5 h, the reaction mixture was concentrated under vacuum to yield the acid chloride. The acid chloride was dissolved in tetrahydrofuran (10 mL) stirring under nitrogen at room temperature, and 3-amino-2-naphthoic acid (287 mg, 1.53 mmol) was added followed by triethylamine (1.1 mL, 7.7 mmol). After 2 h, the reaction mixture was quenched by addition of 1.0 M aqueous hydrochloric acid solution and diluted with ethyl acetate. The organic layer was washed sequentially with 1.0 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum to yield a residue. The residue was suspended in methanol and filtered to collect Example 2 (300 mg, 54%) as a light yellow solid. 1H NMR (500 MHz, d8-tetrahydrofuran) delta 12.42 (s, 1H), 11.38 (s, 1H), 9.33 (s, 1H), 8.79 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.87 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J=6.6 Hz, 1H), 7.45 (m, 2H), 7.21 (d, J=6.5 Hz, 1H), 7.13 (s, 1H). HPLC/MS [M+H]+, 365; [M-H]-, 363.
	With thionyl chloride; for 0.25h;Reflux; Inert atmosphere;	General procedure: Commercial indole-2-carboxylic acid was dissolved in thionyl chloride (1.5 mL/mmol) and the suspension was boiled for 15 min, during which time typically a dark green solution was formed. Excess thionyl chloride was removed under reduced pressure and the solid residue was suspended in toluene and the suspension was evaporated to dryness (toluene treatment was repeated three times). The green-grayish solid residues were used without further purification.
	With oxalyl dichloride; N,N-dimethyl-formamide; In tetrahydrofuran; at 0℃; for 1.5h;Inert atmosphere;	General procedure: To the acid (1 eq) in 1 mL of THF and 1 drop of DMF at 0C, oxalyl chloride (1.2 eq) was added. The reaction was stirred under nitrogen for 1.5 hours and then the solution was concentrated. The acid chloride was continued to the next step.
	With thionyl chloride; at 80℃; for 1h;	Example X; <n="80"/>tert-butyl r?-(5-chloro-1 H-indol-2-carbonyl)-2.3-dihvdro-1 H-indol-5-yll-(3.5- dichloro-phenylsulphonvD-anninoi-acetate; 55 mg delta-chloro-I H-indol^-carboxylic acid are dissolved in 2 ml of thionyl chloride and heated to 800C for 1 hour. The solvent is eliminated in vacuo and the residue is twice combined with dichloromethane and the latter is eliminated again in vacuo. The residue is taken up in 5 ml dichloromethane and the solution is added dropwise to a mixture of 100 mg tert-butyl [(3,5- dichloro-phenylsulphonyl)-(2,3-dihydro-1 H-indol-5-yl)-amino]-acetate and 60 mg potassium carbonate in 2 ml dimethylformamide. The mixture is stirred for 2 hours at ambient temperature, diluted with ethyl acetate and washed with 1 N HCI and saturated sodium chloride solution. After drying with magnesium sulphate the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1 :2). Yield: 60 mg (43 % of theory) Mass spectrum (ESI+): m/z = 634 [M+H]+

Reference： [1]Patent: WO2008/74755,2008,A2 .Location in patent: Page/Page column 31-32
[2]Patent: WO2008/74755,2008,A2 .Location in patent: Page/Page column 32
[3]Molecules,2011,vol. 16,p. 8292 - 8304
[4]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 3345 - 3349
[5]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 5439 - 5441
[6]Patent: EP1577301,2005,A1 .Location in patent: Page/Page column 93
[7]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 782 - 787
[8]Patent: WO2008/118747,2008,A1 .Location in patent: Page/Page column 35
[9]Patent: EP1405852,2004,A1 .Location in patent: Page 85
[10]Patent: WO2009/16119,2009,A1 .Location in patent: Page/Page column 48
[11]Journal of Medicinal Chemistry,2009,vol. 52,p. 5093 - 5107
[12]Patent: US2006/111415,2006,A1 .Location in patent: Page/Page column 14
[13]Bioorganic and Medicinal Chemistry,2011,vol. 19,p. 1550 - 1561
[14]Phosphorus, Sulfur and Silicon and the Related Elements,2011,vol. 186,p. 1790 - 1800
[15]Synthesis,2015,vol. 47,p. 489 - 496
[16]Journal of Receptors and Signal Transduction,2017,vol. 37,p. 304 - 313
[17]Bioorganic and Medicinal Chemistry Letters,2018,vol. 28,p. 1127 - 1131
[18]Patent: WO2008/113760,2008,A2 .Location in patent: Page/Page column 78-79
[19]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 499 - 503
[20]Journal of Organic Chemistry,2019,vol. 84,p. 5886 - 5892

8
[ 110-91-8 ]
[ 10517-21-2 ]
(5-chloro-1H-indole-2-yl)(morpholino)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
61%	With benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; triethylamine; In N,N-dimethyl-formamide; at 20℃;	5-chloro-1H-indole-2-carboxylic acid (1 eq) was dissolved in DMF, to which morpholine (1.01 eq), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 1.1 eq), 1-hydroxybenzotriazole (HOBT, 1.1 eq), and TEA (3 eq) were addedstepwise, followed by stirring at room temperature for overnight. The reaction was terminated with a small amount ofwater, followed by extraction using water and EtOAc. The small amount of water remaining in the organic layer wasdried over anhydrous MgSO4. The solvent was eliminated by vacuum distillation, followed by vacuum drying. Then, atarget compound was obtained by column separation with the yield of 61%. 1H NMR (300MHz, DMSO-d6) delta 7.65 (d, 1H), 7.43 (d, 1H), 7.19 (dd, 1H), 6.79 (s, 1H), 3.74 (s, 4H), 3.66 (d, 4H).

Reference： [1]Patent: EP3176163,2017,A1 .Location in patent: Paragraph 0107-0109
[2]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 5251 - 5256

9
[ 67-56-1 ]
[ 10517-21-2 ]
[ 87802-11-7 ]

Yield	Reaction Conditions	Operation in experiment
93%	With thionyl chloride; for 2.5h;	To a solution of 5-Chloroindole-2-carboxylic acid (5g,25.6 mmol, 1 eq) in 30 mL of MeOH was added SOCl2 (3.7g,30.8 mmol, 1.2 eq) dropwise within 30 min at 0 C. Subsequently,the reaction mixture was stirred at 35 C for 2 h. Then, the solventwas evaporated under reduced pressure, and the residue was purifiedby column chromatography using ethylacetate/petroleum,giving intermediate 2 as a yellow solid, yield 93%. m.p.212.2-214.7 C. 1H NMR (400 MHz, CDCl3) delta 8.95 (s, 1H, NH), 7.67 (s,1H, ArH), 7.35 (d, J 8.7 Hz, 1H, ArH), 7.31-7.25 (m, 2H, ArH, ArCH), 3.95 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) delta 162.1, 135.1, 128.4,126.6, 126.0, 121.8, 112.98, 112.93, 108.1, 52.2.

Reference： [1]Synlett,2007,p. 1707 - 1710
[2]European Journal of Medicinal Chemistry,2019,vol. 180,p. 41 - 50
[3]Angewandte Chemie - International Edition,2015,vol. 54,p. 8809 - 8813
Angew. Chem.,2015,vol. 127,p. 8933 - 8937,5
[4]Journal of Medicinal Chemistry,2005,vol. 48,p. 4511 - 4525
[5]Chemistry - A European Journal,2019,vol. 25,p. 4330 - 4334
[6]Archiv der Pharmazie,2020

10
[ 10517-21-2 ]
[ 5720-07-0 ]
5-(4-methoxyphenyl)-1H-indole-2-carboxylic acid [ No CAS ]

Reference： [1]Angewandte Chemie - International Edition,2005,vol. 44,p. 6173 - 6177

11
[ 10517-21-2 ]
[ 53590-47-9 ]

Reference： [1]Chemical Communications,2013,vol. 49,p. 2894 - 2896
[2]Synlett,2007,p. 1707 - 1710
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 364 - 377
[4]Journal of the American Chemical Society,2015,vol. 137,p. 9567 - 9570
[5]Chemical Communications,2019,vol. 55,p. 4363 - 4366
[6]ACS Medicinal Chemistry Letters,2021,vol. 12,p. 704 - 712

12
[ 10517-21-2 ]
[ 53590-49-1 ]

Reference： [1]Synlett,2007,p. 1707 - 1710
[2]Chemical Communications,2013,vol. 49,p. 2894 - 2896
[3]Journal of Medicinal Chemistry,2013,vol. 56,p. 3725 - 3732
[4]Journal of Medicinal Chemistry,2014,vol. 57,p. 364 - 377
[5]Journal of Organic Chemistry,2018,vol. 83,p. 2486 - 2493
[6]Chemical Communications,2019,vol. 55,p. 4363 - 4366

13
[ 480449-84-1 ]
[ 10517-21-2 ]
[ 365997-38-2 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	[Referential Example 97] ethyl (1S,3R,4S)-3-[(tert-butoxycarbonyl)amino]-4-[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate: The compound (4.2 g) obtained in Referential Example 96 was dissolved in methylene chloride (50 ml), 5-chloroindole-2-carboxylic acid (3.33 g), 1-hydroxybenzotriazole monohydrate (2.52 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.15 g) were added at room temperature, and the mixture was stirred for 12 hours.. After 0.1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with methylene chloride, the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane = 1:1) to obtain the title compound (4.36 g). [α]D25 = -27 (C=1.0, chloroform).

Reference： [1]Bioorganic and Medicinal Chemistry,2009,vol. 17,p. 1193 - 1206
[2]Patent: EP1405852,2004,A1 .Location in patent: Page 106

14
racemate-ethyl 4-amino-3-(tert-butoxycarbonylamino)cyclohexanecarboxylate [ No CAS ]
[ 10517-21-2 ]
ethyl (1RS,3SR,4RS)-3-[(tert-butoxycarbonyl)amino]-4-[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 12h;	[Referential Example 91] ethyl (1RS,3SR,4RS)-3- [(tert-butoxycarbonyl)amino]-4-[(5-chloroindol-2-yl)carbonyl]amino}cyclohexanecarboxylate: The compound (4.62 g) obtained in Referential Example 90 was dissolved in methylene chloride (50 ml), 5-chloroindole-2-carboxylic acid (3.63 g), 1-hydroxybenzotriazole monohydrate (2.43 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.45 g) were added at room temperature, and the mixture was stirred for 12 hours.. After 0.1N hydrochloric acid was added, and the mixture was extracted with methylene chloride, the resultant organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate.. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane = 2:3) to obtain the title compound (5.3 g).1H-NMR (CDCl3) δ: 1.26(3H,t,J=7.1Hz), 1.43(9H,s), 1.35-2.46(7H,m), 3.91-4.02(1H,m), 4.10-4.22(2H,m), 4.79(1H,br.s), 6.79(1H,s), 7.18-7.40(2H,m), 7.59(1H,s), 8.00(1H,br.s), 9.13(1H,br.s).

Reference： [1]Patent: EP1405852,2004,A1 .Location in patent: Page 104-105
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4587 - 4592

15
[ 10517-21-2 ]
[ 20948-67-8 ]

Yield	Reaction Conditions	Operation in experiment
		5-Chloro-1H-indole-2-carboxylic acid (1.96 g) and 1-hydroxybenzotriazole monohydrate (HOBt·H2O) (1.58 g) were dissolved in N,N-dimethylformamide (DMF) (10 ml) and 1-(3-(dimethylamino)propyl)-3-ethylcarhodiimide hydrochloride (EDC) (2.58 g) was added. This solution was stirred at room temperature for 3 hr. This solution was cooled in an ice-bath and hydrazine hydrate (2.4 ml) was added. This solution was stirred at room temperature for 11 hr. Water (20ml) was added slowly to this reaction mixture. The precipitated solid was collected by filtration and dried in vacuo to give the title compound (2.24 g) (containing DMF (15%) as a residual solvent). This sample was boiled in tetrahydrofuran (THF), allowed to cool and filtered to give a purer sample.1H-NMR(δ, 300MHz,DMSO-d6). 4.52(2H,brs),7.05(1H,d,J=1.5Hz),7.16(1H,dd,J=8.7Hz,2.1Hz),7.42 (1H,d,J=8.7Hz),7.66(1H,d,J=1.9Hz),9.86(1H,brs),11.84(1H,s).

Reference： [1]Patent: EP1452526,2004,A1 .Location in patent: Page 54
[2]ChemMedChem,2018,vol. 13,p. 1181 - 1192
[3]Archiv der Pharmazie,2020,vol. 353

16
[ 1483-24-5 ]
[ 10517-21-2 ]
[ 521960-53-2 ]

Yield	Reaction Conditions	Operation in experiment
66%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h;	To a solution (10 ml) of 5-chloro-1H-indole-2-carboxylic acid (100 mg) and benzoic acid 1-methylhydrazide obtained in Example 1-5 a) (130 mg) in DMF were added 1-hydroxybenzotriazole (122 mg) and EDC (153 mg). The mixture was stirred at room temperature for 16 hr and water was added to the reaction solution. The precipitated solid was collected by filtration and washed with water and diethyl ether. The resulting solid was dried in vacuo to give the title compound (144 mg, yield 66%) (see Table 1).

Reference： [1]Patent: EP1452526,2004,A1 .Location in patent: Page 56

17
trans 3-amino-4-carbomethoxymethyl-3,4-dihydrocarbostyril trifluoroacetic acid salt [ No CAS ]
[ 10517-21-2 ]
(3R*,4S*)-4-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
56%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 1h;	A 1 mL reaction vessel was charged with trans 3-amino-4-carbomethoxymethyl-3,4-dihydrocarbostyril trifluoroacetic acid salt (13 mg, 0.04 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (9 mg, 0.05 mmol), 1-hydroxy-7-azabenzotriazole (7 mg, 0.05 mmol), 5-chloroindole-2-carboxylic acid (8 mg, 0.04 mmol) and N,N-dimethylformamide (0.3 mL). After the solids dissolved during stirring at room temperature under argon, diisopropylethylamine (14 mg, 0.11 mmol) was added, and the solution was stirred for 1 h before it was diluted with water (0.2 mL) and methanol (0.8 mL). Purification by reverse phase preparative HPLC using trifluoroacetic acid containing solvents gave the title compound (8.5 mg, 56% yield) as a white solid. 1H NMR (d8-THF, 400 MHz) delta 11.2 (s, 1H), 9.6 (s, 1H), 8.06 (d, 1H, J=8.9 Hz), 7.64 (d, 1H, J=1.9 Hz), 7.43 (d, 1H, J=8.7 Hz), 7.24-6.87 (m, 6H), 4.84 (dd, 1H, J=8.8, 13.0 Hz), 3.67 (m, 1H), 3.59 (s, 3H), 2.89 (d, 2H, J=6.2 Hz). HPLC/MS [M+H]+, 412.

Reference： [1]Patent: US2004/2495,2004,A1 .Location in patent: Page/Page column 41

18
[ 10517-21-2 ]
[ 506-59-2 ]
[ 878156-87-7 ]

Yield	Reaction Conditions	Operation in experiment
55%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 20℃;	OENEM) PROCEDURE A : Amide coupling (Scheme 2) Under nitrogen, at room temperature and in A FLASK adapted with A mechanical stirrer, indole-carboxylic acid VLLL (1 eq. ) was dissoveld in DMF. To this solution, the corresponding amine IX (1.1 to 5 eq. ) EDC (1.2 eq), HOBT (1,2 eq) and were added followed by triethylamine (3 eq. ). The mixture was stirred overnight at room temperature. After the reaction is completed, the mixture was poured slowly to a NaHCO3 solution. After extration with DICHLOROMETHANE the organic layer was washed with 1 N HCI, and brine, dried on MgS04 and evaporated under reduced pressure. The compound VI was obtained as a solid and was used without further purification. Example 1: 5-Chloro-1 H-indole-2-carboxylic acid dimethylamide (633mg, 55%) was obtained by reacting <strong>[10517-21-2]5-chloro-1H-Indole-2-carboxylic acid</strong> (1. 0G, 5. 10MMOL) with DIMETHYLAMINE hydrochloride (500mg, 6.13 MMOL), EDC (1.175g, 6. 13MMOL) and HOBT (826mg, 6. 13MMOL). MS ESI m/z. : 223.0 [M+H] +.

Reference： [1]Patent: WO2005/5418,2005,A1 .Location in patent: Page/Page column 12-13

19
[ 10517-21-2 ]
[ 109-07-9 ]
[ 459169-44-9 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	A mixture of 5-chloroindole-2-carboxylic acid (0.196 g) and [1- (3-] dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 [G)] in dichloromethane (10 mL) was treated with 2-Methyl-piperazine (0.15 g) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (50 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% [METHANOL/DICHLOROMETHANE)] to give the title compound (0.229 g). 1H NMR (400 MHz, CDCl3) : [8] 10.99 (br s, 1H), 7.55 (d, J = 1.76 Hz, [1H),] 7.33 (d, J = 8.80 Hz, [1H),] 7.14 (dd, J = 1.96, 6.65 Hz, [1H),] 6.63 (br s, 1 H), 4.55 (br s, 2H), 3.23-2. 61 (m, 5H), 1.76 (br s, 1 H), 1.08 (d, J = 5.87 Hz, [1H).] MS (electrospray) : exact mass calculated for [C14H16CIN3O,] 277.10 ; m/z found, 278.1 [M+H] +.
0.229 g	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 16h;	A mixture of 5-chloroindole-2-carboxylic acid (0.196 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.288 g) in dichloromethane (10 mL) was treated with 2-Methyl-piperazine (0.15 g) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (50 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.229 g). 1H NMR (400 MHz, CDCl3): delta 10.99 (br s, 1 H), 7.55 (d, J = 1.76 Hz, 1 H), 7.33 (d, J = 8.80 Hz, 1 H), 7.14 (dd, J = 1.96, 6.65 Hz, 1 H), 6.63 (br s, 1 H), 4.55 (br s, 2H), 3.23-2.61 (m, 5H), 1.76 (br s, 1 H), 1.08 (d, J = 5.87 Hz, 1 H). MS (electrospray): exact mass calculated for C14H16ClN3O, 277.10; m/z found, 278.1 [M+H]+

Reference： [1]Patent: WO2004/22061,2004,A1 .Location in patent: Page/Page column 72
[2]Patent: EP1373204,2016,B1 .Location in patent: Paragraph 0218

20
[ 403860-48-0 ]
[ 10517-21-2 ]
[ 597555-50-5 ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 3h;	Intermediate 5: TERT-BUTVL (1R, 2R)-2- [ (5-CHLORO-LH-INDOL-2-VL) CARBONVLLAMINO-2, 3- DIHVDRO-IH-INDEN-L-VL) CARBAMATE 5-Chloroindole-2-carboxylic acid (391 mg, 2 mmol), tert-Butyl [(LR, 2R)-2-AMINO-2, 3- dihydro-lH-inden-l-yl] carbamate (Intermediate 6; 497 mg, 2 mmol), DIPEA (350 . IL, 2 mmol) and HOBt (270 mg, 2 mmol) were dissolved in DCM (10 mL), stirred for 5 mins, then EDCI (479mg, 2.5 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (25 ML) was added and the organic solution washed with water (2 x 10 ML), brine (10 mL), dried (MGS04) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam. H NMR 8 : 1.47 (s, 9H), 2.9 (dd, 1H), 3.27 (dd, 1H), 4.7 (m, 1H), 5.25 (m, 1H), 7.24 (m, 6H), 7.5 (m, 2H), 7.79 (s, 1H), 8. 91 (d, 1H), 11.85 (s, 1H), MS M/Z 426,428.
94%		Method 5a ;tert-Butyl ((1R, 2R)-2-f [(5-chloro-lH-indol-2-yl) carbonyllamino}-2. 3-dihydro-lH-inden-1- yl) carbamate; 5-Chloroindole-2-carboxylic acid (391 mg, 2 mmol), tert-Butyl [(1R,2R)-2-amino-2, 3- dihydro-lH-inden-1-yl] carbamate (497 mg, 2 mmol), DIPEA (350 muL, 2 mmol) and HOBT (270 mg, 2 mmol) were dissolved in DCM (10 mL), stirred for 5 mins, then EDCI (479mg, 2.5 mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (25 mL) was added and the organic solution washed with water (2 x 10 mL), brine (10 mL), dried (MgS04) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam. 'H NMR 1.47 (s, 9H), 2.9 (dd, 1H), 3.27 (dd, 1H), 4.7 (m, 1H), 5.25 (m, 1H), 7.24 (m, 6H), 7.5 (m, 2H), 7.79 (s, 1H), 8.91 (d, 1H), 11.85 (s, 1H), MS m/z 426,428.
94%		5-CHLOROINDOLE-2-CARBOXYLIC acid (391 mg, 2 MMOL), TERT-BUTYL [(LR, 2R)-2-AMINO-2, 3- dihydro-lH-inden-1-yl] carbamate (Intermediate 24; 497 mg, 2 MMOL), DIPEA (350 RL, 2 mmol) and HOBT (270 mg, 2 mmol) were dissolved in DCM (10 ML), stirred for 5 mins, EDCI (479mg, 2.5 MMOL), the reaction stirred for 3 hours and the volatiles removed by evaporation under reduced pressure. EtOAc (25 ML) was added and the organic solution washed with water (2 x 10 mL), brine (10 mL), dried (MGS04) and the volatiles removed by evaporation under reduced pressure to give the title compound (800 mg, 94%) as a pale brown foam. 'H NMR 8 : 1.47 (s, 9H), 2.9 (dd, 1H), 3.27 (dd, 1H), 4.7 (m, 1H), 5.25 (m, 1H), 7.24 (m, 6H), 7.5 (m, 2H), 7.79 (s, 1H), 8.91 (d, 1H), 11.85 (s, 1H), MS m/z 426,428.

Reference： [1]Patent: WO2005/20985,2005,A1 .Location in patent: Page/Page column 45-46
[2]Patent: WO2003/74484,2003,A1 .Location in patent: Page/Page column 73
[3]Patent: WO2005/19172,2005,A1 .Location in patent: Page/Page column 65

21
[ 845269-03-6 ]
[ 10517-21-2 ]
[ 845273-85-0 ]

Yield	Reaction Conditions	Operation in experiment
89%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 2h;	Intermediate 11: N-[(1R,2R)-1-([tert-Butyl(dimethyl)silyl]oxy}methyl)-2,3-dihydro-1H- INDEN-2-VLL-5-CHLORO-LH-INDOLE-2-CARBOXAMIDE [ (LR, 2R)-L- (F [TERT-BUTYL (DIMETHYL) silyl] oxy} methyl)-2, 3-dihydro-lH-inden-2-yl] amine (Intermediate 6; 277.0 mg, 1.0 MMOL), 5-CHLORO-LH-INDOLE-2-CARBOXYLIC acid (293 mg, 1.5 mmol) and DIPEA (260 P1, 1.5 mmol) were dissolved in DCM (10 ml). HOBT (200 mg, 1.5 mmol) and EDCI (360 mg, 1.87 mmol) were added and the mixture stirred at ambient temperature for 2 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (30 ml), washed with water (10 ml), 1N citric acid (10 ml), water (10 ml), saturated aqueous sodium bicarbonate (10 ml), water (10 ml) and brine (10 ml), dried (MGS04) and the solvent removed under reduced pressure. The crude residue was purified by flash silica gel chromatography (9: 1, iso-hexane : ethyl acetate) to give the title compound (682 mg, 89%) as a pale orange foam. H NMR (CDCLQ, 300MHz) 8 : 0.02 (d, 6H), 0.85 (s, 9H), 2.95 (dd, 1H), 3.35 (m, 1H), 3.6 (dd, 1H), 3.85 (m, 1H), 4.05 (dd, 1H), 4.73 (m, 1H), 6.55 (d, 1H), 6.75 (s, 1H), 7.25 (m, 5H), 7.4 (d, 1H), 7.6 (s, 1H), 9.6 (s, 1H).

Reference： [1]Patent: WO2005/13975,2005,A1 .Location in patent: Page/Page column 65-66

22
[ 845268-95-3 ]
[ 10517-21-2 ]
methyl (1R,2R)-2-[(5-chloro-1H-indole-2-yl)carbonyl]amino}indane-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
86%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 16h;	Example 1: Methyl (1R, 2R)-2-DF (5-CHLORO-1H-INDOLE-2-VL) CARBONVLLAMINO INDANE-1- carboxylate Methyl (LR, 2R)-2-aminoindane-1-carboxylate trifluoroacetic acid salt (Intermediate 1; 201 mg, 0. 65 mmol), 5-CHLORO-LH-INDOLE-2-CARBOXYLIC acid (129 mg, 0.66 mmol) and DIPEA (0.229 ml, 1.3 mmol) were dissolved in DCM (3 mL). HOBT (89mg, 0.66 mmol) and EDCI (134g, 0.69 mmol) were added and the mixture stirred at ambient temperature for 16 h. The volatiles were removed under reduced pressure and the residue dissolved in ethyl acetate (20 ml), washed with water (10 ml), 1N citric acid (5 ml), water (5 ml), saturated aqueous sodium bicarbonate (5 ml), water (5 ml) and brine (5 ml), dried (MgSO4) and the volatiles removed under reduced pressure. The crude residue was purified by silica gel chromatography (3: 1, iso-hexane : ethyl acetate) to give the title compound (171 mg, 86%) as a pale yellow solid. 'H NMR (D6-DMSO, 300MHz,) O : 3.05 (dd, 1H), 3.42 (dd, 1H), 4.1 (d, 1H), 5.0 (m, 1H), 7.1- 7.3 (m, 6H), 7.4 (d, 1H), 7.7 (s, 1H), 8.85 (d, 1H), 11. 8 (s, 1H); MS M/Z 369,371 (M+H).

Reference： [1]Patent: WO2005/13975,2005,A1 .Location in patent: Page/Page column 52

23
[ 847658-15-5 ]
[ 10517-21-2 ]
5-chloro-N-{(1R,2R)-1-[(3S)-3-hydroxy-2-oxopyrrolidin-1-yl]-2,3-dihydro-1H-inden-2-yl}-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl acetamide; at 20℃; for 24h;	Example 2: 5-CHLORO-N- (1R, 2R)-L-R (3S)-3-HVDROXV-2-OXOPVRROLIDIN-1-VLL-2, 3-DIHVDRO- LH-INDEN-2-VLL-LH-INDOLE-2-CARBOXAMIDE (3S)-L- [ (LR, 2R)-2-AMINO-2, 3-DIHYDRO-LH-INDEN-1-YL]-3-HYDROXYPYRROLIDIN-2-ONE (Intermediate 9; 116 mg, 0.5 MMOL), 5-chloroindole-2-caboxylic acid (98 mg, 0.5 mmol), DIPEA (86 uL, 0.5 mmol) and HOBt (68 mg, 0.5 mmol) were dissolved in DMA (2 mL). EDCI (120 mg, 0.63 mmol) was added and the reaction mixture stirred at ambient temperature for 24 h. Water (20 mL) was added and the resulting precipitate was filtered. The crude material was purified by flash column chromatography (SI02, eluent: 1 : 1, isohexane: EtOAc to EtOAc) to afford the title compound (160 mg, 78%) as a white solid. H NMR 8 : 1.75 (m, 1H), 2. 28 (m, 1H), 3. 05 (m, 2H), 3.22 (dd, 1H), 3.39 (dd, 1H), 4.07 (m, 1H), 4.81 (m, 1H), 5. 58 (2H, m), 7.01 (d, 1H), 7.11 (s, 1H), 7. 18 (dd, 1H), 7.23 (m, 3H), 7.41 (d, 1H), 7.71 (s, 1H), 8.87 (d, 1H), 11.77 (br s, 1H). MS m/z 408/410 [M-H]-.

Reference： [1]Patent: WO2005/20985,2005,A1 .Location in patent: Page/Page column 41-42

24
[ 403860-58-2 ]
[ 10517-21-2 ]
[ 846542-74-3 ]

Yield	Reaction Conditions	Operation in experiment
62%		5-Chloroindole-2-carboxylic acid (CAS Reg no: 10517-21-2; 560mg, 2.86 mmol), tert-butyl [(1R,2R)-2-amino-2,3-dihydro-1H-inden-1-yl]methylcarbamate (Intermediate 4; 750mg, 2.86 mmol), DIPEA (490 1, 2.86 mmol) and HOBT (386 mg, 2.86 mmol) were dissolved in DCM (20 ml), stirred for 5 minutes, EDCI (685 mg, 3.58 mmol) added and the mixture stirred at ambient temperature for 24 hours. The volatiles were removed by evaporation under reduced pressure and EtOAc (50 mL) added. The organic phase was washed with water (25 mL), brine (25 mL) and dried (MGS04), filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography (SiO2, EtOAc: Hexane) to afford the title compound (800 mg, 62%) as a powder. H NMR 8 : 1.2 (s, 4. 5H), 1.35 (s, 4. 5H), 2.65 (s, 3H), 3.13 (m, 2H), 4.8 (m, 1H), 5.65 (m, 1H), 7.2 (m, 6H), 7.42 (d, 1H), 7.71 (d, 1H), 8.83 (m, 1H), 11.79 (s, 1H); MS M/Z438, 440 (M-H).

Reference： [1]Patent: WO2005/19172,2005,A1 .Location in patent: Page/Page column 55

25
[ 10517-21-2 ]
[ 57260-71-6 ]
[ 459168-94-6 ]

Yield	Reaction Conditions	Operation in experiment
	With dmap;benzotriazol-1-ol; In dichloromethane; water;	A. 4-(5-Chloro-1H-indole-2-carbonyl)-piperazine-1-carboxylic Acid tert-butyl Ester. A mixture of 5-chloroindole-2-carboxylic acid (10 g), tert-butyl 1-piperazinecarboxylate (10.5 g) and 4-dimethylaminopyridine (6.3 g) in CH2Cl2 (200 mL) was treated with a catalytic amount of HOBT (0.2 g). The resulting mixture was cooled to 0 C., and EDCl (10.8 g) was added. The reaction was then slowly warmed to ambient temperature and stirred for 24 h then concentrated under reduced pressure. Water was added to the resulting residue. The product precipitated and was washed with water (2*50 mL) and Et2O (30 mL). The resulting solid was dried under reduced pressure to yield (18.2 g). MS (electrospray): exact mass calculated for C18H22ClN3O3, 363.13; m/z found, 362.3 [M-H]-.
	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;benzotriazol-1-ol; In dichloromethane; at 0 - 20℃; for 24h;	A mixture of 5-chloroindole-2-carboxylic acid (10 g), tert-butyl 1- [PIPERAZINECARBOXYLATE] (10.5 g) and 4-dimethylaminopyridine (6.3 g) in CH2Cl2 (200 mL) was treated with a catalytic amount of HOBT (0.2 g). The resulting mixture was cooled to [0 C,] and [EDCI] (10.8 g) was added. The reaction was then slowly warmed to ambient temperature and stirred for 24 h then concentrated under reduced pressure. Water was added to the resulting residue. The product precipitated and was washed with water [{2] x 50 mL) and Et2O (30 mL). The resulting solid was dried under reduced pressure to yield (18.2 g). MS (electrospray) : exact mass calculated for [C18H22CIN303,] 363.13 ; [M/Z] found, 362.3 [M-H]-.
		General procedure: (5-Chloro-7-fluoro-1H-indole-2-yl)-carboxylic acid (5a) (50 mg, 0.23 mmol), N,N-diisopropylethylamine (82 mul, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) were dissolved in 550 mul N,N-dimethylformamide. After stirring for 10 min 4-methyl-piperazin 6a (26 mul, 0.23 mmol) was added and the reaction mixture was stirred for 16 h at 20 C. The solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P1, yielding 37 mg (53%) of the title compound.

18.2 g

With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 0 - 20℃;

A mixture of 5-chloroindole-2-carboxylic acid (10 g), tert-butyl 1-piperazinecarboxylate (10.5 g) and 4-dimethylaminopyridine (6.3 g) in CH2Cl2 (200 mL) was treated with a catalytic amount of HOBT (0.2 g). The resulting mixture was cooled to 0 C, and EDCl (10.8 g) was added. The reaction was then slowly warmed to ambient temperature and stirred for 24 h then concentrated under reduced pressure. Water was added to the resulting residue. The product precipitated and was washed with water (2 x 50 mL) and Et2O (30 mL). The resulting solid was dried under reduced pressure to yield (18.2 g). MS (electrospray): exact mass calculated for C18H22ClN3O3, 363.13; m/z found, 362.3 [M-H]-.

Reference： [1]Patent: US2003/207893,2003,A1
[2]Patent: WO2004/22061,2004,A1 .Location in patent: Page/Page column 80
[3]European Journal of Medicinal Chemistry,2012,vol. 54,p. 660 - 668
[4]Patent: EP1373204,2016,B1 .Location in patent: Paragraph 0241

26
[ 10517-21-2 ]
N-[(1R*,2S*)-2-amino-4,4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide [ No CAS ]
N-[(1R*,2S*)-2-amino-5,5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		The compound obtained in Referential Example 117 (1.45 g) was dissolved in methanol (12 mL), and 10% palladium on carbon (290 mg) was added thereto, followed by stirring at room temperature for 20 hours under hydrogen atmosphere. Additional 10% palladium on carbon (290 mg) and methanol (10 mL) were added thereto, and the thus-obtained mixture was stirred for 8 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was dissolved in N,N-dimethylformamide (10 mL), and to the solution were added 5-chloroindole-2-carboxylic acid (320 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377 mg), 1-hydroxybenzotriazole monohydrate (301 mg), and N-methylmorpholine (360 mL), followed by stirring at room temperature for 14 hours. The reaction mixture was poured into aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, and the residue was purified by silica gel thin layer chromatography (methylene chloride : methanol = 93:7), to thereby isolate N-[(1R,2S)-2-amino-4, 4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide (or N-[(1R, 2S)-2-amino-5, 5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide) (98 mg) and N-[(1R, 2S)-2-amino-5, 5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide (or N-[(1R, 2S)-2-amino-4, 4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide) (105 mg). N-[(1R, 2S)-2-amino-4, 4-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide:1H-NMR(CDCl3) δ:1.45-1.50(2H, m), 2.06-2.10(2H, m), 2.34(1H, d, J=13.1Hz), 2.78(1H, dt, J=2.9, 13.1Hz), 3.18(3H, s), 3.23(3H, s), 3.75-3.77(1H, m), 6.24(1H, d, J=8.3Hz), 6.79(1H, s), 7.23(1H, dd, J=8.8, 2.0Hz), 7.35(1H, d, J=8.8Hz), 7.60(1H, d, J=8.8Hz), 9.53(1H, br.s). MS(ESI)m/z:352(M+H)+. N-[(1R, 2S)-2-amino-5, 5-dimethoxycyclohexyl]-5-chloroindole-2-carboxamide:1H-NMR(CDCl3) δ:1.83-1.87(1H, m), 1.97-2.01(1H, m), 2.39(1H, br, J=13.2Hz), 2.86-2.90(1H, m), 3.22-3.28(10H, m), 4.00-4.02(1H, m), 6.77(1H, s), 7.23(1H, d, J=8.5Hz), 7.37(1H, d, J=8.5Hz), 7.61(1H, s), 9.49(1H, br. s). MS (ESI) m/z:352(M+H)+.

Reference： [1]Patent: EP1577301,2005,A1 .Location in patent: Page/Page column 126-127

27
[ 10517-21-2 ]
[ 35849-31-1 ]
5-chloro-N-(2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In DMF (N,N-dimethyl-formamide); at 18 - 25℃; for 18h;	Example 3 : 5-Chloro-N- (2-oxo-1, 2, 34-tetrahydroquinolin-3-vl)-lH-indole-2- carboxamide; 5-Chloroindole-2-carboxylic acid (196mg, lmmol) was dissolved in DMF (5 mL) containing 3-amino-3,4-dihydroquinolin-2 (1I1)-one hydrochloride (J. Med. Chem. 28, 1985, 1511-16; 162mg, lmmol), EDCI (192 mg, 1 mmol) and HOBT (135 mg, 1 mmol). The mixture was stirred at ambient temperature for approximately 18 h before being partitioned between water and EtOAc. The organics were washed with water, saturated aqueous NaHC03, saturated brine and dried over MgS04 ; then filtered and evaporated to afford the title compound (212 mg, 66%) as an amorphous white solid. 1H NMR 3.13 (m, 2H), 4.77 (m, 1H), 6.92 (d, 1H), 6.96 (t, 1H), 7.21 (m, 4H), 7.47 (d, 1H), 7.76 (d, 1H), 8.80 (d, 1H), 10.38 (s, 1H), 11.84 (s, 1H); MS m/z MH 340, 342.

Reference： [1]Patent: WO2003/74513,2003,A2 .Location in patent: Page/Page column 52-53

28
[ 403860-46-8 ]
[ 10517-21-2 ]
5-chloro-N-((1R,2R)-1-[(methylsulfonyl)amino]-2,3-dihydro-1H-inden-2-yl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%		Example 2 ;: 5-Chloro-N-f (1R, 2R)-1-f (methvlsulfonvl) aminol-2, 3-dihvdro-1H-inden-2- vll-lH-indole-2-carboxamide; 5-Chloro-lH-indol-2-carboxylic acid (196mg, l. Ommol), N- [ (lR, 2R)-2-amino-2, 3- dihydro-lH-inden-1-yl] methanesulfonamide (Method 2; 226mg, l. Ommol), DIPEA (0.17 ml, l. Ommol), and HOBT (130mg, l. Ommol) was stirred in DCM (10 ml) for one minute. EDCI (240mg, 1. 25mmol) was added and the mixture stirred at room temperature for 20 hours. The mixture was diluted with EtOAc, washed with water (2 x 25 ml), dried over magnesium sulphate and evaporated to give the title compound (320mg, 79%) as a foam. 'H NMR 2.85 (dd, 1H), 3.25 (dd, 1H), 4.60 (m, 1H), 5.00 (m, 1H), 7.20 (m, 6H), 7.42 (d, 1H), 6.70 (s, 1H), 7.90 (d, 1H), 8.90 (d, 1H), 11.80 (broad s, 1H); m/z 402.4.

Reference： [1]Patent: WO2003/74484,2003,A1 .Location in patent: Page/Page column 53

29
[ 403860-28-6 ]
[ 10517-21-2 ]
methyl (S)-5-{1-[(5-chloro-1H-indol-2-ylcarbonyl)amino]-2-phenylethyl}oxazole-4-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 18 - 25℃; for 4h;	Example 1; Methyl (5)-5-{l-r (5-chloro-lH-indol-2-ylcarbonvl) aminol-2-phenylethylToxazole-4 carboxylate; 2-Carboxy-5-chloro-indole (146mg, 0. 75mmol) was dissolved in DCM (5ml) containing HOBT (126mg, 0. 93mmol), DIPEA (290mg, 2. 25mmol) and methyl (S)-5- (1- amino-2-phenylethyl) oxazole-4-carboxylate trifluoroacetate (Method 1; 360mg, 0. 75mmol). EDAC (178mg, 0. 93mmol) was added and the mixture stirred at ambient temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (30ml), washed with dilute citric acid, water and brine, dried over magnesium sulphate and concentrated. The crude material was purified by trituration with diethyl ether to give the title compound as a white solid. (227mg, 65%) NMR 3.1-3. 2 (lH, m); 3.25-3. 3 (lH, m); 3.8 (3H, s); 5.9-6. 0 (lH, m); 7.1-7. 3 (7H, m); 7.4 (lH, d); 7.75 (lH, d); 8.46 (lH, s); 9.1 (lH, d); 11.68 (lH, bs)

Reference： [1]Patent: WO2003/74517,2003,A1 .Location in patent: Page/Page column 35

30
[ 597555-55-0 ]
[ 10517-21-2 ]
[ 597555-29-8 ]

Yield	Reaction Conditions	Operation in experiment
93%		Method 5b; tert-Butyl ((1S, 2S)-2-f [(5-chloro-lH-indol-2-vl) carbonvllamino}-2, 3-dihvdro-lH-inden-1- yl') carbamate 5-Chloroindole-2-carboxylic acid (2.8g, 14 mmol), tert-Butyl[(1S,2S)-2-amino-2, 3- dihydro-lH-inden-1-yl] carbamate (3.47g, 14mmol), DIPEA (4. 9ml, 28mmol) and HOBT (1.89g, 14mmol) were dissolved in DCM (100 mL), stirred for 5 mins, then EDCI (3.2g, 16.7mmol) was added and the reaction stirred for 3 hours. The volatiles were removed by evaporation under reduced pressure, EtOAc (125 mL) was added and the organic solution washed with water (2 x 50 mL), brine (50 mL), dried (MgS04) and the volatiles removed by evaporation under reduced pressure to give the title compound (5.7g, 93%) as a pale brown foam. 'H NMR 1.47 (s, 9H), 2.9 (dd, 1H), 3.27 (dd, 1H), 4.7 (m, 1H), 5.25 (m, 1H), 7.24 (m, 6H), 7.5 (m, 2H), 7.79 (s, 1H), 8.91 (d, 1H), 11.85 (s, 1H), MS m/z 426,428.

Reference： [1]Patent: WO2003/74484,2003,A1 .Location in patent: Page/Page column 74

31
(+/-)-trans-2-amino-1-{N-[(1,1-dimethylethoxy)]carbonylamino}indan [ No CAS ]
[ 10517-21-2 ]
5-chloro-2-(N-{1-[N-(1,1-dimethylethoxy)carbonylamino]indan-2-yl}carbamoyl)indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		Method 3; 5-Chloro-2-(N-f N-(1. 1-dimethylethoxy) carbonelaminolindan-2-yl carbamoyl) indole 5-Chloro-indole-2-carboxylic acid (5. 0g, 25. 6mmol), (+/-)-trans-2-amino-1-{N-[(1, 1- dimethylethoxy) ] carbonylamino} indan (6.3g, 25.6mmol), DIPEA (4.5 ml, 25.6mmol) and HOBT (3.5g, 25. 6mmol) was stirred in DCM (100 ml) at room temperature for 2 minutes. EDCI (6.1g, 32. 0mmol) was added and the mixture stirred at room temperature for 20 hours. The mixture was diluted with EtOAc (250 ml) and washed with water and brine. Drying over magnesium sulphate followed by evaporation gave the crude material which was purified by silica chromatography with hexane: EtOAc to give the title compound (9.1 g, 83%) as a pale pink foam. 'H NMR 2.85 (dd, 1H), 3.20 (dd, 1H), 4.50 (m, 1H), 5.10 (m, 1H), 7.15 (m, 6H), 7.35 (d, 1H), 7.45 (d, 1H), 7.70 (s, 1H), 8.80 (d, 1H), 11.78 (broad s, 1H).

Reference： [1]Patent: WO2003/74484,2003,A1 .Location in patent: Page/Page column 71-72

32
[ 599193-34-7 ]
[ 10517-21-2 ]
[ 599193-32-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 18 - 25℃; for 18h;	Method 11; 5-Chloro-N-f l(cyanomethyl)-2-oxo-1, 2, 3, 4-tetrahydroquinolin-3-yll-lH-indole-2- carboxamide ;HOBT (168 mg, 1.24 mmol), 5-chloroindole-2-carboxylic acid (243 mg, 1.24 mmol), DIPEA (0.22 mL, 1.24 mmol) and then EDCI (296 mg, 1.55 mmol) were added to a solution of (3-amino-2-oxo-3, 4-dihydroquinolin-1 (2H)-yl) acetonitrile (Method 12,250 mg, 1.24 mmol) in DCM (10 mL). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (15 mL), washed with 1 N NaOH (15 mL), 1 N HC1 (15 mL), saturated aqueous NaHC03 solution (15 mL), dried (MgS04) and the volatiles removed under reduced pressure to give the title compound (366 mg, 78%) as a tan solid. 'H NMR 3.20 (m, 2H), 4.85 (m, 1H), 5.11 (s, 2H), 7.30 (m, 7H), 7.74 (s, 1H), 8.91 (d, 1H), 11.84 (s, 1H) ; MS m/z 377/379 (M-H)

Reference： [1]Patent: WO2003/74513,2003,A2 .Location in patent: Page/Page column 74

33
[ 10517-21-2 ]
[ 82420-54-0 ]
[ 599193-05-2 ]

Yield	Reaction Conditions	Operation in experiment
85%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In DMF (N,N-dimethyl-formamide); at 18 - 25℃; for 16h;	Example 47: 5-Chloro-N- (6-fluoro-2-oxo-1, 2,3, 4-tetrahvdroquinolin-3-vl)-lH-indole-2- carboxamide; Triethylamine (184 uL, 1.32 mmol), HOBt (89 mg, 0.66 mmol), 3-amino-6-fluoro-3, 4- dihydro-2 (lH)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and EDAC (127 mg, 0.66 mmol) were added to a solution of 5-chloroindole-2- carboxylic acid (129 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40C, to give the title compound (200 mg, 85%) as an amorphous solid. 1H NMR 3.15 (m, 2H), 4.76 (m, 1H), 8.92 (m, 1H), 7.06 (m, 1H), 7.17 (m, 1H), 7.20 (m, 2H), 7.46 (d, 1H), 7.76 (s, 1H), 8.80 (d, 1H), 10.40 (s, 1H), 11.86 (s, 1H) ; MS m/z 358,360.

Reference： [1]Patent: WO2003/74513,2003,A2 .Location in patent: Page/Page column 67

34
[ 599193-25-6 ]
[ 10517-21-2 ]
5-chloro-N-(1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
97%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 18 - 25℃; for 18h;	Method 7; 5-Chloro-N- (l-ff (4R)-2, 2-dimethyl-1, 3-dioxolan-4-yllmethvl}-2-oxo-1, 2, 3, 4- tetrahydroquinolin-3-yl)-lH-indole-2-carboxamide; HOBT (209 mg, 1.55 mmol), 5-chloroindole-2-carboxylic acid (303 mg, 1.55 mmol), DIPEA (0.27 mL, 1.55 mmol) and then EDCI (370 mg, 1.94 mmol) were added to a solution of 3-amino-1-{ [(4R)-2, 2-dimethyl-1, 3-dioxolan-4-yl] methyl}-3, 4-dihydroquinolin-2 (1H)-one (Method 8,428 mg, 1.55 mmol) in DCM (10 mL). The reaction was stirred for 18 h at ambient temperature, diluted with EtOAc (20 mL), washed with 1 N NaOH (15 mL), 0.1 N HC1 (15 mL), saturated aqueous NaHC03 solution (15 mL), dried (Na2S04) and the volatiles removed under reduced pressure to give the title compound (684 mg, 97%) as a pale yellow solid. 'H NMR 1.27 (m, 6H), 3.06 (m, 1H), 3.17 (app. t, 1H), 3.71 (m, 1H), 4.17 (m, 4H), 4.73 (m, 1H), 7.38 (m, 8H), 8.80 (d, 1H), 11.82 (s, 1H) ; MS m/z 476/478 (M+Na)

Reference： [1]Patent: WO2003/74513,2003,A2 .Location in patent: Page/Page column 72

35
[ 10517-21-2 ]
[ 32151-02-3 ]
5-chloro-2-[N-(1-hydroxyindan-2-yl)carbamoyl]indole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 18 - 25℃; for 18h;	Example 1;: 5-Chloro-2-fN- (l-hvdroxvindan-2-vl) carbamovllindole; 5-Chloro-lH-indole-2-carboxylic acid (116mg, 0. 67mmol) was dissolved in DCM (10 ml) containing DIPEA (0.21 ml, 1. 19mmol) and 2-aminoindan-1-ol (Method 1; 101mg, 0. 67mmol) and HATU (247mg, 0. 67mmol). The reaction mixture was stirred at room temperature for approximately 18 hours. The resulting solution was washed with water (20 ml) and the aqueous layer extracted with DCM (2 x 20 ml). The organic extracts were combined, dried over magnesium sulphate and concentrated under reduced pressure to give the title compound (195mg, 100%) as a white solid. 'H NMR 2.83 (dd, 1H), 3.22 (dd, 1H), 4.40 (quin, 1H), 5.14 (d, 1H), 7.40 (m, 8H), 8.80 (d, 1H), 12.37 (s, 1H); m/z 325.

Reference： [1]Patent: WO2003/74484,2003,A1 .Location in patent: Page/Page column 52-53

36
[ 10517-21-2 ]
[ 477532-03-9 ]
5-Chloro-1H-indole-2-carboxylic acid (5,6,7,8-tetrahydro-quinolin-6-yl)amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 2h;	Example 34 5-Chloro-1H-indole-2-carboxylic acid (5,6,7,8-tetrahydro-quinolin-6-yl)amide To a stirred solution of 6-amino-5,6,7,8-tetrahydroquinoline (prepared in the manner disclosed by Skupinska, J. Org. Chem. 2002, 67, 7890-7893, 12.2 mg, 0.082 mmol) and 5-chloroindole-2-carboxylic acid (17.7 mg, 0.091 mmol) in tetrahydrofuran (1.0 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (31.5 mg, 0.165 mmol), 1-hydroxy-7-azabenzotriazole (22.4 mg, 0.165 mmol), and diisopropylethylamine (21.3 mg, 0.165 mmol). After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain Example 34 (11.5 mg, 43%) as a white solid. 13C NMR (400 MHz, (CD3)2SO) δ 160.1, 155.0, 146.6, 136.8, 135.3, 133.8, 130.6, 128.5, 123.3, 123.0, 121.1, 120.4, 113.8, 102.3, 44.4, 33.8, 30.5, 28.4. 1H NMR (400 MHz, (CD3)2SO) δ 11.84 (s, 1H), 8.59 (d, J=7.5 Hz, 1H), 8.32 (d, J=4.4 Hz, 1H), 7.69 (d, J=1.8 Hz, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.18 (m, 2H), 4.24 (m, 1H), 3.08 (dd, J=4.2, 16.8 Hz, 1H), 2.97 (m, 2H), 2.88 (dd, J=9.0, 15.2 Hz, 1H), 2.10 (m, 1H), 1.93 (m, 1H). HPLC/MS [M+H]+, 328.

Reference： [1]Patent: US2006/111413,2006,A1 .Location in patent: Page/Page column 30

37
[ 10517-21-2 ]
[ 250275-15-1 ]
C₂₀H₂₄ClN₃O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; In N,N-dimethyl acetamide; at 20℃; for 16h;	A solution of 5-chloro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol) in N,N-dimethylacetamide (5 ml) was treated with <strong>[250275-15-1]tert-butyl (3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate</strong> (108 mg, 0.51 mmol) and O-benzotriazo-1-yl-N,N,N'N'-tetramethyluronium hexafluorophosphate (256 mg, 0.67 mmol) and the resulting solution left to stir at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml) and the organic phase separated, dried (sodium sulphate) and the solvent reduced in vacuo. The residue was treated with a 1M solution of HCl in methanol (15 ml) and left to stir at room temperature for 16 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel eluding with dichloromethane:methanol:880 ammonia (99:1:0.1 changing to 90:10:1, by volume) to give the title compound as a pale yellow solid (42 mg). 1H NMR (400 MHz, DMSOd6): delta 11.77 (1H, bs), 7.69 (1H, bs), 7.45 (1H, d), 7.20 (1H, d), 6.93 (1H, s), 4.13-3.45 (4H, m), 2.99-2.63 (6H, m), 2.52 (3H, s) ppm (poorly resolved spectrum). MS (APCI) m/z 290/292 [M+H]+, 288/290 [M-H]-

Reference： [1]Patent: US2006/111416,2006,A1 .Location in patent: Page/Page column 16

38
trans-2-amino-3-carboethoxy-1,2,3,4-tetrahydronaphthalene trifluoroacetic acid salt [ No CAS ]
[ 10517-21-2 ]
trans-3-[(5-chloro-1H-indole-2-carbonyl)amino]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid ethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
77%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 2h;	Part VI: Trans 3-[(5-Chloro-1H-indole-2-carbonyl)amino]-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid ethyl ester To a stirred solution of trans 2-amino-3-carboethoxy-1,2,3,4-tetrahydronaphthalene trifluoroacetic acid salt (130 mg, 0.39 mmol) and 5-chloroindole-2-carboxylic acid (92 mg, 0.47 mmol) in tetrahydrofuran (8 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (153 mg, 0.78 mmol), 1-hydroxy-7-azabenzotriazole (106, 0.78 mmol), and diisopropylethylamine (0.14 mL, 0.78 mmol). After 2 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and concentrated under vacuum. The resulting residue was suspended in methanol. The suspension was filtered and the solid was washed with methanol to obtain the title compound (120 mg, 77%). 13C NMR (400 MHz, d8-tetrahydrofuran) delta 173.5, 161.3, 136.1, 135.2, 135.0, 134.6, 129.8, 129.5, 129.1, 126.9, 126.8, 126.0, 124.4, 121.5, 114.0, 101.8, 61.1, 48.5, 46.5, 36.0, 32.5, 14.5. 1H NMR (400 MHz, d8-tetrahydrofuran) delta 11.18 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.56 (s, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.04-7.17 (m, 4H), 6.89 (s, 1H), 4.62 (m, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.15-3.26 (m, 2H), 2.87-3.09 (m, 3H), 1.11 (t, J=7.0 Hz, 3H). MS [M+H]+, 397; [M-H]-, 395.

Reference： [1]Patent: US2006/111413,2006,A1 .Location in patent: Page/Page column 22

39
trans-3-amino-2-carbo-t-butoxymethoxy-1,2,3,4-tetrahydronaphthalene [ No CAS ]
[ 10517-21-2 ]
trans-{3-[(5-chloro-1H-indole-2-carbonyl)amino]-1,2,3,4-tetrahydronaphthalen-2-yloxy}acetic acid t-butyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 1h;	Part IV: Trans {3-[(5-Chloro-1H-indole-2-carbonyl)amino]-1,2,3,4-tetrahydronaphthalen-2-yloxy}acetic acid t-butyl ester To a stirred solution of trans 3-amino-2-carbo-t-butoxymethoxy-1,2,3,4-tetrahydronaphthalene (550 mg, 1.98 mmol) and 5-chloroindole-2-carboxylic acid (466 mg, 2.39 mmol) in tetrahydrofuran (12 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (760 mg, 2.39 mmol), 1-hydroxy-7-azabenzotriazole (540, 2.39 mmol), and diisopropylethylamine (0.4 mL). After 1 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel chromatography (20% ethyl acetate in hexane was used) to obtain the title compound (653 mg, 72%). 13C NMR (400 MHz, CDCl3) delta 172.31, 162.11, 134.72, 133.82, 132.8, 132.7, 128.8, 128.7, 126.6, 126.3, 125.7, 124.3, 121.0, 113.2, 102.6, 83.3, 77.6, 66.1, 51.7, 35.8, 34.4, 28.2. 1H NMR (400 MHz, CDCl3) delta 9.22 (s, 1H), 8.92 (d, J=4.0 Hz, 1H), 7.60 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 7.22 (dd, J=2.2, 7.8 Hz, 1H), 7.07-7.19 (m, 3H), 4.27 (d, J=17.6 Hz, 1H), 4.20 (m, 1H), 4.12 (d, J=17.6 Hz, 1H), 3.91 (dd, J=4.5, 16.8 Hz, 1H), 3.76 (dt, J=5.3, 8.0 Hz, 1H), 3.24 (dd, J=5.2, 16.8 Hz, 1H), 2.92 (dd, J=9.5, 15.0 Hz, 1H), 2.77 (dd, J=9.5, 15.0 Hz, 1H). MS [M+H]+, 455; [M-H]-, 453.

Reference： [1]Patent: US2006/111413,2006,A1 .Location in patent: Page/Page column 25; 26

40
(R/S)-6-amino-8-hydroxy-8-phenylsulfonylmethyl-5,6,7,8-tetrahydroquinoline [ No CAS ]
[ 10517-21-2 ]
C₂₅H₂₈ClN₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
68%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃;	To a stirred solution of (R/S)-(6R,8S)-6-amino-8-hydroxy-8-phenylsulfonylmethyl-5,6,7,8-tetrahydroquinoline (38.6 mg, 0.121 mmol) and 5-chloroindole-2-carboxylic acid (26 mg, 0.133 mmol) in tetrahydrofuran (1.5 mL) and N,N-dimethylformamide (0.3 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (46.4 mg, 0.242 mmol), 1-hydroxy-7-azabenzotriazole (33.1 mg, 0.242 mmol), and diisopropylethylamine (31.3 mg, 0.242 mmol). After 3 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed sequentially with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, and evaporated to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain Example 49 (41.4 mg, 68%) as a white solid. 1H NMR (500 MHz, d8-tetrahydrofuran) delta 11.13 (s, 1H), 10.85 (s, 1H), 8.28 (d, J=3.8 Hz, 1H), 8.21 (d, J=2.2 Hz, 1H), 7.78 (d, J=6.8 Hz, 2H), 7.54 (t, J=6.4 Hz, 1H), 7.47 (m, 4H), 7.34 (d, J=7.6 Hz, 1H), 7.10 (m, 2H), 4.60 (br s, 1H), 4.17 (d, J=14.0 Hz, 1H), 3.94 (d, J=14.0 Hz, 1H), 3.14 (m, 2H), 3.02 (d, J=12.6 Hz, 1H), 2.53 (m, 1H). HPLC/MS [M+Na]+, 520.

Reference： [1]Patent: US2006/111338,2006,A1 .Location in patent: Page/Page column 31

41
(R/S)-6-amino-8-hydroxy-8-phenylsulfonylmethyl-5,6,7,8-tetrahydroquinoline trifluoroacetic acid salt [ No CAS ]
[ 10517-21-2 ]
C₂₅H₂₈ClN₃O₄S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
44%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 16h;	To a stirred solution of (R/S)-(6R,8R)-6-amino-8-hydroxy-8-phenylsulfonylmethyl-5,6,7,8-tetrahydroquinoline, trifluoroacetic acid salt (5.5 mg, 0.017 mmol) and 5-chloroindole-2-carboxylic acid (3.7 mg, 0.019 mmol) in tetrahydrofuran (0.4 mL) at room temperature under nitrogen was added 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.6 mg, 0.035 mmol), 1-hydroxy-7-azabenzotriazole (4.7 mg, 0.035 mmol), and diisopropylethylamine (4.5 mg, 0.035 mmol). After 16 h, the reaction mixture was diluted with ethyl acetate. The organic layer was washed sequentially with 1.0 M aqueous hydrochloric acid solution, 1.0 M aqueous sodium hydroxide solution, and brine, dried over anhydrous magnesium sulfate, and evaporated to yield a residue. The residue was purified by reverse phase preparative HPLC (trifluoroacetic acid containing solvents were used) to obtain Example 50 (3.8 mg, 44%) as a white solid. 1H NMR (500 MHz, d8-tetrahydrofuran) δ 11.18 (s, 1H), 10.85 (s, 1H), 8.21 (d, J=2.5 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.43 (d, J=8.0 Hz, 2H), 7.61 (d, J=1.7 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 746 (t, J=8.0 Hz, 3H), 7.42 (d, J=8.2 Hz, 1H), 7.15 (dd, J=1.8, 7.6 Hz, 1H), 7.08 (dd, J=4.4, 7.8 Hz, 1H), 7.03 (s, 1H), 4.66 (m, 1H), 4.35 (d, J=14.4 Hz, 1H), 3.84 (d, J=14.4 Hz, 1H), 3.22 (d, J=15.6 Hz, 1H), 2.80 (m, 2H), 2.55 (m, 1H). HPLC/MS [M+H]+, 498.

Reference： [1]Patent: US2006/111338,2006,A1 .Location in patent: Page/Page column 32

42
[ 904293-74-9 ]
[ 10517-21-2 ]
[ 904293-72-7 ]

Yield	Reaction Conditions	Operation in experiment
53%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ISOPROPYLAMIDE; at 20℃; for 20h;	ΗOBT (280 mg, 2.07 mmol), tert-butyl [(li?,2i?)-2-amino-2,3-dihydro-lH-inden-l- yl]methoxy} acetate (Intermediate 3; 575 mg, 2.07 mmol) and EDAC (496 mg, 2.6 mmol) were added to a suspension of 5-chloroindole-2-carboxylic acid (404 mg, 2.07 mmol) inDMA (5 mL) . The reaction was stirred at ambient temperature for 2Oh. Water (25 mL) was added and the precipitate filtered, washed with water (2 x 20 mL) and dried.Purification by flash chromatography (SiO2, o-hexane:EtOAc, 1:1) gave the title compound (500 mg, 53%) as a foam. 1H NMR δ: 1.48 (s, 9H), 3.0 (dd, IH), 3.55 (m, IH), 3.65 (dd, IH), 3.8 (m, IH), 3.95 (m,IH), 4.05 (d, 2H), 4.61 (m, IH), 6.86 (s, IH), 7.05 (m, IH), 7.47 (m, 5H), 7.35 (d, IH),7.59 (s, IH), 9.63 (s, IH); MS m/z 453/455 (M-H)

Reference： [1]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 40

43
[ 904293-82-9 ]
[ 10517-21-2 ]
[ 904293-80-7 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In ISOPROPYLAMIDE; at 20℃; for 20h;	?OBT (185 mg, 1.37 mmol), tert-butyl (2i?/1S)-[(li?,2i?)-2-amino-2,3-dihydro-lH-inden- l-yl]methoxy}propanoate (Intermediate 15; 400 mg, 1.37 mmol) and EDAC (328 mg, 1.71 mmol) were added to a suspension of 5-chloroindole-2-carboxylic acid (267 mg, 1.37 mmol) in DMA (5 mL) . The reaction was stirred at ambient temperature for 20 h. Water (25 mL) was added and the precipitate filtered, washed with water (2 x 20 mL) and dried. Purification by flash chromatography (SiO2, zsohexane: EtOAc, 2:1) gave the title compound (430 mg, 67%) as a foam. 1H NMR ?: 1.38 (dd, 3H), 1.47 (d, 9H), 3.0 (m, IH), 3.65 (m, 4.5H), 4.1 (m, 0.5H), 4.56 (m, IH), 6.82 (dd, IH), 6.84 (d, 0.5H), 7.22 (m, 5.5H), 7.37 (d, IH), 7.59 (s, IH), 9.65 (d, IH); MS m/z 467/469 (M-H).

Reference： [1]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 47

44
[ 904295-50-7 ]
[ 10517-21-2 ]
[ 904295-49-4 ]

Yield	Reaction Conditions	Operation in experiment
75%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;	5-Chloro-lH-indole-2-carboxylic (109 mg, 0.55 mmol), 2-((lS,2R)-2~Ammo-indan-l-yi)- 2-(2-methoxy-ethyl)-malonic acid diethyl ester hydrochloride (Intermediate 32, 160 mg, 0.51 mmol), DIPEA (0.11 mL, 0.31 mmol) and EtaOBT (99.5 mg, 0.51 mmol) were dissolved in DCM (10 mL). EDAC (122 g, 0.64 mmol) was added and the reaction stirred at ambient temperature for 19 h. DCM was evaporated under reduced pressure, water (10 mL) was added then the mixture extracted with EtOAc (2x 20 mL). The organic phases were combined and washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL), dried (MgSO4) and the solvent was removed in vacuo to afford the title compound (200 mg, 75%) as an oil. MS m/z 526.

Reference： [1]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 57

45
[ 904295-53-0 ]
[ 10517-21-2 ]
[ 904295-52-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 19h;	S-Chloro-lH-indole-^-carboxylic (69 rag, 0.35 mmol), 2-((lR,2R)-2-Amino-indan-l-yl)- propionic acid methyl ester hydrochloride salt (Intermediate 37, 80 mg, 0.32 mmol), DIPEA (0.07 mL, 0.38 mmol) and EtaOBT (43 mg, 0.32 mmol) were dissolved in DCM (10 mL). EDAC (77 mg, 0.40 mmol) was added and the reaction stirred at ambient temperature for 19 h. The volatiles were removed under reduced pressure and the crude EPO <DP n="61"/>material dissolved in EtOAc (15 mL). The organic phase was washed with a solution of saturated bicarbonate (10 mL), water (10 mL), brine (10 mL), dried (MgSO4) and the solvent removed in vacuo to give the title compound (120 mg, 94%) as a solid. MS m/z419 [M + Na].

Reference： [1]Patent: WO2006/82400,2006,A1 .Location in patent: Page/Page column 59; 60

46
(2S,3R)-3-amino-2-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride [ No CAS ]
[ 10517-21-2 ]
5-Chloro-1H-indole-2-carboxylic acid {(1R)-[(S)-hydroxy-(methoxy-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
57%	With sodium hydroxide; In methanol; ethyl acetate;	EXAMPLE 67 5-Chloro-1H-indole-2-carboxylic acid {(1R)-[(S)-hydroxy-(methoxy-methyl-carbamoyl)-methyl]-2-phenyl-ethyl}-amide 5-Chloro-1H-indole-2-carboxylic acid (0.25 mmol) and (2S,3R)-3-amino-2-hydroxy-N-methoxy-N-methyl-4-phenyl-butyramide hydrochloride (0.25 mmol) were coupled according to Procedure A (0-25 C. acid then base wash). The crude product was dissolved in methanol containing 0.25 equivalent 1N NaOH for 2 hours at 25 C. and another hour with a second 0.25 equivalent portion of 1N NaOH (to hydrolyze the less polar N,O-bis-5-chloro-1H-indolecarbonyl derivative), the solution concentrated, the residue dissolved in ethyl acetate, the resulting solution washed with 2N HCl, brine, dried, and concentrated. The residue was purified by chromatography on silica eluted with 30-50% ethyl acetate-hexane. The chromatographed material (containing a polar impurity) was dissolved in ethyl acetate and the resulting solution washed twice with 2N NaOH, dried, and concentrated: Yield 57%; HPLC (60/40) 5.36 minutes (98%); mp 165-167 C.; PBMS 416/418 (MH+,100%); 1H NMR (CDCl3) δ9.45 (br, 1H), 7.58 (d, 1H, J=2 Hz), 7.4-7.1 (m, 7H), 6.77 (d, 1H, J=2 Hz), 6.51 (d, 1H, J=10 Hz), 4.91 (m, 1H), 4.30 (d, 1H, J=5 Hz), 3.83 (d, 1H, J=5 Hz), 3.35 (s, 3H), 3.13 (s, 3H), 3.09 (m, 2H). Anal. Calcd for C21H22ClN3O4+1.0H2O: C, 58.13; H, 5.58; N, 9.68; Found: C, 58.05; H, 5.24; N, 9.54.

Reference： [1]Patent: US6297269,2001,B1

47
[ 10517-21-2 ]
3-bromo-5-chloro-1H-indole-2-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
89%	With bromine; In acetic acid;	EXAMPLE 104a 3-Bromo-5-chloro-1H-indole-2-carboxylic acid To a solution of 5-chloro-1H-indole-2-carboxylic acid (2.0 g, 10.2 mmol) in acetic acid (24 mL) was added a solution of bromine (0.53 mL, 10.2 mmol) in acetic acid (16 mL). After 20 minutes, the mixture was poured into water and extracted with chloroform twice. The combined extracts were washed with water twice and brine, dried over magnesium sulfate and concentrated. The product was obtained as a solid (2.6 g, 89%).
89%	With bromine; In acetic acid;	Example 104a 3-Bromo-5-chloro-1H-indole-2-carboxylic acid To a solution of 5-chloro-1H-indole-2-carboxylic acid (2.0 g, 10.2 mmol) in acetic acid (24 mL) was added a solution of bromine (0.53 mL, 10.2 mmol) in acetic acid (16 mL). After 20 minutes, the mixture was poured into water and extracted with chloroform twice. The combined extracts were washed with water twice and brine, dried over magnesium sulfate and concentrated. The product was obtained as a solid (2.5 g, 89 %).

Reference： [1]Patent: US6107329,2000,A
[2]Patent: EP1134213,2001,A2

48
[ 10517-21-2 ]
[ 74-88-4 ]
[ 59908-47-3 ]

Yield	Reaction Conditions	Operation in experiment
	With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetonitrile; at 65℃; for 8h;	5-Chloroindole-2-carboxylic acid (2.5 mmol) was dissolved in CH3CN (20 ml). DBU (6.5 mmol) and MeI (5.6 mmol) were added. The mixture was stirred at 65C for 8 hours. The solvent was removed under reduced pressure. The residue (2.5 mmol) was dissolved in dry 1 , 4-dioxane (20 ml) and the solution was cooled to O0C. NaH (8.1 mmol) was added and the mixture was stirred at O0C for 15 minutes. MeI (10 mmol) was added and the mixture was stirred at 00C for 1 hour and at room temperature for 2 days. The reaction mixture was poured into water (150 ml). The water layer was extracted with Et2O (3 x 100 ml). The combined organic layers were EPO <DP n="50"/>washed with 1N HCI (3 x 200 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash chromatography.

Reference： [1]Patent: WO2006/66879,2006,A2 .Location in patent: Page/Page column 48-49; 53

49
[ 10517-21-2 ]
[ 6638-79-5 ]
[ 231295-57-1 ]

Yield	Reaction Conditions	Operation in experiment
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 40℃; for 18h;	EXAMPLE 1; Step A. 5-Chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide; To a flask containing 5-chloroindole-2-carboxylic acid (8.33 g, 42.6 mmol) were added EDC (12.6 g, 63.9 mmol), HOBt (8.63 g, 63.9 mmol), N,O-dimethylhydroxylamine hydrochloride (6.23 g, 63.9 mmol) sequentially. N,N-Dimethylformamide (100 mL) was added, followed by DIEA (22.6 mL, 128 mmol), and the resulting solution was stirred at 40 C. for 18 h. The reaction mixture was allowed to cool to room temperature, then was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting amide was taken forward without further purification: LCMS B, tr=2.03 min, m/z 239.1 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.55 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 7.24 (dd, J=8.5, 2.0 Hz, 1H), 7.16 (s, 1H), 3.85 (s, 3H), 3.44 (s, 3H).

Reference： [1]Patent: US2007/88071,2007,A1 .Location in patent: Page/Page column 17
[2]Medicinal Chemistry Research,2021,vol. 30,p. 1309 - 1316

50
[ 10517-21-2 ]
[ 53324-38-2 ]
[ 1036751-06-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 5452 - 5464

51
[ 10517-21-2 ]
[ 52273-77-5 ]
[ 1036750-34-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 5452 - 5464

52
polymer supported tetrafluorophenol [ No CAS ]
[ 10517-21-2 ]
resin bound activated 5-chloroindole-2-carboxylic acid tetrafluorophenyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a suspension of triphenylphosphine (3.9 g) and 5-chloroindole-2-carboxylic acid (2.9 g) in tetrahydrofuran (100 mL) at room temperature, was added trichloroacetonitrile (2.2 g). The resulting yellow mixture was shaken for 2 h before diisopropylethylamine (2.0 g) and polymer-supported tetrafluorophenol (5.0 g, J. M. Salvino, et al., J. Combinatorial Chem. 2000, 2, 691-697) were added, followed by additional tetrahydrofuran (100 mL). After shaking for 5 h, the solution was drained from the now light brown mixture, and the resin was washed sequentially with N,N-dimethylformamide (50 mL twice), tetrahydrofuran (50 mL twice), and dichloromethane (50 mL twice). Mixed with the resin was a small amount of a yellow, insoluble solid, which was removed by separation in dichloromethane, in which the insoluble solid sank and the resin floated. Resin bound activated ester (5.9 g) was obtained after drying under vacuum. Loading was determined to be 1.0 mmol/g by measurement of the amount of 5-chloro-N-isopropyl-indolecarboxamide obtained after reaction with,a large excess isopropylamine in dichloromethane.

Reference： [1]Patent: US2004/2495,2004,A1 .Location in patent: Page/Page column 32

53
[ 503832-26-6 ]
[ 10517-21-2 ]
[ 721446-43-1 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 10001 - 10012

54
[ 10517-21-2 ]
[ 3470-54-0 ]
[ 721446-28-2 ]

Reference： [1]Bioorganic and Medicinal Chemistry,2008,vol. 16,p. 10001 - 10012

55
[ 216217-94-6 ]
[ 10517-21-2 ]
[ 216218-17-6 ]

Yield	Reaction Conditions	Operation in experiment
73%		0.2 ml of thionyl chloride (0.0028 mol) is added, at 0 C., to a solution of 1 ml of pyridine (0.013 mol) in 30 ml of methylene chloride. After 15 minutes at 0 C., 500 mg (0.0025 mol) of 5-chloroindolecarboxylic acid are intro duced and the reaction miXture is left for 30 minutes at 0 C. 0.91 g (0.0028 mol) of 1- dimethoxy-4-methylphenyl hydrochloride is added to the acyl chloride formed and the miXture is left for 18 hours at 20 C. The reaction miXture is washed with 1 M sodium hydroxide solution. The organic phase is dried over anhy drous sodium sulphate and evaporated to dryness. The residue is chromatographed on silica gel with the eluent: 95/5 (v/v) dichloromethane/methanol, to give 0.980 g of crystals: m.p.=262 C.; yield=73%.

Reference： [1]Patent: US2004/43995,2004,A1 .Location in patent: Page 20

56
[ 10517-21-2 ]
[ 75-36-5 ]
[ 521963-25-7 ]

Yield	Reaction Conditions	Operation in experiment
49%		5-Chloro-1H-indole-2-carboxylic acid (5.50 g) was dissolved in dry DMF (50 ml) and ice-cooled. Sodium hydride (60% in oil) (2.35 g) was added to this solution. The mixture was stirred at room temperature for 20 min. This solution was cooled again in an ice bath and acetyl chloride (2.3 ml) was added dropwise. This solution was stirred at room temperature for 1 hr, and cooled in an ice bath. Acetic acid (4 ml) was added to this solution, after which ethyl acetate and ice water (each 200 ml) were added. The separated organic layer was washed with water and dried over anhydrous sodium sulfate. The extract solution was filtered and concentrated. The thick solution was stood to give pale-yellow crystals. The crystals were collected by filtration and dried in vacuo to give the title compound (3.12 g, yield 49%).1H-NMR (δ, 300MHz,DMSO-d6). 2.77 (3H,s) ,7.37 (3H,s) ,7.49 (1H,m),7.82 (1H,m),7.97 (1H,d)

Reference： [1]Patent: EP1452526,2004,A1 .Location in patent: Page 57

57
[ 10517-21-2 ]
[ 698-19-1 ]
[ 1263787-93-4 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 541 - 543

58
[ 10517-21-2 ]
[ 698-19-1 ]
[ 1263788-22-2 ]

Reference： [1]Tetrahedron Letters,2011,vol. 52,p. 541 - 543

59
[ 10517-21-2 ]
[ 51843-24-4 ]

Reference： [1]European Journal of Medicinal Chemistry,2011,vol. 46,p. 3149 - 3157

60
[ 10517-21-2 ]
[ 29968-78-3 ]
[ 1377838-17-9 ]

Reference： [1]Journal of Medicinal Chemistry,2012,vol. 55,p. 5627 - 5631

61
[ 4318-37-0 ]
[ 10517-21-2 ]
[ 1394078-52-4 ]

Yield	Reaction Conditions	Operation in experiment
		General procedure: (5-Chloro-7-fluoro-1H-indole-2-yl)-carboxylic acid (5a) (50 mg, 0.23 mmol), N,N-diisopropylethylamine (82 mul, 0.47 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) were dissolved in 550 mul N,N-dimethylformamide. After stirring for 10 min 4-methyl-piperazin 6a (26 mul, 0.23 mmol) was added and the reaction mixture was stirred for 16 h at 20 C. The solvent was evaporated under reduced pressure and the crude product was purified using chromatography method P1, yielding 37 mg (53%) of the title compound.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 54,p. 660 - 668

62
[ 6633-61-0 ]
[ 10517-21-2 ]
[ 1416810-63-3 ]

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 624 - 639

63
[ 10517-21-2 ]
[ 1416811-50-1 ]
[ 1416810-29-1 ]

Yield	Reaction Conditions	Operation in experiment
53%		A mixture of 5-chloro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol), PyBOP (443 mg, 0.85 mmol) and DIPEA (141 μL, 0.85 mmol) in DMF was stirred for 30 min, then added methyl 2-[(2S)-2-amino-3-phenylpropanamido]-1,3-thiazole-5-carboxylate (130 mg, 0.43 mmol). After the reaction was completed monitored by TLC, the reaction mixture was extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as a white solid (109 mg, 53%). 1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 11.69 (s, 1H), 9.02 (d, J = 7.5 Hz, 1H), 8.20 (s, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.44-7.38 (m, 3H), 7.30-7.25 (m, 3H), 7.20-7.16 (m, 2H), 5.04-4.96 (m, 1H), 3.82 (s, 3H), 3.25-3.06 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 171.51, 162.12, 161.84, 161.08, 145.36, 137.49, 134.92, 132.23, 129.28, 128.22, 128.02, 126.60, 124.33, 123.71, 121.23, 120.77, 113.92, 103.21, 54.90, 52.20, 36.58; LRMS (ESI) m/z 483 [M + H]+.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 624 - 639

64
[ 504-29-0 ]
[ 10517-21-2 ]
[ 1416810-51-9 ]

Yield	Reaction Conditions	Operation in experiment
64%		A mixture of 5-chloro-1H-indole-2-carboxylic acid (100 mg, 0.51 mmol), PyBOP (443 mg, 0.85 mmol) and DIPEA (141 μL, 0.85 mmol) in DMF was stirred for 30 min, then added pyridin-2-amine (40 mg, 0.43 mmol). After the reaction was completed monitored by TLC, the reaction mixture was extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give the title compound as a white solid (74 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ 12.03 (s, 1H), 10.93 (s, 1H), 8.41 (d, J = 5.1 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.87 (t, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.19 (t, J = 5.4 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 159.76, 151.94, 148.01, 138.24, 135.39, 132.31, 128.06, 124.47, 124.21, 121.00, 119.81, 114.67, 114.06, 104.71; LRMS (ESI) m/z 272 [M + H]+.

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 624 - 639

65
[ 10517-21-2 ]
[ 1416811-65-8 ]
[ 1416811-67-0 ]

Yield	Reaction Conditions	Operation in experiment
67%	With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃;	(iii) 2-Amino-N-(5-vinylpyridin-2-yl)acetamide (250 mg, 1.41 mmol) and 5-chloro-1H-indole-2-carboxylic acid (330 mg, 1.69 mmol) were condensed with PyBOP (1.46 g, 2.81 mmol) and DIPEA (466 muL, 2.81 mmol) in DMF at room temperature. After the reaction was completed monitored by TLC, the reaction mixture was extracted with EtOAc, washed with water and brine, dried with anhydrous Na2SO4 and concentrated. The residue was purified by column chromatography to give 2-[(5-chloro-1H-indol-2-yl)formamido]-N-(5-ethenylpyridin-2-yl)acetamide as a white solid (334 mg, 67%). LRMS (ESI) m/z 355 [M + H]+

Reference： [1]European Journal of Medicinal Chemistry,2012,vol. 58,p. 624 - 639

66
[ 10517-21-2 ]
[ 1093254-29-5 ]
[ 1093255-66-3 ]

Yield	Reaction Conditions	Operation in experiment
57%	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 1h;	HATU (91 mg, 0.24 mmol) was added to a solution of 3-[3-(aminomethyl)-6-chloro-2- fluorophenyl]oxy}-5-chlorobenzonitrile (50 mg, 0.16 mmol), 5-chloro-1 H-indole-2- carboxylic acid (50 mg, 0.24 mmol) and DIPEA (0.042 ml, 0.24 mmol) in DMF (1.5 ml_). After 1 h, the reaction mixture was diluted with ethyl acetate and water. A solid precipitated which was filtered, triturated with methanol and dried under vacuum to give the title compound (0.045 g, 57%) as an off-white solid. 1H NMR (400 MHz, DMSOd6): δ ppm 1 1.82 (s, 1 H), 9.10 (s, 1 H), 7.80 (s, 1 H), 7.69 (s, 1 H), 7.45 - 7.55 (m, 3 H), 7.35 - 7.44 (m, 2 H), 7.1 1 - 7.21 (m, 2 H), 4.56 (d, 2 H). MS: m/z 488 (M+1 ).

Reference： [1]Patent: WO2008/154271,2008,A1 .Location in patent: Page/Page column 121

67
[ 10517-21-2 ]
[ 21691-53-2 ]
[ 1471484-92-0 ]

Yield	Reaction Conditions	Operation in experiment
72%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 2h;	General procedure: To a solution of the commercially available L-leucine tert-butyl ester (12, 0.89mmol) in DMF (15mL) were added an appropriate carboxylic acid (8, 1.1mmol), HOBt·H2O (1.1mmol), and EDC·HCl (1.1mmol). The resulting solution was cooled to 0C under ice bath conditions, and TEA was added dropwise. After 5min, the ice bath was removed, and the mixture was allowed to stir for 2h at ambient temperature. DMF was removed under high vacuum, and the resulting residue was dissolved in EtOAc (30mL). The organic layer was washed with 5% citric acid (20mL×2), 5% NaHCO3 (20mL×2), and brine (20mL). The solution was dried over Na2SO4, filtered, and evaporated under reduced pressure to give compound 13. The resulting crude compound was purified by silica gel column chromatography using hexane-EtOAc as eluents.

Reference： [1]European Journal of Medicinal Chemistry,2013,vol. 68,p. 372 - 384

68
[ 10517-21-2 ]
[ 1574306-17-4 ]
tert-butyl 2-amino-4-(3-(5-chloro-1H-indole-2-carboxamido)phenyl)-1H-imidazole-1-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
65%		General procedure: To a suspension of 5-methoxy-indole-2-carboxylic acid (251 mg, 1.31 mmol) and TBTU (456 mg, 1.42 mmol) in dichloromethane (5 mL), N-methylmorpholine (0.601 mL, 5.47 mmol) was added and the mixture stirred at rt for 0.5 h upon which a clear solution formed. Compound 3 (300 mg, 1.09 mmol) was added and the mixture stirred at 35 C for 24 h. The solvent was evaporated in vacuo, the residue dissolved in ethyl acetate (30 mL) and washed successively with water (2 × 10 mL), saturated aqueous NaHCO3 solution (2 × 10 mL) and brine (1 × 10 mL). The organic phase was dried over Na2SO4, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/petroleum ether or dichloromethane/ methanol as an eluent, to afford 5f (305 mg, 62% yield) as a white solid.

Reference： [1]Marine Drugs,2014,vol. 12,p. 940 - 963
[2]MedChemComm,2015,vol. 6,p. 105 - 110

69
[ 10517-21-2 ]
[ 20529-23-1 ]
5-chloro-N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
71%	With N-ethyl-N,N-diisopropylamine; HATU; In dichloromethane; at 20℃;Inert atmosphere;	General procedure: HATU (0.76 g, 0.002 mol), DIPEA (0.26 g, 0.002 mol), and an equivalent amount of 15 were added to a solution of 14 (0.5 g, 0.002 mol) in CH2Cl2. The reaction was protected by N2 and then stirred at room temperature for 6-10 h. The mixture was washed with water, and the combined organic layer was dried (Na2SO4) and evaporated under a reduced pressure. The crude was purified 2using silica gel chromatography with acetone and petroleum ether as eluents to produce target compounds 2-12 (yield 69%-81%).

Reference： [1]European Journal of Medicinal Chemistry,2015,vol. 96,p. 83 - 91

70
[ 10517-21-2 ]
[ 106092-09-5 ]
(S)-N-(2-amino-4,5,6,7-tetrahydrobenzo[1,2-d]thiazol-6-yl)-5-chloro-1H-indole-2-carboxamide [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 5501 - 5521
[2]Journal of Medicinal Chemistry,2015,vol. 58,p. 5501 - 5521

71
[ 10517-21-2 ]
[ 74-88-4 ]
[ 148356-79-0 ]

Yield	Reaction Conditions	Operation in experiment
98%	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h;Inert atmosphere; Sealed tube;	Step 1: Synthesis of 5-chloro-l-methyl-lH-indole-2-carboxylate 43.1 [00507] To a solution of 5-chloro-lH-indole-2-carboxylic acid (200mg, 1.02 mmol) in DMF (2 ml) was added at rt K2CO3 (1.23g, 8.79 mmol). To this solution was added iodomethane (950 mu, 15.26 mmol) and the mixture was stirred under nitrogen at rt in a sealed tube. After 20h the reaction mixture was concentrated in vacuo and partitioned between DCM (100ml) and water (10ml). The two layers were separated and the organic layer was extracted further with water (2 x 10ml) and saturated aqueous sodium chloride (10ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuo. The residue was azeotroped from heptane to afford 224 mg (98%) of methyl 5 -chloro-1 -methyl- lH-indole-2-carboxylate 43.1 as a pale yellow solid.
	With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 20h;	General procedure: To a solution of 1a (100 mg, 510 mumol) in DMF (1.89 mL) were added K2CO3 (2.11 g, 15.3 mmol) and MeI (160 muL, 2.55 mmol) at room temperature. The reaction mixture was stirred for 20 h. After stirring, the reaction mixture was dissolved in EtOAc, washed with H2O, and dried over MgSO4 followed by concentration under reduced pressure. The residue was dissolved in THF/H2O (5/1, 2.50 mL), and 1 M LiOH aq. (750 muL, 750 mumol) was added at room temperature. The reaction mixture was refluxed and stirred for 2 h. After being cooled to room temperature, the reaction mixture was quenched by saturated aqueous NH4Cl solution and extracted with EtOAc. The extract was washed with brine and dried over MgSO4. Concentration under reduced pressure provided the title compound 1b (58.8 mg, 55% yield) as white powder.;

Reference： [1]Journal of Medicinal Chemistry,2016,vol. 59,p. 10127 - 10146
[2]Patent: WO2016/40449,2016,A1 .Location in patent: Paragraph 00506-00507
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5664 - 5671

72
[ 10517-21-2 ]
[ 59908-47-3 ]

Reference： [1]Patent: WO2016/40449,2016,A1
[2]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5664 - 5671

73
[ 10517-21-2 ]
[ 837-52-5 ]
(4-(7-chloroquinolin-4-yl)piperazin-1-yl)(5-chloro-1H-indol-2-yl)methanone [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74.4%	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; at 0 - 30℃; for 6h;	General procedure: To a solution of 7-chloro-4-(piperazin-1-yl)quinoline (1mmol) in dry dichloromethane (3mL) was added triethyl amine (1.5mmol) and corresponding acid (1mmol) at 0C. propylphosphonic anhydride (2mmol) was then added drop wise to the reaction mixture and the reaction mixture was stirred at 30 for 6h (monitored by TLC & LCMS for completion). The reaction mixture was washed with water (2mL), brine (2mL), dried over anhydrous sodium sulphate and evaporated in vacuo to give the desired product as mentioned below.

Reference： [1]European Journal of Medicinal Chemistry,2016,vol. 122,p. 216 - 231

74
[ 10517-21-2 ]
[ 109-07-9 ]
(5-chloro-1H-indol-2-yl)-(3,4-dimethylpiperazin-1-yl)methanone [ No CAS ]

Reference： [1]Patent: EP1373204,2016,B1

75
[ 10517-21-2 ]
(S)-1-[4-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxy)piperidine-1-yl]-2-amino-3-(4-fluorophenyl)-1-propanone hydrochloride [ No CAS ]
N-{(S)-1-[4-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxy)piperidin-1-yl]-3-(4-fluorophenyl)-1-oxopropan-2-yl}-5-chloro-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73.4%		The (S)-1-{4-[2-(2-{2-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]ethoxy}ethoxy)ethoxy]piperidin-1-yl}-2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-1-propanone (0.50g, 0 . 80mmol) dissolved in dichloromethane (10 ml), under ice bath, slowly dropping fresh preparation of methylene chloride solution of hydrogen chloride (2N, 2 ml), stirring the mixture at room temperature for overnight. Morrows, pressure reaction solution is concentrated to obtain (S)-1-[4-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxy)piperidine-1-yl]-2-amino-3-(4-fluorophenyl)-1-propanone hydrochloride (0.13g, 0 . 66mmol) dissolved in anhydrous dichloromethane (10 ml) in, added under ice bath 2- (7-azo-benzotriazole) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (HATU, 0.30g, 0 . 79mmo1) and N, N-diisopropylethylamine (DIPEA, 0.28 ml, 1 . 58mmol), stirring the mixture at room temperature for 10 minutes, then adding (S)-1-[4-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethoxy)piperidine-1-yl]-2-amino-3-(4-fluorophenyl)-1-propanone hydrochloride (0.38g, 0 . 79mmol), stirring the mixture at room temperature for overnight. The saturated salt water washing, anhydrous Na 2 SO 4 drying. Rapid column chromatography (petroleum ether/ethyl acetate: 1/4, V/V), get white solid (0.30g, 73.4%).
		General procedure: HATU (1.0 equiv., dissolved in 1.5 mL DMF) and DIPEA (3.0 equiv., dissolved in1.5 mL DMF) were added to a solution of N-(tert-Butoxycarbonyl)-4-fluoro-L-phenylalanine or 5-chloroindole-2-carboxylicacid (1.0 equiv.) in anhydrous DMF (1.5 mL). The reaction mixture wasstirred at room temperature for 10 min. Then, compound 8 or 10 (1.0 equiv.) was added to the reaction.The mixture was stirred at 45 C for 5 h. After cooling to room temperature, the mixture was dilutedwith water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic phase was washedwith brine (1 L x 2), dried over anhydrous Na2SO4, and evaporated. The residue was purified byreversed-phase chromatography (methanol-water (20-90%)) to give the product 9 or 11.

Reference： [1]Patent: CN103819486,2016,B .Location in patent: Paragraph 0054-0056
[2]Molecules,2019,vol. 24

76
[ 10517-21-2 ]
5,5'-dichloro-2,2'-difluoro-1H,1'H-3,3'-biindole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
50%	With selectfluor II; lithium acetate; In water; 1,2-dichloro-ethane; at 50℃; for 15h;Sealed tube;	A mixture of 5-chloroindole-2-carboxylic acid (195 mg, 1.0 mmol, 1.0 eq), Selectfluor(708 mg, 2.0 mmol, 2.0 eq), lithium acetate (264 mg, 4.0 mmol, 4.0 eq) ); Then add dichloroethane(3.3 mL) and water (1.7 mL) as solvent. The reaction vessel was sealed in an oil bath at 50 C and stirred for 15 hours.After completion of the reaction, the reaction mixture was extracted twice with 20 mL of ether, the organic phases were combined and washed with saturated brine, thenAnd dried over anhydrous sodium sulfate. After drying, the organic solvent was dried under reduced pressure to give the crude product. The crude product was analyzed by purePentane as eluant to give the final product: 5,5'-dichloro-2,2'-difluoro-1-hydrogen, 1'-hydrogen-The indole was a pale yellow solid in 50% yield.

Reference： [1]Organic Letters,2017,vol. 19,p. 1410 - 1413
[2]Patent: CN106397377,2017,A .Location in patent: Paragraph 0103; 0104; 0105

77
[ 10517-21-2 ]
[ 1795-98-8 ]
5-chloro-N-(1-hydroxy-3-phenylpropan-2-yl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%		General procedure: A mixture of appropriate indole-2-carboxylic acid 1a-f (2.24mmol, 1eq), BOP (1.29g, 2.91mmol, 1.3 eq) and DIPEA (0.78mL, 4.48mmol, 2 eq) in DCM (30mL) was stirred for 10minat rt before addition of appropriate 2-amino-3-phenylpropanol 2a-b (2.69mmol, 1.2 eq) and the resulting reaction mixture was stirred overnight at rt. After removing of the solvent in vacuo, the residue was extracted with EtOAc, washed with 5% HCl, saturated NaHCO3 solution, brine, dried over MgSO4, and evaporated under reduced pressure to give a crude product, which was purified by flash chromatography on silica gel using EtOAc/hexanes (1:1).

Reference： [1]European Journal of Medicinal Chemistry,2018,vol. 146,p. 260 - 273

78
[ 36768-62-4 ]
[ 10517-21-2 ]
5-chloro-N-(2,2,6,6-tetramethylpiperidin-4-yl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In N,N-dimethyl-formamide; at 0 - 20℃; for 20h;	General procedure: To a solution of 1a (196 mg, 1.00 mmol) in DMF (3.30 mL) were added HOBt·H2O (149 mg, 1.10 mmol), EDCI·HCl (211 mg, 1.10 mmol), 2,2,6,6-tetramethylpiperidin-4-amine (156 muL, 900 mumol) and Et3N (152 muL, 1.10 mmol) at 0 C. The reaction mixture was heated to room temperature and stirred for 20 h. The reaction was quenched with saturated aqueous NaHCO3 solution and extracted with CHCl3. The extract was washed with brine and dried over MgSO4. Concentration under reduced pressure provided the title compound 9a (210 mg, 74% yield) as a white powder.; 1H NMR (500 MHz, CDCl3) delta 0.84-1.34 (m, 14H), 1.19 (s, 6H), 1.35 (s, 6H), 2.06 (dd, J = 7.0, 3.5 Hz, 2H), 4.49-4.62 (m, 1H), 6.11 (d, J = 7.5 Hz, 1H), 6.78 (d, J = 1.0 Hz, 1H), 7.21 (dd, J = 4.0, 2.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H), 7.61 (d, J = 2.0 Hz, 1H), 10.4 (br, 1H); 13C NMR (125 MHz, CDCl3) delta 28.6, 34.9, 43.1, 45.3, 51.2, 101.0, 113.2, 121.0, 124.8, 126.2, 128.5, 132.0, 134.7, 160.5; HRMS (ESI), m/z calcd for C18H23ClN3O [M-H]- 332.1535, found 332.1545.

Reference： [1]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5664 - 5671

79
[ 10517-21-2 ]
[ 28957-04-2 ]
(1S,4aR,5S,6S,6aR,9S,11aS,14R)-1,5,6-trihydroxy-4,4-dimethyl-8-methylene-7- oxododecahydro-1H-6,11b-(epoxymethano)-6a,9-methanocyclohepta[a]naphthalen-14-yl 5-chloro-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane;	General procedure: To a solution of <strong>[28957-04-2]oridonin</strong> (36.4mg, 0.1mmol) in 10mL dry CH2Cl2 and different carboxyl compounds (0.15mmol), the solution was treated with EDCI (0.3mmol) and 4-dimethylaminopyridine (DMAP) (10mg). The mixture was stirred at 25C for 2-8h and monitored by TLC. After completion of the reaction, water was added and the mixture was extracted with dichloromethane and the organic phase was washed with saturated sodium bicarbonate solution and brine, and dried over Na2SO4. The evaporation of the solvents gave the crude products, which were purified by silica gel column (CH2Cl2/MeOH, 100:1) to afford compounds A1-9, B1-3, C1-9, D1, E, F.

Reference： [1]European Journal of Medicinal Chemistry,2019,vol. 173,p. 15 - 31

80
[ 10517-21-2 ]
[ 131230-76-7 ]
[ 620596-79-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 499 - 503

81
[ 10517-21-2 ]
[ 131230-76-7 ]
N-(4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)-5-chloro-1H-indole-2-carboxamide [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2019,vol. 10,p. 499 - 503

82
[ 173522-95-7 ]
[ 10517-21-2 ]
methyl (S)-2-(5-chloro-1H-indole-2-carboxamido)-3-(3,4-dichlorophenyl)propanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3617 - 3635

83
[ 10517-21-2 ]
[ 14173-40-1 ]
methyl (S)-2-(5-chloro-1H-indole-2-carboxamido)-3-(4-chlorophenyl)propanoate [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2019,vol. 62,p. 3617 - 3635

84
[ 591-50-4 ]
[ 10517-21-2 ]
[ 436160-58-6 ]

Yield	Reaction Conditions	Operation in experiment
87%	With copper(I) oxide; potassium phosphate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 12h;Inert atmosphere; Schlenk technique;	General procedure: A mixture of Cu2O (0.02 mmol), K3PO4 (0.4 mmol), indole-2-carboxylic acid (1) (0.2 mmol), and aryl halide (2) (0.2 mmol) in NMP (2.0 mL) was stirred at room temperature under a N2 atmosphere. The mixture was then heated to 160 C and stirred at this temperature for 12 h. After completion of the reaction, the mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with H2O and aq NaCl, dried over MgSO4 and filtered. After evaporation of the solvent, the residue was purified by preparative thin-layer chromatography on silica gel with PE/EtOAc (50:1) as eluent to give the product 3.

Reference： [1]Synthesis,2019,vol. 51,p. 1803 - 1808

85
[ 10517-21-2 ]
4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-ylamine dihydrochloride [ No CAS ]
5-(5-chloro-1H-indole-2-carbonyl)-4H,5H,6H,7H-[1,3]thiazolo[5,4-c]pyridin-2-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
66%		To a solution of 5-chloro-1H-indole-2-carboxylic acid (0.0283 g, 0.145 mmol) in DMF (0.8 mL) was HATU (0.0525 g, 0.138 mmol) and the resulting solution stirred for 4 mm. 4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine dihydrochioride (0.0300 g, 0.132 mmol) and triethylamine (0.110 mL, 0.789 mmol) were then added. The mixture was stirred at r.t. for 72h. The mixture diluted with DMSO (2 mL), filtered, and the filtrate purified by basic HPLC to give the desired product (0.0290 g, 66% yield).Rt (Method A) 3.08 mins, m/z 333/335 [M+H].

Reference： [1]Patent: WO2019/86141,2019,A1 .Location in patent: Page/Page column 202; 203

86
[ 10517-21-2 ]
[ 122536-77-0 ]
tert-butyl (R)-(1-(5-chloro-1H-indole-2-carbonyl)pyrrolidin-3-yl)carbamate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
79%	With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h;	To a mixture of 5-chloro-lif-indole-2-carboxylic acid (196 mg, 1 mmol), (i?)-3-(Boc- amino)pyrrolidine(204 mg, 1.1 mmol) and HATEG (456 mg, 1.2 mmol) in DMF (3 mL) was added N,N-diisopropylethylamine (0.29 mL, 1.2 mmol). The reaction mixture was stirred at RT for 3 h, quenched with water and extracted with EtOAc (5mL, 3x). The extracts were washed with saturated sodium bicarbonate, 0.1 M aqueous HC1 solution, brine, dried (Na2S04), filtered and concentrated. The residue was purified by silica gel chromatography (EA/Hexanes, 0-100 %) to give 287 mg (79%) of tert-butyl (R)-(l-(5-chloro-lH-indole-2-carbonyl)pyrrolidin-3- yl)carbamate. MS Calcd: 363, MS Found: 364 ([M+H]+).

Reference： [1]Patent: WO2019/152883,2019,A1 .Location in patent: Paragraph 00158

87
[ 10517-21-2 ]
[ 2450-71-7 ]
5-chloro-N-(prop-2-yn-1-yl)-1H-indole-2-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
85%		General procedure: To a solution of 1H-indole-2-carboxylic acid (18.63 mmol, 3.000 g) in anhydrous DMF (20 mL), carbonyldiimidazole (CDI) (20.49 mmol, 3.320 g) was added in small portions. After 1 h of stirring the reaction mixture at room temperature. propargylaminde (20.49 mmol, 1.31 mL) was added and stirring was continued for 5 h. The reaction mixture was diluted with water (200 mL) and the resulting precipitate was filtered off and dried in vauo to give analytically pure title product. Yield 2.693 g (73%).
		General procedure: For compounds of group C, 0.5 mmol 2-propynylaminewas usedto form amides with corresponding carboxylic acid derivativesmediated by N,N0-dicyclohexylcarbodiimide (DCC, 1.0 eq.) in dryacetonitrile (MeCN). Conditions and procedures used here weresame as these in group A. Afterwards, different amides were mixedwith 4-azidophenol (1.0 eq), fresh prepared solutions of CuSO4 (0.1eq) in demi-water (0.20 mL), sodium ascorbate (0.20 eq) in demiwater(0.20 mL) in MeOH (4 mL). The reaction mixture was leftstirring overnight for at 60 C. The CuAAC reaction and purificationwere also done in the same way as for group A described above.

Reference： [1]Tetrahedron Letters,2020
[2]European Journal of Medicinal Chemistry,2020,vol. 186

88
[ 10517-21-2 ]
[ 71939-50-9 ]
(3R,5aS,6R,8aS,9R,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl 5-chloro-1H-indole-2-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃;	General procedure: A solution of DHA (0.5 mmol) and appropriate carboxyl compounds(1.0 mmol) in dry DCM (5 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1.0 mmol) andN,N-dimethylaminopyridine (DMAP) (0.5 mmol). The mixture wasstirred 5-8 h at room temperature. Until the reaction completed, it wasextracted with DCM and the organic phase was washed with 10% sodiumbicarbonate solution and saturated brine, and dried over Na2SO4.The solid was removed by filtration and the solvent was evaporatedunder reduced pressure to afford the crude product that was furtherpurificated by column chromatography (DCM:methanol = 200:1-75:1,V/V) to give a white solid. And further characterized by the physicaland spectroscopic data shown below.

Reference： [1]Bioorganic Chemistry,2020,vol. 94

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

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

[ CAS No. 10517-21-2 ] {[proInfo.proName]}

Quality Control of [ 10517-21-2 ]

Related Doc. of [ 10517-21-2 ]

Product Details of [ 10517-21-2 ]

Calculated chemistry of [ 10517-21-2 ]

Physicochemical Properties

Pharmacokinetics

Lipophilicity

Druglikeness

Water Solubility

Medicinal Chemistry

Safety of [ 10517-21-2 ]

Application In Synthesis of [ 10517-21-2 ]

[ 10517-21-2 ] Synthesis Path-Upstream 1~16

[ 10517-21-2 ] Synthesis Path-Downstream 1~88

Related Functional Groups of [ 10517-21-2 ]

Chlorides

Carboxylic Acids

Related Parent Nucleus of [ 10517-21-2 ]

Indoles

Precautionary Statements-General

Prevention

Response

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Physical hazards

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Inquiry

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[ 10517-21-2 ]

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[ 10517-21-2 ]