230301-11-8|tert-Butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate| Ambeed

Structure of 230301-11-8

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Quality Control of [ 230301-11-8 ] Purity: 97% SDS Specification

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Product Details of [ 230301-11-8 ]

CAS No. :	230301-11-8
Formula :	C₁₁H₁₇N₃O₂
M.W :	223.27
SMILES Code :	O=C(N1CCC(NN=C2)=C2C1)OC(C)(C)C
MDL No. :	MFCD08059268
Boiling Point :	No data available
InChI Key :	BHYPERDTLBCHAE-UHFFFAOYSA-N
Pubchem ID :	10398680

Safety of [ 230301-11-8 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 230301-11-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	5
Fraction Csp3	0.64
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	63.77
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	58.22 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.87
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	0.97
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.17
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.	0.89
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	1.4
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.26

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.87
Solubility	3.02 mg/ml ; 0.0135 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.78
Solubility	3.7 mg/ml ; 0.0166 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very 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	-2.31
Solubility	1.1 mg/ml ; 0.00491 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	Yes
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	No
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.	-6.97 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	0.0 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)	2.44

Application In Synthesis of [ 230301-11-8 ]

* 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 [ 230301-11-8 ]
Downstream synthetic route of [ 230301-11-8 ]

[ 230301-11-8 ] Synthesis Path-Upstream 1~2

1
[ 1310796-19-0 ]
[ 230301-11-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrazine hydrate In ethanol at 20℃; for 12 h;	To a solution of (Z)-tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-i- carboxylate (8.8 g, 34.6 mmol) in EtOH (50 mL) was added N2H4/H20 (200 mL) at 20 °C. The mixture was stuffed at 20 °C for 12 h. After that, the reaction mixture was concentrated in vacuum. The residue mixture was purified with column separation to afford desired product (7 g, Yield 95 percent). LCMS (mlz): 224.2 [M+H] .

References: [1] Patent: WO2015/200677, 2015, A2, . Location in patent: Paragraph 00806; 00807.

2
[ 79099-07-3 ]
[ 230301-11-8 ]

References: [1] Patent: WO2015/200677, 2015, A2, .
[2] Patent: CN108250128, 2018, A, .

[ 230301-11-8 ] Synthesis Path-Downstream 1~31

1
[ 230301-11-8 ]
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine dihydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
83%		[1,] 4,6, 7-Tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid [TERT-BUTYL] ester (0.70 g, 3.1 mmol) was dissolved in trifluoroacetic acid (10 mL) at [0C,] stirred for 1 h, and was concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-hydrochloride salt precipitated out as a white solid which was filtered to give 510 mg [(83%).] The free base was prepared as needed by dissolving the salt in water, loading it onto an SCX column, flushing with methanol, and then eluting with 2 M ammonia in methanol.

References: [1]Patent: WO2003/104236,2003,A1 .Location in patent: Page 156-157.

2
3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester [ No CAS ]
[ 230301-11-8 ]

Yield	Reaction Conditions	Operation in experiment
88%	With hydrazine; In methanol; for 1h;Reflux;	(E)-tert-Butyl 3-((dimethylamino)methylidene)-4-piperidone-1-carboxylate (3 g, 11.8 mmol) was dissolved in methanol (50 mL)Hydrazine hydrate (0.3 mL, 1.25 eq) was added slowly.The reaction mixture was heated to reflux for 1 hour,Cool to room temperature,Concentrated and the residue was dissolved in ethyl acetate.Washed with water, washed with salt water,Dry over anhydrous sodium sulfate,filter,Spin dry to give compound 43A as a white solid(2.30g, 88%).
63%	With hydrazine; In methanol; at 20℃;Heating / reflux;	To a solution of [3-DIMETHYLAMINOMETHYLENE-4-OXO-PIPERIDINE-1-CARBOXYLIC] acid [TERT-BUTYL] ester (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). The solution was heated to reflux, immediately allowed to cool to room temperature, and concentrated to give 1.4 g (63%) which was used without purification. Mass spec.: 224.11 (MH) [+.]
1.4 g (63%)	With hydrazine hydrate; In methanol;	1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester To a solution of 3-dimethylaminomethylene-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.55 g, 10 mmol) in methanol (50 mL) was added hydrazine hydrate (0.61 mL, 1.25 equiv). The solution was heated to reflux, immediately allowed to cool to room temperature, and concentrated to give 1.4 g (63%) which was used without purification. Mass spec.: 224.11 (MH)+.

With hydrazine hydrate; In methanol; for 4h;Reflux;

To a solution of tert-butyl (3E)-3-(dimethylaminomethylene)-4-oxo- piperidine-1-carboxylate (1.00 g, 3.93 mmol) in MeOH (50 mL), N2H4.H20 (0.24 g, 4.90 mmol) was added and the reaction mixture was heated to reflux for 4h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was concentrated and dried in vacuo. The crude residue obtained was washed with pentane (80 mL) to afford tert-butyl 1 ,4,6,7- tetrahydropyrazolo[4,3-c]pyridine-5-carboxylate (1.1 g crude) as a brown liquid. MS (ESI) m/e [M+H]+/Rt/%: 224.00/2.35/74.7% 1H NMR (400 MHz, CDCl3) delta 1.49 (s, 9H) 2.76-2.84 (m, 2H) 3.68-3.78 (m, 2H) 4.50 (s, 2H) 6.50 (brs, 1 H) 7.37 (s, 1 H).

References: [1]Patent: CN108250128,2018,A .Location in patent: Paragraph 0717; 0719; 0720; 0721.
[2]Patent: WO2003/104236,2003,A1 .Location in patent: Page 156.
[3]Patent: US2004/204397,2004,A1 .
[4]Patent: WO2018/138088,2018,A1 .Location in patent: Page/Page column 52.

3
[ 230301-11-8 ]
[ 933742-87-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With trifluoroacetic acid; In dichloromethane; at 20℃; for 3h;	Compound 43A (0.44 g, 2 mmol)Soluble in dichloromethane (10 mL),Trifluoroacetic acid (1 mL) was added.After reacting for 3 hours at room temperature,concentrate,Compound 43B was obtained as a white solid(0.7g, 100%).
	With hydrogenchloride; In ethanol; trifluoroacetic acid;	4,5,6,7-Tetrahydro-1H-pyrazolo[4,3-c]pyridine 1,4,6,7-Tetrahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (0.70 g, 3.1 mmol) was dissolved in trifluoroacetic acid (10 mL) at 0 C., stirred for 1 h, and was concentrated. The residue was dissolved in ethanol and treated with concentrated hydrochloric acid (1 mL). The bis-hydrochloride salt precipitated out as a white solid which was filtered to give 510 mg (83%). The free base was prepared as needed by dissolving the salt in water, loading it onto an SCX column, flushing with methanol, and then eluding with 2 M ammonia in methanol.
	With hydrogenchloride; In 1,4-dioxane; water; at 20℃; for 1h;	General procedure: A suspension of intermediate 16.3 (280mg) in 4M HCI in dioxane (5 ml) was stirred at RT for 1 h. The solvent was removed in reduced pressure to afford 260mg of beige solid. LC- MS (B): tR = 0.42 min; [M+H]+: 300.02.

References: [1]Patent: CN108250128,2018,A .Location in patent: Paragraph 0717; 0719; 0722; 0723.
[2]Patent: US2004/204397,2004,A1 .
[3]Patent: WO2013/114332,2013,A1 .Location in patent: Page/Page column 78; 134.

4
[ 50-00-0 ]
[ 230301-11-8 ]
[ 5437-45-6 ]
[ 1449369-14-5 ]
[ 1449369-15-6 ]

Yield	Reaction Conditions	Operation in experiment
111 mg; 45 mg		Step 209.2: To a solution of 1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert- butyl ester (279mg) in MeCN (10ml) was added Cs2CO3 (407mg) followed by benzyl bromoacetate (0.2ml). The resulting white suspension was stirred at RT for 48h, diluted with EA and washed with water and brine. The aq. phases were extracted with EA. The combined org. layers were dried (MgS04), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 25g cartridge, DCM/MeOH 97/3 for 10CV) to afford 371 mg of oil. The oil was purified by preparative chiral HPLC (I) to afford the two regioisomers, both as mixture of benzyl and ethyl ester that formed during the evaporation of the fractions after HPLC purification: Step 209.3: The Boc protecting group of 1-benzyloxycarbonylmethyl-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester was cleaved using a method analogous to that of Example 16 step 16.4 to give (4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester. Step 209.4: To a solution of (4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (176mg) in MeOH was added formaldehyde (36.5% in water, 0.052ml_) followed by NaBH3CN (29mg) and AcOH (0.5ml_). The reaction mixture was stirred at RT overnight. DCM was added and the mixture was washed with sat. NaHCO3. The aq. layer was extracted with DCM, the combined org. layers were dried (MgS04), filtered off and evaporated to dryness. The residue was purified by CC (Biotage, SNAP 10g cartridge, solvent A: DCM; solvent B: DCM/MeOH 8/2; gradient in %B: 25 for 3CV, 25 to 50 over 2CV, 50 for 5CV, 50 to 100 over 3CV, 100 for 2CV) to afford (5-methyl-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridin-1-yl)-acetic acid benzyl ester (39mg, yellow oil). (5-Methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-2-yl)-acetic acid benzyl ester (1 1 1 mg, colourless oil). LC-MS (B): tR = 0.54min; [M+H]+: 286.16. 1H-NMR (CDCl3): 7.40-7.33 (m, 5H); 7.18 (s, 1 H); 5.21 (s, 2H); 4.89 (s, 2H); 3.50 (s, 2H); 2.86 (t, 2H, 6.0Hz); 2.76 (t, 2H, 5.5Hz); 2.49 (s, 3H). Roesy signal seen between CH2 at 4.89ppm and CH at 7.18ppm. (5-Methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-1 -yl)-acetic acid benzyl ester (45mg, pale yellow solid). LC-MS (B): tR = 0.54min; [M+H]+: 286.16. 1H-NMR (CDCl3): 7.40-7.33 (m, 6H); 5.21 (s, 2H); 4.85 (s, 2H); 3.47 (s, 2H); 2.75 (t, 2H, 6.0Hz); 2.67 (t, 2H, 5.5Hz); 2.49 (s, 3H). Roesy signal seen between CH2 at 4.85ppm and CH2 at 2.67ppm. Step 215.2: The final compound was prepared using a method analogous to that of Example 14 step 14.2, (5-methyl-4,5,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-2-yl)-acetic acid benzyl ester replacing intermediate 14.1 and using MeOH instead of MeOH/AcOH. LC-MS (B): tR = 0.17min; [M+H]+: 196.29.

References: [1]Patent: WO2013/114332,2013,A1 .Location in patent: Page/Page column 133.

5
[ 230301-11-8 ]
[ 1449369-18-9 ]

References: [1]Patent: WO2013/114332,2013,A1 .

6
[ 230301-11-8 ]
[ 411235-57-9 ]
tert-butyl 2-cyclopropyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
36%	With [2,2]bipyridinyl; copper diacetate; In 1,2-dichloro-ethane; at 60℃; for 18h;	tert-Butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate (4.0 g, 18 mmol) and cyclopropylboronic acid (3.08 g, 35.8 mmol) were combined in dichloroethane (200 mL). After sequential addition of sodium carbonate (3.80 g, 35.8 mmol), copper(II) acetate (3.58 g, 17.9 mmol) and 2,2?-bipyridine (2.80 g, 17.9 mmol), the reaction mixture was stirred at 60 C. for 18 hours while open to the atmosphere. The reaction mixture was then diluted with ethyl acetate (500 mL) and filtered through diatomaceous earth; the filtrate was washed with saturated ammonium chloride solution and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) was followed by supercritical fluid chromatography (Column: Chiral Technologies, Chiralpak AD-H, 5 mum; Eluent: 85:15 carbon dioxide/methanol) to obtain the major regioisomer, which was the first-eluting peak. The indicated regiochemistry was assigned on the basis of NOE studies carried out on C46. Yield: 1.7 g, 6.5 mmol, 36%. LCMS m/z 264.5 [M+H]+. 1H NMR (400 MHz, CD3OD) delta 7.43 (br s, 1H), 4.42 (br s, 2H), 3.65-3.70 (m, 2H), 3.52-3.58 (m, 1H), 2.64-2.69 (m, 2H), 1.47 (s, 9H), 0.98-1.03 (m, 4H).

References: [1]Patent: US2014/329820,2014,A1 .Location in patent: Paragraph 0219.

7
[ 230301-11-8 ]
4-(2-cyclopropyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)-7-methyl-5-[(3S)-tetrahydrofuran-3-yl]imidazo[5,1-f][1,2,4]triazine [ No CAS ]

References: [1]Patent: US2014/329820,2014,A1 .

8
[ 230301-11-8 ]
2-cyclopropyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine trifluoroacetate [ No CAS ]

References: [1]Patent: US2014/329820,2014,A1 .

9
[ 230301-11-8 ]
[ 139585-70-9 ]
6-(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)nicotinonitrile [ No CAS ]

References: [1]Patent: WO2015/95097,2015,A2 .

10
[ 230301-11-8 ]
[ 139585-70-9 ]
tert-butyl 1-(5-cyanopyridin-2-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With copper(l) iodide; potassium carbonate; L-proline; In dimethyl sulfoxide; at 110℃; for 16h;Sealed tube;	tert-butyl 6,7-dihydro-lH-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (931mg, 4.17 mmol), 6-bromonicotinonitrile (2.29g, 12.51 mmol), copper iodide (794 mg, 4.17 mmol), L- proline (576 mg, 5.0 mmol), and potassium carbonate (1.73g, 12.51 mmol) were combined in DLC/MSO (25 ml) in a sealed tube and heated 16 h at 110C. The solution was diluted with distilled H20 and extracted with EtOAc. The organic layer was separated, dried, filtered and concentrated to give the crude product as an oil which was purified by silica gel column chromatography (Biotage 100 g SNAP) using (12-100)% EtOAc/Hexanes as mobile phase to give the title product as a mixture of regioisomers (2: 1 ratio). LC/MS:[M+H]+ = 326.1

References: [1]Patent: WO2015/95097,2015,A2 .Location in patent: Page/Page column 58-59.

11
[ 79099-07-3 ]
[ 230301-11-8 ]

References: [1]Patent: WO2015/200677,2015,A2 .
[2]Patent: CN108250128,2018,A .

12
[ 230301-11-8 ]
1‐(3‐aminoazetidin‐1‐yl)ethan‐1‐one [ No CAS ]
[ 74-88-4 ]
C₂₀H₂₈N₈O₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of (S)-6-chloro-N- (2-hydroxy-3 -(1 -methyl-6,7-dihydro- 1 Hpyrazolo [4,3-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4-carboxamide and (S) -6-chloro-N-(2- hydroxy-3-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo [4,3-c]pyridin-5-yl)propyl)pyrimidine- 4-carboxamide (350 mg, immol) and i-(3-aminoazetidin- i-yl)ethanone(17 1 mg, 1 .Smmol) in i-PrOH (20 mL) was added Et3N (1 mL) at 25 C. The mixture was stuffed at 80 C for 12 h. LCMS showed the completion of the reactions, the reaction mixture was concentrated to give a crude mixture of products. The title compound (S)-6-((i-acetylazetidin-3-yl)amino)-N-(2-hydroxy-3-(1-methyl-6,7-dihydro-1H-pyrazolo [4,3-c]pyridin-5 (4H)-yl)propyl)pyrimidine-4- carboxamide was isolated after purification by prep-HPLC first and then further purification by SFC as white solid (78 mg, 18.2%). 1H NMR (CD3OD, 400 MHz) (ppm): 8.41 (s, 1 H) 7.25 - 7.32 (m, 1 H) 7.16 (br. s., 1 H) 4.77 (br. s., 1 H) 4.59 (t, J=8.41 Hz, 1 H) 4.36 (t, J=9.03 Hz, 1 H) 4.02 - 4.12 (m, 2 H) 3.90 (dd, J=i0.16, 5.14 Hz, 1 H) 3.82 (s, 3 H) 3.63 (s, 2H) 3.46 - 3.57 (m, 2 H) 2.93 (tq, J=11.29, 5.94 Hz, 2 H) 2.76 -2.83 (m, 2 H) 2.70 (d, J=6.02 Hz, 2 H) 1.91 (s, 3 H). LCMS (m/z): 429.2 [M+H]+.

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00818; 00819.

13
[ 230301-11-8 ]
[ 74-88-4 ]
[ 100501-57-3 ]
tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a stuffed solution of tert-butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)- carboxylate (4 g, 17.9 mmol) in THF (100 mL) was added NaH (859 mg, 35.8 mmol) at 0 C. The mixture was stuffed at 0 C for 2h, then Mel (5g , 35.8mmol) was added dropwise at 0 C. The mixture was stuffed at 0 C for 3h, and then the 50 mL of H20 was added dropwise to the mixture. The resulting mixture was extracted with DCM (1 OOmLx3) and the combined organic layer was concentrated under reduce pressure to give the crude mixture of products as yellow solid (4 g, crude), which was used in next step without further purification. LCMS (mlz): 238.3 [M+H] .

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00808; 00809.

14
[ 230301-11-8 ]
[ 74-88-4 ]
2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine [ No CAS ]
1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of tert-butyl 1-methyl-i ,4,6,7-tetrahydro-5H-pyrazolo [4,3- c]pyridine-5 -carboxylate and tert-butyl 2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo [4,3- c]pyridine-5-carboxylate (4 g, crude) in DCM (40 mL) was added HC1/MeOH (10 mL) dropwise at 0 C. After addition, the mixture was warmed up to 20 C slowly, and the stuffing was continued for 3 h. The solid was precipitate and collected by filtration to give the crude product mixture as a yellow solid (2.8 g, crude). LCMS (mlz): 138.2 [M+H] .

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00810; 00811.

15
[ 230301-11-8 ]
[ 74-88-4 ]
(S)-1-amino-3-(1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-2-ol [ No CAS ]
(S)-1-amino-3-(2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)propan-2-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of (R)- 1 -methyl-5-(oxiran-2-ylmethyl)-4,5 ,6,7-tetrahydro- 1 Hpyrazolo [4,3-c]pyridine and (R)-2-methyl-5- (oxiran-2-ylmethyl)-4,5 ,6,7-tetrahydro-2H- pyrazolo[4,3-c]pyridine (4.9 g, crude) in EtOH (50 mL) was added NH3/H20 (100 mL) at 20C. The mixture was stuffed at 40 C for 12 h, at which time LCMS showed the completion of the reactions. The mixture was concentrated to give the crude mixed product (1.16 g, crude), which was used in next step without further purification. LCMS (mlz): 211.2 [M+H]+.

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00814; 00815.

16
[ 230301-11-8 ]
[ 115314-14-2 ]
[ 74-88-4 ]
(R)-1-methyl-5-(oxiran-2-ylmethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [ No CAS ]
(R)-2-methyl-5-(oxiran-2-ylmethyl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of 1 -methyl-4,5 ,6,7-tetrahydro- 1 H-pyrazolo [4,3-c]pyridine and 2- methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine (2.8 g, crude) and KF (3.1 g, 53.7 mmol) in THF(200 mL) was added (S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (9.2 g, 35.8 mmol) at 20 C. The mixture was stirred at 40 C for 16 h, at which time LCMS showed the completion of the reactions. The mixture was filtered and concentrated to give the crude mixed product (4.9 g, crude), which was used in next step without further purification. LCMS (mlz): 194.2 [M+H]+.

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00812; 00813.

17
[ 263270-52-6 ]
[ 230301-11-8 ]
[ 74-88-4 ]
(S)-6-chloro-N-(2-hydroxy-3-(1-methyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)propyl)pyrimidine-4-carboxamide [ No CAS ]
C₂₁H₃₀N₈O₃S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a mixture of (S)- 1 -amino-3-( 1-methyl-i ,4,6,7-tetrahydro-5H-pyrazolo [4,3- c]pyridin-5-yl)propan-2-ol and (S)- 1 -amino-3- (2-methyl-2,4,6,7-tetrahydro-5H-pyrazolo [4,3- c]pyridin-5-yl)propan-2-ol (1.16 g, crude) in DCM (40 mL) was added Et3N (2 mL) at 17 C. The mixture was stuffed at 17 C for 0.5 h, and then 6-chloropyrimidine-4-carbonyl chloride (800 mg, 4.5mmol) was added at 17 C. LCMS showed the reaction completed, the reaction mixture was diluted with water (50 mL), extracted with DCM(100 mLx3). The combined organic layer was concentrated to give the crude product which were then purified by column chromatography on silica gel to give the mixture of title compounds as a yellow oil (1.2 g, 75.9%). LCMS (mlz): 351.2 [M+H]+.

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00816; 00817.

18
[ 1310796-19-0 ]
[ 230301-11-8 ]

Yield	Reaction Conditions	Operation in experiment
95%	With hydrazine hydrate; In ethanol; at 20℃; for 12h;	To a solution of (Z)-tert-butyl 3-((dimethylamino)methylene)-4-oxopiperidine-i- carboxylate (8.8 g, 34.6 mmol) in EtOH (50 mL) was added N2H4/H20 (200 mL) at 20 C. The mixture was stuffed at 20 C for 12 h. After that, the reaction mixture was concentrated in vacuum. The residue mixture was purified with column separation to afford desired product (7 g, Yield 95 %). LCMS (mlz): 224.2 [M+H] .

References: [1]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00806; 00807.

19
[ 230301-11-8 ]
[ 172976-00-0 ]
2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine trifluoroacetate [ No CAS ]

References: [1]Patent: US2017/320875,2017,A1 .

20
[ 230301-11-8 ]
[ 172976-00-0 ]
tert-butyl 2-(2-methylbiphenyl-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With chloro(2-dicyclohexylphosphino-2?,6?-diisopropoxy-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) 2nd generation; sodium t-butanolate; In 1,4-dioxane; at 110℃; for 15h;Inert atmosphere;	To a mixture of 3-bromo-2-methylbiphenyl (100 mg, 0.405 mmol), <strong>[230301-11-8]tert-butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate</strong> (Ark Pharm, CatAK-24984: 180 mg, 0.81 mmol), (2?-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2?,6?-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium (30.9 mg, 39.7 mumol) (RuPhos G2, Aldrich, cat753246) in 1,4-dioxane (1.1 mL) was added sodium tert-butoxide (76.4 mg, 0.795 mmol). The resulting mixture was heated at 110 C. under the atmosphere of N2 for 15 h, then diluted with methylene chloride, washed with saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was used in the next step without further purification. LC-MS calculated for C24H28N3O2 (M+H)+: m/z=390.2; found 390.2.

References: [1]Patent: US2017/320875,2017,A1 .Location in patent: Paragraph 0272-0273.

21
[ 230301-11-8 ]
6-chloro-N-[4-ethyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl]pyrimidin-4-amine [ No CAS ]
tert-butyl 2-(6-[4-ethyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}pyrimidin-4-yl)-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate [ No CAS ]
tert-butyl 1-(6-[4-ethyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl]amino}pyrimidin-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
6%	With caesium carbonate; In N,N-dimethyl-formamide; at 120 - 140℃;	A solution of 6-chloro-N-[4-ethyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl]pyrimidin-4-amine (150 mg, 472 muetaiotaomicron) and <strong>[230301-11-8]tert-butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate</strong> (158 mg, 708 muiotaetaomicron, CAS 230301-11-8) in DMF (2.5 mL) was treated with caesium carbonate (461 mg, 1.42 mmol). The reaction mixture was stirred at 120C overnight and an additional night at 140C. The mixture was diluted with water, three times extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was purified by preparative reverse phase HPLC (method: column: Reprosil CI 8; 10 muiotaeta; 125x30 mm / flow: 50 ml/min / eluent: A = water (0,01% formic acid), B = acetonitrile / gradient: 0.00-5.00 min = 10% B, 6.50 min = 20% B, 17.0-19.75 min = 100% B, 19.75-23.00 min = 90% B). Subsequently the obtained regioisomeric mixture was separated using (HPLC) method to yield 13.2 mg (6% yield) of the desired product. LC-MS (method 9): Rt = 1.18 min; MS (ESIpos): m/z = 505 [M+H]+1H-NMR (400 MHz, DMSO-d6) delta [ppm] : -0.008 (3.40), 0.008 (2.05), 0.988 (1.10), 1.007 (2.36), 1.025 (1.06), 1.073 (0.74), 1.091 (1.48), 1.108 (0.71), 1.424 (16.00), 2.328 (0.41), 2.519 (2.00), 2.524 (1.93), 3.214 (0.83), 3.375 (0.71), 3.392 (0.70), 3.593 (0.62), 3.607 (1.06), 3.621 (0.50), 4.382 (1.39), 7.339 (0.53), 7.361 (1.03), 7.383 (0.62), 7.586 (0.61), 7.600 (0.70), 7.622 (0.53), 7.661 (1.24), 8.459 (0.81), 9.416 (0.72), 12.813 (0.67).

References: [1]Patent: WO2018/69222,2018,A1 .Location in patent: Page/Page column 366-367.

22
[ 230301-11-8 ]
1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine [ No CAS ]

References: [1]Patent: CN108250128,2018,A .

23
[ 230301-11-8 ]
[ 74-88-4 ]
tert-butyl 1-methyl-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 20℃; for 3h;	To a solution of 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-tert-butylcarboxylate (550 mg, 2.5 mmol) in tetrahydrofuranSodium hydride (150 mg, 1.5 eq) and methyl iodide (150 muL, 1.2 eq) were added slowly (20 mL).Stir at room temperature for 3 hours.Add water to quench the reaction,Extracted with ethyl acetate,The organic phase was washed with brine and dried over anhydrous sodium sulfate.Filtration and concentration of the filtrate gave a mixture of methylated isomer compound 44A and compound 45A (500 mg).The crude product was used directly in the next reaction.
	With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 3h;	To a solution of tert-butyl 1 ,4,6,7-tetrahydropyrazolo[4,3-c]pyridine-5- carboxylate (1.00 g crude, from previous step, assume 3.93 mmol) in DMF (50 mL), NaH (0.21 g, 5.00 mmol) was added at 0C followed by addition of CH3I (0.76 g, 5.00 mmol). The reaction mixture was stirred at room temperature for 3h. Progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mixture was diluted with H2O (40 mL) and extracted with EtOAc (2 chi 60 mL). The organic layer was separated, washed with brine (100 mL), dried over anhydrous Na2SC>4 and concentrated in vacuo to afford tert-butyl 1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (1.00 g crude) as a brown liquid. This compound was used as such for the next reaction without further purification. MS (ESI) m/e [M+H]+/Rt/%: 238.00/2.52/81.7%

References: [1]Patent: CN108250128,2018,A .Location in patent: Paragraph 0727; 0729; 0730; 0731.
[2]Patent: WO2018/138088,2018,A1 .Location in patent: Page/Page column 52; 53.

24
[ 230301-11-8 ]
1-methyl-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine bis(trifluoroacetic acid) [ No CAS ]

References: [1]Patent: WO2018/138088,2018,A1 .

25
[ 230301-11-8 ]
N-[1-(1H-indol-3-ylmethyl)pentyl]-2-(1-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridin-5-yl)thiazole-5-carboxamide [ No CAS ]

References: [1]Patent: WO2018/138088,2018,A1 .

26
[ 230301-11-8 ]
tert-butyl 3-iodo-6,7-dihydro-1H-pyrazolo [4,3-c]pyridine-5(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
24.94%	With N-iodo-succinimide; In acetonitrile; at 60℃; for 4h;	To a stirred solution of <strong>[230301-11-8]tert-butyl 1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate</strong>(1 g, 4.479 mmol, 1 equiv.) in MeCN(120 mL) was added NIS(1.11 g, 4.927 mmol, 1.1 equiv.) at room temperature. The resulting mixture was stirred for 4 h at 60 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash with the following conditions (Column: C18, 330 g; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN; Flow rate: 80 mL/min; Gradient: 35%B to 55%B in 25 min; Detector, 220nm; Monitor,254 nm) to afford tert-butyl 3-iodo- 1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate(390 mg, 24.94%) as a dark yellow solid

References: [1]Patent: WO2019/55966,2019,A2 .Location in patent: Page/Page column 487.

27
[ 230301-11-8 ]
tert-butyl 3-(ethanesulfonyl)-1H,4H,5H,6H,7H-pyrazolo[4,3-c]pyridine-5-carboxylate [ No CAS ]