319474-34-5|4-Iodo-7-azaindole| Ambeed

Structure of 319474-34-5

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Quality Control of [ 319474-34-5 ] Purity: 97% SDS Specification

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Product Details of [ 319474-34-5 ]

CAS No. :	319474-34-5
Formula :	C₇H₅IN₂
M.W :	244.03
SMILES Code :	IC1=C2C(=NC=C1)[NH]C=C2
MDL No. :	MFCD08272234
InChI Key :	PCHGYPNRADCIKG-UHFFFAOYSA-N
Pubchem ID :	21877415

Safety of [ 319474-34-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 319474-34-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	48.81
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	28.68 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.58
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	1.96
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.17
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.9
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	3.04
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.13

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.25
Solubility	0.136 mg/ml ; 0.000557 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-2.19
Solubility	1.59 mg/ml ; 0.0065 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-3.87
Solubility	0.0331 mg/ml ; 0.000136 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.4 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	0.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	1.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.79

Application In Synthesis of [ 319474-34-5 ]

* 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.

Downstream synthetic route of [ 319474-34-5 ]

[ 319474-34-5 ] Synthesis Path-Downstream 1~35

1
K₂CO₃ (aq) [ No CAS ]
[ 75-36-5 ]
[ 55052-28-3 ]
[ 319474-34-5 ]

Yield	Reaction Conditions	Operation in experiment
48%	With sodium hydroxide; sodium iodide; In tetrahydrofuran; acetonitrile;	Part 2 4-Iodo-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80 C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10% K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3*100 mL). The combined organic extracts were washed with 10% sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48%). MS (ES+): 245 [MH+].

References: [1]Patent: US2005/154014,2005,A1 .

2
[ 55052-28-3 ]
[ 319474-34-5 ]

Yield	Reaction Conditions	Operation in experiment
48%		Part 2: [0195] 4-Iodo-1H-pyrrolo[2,3-b]pyridine: To a solution of 4-Chloro-1H-pyrrolo[2,3-b]pyridine (12.9 g, 84.3 mmol) and NaI (40 g, 168 mmol) in acetonitrile (150 mL) was slowly added acetyl chloride (12.6 mL, 176 mmol). The mixture was allowed to stir at 80 C. for 4 days, and then the excess acetonitrile was removed in vacuo. 300 mL of 10% K2CO3 (aq) was added to the residue and the mixture extracted with CH2Cl2 (3x100 mL). The combined organic extracts were washed with 10% sodium bisulfite (aq) and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give crude product (22.2 g). To a solution of this crude product in THF (150 mL) was added 1M NaOH (100 mL). The mixture was stirred at room temperature for 2 hr prior to evaporation of the solvent in vacuo, dilution with water and extraction with CH2Cl2. The extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting brown solid was purified by chromatography over silica gel and recrystallized from acetonitrile to give pure 4-Iodo-1H-pyrrolo[2,3-b]pyridine (9.75 g, 48%). MS (ES+): 245 [MH+].
39%		Intermediate 1.1: 4-iodo-1H-pyrrolo[2,3-b]pyridine Acetyl chloride (2.34 mL, 2.57 g, 32.8 mmol) was added dropwise to a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) and sodium iodide (13.8 g, 91.8 mmol) in acetonitrile (25 mL). The resulting suspension was heated at 80 C. for 7 days. After cooling to room temperature, the reaction mixture was concentrated under vacuo, and a saturated aqueous solution of potassium carbonate (50 mL) was added to the residue. The mixture was then extracted with dichloromethane (350 mL), the combined organic phase was washed with a saturated solution of sodium bisulfite (250 mL) and brine (50 mL), dried over sodium sulfate and concentrated under vacuo. The residue was dissolved in THF (25 mL) and added to an aqueous solution 1N of sodium hydroxide (15 mL). The resulting solution was stirred at 25 C. for 3 h. The reaction mixture was then concentrated under vacuo, and water (100 mL) was added to the residue. The mixture was extracted with dichloromethane (3*50 mL), the combined organic phase was washed with brine (50 mL), dried over sodium sulfate and concentrated under vacuo. The residue was purified by chromatography on a SP1 Biotage system, using hexanes and ethyl acetate as eluents to afford the title compound (1.26 g, 39%) as a yellow solid (HPLC: 66%, RT: 5.77 min) 1H NMR (CDCl3) delta=11.77 (br s, 1H), 7.94 (d, J=5.1 Hz, 1H), 7.51 (d, J=5.1 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 6.41 (d, J=3.3 Hz, 1H); MS (m/z) 245 [M+H]+ (127I).
39%	With acetyl chloride; sodium iodide; In acetonitrile; at 80℃; for 168h;	Step 1 : To a solution of 4-chloro-1 H-pyrrolo[2,3-b]pyridine (2.00 g, 13.1 mmol) and sodium iodide (13.8 g, 91.8 mmol) in acetonitrile (25 mL) was added dropwise acetyl chloride (2.34 mL, 2.57 g, 32.8 mmol) and the resulting suspension was heated at 80 C for 7 days. After cooling the reaction mixture was concentrated under vacuo and a saturated aqueous solution of potassium carbonate (50 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 50 mL), the combined organic phase washed with a saturated solution of sodium bisulfite (2 x 50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. To a solution of the residue in THF (25 mL) was added an aqueous solution 1 N of sodium hydroxide (15 mL) and the resulting solution was stirred at room temperature for 3 h. The reaction mixture was then concentrated under vacuo and water (100 mL) was added to the residue. The mixture was extracted with dichloromethane (3 x 50 mL), the combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under vacuo. The residue was purified on silica gel column using column using hexane / ethyl acetate as eluent to give 4-iodo- H-pyrrolo[2,3- b]pyridine (1.26 g, 39%) as a yellow solid; LCMS (ESI) 245 (M+H); HPLC 66%, RT: 5.77 min; H NMR (400 MHz, CHLOROFORM-d) delta ppm: 1 1.77 (br s, 1 H), 7.94 (d, J=5.1 Hz, 1 H), 7.51 (d, J=5.1 Hz, H), 7.44 (d, J=3.7 Hz, 1 H), 6.41 (d, J=3.3 Hz, 1 H).

References: [1]Journal of Medicinal Chemistry,2018,vol. 61,p. 10415 - 10439.
[2]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[3]Patent: US2004/186124,2004,A1 .Location in patent: Page/Page column 14.
[4]Patent: US2011/282056,2011,A1 .Location in patent: Page/Page column 16.
[5]Patent: WO2014/121883,2014,A1 .Location in patent: Page/Page column 54.
[6]Patent: EP2487180,2012,A1 .

3
[ 319474-34-5 ]
[ 13154-24-0 ]
[ 920501-58-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 4; Preparation of N-[(1S)-2-amino-1-benzylethyl]-6,7-dihydro-2H-2,3-diazabenzo[cd]azulene-8-carboxamide dihydrochloride [(Ic), (A= -CH=, X= -CH2-CH2-, Y= -CH=, R2= H, R1 = (1S)-2-amino-1-benzylethyl)]; Step 1. 4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine, [(XX) (R9= TIPS) ]; 1.8 g (7.4 mmol) of <strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (X) were dissolved with 30 mL of dry tetrahydrofuran. The resulting solution was cooled to 0C and 8.2 ml of 1N solution in THF of sodium bis(trimethylsilyl)amide were added under stirring and in argon atmosphere. After 15 minutes in the same conditions 2 mL of trisopropylsilyl chloride (9.3 mmol) were added dropwise. The reaction mixture was stirred at 0C for 30 minutes and further 30 minutes at room temperature. The solvent was then removed in vacuo, the residue taken up with dichloromethane and icy water and the layers separated. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude was chromatographed on a silica gel column (eluent: n-hexane) to afford the title compound (1.7 g 57 % yield) as an yellowish oil.

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[2]Patent: EP2002836,2008,A1 .Location in patent: Page/Page column 31.

4
[ 319474-34-5 ]
4-(morpholin-4-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[2]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

5
[ 319474-34-5 ]
4-(1-piperidyl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[2]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

6
[ 319474-34-5 ]
C₁₁H₁₃N₃ [ No CAS ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[2]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

7
[ 319474-34-5 ]
4-(4-methylpiperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine [ No CAS ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[2]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

8
[ 319474-34-5 ]
C₁₉H₂₁N₃ [ No CAS ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.
[2]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

9
[ 319474-34-5 ]
C₁₃H₁₆N₄O [ No CAS ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

10
[ 319474-34-5 ]
[ 577768-59-3 ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

11
[ 319474-34-5 ]
[ 640735-25-7 ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

12
[ 319474-34-5 ]
[ 640735-23-5 ]

References: [1]Tetrahedron Letters,2007,vol. 48,p. 1527 - 1529.

13
[ 557-21-1 ]
[ 319474-34-5 ]
[ 344327-11-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	tris-(dibenzylideneacetone)dipalladium(0); 1,1'-bis(diphenylphosphino)ferrocene; In water; N,N-dimethyl-formamide; at 90℃; for 20h;	Part 3: [0197] 1H-Pyrrolo[2,3-b]pyridine-4-carbonitrile: To a solution of (4.7 g, 19.3 mmol) of 4-Iodo-1H-pyrrolo[2,3-b]pyridine in degassed DMF (25 mL) was added Pd2(dba)3 (10 mg), dppf (15 mg), degassed H2O (2 mL) and Zn(CN)2 (1.4 g, 11.6 mmol). The mixture was stirred at 90 C. under nitrogen for 20 hr, then cooled to 70 C. and 75 mL of a 4:1:4 mixture of saturated NH4Cl:NH4OH:H2O was added. The mixture was stirred at 5 C. for 20 min. and the resulting precipitate filtered off, washed with 75 mL 4:1:5 mixture of saturated NH4Cl:NH4OH:H2O, 500 mL H2O and 100 mL toluene, then dried in vacuo to give 2.06 g (74%) 1H-Pyrrolo[2,3-b]pyridine-4-carbonitrile. MS (ES+): 143 [MH+]. 1H NMR (DMSO-d6, 400 MHz): delta 6.65 (d, 1H, J=3.2), 7.56 (d, 1H, J=4.8 Hz), 7.84 (d, 1H, J=4.0 Hz), 8.40 (d, 1H, J=4.8 Hz).

References: [1]Patent: US2004/186124,2004,A1 .Location in patent: Page/Page column 14.

Yield	Reaction Conditions	Operation in experiment
		4-Chloro-1H-pyrrolo[2,3-b]pyridine (Clark, B. A. et al., J. Chem. Soc. P1, 2270-74 (1974)) was converted to 4-iodo-1H-pyrrolo[2,3-b]pyridine in a similar manner to that described for Example 52(a). 1H NMR (300 MHz, MeOH-d4) delta 8.10 (m, 1H), 7.89 (d, 1H, J=5.0 Hz), 7.58 (m, 1H), 7.50 (d, 1H, J=5.0 Hz), 6.26 (br s, 1H).

15
[ 319474-34-5 ]
[ 98-59-9 ]
[ 1092579-97-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydroxide; tetra(n-butyl)ammonium hydrogensulfate; In toluene; at 20℃; for 16h;	f) 1-(Toluene-4-sulfonyl)-<strong>[319474-34-5]1H-4-iodo-pyrrolo[2,3-b]pyridine</strong> is prepared in the following manner: 10.6 g of para-toluenesulfonyl chloride and 0.331 g of tetrabutylammonium hydrogen sulfate are added to a solution of 12 g of <strong>[319474-34-5]1H-4-iodo-pyrrolo[2,3-b]pyridine</strong> in 425 cm3 of toluene, under an inert atmosphere of argon at a temperature in the region of 20 C., followed by dropwise addition of a 3.1N sodium hydroxide solution. The reaction medium is stirred at a temperature in the region of 20 C. for 16 hours. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and then concentrated under reduced pressure. 19.3 g of 1-(toluene-4-sulfonyl)-<strong>[319474-34-5]1H-4-iodo-pyrrolo[2,3-b]pyridine</strong> are thus obtained, the characteristics of which are as follows: Mass spectrum (EI): m/z=398; (M)+; m/z=334 (M-S2)+ base peak; m/z=91 (C7H7)+

References: [1]Patent: US2007/93480,2007,A1 .Location in patent: Page/Page column 83.

16
[ 319474-34-5 ]
[ 201733-56-4 ]
[ 944956-50-7 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In ethanol; for 20h;Heating / reflux;	[306] 4-Iodo-7-Azaindole (1.0Og, 4.12mmol), bis(neopentylglycolato)diboron (1.49g, 6.59mmol), potassium acetate (0.65g, 6.59mmol), and l,r-bis(diphenylphosphino)ferrocene dichloro palladium (II) dichloromethane complex (0.09g, 0.12mmol) were added to a round bottom flask. The flask was evacuated and backfilled with N2 (3 x). Anhydrous ethanol (2OmL) was added and the mixture was heated to reflux for 2Oh. After cooling to rt, the reaction mixture was diluted with diethyl ether (35mL) and then filtered through celite. The resulting filtrate was concentrated in vacuo and dissolved in ethyl acetate (5OmL). The solution was washed with water (15mL), brine (15mL), and dried over MgSO4. The filtrate was concentrated to a brown solid which was recrystallized with ethyl acetate to yield the title compound as a tan solid. The mother liquor was concentrated in vacuo and purified by column chromatography (HexanesrEtOAc = 80:20 ? 60:40) to yield the title compound. 1H NMR (400 MHz, DMSO-d6) delta 0.99 (s, 6H), 3.83 (s, 4H), 6.69 (dd, IH3 J= 1.8, 1.0 Hz), 7.30 (d, IH, J = 2.4 Hz), 7.45 (dd, IH3 J= 2.8, 2.4 Hz), 8.18 (d, IH, J= 2.2 Hz), 11.52 (bs, IH).

References: [1]Patent: WO2007/84667,2007,A2 .Location in patent: Page/Page column 93-94.

17
[ 443729-67-7 ]
[ 319474-34-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With sodium methylate; In methanol; ethanol; for 1h;Reflux;	A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30% K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0C for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58%) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50C, and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70C. This reaction solution was stirred at 75C for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0C, followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60C under reduced pressure to yield 2.7 g (80%) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85C for 12 hr and then cooled to room temperature, and 10% Na2CO3 (28 mL) and 10% NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28% sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92%). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) delta 12.01 (s, 1H), 7.89 (d, 1H, J = 5.0 Hz), 7.59 (t, 1H, J = 3.1 Hz), 7.51 (d, 1H, J = 5.0 Hz), 6.27 (d, 1H, J = 3.4 Hz).
	With sodium hydroxide; water; In tetrahydrofuran; for 2.5h;	[305] 4-Chloro-7-azaindole (1.26g, 8.25mmol) was dissolved in dry acetonitrile (25mL) in a10OmL round bottom flask fitted with a condenser. Sodium iodide (1.96g, 13.1mmol) and acetyl chloride (1.37g, 17.4mmol) were then added and the reaction was put under N2 atmosphere and the reaction was heated at reflux until complete (~48h). The reaction was then concentrated in vacuo. A 10% solution OfK2CO3 (1OmL) was then added and extracted with CH2Cl2 three times. The combined organic extracts were washed with 10% sodium sulfite, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified using column chromatography (100% hexanes - > hexanesrEtOAc = 90:10) to yield l-(4-iodo-pyrrolo[2,3-b]pyridin-l-yl)-ethanone. l-(4-iodo-pyrrolo[2,3-b]pyridin-l-yl)- ethanone was then dissolved in 15mL of THF. Sodium hydroxide (IM3 1 OmL) was then added and the reaction stirred for 2.5h. The reaction was concentrated in vacuo and then partitioned between CH2Cl2 (40 mL) and water (2OmL). The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to yield the title compound as a white solid. MS (ES+): m/z 245 [MH+].

References: [1]Patent: EP2487180,2012,A1 .Location in patent: Page/Page column 20.
[2]Patent: WO2007/84667,2007,A2 .Location in patent: Page/Page column 93.

18
[ 319474-34-5 ]
[ 18162-48-6 ]
[ 1093085-27-8 ]

Yield	Reaction Conditions	Operation in experiment
96%		To a solution of <strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (1 g, 4.10 mmol) in THF (16 mL) cooled to 0C, was added NaHMDS (1M in THF, 4.51 mL, 4.51 mmol) dropwise. After 15 mi TBDMS-Cl (0.803 g, 5.33 mmol) was added. The reaction was stirred for 30 mm at 0 C and 30 mm at rt. Water (75 mL) and DCM (75 mL) were added and the layers were separated (a small amount of MeOH was added to aid separation). The aqueous layer was further extracted with DCM (2 x 50 mL). The combined organicswere dried (Na2SO4), filtered and concentrated in vacuo to afford the desired crude product as a brown oil. This was taken up in cyclohexane and purified by flash SP4 chromatography using a 50 g SNAP silica cartridge and eluting with lOO% cyclohexane. The appropriate fractions were collected and concentrated in vacuo, redissolved in toluene and concentrated again to remove any residual waster, to afford the desired product as a clear oil - 1-(tert-butyldimethylsilyl)-<strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (1.41 g, 3.94 mmol, 96 % yield)LCMS (2 mm High pH): Rt = 1.71 mi [MH]+ = 359.1.1H NMR (400 MHz, DMSO-o) O ppm 7.91 (d, J=5.0 Hz, 1 H) 7.56 (d, J=3.5 Hz, 1 H) 7.53 (d, J=5.0 Hz, 1 H) 6.42 (d, J=3.5 Hz, 1 H) 0.87 (5, 9 H) 0.62 (5, 6 H)
57%		Example 5; Preparation of N-[(1S)-2-amino-1-benzylethyl]-1,2-dihydropyrrolo[4,3,2-ij]isoquinoline-4-carboxamide dihydrochloride [(Id), (A= -CH=, X= -CH=, Y= - CH2-, R2=H, R1 = (1S)-2-amino-1-benzylethyl)]; Step 1. 1-[tert-butyl(dimethyl)silyl]-<strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> [ (XX), (R9= TBDMS).; 1.8 g (7.4 mmol) of <strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (X) were dissolved with 30 mL of dry tetrahydrofuran. The resulting solution was cooled to 0C and 8.2 mL of 1N solution in THF of sodium bis(trimethylsilyl)amide were added under stirring and in argon atmosphere. After 15 minutes in the same conditions 1.6 mL (9.3 mmol) of tertbutyldimethylsilyl chloride were added dropwise. The reaction mixture was stirred at 0C for 30 minutes and further 30 minutes at room temperature. The solvent was then removed in vacuo, the residue taken up with dichloromethane and icy water and the layers separated. The organic phase was dried over sodium sulfate and evaporated to dryness. The crude was chromatographed on a silica gel column (eluent: n-hexane) to afford the title compound (1.51 g 57 % yield) as an yellowish oil.

References: [1]Patent: WO2017/202742,2017,A1 .Location in patent: Page/Page column 105.
[2]Patent: EP2002836,2008,A1 .Location in patent: Page/Page column 33.

19
[ 319474-34-5 ]
[ 50-00-0 ]
[ 506-59-2 ]
[ 1093084-93-5 ]

Yield	Reaction Conditions	Operation in experiment
46%		Example 1; Preparation of N-[(1S)-2-amino-1-benzylethyl]-6,7,8,9-tetrahydro-2H-2,3,6-triazabenzo[cd]azulene-8-carboxamide dihydrochloride [(Ia), (A= -CH2-, X = - N(R6)CH2-, Y= -CH=, R2= H, R1 = (1S)-2-amino-1-benzylethyl), R6=H]; Step 1. 1-(4-iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)-N,N-dimethylmethanamine [(III), (R11 = R12 = Me)]; 730 mg (2.99 mmol) of <strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (X) were dissolved in 12 ml of n-butanol 264 mg (3.2 mmol) of dimethylamine hydrochloride and 100 mg (3.3 mmol) of paraformaldehyde were then added. The mixture was refluxed under stirring for 45 minutes. After that time the solvent was removed, the residue re-dissolved with water, basified with solid potassium carbonate and the product extracted with diethylether. The organic layer was finally dried over anhydrous sodium sulfate and the solvent evaporated. The crude was purified by chromatography on a silica gel column (eluant: CH2Cl2-CH3OH-NH4OH 95-5-1) affording the title compound (420 mg 46 % yield) as yellowish solid. 1H NMR (400 MHz, DMSO-d6) delta ppm 11.74 (s, 1H), 7.81 (d, J=5 Hz, 1H); 7.55 (d, J=5 Hz, 1H); 7.47 (m, 1H); 3.60 (bs, 1H); 2.21 (s, 1H).. MS ESI (M+H) calc. 302.0149; found 302.0150 (C10H12IN3)

References: [1]Patent: EP2002836,2008,A1 .Location in patent: Page/Page column 26.

20
[ 319474-34-5 ]
[ 1066-54-2 ]
[ 1015609-91-2 ]

References: [1]Tetrahedron Letters,2009,vol. 50,p. 5156 - 5158.

21
[ 319474-34-5 ]
[ 536-74-3 ]
[ 918513-52-7 ]

Yield	Reaction Conditions	Operation in experiment
88%	With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In 1,4-dioxane; at 90℃; for 2h;Inert atmosphere; Sealed tube;	Example 1 4-(phenylethynyl)-1H-pyrrolo[2,3-b]pyridine Dichloro bis(triphenylphosphine) palladium (II) (5.8 mg, 0.0082 mmol), copper (I) iodide (3.1 mg, 0.016 mmol) and triethylamine (288 mul, 207 mg, 2.05 mmol) were added to a solution of intermediate 1.1 (100 mg, 0.410 mmol) and phenylacetylene (89.1 mul, 83.7 mg, 0.820 mmol) in 1,4-dioxane (2 mL), and placed in a sealable tube. Nitrogen gas was bubbled in the reaction mixture for 5 min, before the tube was sealed and the reaction mixture was heated at 90 C. for 2 h. After cooling, the brown solution was filtered through Celite and concentrated under vacuo. The residue was purified by chromatography on a SP1 Biotage system, using hexanes and ethyl acetate as eluents to afford the title compound (79 mg, 88%) as a yellow solid (HPLC: 99%, RT: 6.69 min). 1H NMR (DMSO-d6) delta=11.94 (br s, 1H), 8.24 (d, J=4.8 Hz, 1H), 7.70-7.66 (m, 2H), 7.61 (dd, J=3.3, 2.6 Hz, 1H), 7.50-7.46 (m, 3H), 7.22 (d, J=4.8 Hz, 1H), 6.65 (dd, J=3.3, 1.8 Hz, 1H); MS (m/z) 219 [M+H]+.

References: [1]Patent: US2011/282056,2011,A1 .Location in patent: Page/Page column 16-17.

22
[ 319474-34-5 ]
[ 1357587-25-7 ]

References: [1]Patent: WO2012/16993,2012,A1 .

23
[ 319474-34-5 ]
2,5-difluoro-N-{2-fluoro-3-[1-piperidin-4-yl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]phenyl}benzenesulfonamide [ No CAS ]

References: [1]Patent: WO2012/16993,2012,A1 .

24
[ 319474-34-5 ]
[ 1357587-73-5 ]
[ 1357586-85-6 ]

References: [1]Patent: WO2012/16993,2012,A1 .

25
[ 319474-34-5 ]
[ 1357587-73-5 ]
[ 1357587-86-0 ]

Yield	Reaction Conditions	Operation in experiment
45%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 100℃; for 1h;Microwave irradiation; Inert atmosphere;	Method A, Step cN-{3-[1-Ethyl-4-{1H-pyrrolo[2,3-b3pyrldin-4-yl)-1H-pyrazol-3-yl]-2-fluoro- phenyl}-2,5-difluoro-N-methoxymethyl-benzenesulfonamldeFormula 2, where R4 = 1H-pyrrolo[2,3-b]pyrldin-4-ylf PGi - methoxymethyl, R29 - ethyl, R30 = 2,5-difluoro-benzene-sulfonyl [00237] In a microwave tube a solution of N-{3-[1-Ethyl-4-(4,4,5,5- tetramethyl-tl .S^Jdioxaborolan^-y -I H-pyrazol-S-ylJ^-fluoro-phenyl^.S- difluoro-N-methoxy-methyl-benzenesulfonamide (prepared as described in Example 4) (273 mg, 0.496 mmol) in DME/H20 9:1 (5 mL) was degassed by bubbling argon for 5 minutes. 4-lodo-7-azaindole {121 mg, 0.496 mmol, 1 eq) was then added, followed by cesium carbonate (242 mg, 0.744 mmol, 1.5 eq) and Pd(dppf)CI2.CH2CI2 (30 mg, 0.037 mmol, 0.075 eq).. The mixture was irradiated in the microwave oven at 100C for 1 hr and then diluted with AcOEt and washed with saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04 and evaporated to dryness, the crude product was purified by chromatography on silica gel (DCM/ eOH 96:4) to give 220 mg of product. After recrystailtzation from AcOEt Hex mixture 122 mg (45%) of pure N-{3-[1-Ethyl-4-(1 H-pyrrolo[2,3-b]pyridin-4-yl)-1 H-pyrazol-3-yl]-2- fluoro-phenyl}-2,5-difluoro-N-methoxymethyl-benzenesuifonamide were obtained as a white solid. HPLC (254 nm): Rt: 6.12 min; 1H NMR (DMSO-d6) Shift: 11.59 (br. s., 1 H), 8.32 (s, 1 H), 7.99 (d, J = 5.0 Hz, 1 H), 7.52 - 7.66 (m, 1 H), 7.40 - 7,55 (m, 3 H), 7.36 (dd, J = 2.6, 3.4 Hz, 1 H), 7.16 - 7.33 (m, 2 H), 6.55 (d, J - 4.9 Hz, 1 H), 6.22 (dd, J - 1.9, 3.5 Hz, 1 H), 4.88 (s, 2 H), 4.27 (q, J = 7.3 Hz, 2 H), 3,21 (s, 3 H), 1.49 (t, J = 7.3 Hz, 3 H); HRMS (ESI) calcd for C26H23F3N503S [ +Hf 542.1468, found 542.1465.

References: [1]Patent: WO2012/16993,2012,A1 .Location in patent: Page/Page column 101-102.

26
[ 319474-34-5 ]
[ 1357588-07-8 ]
[ 1357588-08-9 ]

Yield	Reaction Conditions	Operation in experiment
35%	With caesium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; at 90℃; for 1h;Inert atmosphere; Microwave irradiation;	Method A, Step c4-[3-{3-[{2,5-Difluoro-benzenesulfonyl)-methoxymethyl-amino]-2-fiuoro- phenyl}-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-pyrazol-1-yl]-piperidine-1- carboxylic acid tert-butyl esterFormula 2, where R4 = 1H-pyrrolo[2,3-b3pyridln-4-yl, PGi =methoxymethyl, R29 = 2-{4-methyl-piperazin-1-yl)-ethyl, R30 = 2,5- difluoro-benzene-sulfonyl [00286] In a microwave tube a solution of 4-[3-{3-[(2,5-difluoro- benzenesulfonyl)-methoxymethyl-amino]-2-fluoro-phenyl}-4-(4 ,4,5,5- tetramethyl-il .S^ldtoxaborolan^-ylJ-pyrazol-1-ylj-piperidine-1-carboxyiic acid tert-butyl ester (354 mg, 0.501 mmol) in DME/H20 9:1 {5 ml_) was degassed by bubbling argon for 5 minutes. 4~lodo-7-azaindole (134 mg, 0.501 mmol, 1 eq) was then added, followed by cesium carbonate (325 mg, 1.0 mmol, 2 eq) and Pd(dppf)CI2-CH2CI2 (82 mg, 0.050 mmol, 0.2 eq). The mixture was irradiated in the microwave oven at 90C for 1 hr and then filtered through a Celite pad, and was washed with saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04 andevaporated to dryness. The crude product was purified by chromatography on silica gel (DCM/MeOH 98:2) affording 270 mg of the title compound (35% yield) as a white solid. [M?H]+ 697.

References: [1]Patent: WO2012/16993,2012,A1 .Location in patent: Page/Page column 135-136.

27
[ 319474-34-5 ]
[ 4330-21-6 ]
[ 940949-57-5 ]

Yield	Reaction Conditions	Operation in experiment
77%		(3-2) Synthesis of 1-[2-deoxy-3,5-di-O-(toluoyl)-beta-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine NaH (156 mg, 60% dispersion in oil, 3.9 mmol) was added to a solution of <strong>[319474-34-5]4-iodo-1H-pyrrolo[2,3-b]pyridine</strong> (950 mg, 3.9 mmol) in acetonitrile (39 mL). The mixture was stirred at room temperature for 1 hr, and 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythropentofuranosyl chloride (1.8 g, 1.2 equivalent) was added thereto, followed by stirring at room temperature for 1.5 hr. The reaction solution was separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution and saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 1.8 g (77%) of 1-[2-deoxy-3,5-di-O-(toluoyl)-beta-D-ribofuranosyl]-4-iodo-pyrrolo[2,3-b]pyridine.

References: [1]Patent: EP2487180,2012,A1 .Location in patent: Page/Page column 20-21.

28
[ 75-36-5 ]
[ 55052-28-3 ]
[ 319474-34-5 ]
[ 443729-67-7 ]

Yield	Reaction Conditions	Operation in experiment
80%		A solution of meta-chlorobenzoic acid (14 g, 54 mmol) in ethyl acetate (30 mL) was dropwise added to a solution of 1H-pyrrolo[2,3-b]pyridine (5.3 g, 45 mmol) in ethyl acetate (45 mL) over 1 hr with stirring at 0C. After completion of the dropping, the mixture was stirred at room temperature for 3 hr, followed by leaving to stand at 0C. The resulting crystals were collected by filtration, washed with ethyl acetate, and then dried under reduced pressure. The crystals were dissolved in water (30 mL), and then 30% K2CO3 was added until the pH of the solution reached 10. The solution was left to stand at room temperature for 1 hr and then at 0C for 1 hr. The resulting precipitate was collected by filtration and was washed with ether to yield 3.5 g (58%) of N-oxide. The N-oxide (3.0 g, 22 mmol) was dissolved in DMF (16 mL). The resulting solution was heated at 50C, and a solution of methanesulfonyl chloride (4.7 mL, 60 mmol) in DMF (6.4 mL) was dropwise added to the solution at 70C. This reaction solution was stirred at 75C for 2 hr. The reaction solution was added to ice and was neutralized with 10 N NaOH at 0C, followed by stirring at room temperature for 1 hr. The resulting precipitate was collected by filtration, washed with water, and dried at 60C under reduced pressure to yield 2.7 g (80%) of the target 4-chloro-1H-pyrrolo[2,3-b]pyridine. 4-Chloro-1H-pyrrolo[2,3-b]pyridine (2.7 g, 18 mmol) and NaI (13 g, 88 mmol) were dissolved in acetonitrile (28 mL), and CH3COCl (3.5 mL, 50 mmol) was added thereto with stirring at room temperature. The reaction solution was heated at 85C for 12 hr and then cooled to room temperature, and 10% Na2CO3 (28 mL) and 10% NaHSO3 (28 mL) were added thereto, followed by stirring at room temperature for 15 min. Ethyl acetate was added thereto for separation, and the organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified with a silica gel column to yield 4-iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g) and 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g). 4-Iodo-1-N-acetyl-pyrrolo[2,3-b]pyridine (2.0 g, 7.0 mmol) was dissolved in ethanol (70 mL) and refluxed in methanol containing 28% sodium methoxide (1.4 mL, 7.0 mmol) for 1 hr. The reaction solution was concentrated and separated between ethyl acetate and an aqueous saturated ammonium chloride solution. The organic layer was washed with an aqueous saturated ammonium chloride solution, dried over anhydrous sodium sulfate, concentrated, and then combined with 4-iodo-1H-pyrrolo[2,3-b]pyridine (2.3 g) obtained above. The mixture was recrystallized from ethanol to yield 4-iodo-1H-pyrrolo[2,3-b]pyridine (4.0 g, 92%). 4-Iodo-1H-pyrrolo[2,3-b]pyridine: 1H NMR (500 MHz, DMSO-d6) delta 12.01 (s, 1H), 7.89 (d, 1H, J = 5.0 Hz), 7.59 (t, 1H, J = 3.1 Hz), 7.51 (d, 1H, J = 5.0 Hz), 6.27 (d, 1H, J = 3.4 Hz).

References: [1]Patent: EP2487180,2012,A1 .Location in patent: Page/Page column 20.

29
[ 271-63-6 ]
[ 319474-34-5 ]