188869-05-8|tert-Butyl 3-bromo-4-oxopiperidine-1-carboxylate| Ambeed

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Quality Control of [ 188869-05-8 ] Purity: 95% SDS Specification

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Product Details of [ 188869-05-8 ]

CAS No. :	188869-05-8
Formula :	C₁₀H₁₆BrNO₃
M.W :	278.14
SMILES Code :	BrC1C(CCN(C1)C(=O)OC(C)(C)C)=O
MDL No. :	MFCD06738530
InChI Key :	RGWGRRBHQUREDE-UHFFFAOYSA-N
Pubchem ID :	10683970

Safety of [ 188869-05-8 ]

GHS Pictogram:
Signal Word:	Danger
Hazard Statements:	H302-H314
Precautionary Statements:	P264-P270-P271-P280-P303+P361+P353-P304+P340-P305+P351+P338-P310-P330-P331-P363-P403+P233-P501
Class:	8
UN#:	3261
Packing Group:	Ⅱ

Computational Chemistry of [ 188869-05-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	0
Fraction Csp3	0.8
Num. rotatable bonds	3
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	64.66
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	46.61 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.41
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	1.46
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.58
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.	1.19
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	1.43
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.61

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.29
Solubility	1.44 mg/ml ; 0.00517 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.	-2.05
Solubility	2.51 mg/ml ; 0.00901 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	-2.01
Solubility	2.7 mg/ml ; 0.00971 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	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.	-6.96 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<0.0
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)	3.11

Application In Synthesis of [ 188869-05-8 ]

* 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 [ 188869-05-8 ]
Downstream synthetic route of [ 188869-05-8 ]

[ 188869-05-8 ] Synthesis Path-Upstream 1~1

1
[ 16982-21-1 ]
[ 188869-05-8 ]
[ 1053656-51-1 ]

Yield	Reaction Conditions	Operation in experiment
60%	With sodium hydrogencarbonate In isopropyl alcohol for 12 h; Reflux	Compound 18 9 (4.0g, 14.4mmol) was dissolved in IPA (25mL). 20 Ethyl thioxamate (1.60g, 12.0mmol) and 146 NaHCO₃ (2.01g, 24.0mmol) were added. The mixture was refluxed for 12h, followed by concentration. The residue was taken in 63 water and extracted with dichloromethane. The organic layer was washed with water, brine and dried over anhydrous Na₂SO₄ and concentrated to the desired compound (2.2g, 60percent), which is pure enough for the next step. mp: 138–140°C; ¹H NMR (300MHz, CDCl₃): δ 4.71(s, 2H), 4.48(q, J=12Hz, 2H,), 3.72(m, 2H), 2.96(t, J=5.4Hz, 2H), 2.41(t, J=6.3Hz, 2H), 1,51(s, 9H), 1,44(t, J=1.2Hz, 3H,); MS (ESI) m/z: 335.1 [M+Na]⁺.

References: [1] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 23-24, p. 5987 - 5999.
[2] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 2, p. 443 - 454.

[ 188869-05-8 ] Synthesis Path-Downstream 1~35

1
[ 358-23-6 ]
[ 188869-05-8 ]
[ 919491-05-7 ]

References: [1]Chemistry - A European Journal,2006,vol. 12,p. 8336 - 8344.

2
[ 211108-48-4 ]
[ 188869-05-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-Bromosuccinimide; In tetrachloromethane; at 10 - 15℃; for 2h;	To a stirred solution of tert-butyl-4-((trimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate, obtained in step 1, (7.48 g, 27.60 mmol) in dry CCl4 (80 mL, 10 V), N-bromosuccinimide (5.42 g, 30.36 mmol) was added at 10 °C. The reaction mixture was stirred at 10-15 °C for 2 h. It was evaporated under reduced pressure. Water (30 mL) was added and the desired product was extracted with EtOAc (2x60 mL). Organic layer was dried over Na2SO4 and the solvents were evaporated. The resulting crude product was purified by flash chromatography affording the title product (white solid). 1H NMR (400 MHz, DMSO-d6): delta 4.74 (s, 1H), 4.02-4.00 (m, 2H), 3.60-3.58 (m, 2H), 2.69-2.68 (m, 2H), 1.39 (s, 9H).
	With N-Bromosuccinimide; In tetrahydrofuran; at 0 - 20℃;	Chlorotrimethylsilane (5.6 ml, 44 mmol) was added slowly to a solution of foert-butyl 4-oxopiperidine-l-carboxylate (8 g, 40 mmol), triethylamine (12.3 ml, 88 mmol) and DMF (40 ml) at room temperature. The resultant solution was heated to 75 °C and stirred overnight under nitrogen. The reaction mixture was cooled to room temperature and then in an ice bath. Cold hexane (250 ml) was added slowly to the reaction mixture followed by cold (saturated) aqueous sodium bicarbonate (50 ml). The organic phase was separated and washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude silyl enolether was dissolved in THF (15 ml) and cooled to 0 °C. JV-Bromosuccinimide (7.1 g, 40 mmol) was dissolved in THF (120 ml) and was added slowly (45 min.) to the reaction mixture. The resultant mixture was allowed to slowly warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by flash chromatography (hexanes/EtOAc, 5:1) to provide the title compound as a white solid (11 g). MS (ESP): 222.1 (M - t-Bu) for C10H16BrNO3; NMR: 1.25 (s, 9 H), 2.30 (m, 1 H), 2.55 (m, 1 H), 3.42-3.80 (m, 3 H), 3.93 (m, 1 H), 4.60 (m, 1 H).

References: [1]Chemistry - A European Journal,2006,vol. 12,p. 8336 - 8344.
[2]Patent: WO2016/30443,2016,A1 .Location in patent: Page/Page column 189.
[3]Patent: WO2008/20222,2008,A1 .Location in patent: Page/Page column 110.

3
[ 2227-79-4 ]
[ 188869-05-8 ]
[ 1004527-72-3 ]

Yield	Reaction Conditions	Operation in experiment
78%	at 140℃; for 0.333333h;Neat (no solvent);	tert-Butyl 3-bromor4-oxopiperidine-l-carboxylate (1.0 g, 3.6 mmol) and benzothioamide (490 mg, 3.6 mmol) were heated neat at 1400C for 10 minutes. After cooling down, the resulting brown solid was sonicated in AcOEt for 10 minutes. Filtration and drying yielded 2-phenyl-4, 5, 6, 7- tetrahydrothiazolo [5, 4-c] pyridine hydrobromide as a brown solid (829 mg, 78percent): 1H NMR (400 MHz, DMSO-d6) delta 3.06-3.12 (m, 2H), 3.49-3.57 (m, 2H), 4.46-4.53 (m, 2H), 7.50-7.56 (m, 3H), 7.90-7.94 (m, 2H), 9.35 (br, 2H); m/z (APCI pos) 217.1 (10percent) [M+H] .

References: [1]Patent: WO2008/11130,2008,A2 .Location in patent: Page/Page column 150.

4
[ 911134-67-3 ]
[ 188869-05-8 ]
[ 1004764-02-6 ]

Yield	Reaction Conditions	Operation in experiment
43%		suspension of 4-(3-chloropropoxy)benzenecarbothioamide x2 (11.0 g, 47.88 mmol, 1 eq) and te/f-butyl 3-bromo-4-oxopiperidine-1-carboxylate x3 (14.64 g, 52.67 mmol, 1.1 eq) in isopropanol (100 ml) is heated at 80 0C during 20 hours. After cooling and concentration, the mixture is taken up with dioxane (100 ml), a 1 M aqueous aqueous solution of hydrochloric acid (20 ml) is added and the mixture is stirred during 3 hours at room temperature. The dioxane is removed under vacuum and the resulting material is brought to pH 8 by a 1 M solution of sodium hydroxide. The product is extracted with a mixture of ethyl acetate and ethanol (90/10, 2 x 400 ml), the organic solution is dried over magnesium sulfate and concentrated in vacuum. The resulting solid is taken up with <n="60"/>acetone (100 ml) and filtered to afford 6.4 g of 2-{4-[(3-chloropropyl)oxy]phenyl}-4, 5,6,7- tetrahydro[1 ,3]thiazolo[5,4-c]pyridine x4 as a white solid. Yield: 43 percent.LC-MS (MH+): 309/311

References: [1]ChemMedChem,2011,vol. 6,p. 1559 - 1565.
[2]Patent: WO2008/12010,2008,A1 .Location in patent: Page/Page column 58-59.

5
[ 911134-67-3 ]
[ 188869-05-8 ]
[ 1186205-63-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In isopropyl alcohol; at 55℃; for 3h;	4-(3-chloropropoxy)benzenecarbothioamide x2 (20 g, 87 mmol, 1 eq), bromoketone (30.O g, 108 mmol, 1.4 eq) and potassium carbonate (16.2 g, 114 mmol, 1.5 eq) are stirred in iso-propyl alcohol (600 ml) at 55 0C during three hours. The mixture is evaporated to dryness. Ethyl acetate (400 ml) and water are added to the crude. The organic layer is dried over magnesium sulfate and concentrated under reduce pressure to provide 38 g of crude tert-butyl 2-[4-(3-chloropropoxy)phenyl]-7a-hydroxy-3a,6,7,7a- tetrahydro[1 ,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate x73a. This compound is dissolved in dichloromethane (300 ml). Triethylamine (39 ml, 270 mmol, 3 eq) is added followed by the addition of a solution of methanesulfonyl chloride (15 ml, 190 mmol, 2.2 eq) in dichloromethane (15 ml).The mixture is stirred one hour at room temperature. After concentration under reduced pressure, ethylacetate (400 ml) and water (200 ml) is added. The organic layer is dried over magnesium sulfate and concentrated to dryness. After purification by chromatography (dichloromethane/methanol/ammonia 98:1.8:0.2), the solid <n="106"/>is triturated with benzine to afford 18 g of tert-butyl 2-[4-(3-chloropropoxy)phenyl]-6,7- dihydro[1 ,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate x73.Yield: 57 percent.LC-MS (MH+): 409/411

References: [1]Patent: WO2008/12010,2008,A1 .Location in patent: Page/Page column 104-105.

6
[ 288-32-4 ]
[ 188869-05-8 ]
[ 1007596-39-5 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 50℃; for 4h;	A solution of tert-butyl 3-bromo-4-oxopiperidine-l-carboxylate (Intermediate 55, 0.50 g, 1.8 mmol), imidazole (0.14 g, 2 mmol), potassium carbonate (0.25 g, 1.8 mmol) and DMF (3 ml) was warmed to 50 °C and stirred for 4h. The reaction mixture was cooled to room temperature and diluted with EtOAc (50 ml). The resultant mixture was filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography <n="112"/>- Ill -(methanol/DCM gradient, 0-10percent) to provide the title compound as a white solid (0.27 g). MS (ESP) (M-H)': 264.2 for C3HI9N3O3; NMR (CDCl3): 1.41 (s, 9 H), 2.50 (m, 2 H), 2.55 (m, 1 H), 3.14-3.33 (m, 2 H), 4.50 (m, 1 H), 4.79 (dd, 1 H), 6.80 (s, 1 H), 6.98 (s, 1 H), 7.39 (s, 1 H).

References: [1]Patent: WO2008/20222,2008,A1 .Location in patent: Page/Page column 110-111.

7
[ 188869-05-8 ]
[ 919491-08-0 ]

References: [1]Chemistry - A European Journal,2006,vol. 12,p. 8336 - 8344.

8
[ 188869-05-8 ]
[ 919491-11-5 ]

References: [1]Chemistry - A European Journal,2006,vol. 12,p. 8336 - 8344.

9
[ 24424-99-5 ]
[ 188869-05-8 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1409 - 1416.

10
[ 41979-39-9 ]
[ 188869-05-8 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 1409 - 1416.

12
[ 79099-07-3 ]
[ 188869-05-8 ]

Yield	Reaction Conditions	Operation in experiment
78%		At room temperature,TEA (7.7 mL, 55 mmol) wasTMSCl (3.5 mL, 27.6 mmol) was added to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in DMF (30 mL).The mixture was stirred at 75 C overnight.The reaction solution was cooled to room temperature.Cold saturated aqueous sodium bicarbonate solution (200 mL) and cold n-hexane (200 mL) were added sequentially.The organic phase was washed with saturated brine, dried over Na2SO4 and concentrated to give a crude product which was used directly in the next step.The residue was dissolved in THF (15 mL) and stirred at 0 C for 15 min.A solution of NBS (4.47 g, 25 mmol) in THF (80 mL) was slowly added dropwise.After the dropwise addition, the reaction was stirred at room temperature overnight.Water (200 mL) and n-hexane (200 mL) were added to the reaction. The organic phase was washed with saturated brine and dried over Na 2 SO 4 . The resulting crude product was concentrated on a silica gel column (60 g of silica gel, PE/EA=20/1 to 8 /1 gradient) purification,A white solid of tert-butyl 3-bromo-4-oxopiperidine-1 -carboxylate (5.56 g, 78%) was obtained.
41%	With bromine; In dichloromethane; at 0 - 20℃; for 0.5h;	To a solution of 141 N-(tert-Butoxycarbonyl)-4-piperidone (8g, 48.2mmol) in 60 CH2Cl2 (80mL) was added dropwise a solution of 142 bromine (7.06g, 44.17mmol) in CH2Cl2 (80mL) over a period of 1h. After addition, the reaction mixture was stirred for 0.5h at room temperature. The reaction mixture was quenched by the addition of 10% 143 aqueous sodium bisulfite. The layers were separated, and the organic layer was washed with water and brine, dried over anhydrous Na2SO4, and filtered, and then the filtrate was concentrated in vacuo. The residue was recrystallized from ethyl acetate/petroleum (16mL, v/v, 1:1) to afford 18 9 as colorless solid (4.5g, 41%). 1H NMR (300MHz, CDCl3): delta 4.35 (br, 1H), 4.03 (br, 2H), 3.50 (br, 2H), 3.03 (br, 1H), 2.43 (m, 1H), 1.52 (s, 9H).
	With bromine;aluminium trichloride; In tetrahydrofuran;	a) N-tert-Butoxycarbonyl-4-piperidone (5.67 g, 28.5 mol) is dissolved in a mixture of dry THF (50 ml) and dry ether (50 ml), and thereto is added anhydrous aluminum chloride (57 mg). To the mixture is gradually added dropwise bromine (1.47 ml, 28.5 mmol) at 0 C., and the mixture is allowed to stand at 5 C. for 24 hours. The resulting reaction solution is diluted with ethyl acetate, and the mixture is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent is evaporated. The resulting residue is crystallized from ether to give N-tert-butoxycarbonyl-3-bromo-4-piperidone (3.40 g, yield; 43%) as pale yellow crystals. 1H-NMR delta (CDCl3, ppm): 1.51 (9H, s), 2.44 (1H, m), 3.00 (1H, m), 3.5-4.4 (5H, m).

	With phenyltrimethylammonium tribromide; In tetrahydrofuran; at 10 - 30℃; for 0.5h;	(66-1) Synthesis of 6-tertiary butoxycarbonyl-2-mercapto-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine; N-tertiary butoxycarbonyl-4-piperidone (996 mg) was dissolved in THF (15 mL), phenyltrimethylammonium tribromide (2.07 g) was added, and the mixture was stirred at room temperature for 30 min. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. By a similar method as in (1-3), the title compound (310 mg) was obtained as a colorless oil from obtained residue (1.33 g) and ammonium dithiocarbamate (551 mg).
		Example 79 Synthesis of 2-[6-(lH-indazol-6-ylcarbamoyl)-lH-benzimidazol-2-ylamino]-6,7-dihydro-4H- thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl esterTo a solution of l-Boc-4-piperidone (5 mmol) in dry THF (20 mL) was added solidBa2CC>3 (10 mmol). The resulting mixture was stirred vigorously. The reaction mixture was treated with pyrrolidone hydrotribromide (5.5 mmol) in portions at room temperature. After 3h, the contents were filtered and the solvent removed. The crude reaction mixture containing the product, 3-bromo-4-oxo-piperidine-l -carboxylic acid terf-butyl ester, was used for further transformation without further purification.To a solution of the bromo compound (5 mmol) , obtained as above, in acetone (20 mL) was added solid thiourea (6 mmol) and solid K2CO3 (10 mmol), and the reaction mixture was stirred at room temperature for 12h. To the reaction mixture was added BOC anhydride (5 mmol), and the reaction was stirred for 4h. The contents were then filtered, and the solvent was removed. The residue obtained was purified by silica gel chromatography using DCM/methanol as eluent. The product, 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5- carboxylic acid tert-butyl ester, was obtained a light yellow solid. <n="66"/>The amine (0.5 mmol) from above was converted to corresponding isothiocyanate using general procedure A, which was then reacted with 334-diamino-N-(lH-indazol-6-yl)- benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-[6-(1H- indazol-6-ylcarbamoyl)-lH-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4- cjpyridine-S-carboxylic acid tert-butyl ester. MS: m/z 531 (M+H)+.
	With aluminum (III) chloride; bromine; In tetrahydrofuran; diethyl ether; at 0 - 5℃; for 24.5h;	Step (i): Preparation of 3-Bromo-4-oxo-piperidine-l-carboxylic acid tert-buryl ester.A solution of 4-Oxo-piperidin- l -carboxylic acid tert-butyl ester ( 10 grams, 50 mmol) and aluminium chloride (0.67 grams, 5 mmol) in tetrahydrofuran (30 mL) and diethyl ether (30 mL) was cooled to 0 C, and then treated with bromine (2.6 mL, 50 mmol) over a period of 30 minutes. Stirred the reaction mass for 24 hours at 0 - 5 C. After completion of reaction, the obtain solids were filtered and the mother liquor was concentrated under vacuum. The obtain crude was triturated with diethyl ether and solids were filtered and dried under vacuum to obtain the title compound ( 10 grams). - NMR (delta ppm): 1.51 (9H, s), 2.42 - 2.48 ( 1H, m), 3.04 ( 1H, m), 3.59 - 3.74 (2H, m), 3.97 (2H, m), 4.33 (lH, m);Mass (m/z): 278 (M+H) 280 (M+3H)+.
5.56 g		[0425] To a solution of tert-butyl4-oxopiperidine-1-carboxylate (5 g, 25 mmol) in 30 mL ofDMF at RT was added TEA (7.7 mL, 55 mmol) followed by TMSCl (3.5 mL, 27.6 mmol), thenthe mixture was stirred at 75 DC overnight. The reaction was cooled toRT, cold sat. aq. NaHC03(200 mL) was added followed by cold hexane (200 mL). The organic layer was washed withbrine, dried over Na2S04, concentrated to get the crude product directly used in the next step.The residue was dissolved in 15 mL of THF and stirred at 0 DC for 15 min. A solution of NBS(4.47 g, 25 mmol) in 80 mL of THF was added slowly. After addition, the reaction was stirred atRT overnight. Water (200 mL) was added to the reaction followed by 200 mL of hexane. Theorganic layer was washed with brine, dried over Na2S04 and concentrated to get crude productwhich was chromatographed on 60 g of silica gel using PE/EA (2011 to 811) as eluant to afford5.56 g (78%) of tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate as a white solid. 1H NMR(400 MHz, DMSO-d6) 8 4.85-4.70 (m, 1H), 4.20-4.00 (m, 1H), 3.90-3.55 (m, 3H), 2.80-2.68 (m,1H), 2.54-2.44 (m, 1H), 1.43 (s, 9H). MS (ESI) m/e [M-t-But 221.9, 224.0.
	With N-Bromosuccinimide; toluene-4-sulfonic acid; In toluene; at 115℃; for 2h;	General procedure for the synthesis of Zl-a and Zl-b To a stirred solution of starting material (8.81 mmol) in toluene (20 mL) were added N- bromosuccinimide (8.81 mmol) and -toluenesulfonic acid monohydrate (0.88 mmol) and then the resulting mixture was stirred at 115 C for 2 hours. The reaction mixture was diluted with methylene chloride (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous MgS04 and concentrated in vacuo. The crude product was purified by flash column chromatography to give Zl-a orZl-b.

References: [1]ChemMedChem,2012,vol. 7,p. 2087 - 2092.
[2]Patent: TWI602818,2017,B .Location in patent: Paragraph 0424; 0425.
[3]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 5987 - 5999.
[4]Patent: US6599895,2003,B1 .
[5]Patent: EP1801108,2007,A1 .Location in patent: Page/Page column 56.
[6]Patent: WO2007/95124,2007,A2 .Location in patent: Page/Page column 63-64.
[7]Patent: WO2012/29070,2012,A1 .Location in patent: Page/Page column 13-14.
[8]Patent: WO2014/173289,2014,A1 .Location in patent: Paragraph 0422; 0424; 0425.
[9]Patent: WO2016/30443,2016,A1 .
[10]Patent: WO2015/193506,2015,A1 .Location in patent: Page/Page column 63-64.
[11]Patent: EP3248968,2017,A1 .
[12]Patent: WO2008/20222,2008,A1 .

13
[ 1076-67-1 ]
[ 188869-05-8 ]
[ 188869-06-9 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In ice-water; acetonitrile;	b) A solution of 2.78 g (10 mmol) of <strong>[188869-05-8]tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate</strong> and 2.09 g (12 mmol) of 2-mercaptomethylnaphthalene in 100 ml of absolute acetonitrile was treated with 13.8 g (100 mmol) of anhydrous potassium carbonate and thereafter the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, the filtrate was poured on to ice-water and adjusted to pH 2-3 with concentrated hydrochloric acid; the aqueous phase was extracted three times with 200 ml of ethyl acetate each time, the organic phase was washed once with 200 ml of water, dried over magnesium sulphate, filtered and concentrated in a water-jet vacuum. The crude product (5.5 g) was chromatographed on silica gel with hexane and ethyl acetate as the eluent. The product was recrystallized from ethyl acetate and hexane. There were obtained 2.27 g (61percent of theory) of tert-butyl (3RS)-3-(naphthalen-2-ylmethylthio)-4-oxo-piperidine-1-carboxylate as a colourless solid; MS: 371 (M)+.

References: [1]Patent: US6051712,2000,A .

14
disodium hydrogen phosphate [ No CAS ]
[ 79099-07-3 ]
[ 188869-05-8 ]

Yield	Reaction Conditions	Operation in experiment
	With bromine; In chloroform;	a) A solution of 32.5 g (163 mmol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 200 ml of chloroform was treated with 24.0 g (168 mmol) of disodium hydrogen phosphate and cooled to 5° C. A solution of 27.9 g (175 mmol) of bromine in 75 ml of chloroform was added dropwise during 1 hour, thereafter the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was worked-up by extraction with ice-water and methylene chloride, the organic phase was dried over magnesium sulphate, filtered and the solvent was distilled off in a water-jet vacuum. The crude product (38 g) was chromatographed on silica gel with methylene chloride and ethyl acetate as the eluent. The thus-obtained product was recrystallized from ethyl acetate and n-hexane. There were obtained 19.1 g (42percent of theory) of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate as a pale yellow solid; MS: 277, 279 (M)+.

References: [1]Patent: US6051712,2000,A .

15
[ 913731-67-6 ]
[ 188869-05-8 ]
tert-butyl 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
73%	With N-ethyl-N,N-diisopropylamine; In ethanol;Heating / reflux;	Step C: Preparation of tert-butyl 2-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of 2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.300 g, 0.717 mmol) in 10 mL of ethanol was added <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (0.239 g, 0.860 mmol) followed by DIEA (0.25 mL, 1.43 mmol). The mixture was allowed to stir overnight at reflux then treated with <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (100 mg) and stirred at reflux for a further 3 hrs. The cooled mixture was partitioned between saturated NaHCO3 solution (30 mL) and EtOAc (30 mL) and the aqueous layer was extracted with EtOAc (2.x.20 mL). The combined organic phases were washed with brine (20 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10percent ethyl acetate/hexanes) to afford the desired product as a bright yellow foam (0.313 g, 73percent).

References: [1]Patent: US2006/247178,2006,A1 .Location in patent: Page/Page column 46-47; 50.

16
[ 913731-91-6 ]
[ 188869-05-8 ]
[ 913731-92-7 ]

Yield	Reaction Conditions	Operation in experiment
64%	With N-ethyl-N,N-diisopropylamine; In ethanol;Heating / reflux;	Step D: Preparation of tert-butyl 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate: To a solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothioamide (0.500 g, 0.809 mmol) in 20 mL of ethanol was added <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (0.338 g, 1.21 mmol) followed by DIEA (0.423 mL, 2.43 mmol). The mixture was allowed to stir overnight at reflux then treated with <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (200 mg) and stirred at reflux for a further 3 hours. The cooled mixture was partitioned between saturated NaHCO3 solution (50 mL) and EtOAc (50 mL) and the aqueous layer was extracted with EtOAc (2.x.50 mL). The combined organic phases were washed with brine (50 mL) dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography (5-10percent ethyl acetate/hexanes) to afford the desired product as a viscous yellow oil, 0.412 g, 64percent.

References: [1]Patent: US2006/247178,2006,A1 .Location in patent: Page/Page column 53.

17
[ 17356-08-0 ]
[ 188869-05-8 ]
[ 365996-05-0 ]

Yield	Reaction Conditions	Operation in experiment
99%	In isopropyl alcohol; at 90℃; for 1h;	To a solution of i-butyl 3-bromo-4-oxopiperidine-1-carboxylate (1.0 g, 3.59 mmol) in isopropanol (10 mL), thiourea (0.33 g, 4.30 mmol) was added and the reaction mixture was refluxed at 90 °C for 1 h. Completion of the reaction was monitored by TLC. The reaction mixture was then concentrated under vacuum and the resulting crude material was washed with diethyl ether to afford the title compound. Yield: 99percent (0.9 g, white solid). 1H NMR (400 MHz, DMSO-d6): delta 9.05 (bs, 2H), 4.32 (m, 2H), 3.61-3.58 (m, 2H), 2.50 (s, 2H), 1.41 (s, 9H). LCMS: (Method A) 256.0 (M+H), Rt. 2.5 min, 64.8percent (Max).
47%	In N,N-dimethyl-formamide; at 120℃; for 3h;	To the stuffing solution of <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (5.0 g,18 mmol) in DMF (50 mL) was added thiourea (1.37 g, 18 mmol), resulting solution wasthen heated at 120 C for 3h. The solvents were evaporated and the residue purified bycolumn separation to afford desired product as pale yellow oil (2.2 g, yield:47%). LCMS:256.1 (M+1).
	In isopropyl alcohol; for 1h;Reflux;	Step (ii): Preparation of 2-Amino-6,7-dihydro-4H-thiazolo[5,4-c\|pyridine-5-carboxylic acid tert - butyl esterA suspension of 3-Bromo-4-oxo-piperidine- l-carboxylic acid tert-butyl ester (10 grams, 35 mmol, obtained in above step) and thiourea (3.28 grams, 42 mmol) in isopropanol ( 100 mL) was refluxed for 1 hour. After completion of reaction, reaction mass was concentrated and resulted crude was triturated with diethyl ether (50 mL), solids were filtered and dried under vacuum to obtain the title compound (10 grams). - NMR (delta ppm): 1 .39 (9H, s), 2.52 (2H, m), 3.56 - 3.59 (2H, t), 4.30 (2H, s), 7.10 (2H, bs); Mass (m/z): 256 (M+H)+.

	In ethanol; for 2h;Reflux;	General procedure for the synthesis of Z2-a and Z2-b To a stirred solution of Zl-a or Zl-b (5.98 mmol) in EtOH (20 mL) was added thiourea (6.28 mmol) and the mixture was stirred at reflux temperature for 2 hours. After reaction completion, the reaction mixture was diluted with methylene chloride (20 mL) and washed with brine (20 mL). The organic layer was dried over anhydrous MgS04 and concentrated in vacuo to give Z2-a or Z2-b. Z2-a; ]H NMR (400 MHz, DMSO-< 6 6.62 (brs, 2H, N), 4.03 - 4.10 (m, 2H), 2.59 - 2.72 (m, 2H), 2.39 - 2.44 (m, 2H), 1.99 - 2.03 (m, 1H), 1.69 - 1.79 (m, 1H), 1.49 - 1.18 (m, 3H). Z2-b; FontWeight="Bold" FontSize="10" H NMR (400 MHz, CDC13) delta 4.77 (brs, 2H, NH2), 4.42 (s, 2H), 3.67 - 3.71 (m, 2H), 2.61 - 2.65 (m, 2H), 1.46 (s, 9H).
		Intermediate 77 1.1-Dimethylethyl 2-amino-6.7-dihvdroH ,31thiazolof5.4-clpyridine-5(4/-/)-carboxylate; ourea (0.153g) was added to a solution of 1 ,1-dimethylethyl 3-bromo-4-oxo-1- piperidinecarboxylate (Ref. WO2004012684) (0.557g) in acetone (15ml) at ambient temperature and stirred overnight. Triethylamine (418ul) was then added and after 20min the reaction mixture was evaporated in vacuo. The residue was loaded onto a 2Og SCX cartridge preconditioned with MeOH and then eluted with 0%-20% 2M methanolic ammonia in MeOH. Appropriate f ractions were combined and evaporated in vacuo to provide a solid (0.383g) which was stirred in water (5ml) for 10min, filtered, then washed with water and dried in vacuo at 450C to give the title compound (0.319g) as a pale yellow solid.Mass spectrum: Found: MH+ 256 H.p.l.c. R,2.09min

References: [1]Patent: WO2019/37861,2019,A1 .Location in patent: Page/Page column 97.
[2]Patent: WO2015/200677,2015,A2 .Location in patent: Paragraph 00645; 00646.
[3]Patent: WO2012/29070,2012,A1 .Location in patent: Page/Page column 14.
[4]Patent: WO2015/193506,2015,A1 .Location in patent: Page/Page column 64.
[5]Patent: WO2006/108709,2006,A1 .Location in patent: Page/Page column 69.

18
[ 24424-99-5 ]
3-bromo-piperidin-4-one-hydrobromide [ No CAS ]
[ 188869-05-8 ]

Yield	Reaction Conditions	Operation in experiment
89%		To a solution of 1295 mg (5 mmol) 3-bromo-4-piperidone hydrobromide and 61 mg (0.5 mmol) 4-dimethyl aminopyridine in tetrahydrofurane (50 ml) was added at room temperature under nitrogen and stirring 646 mg (5 mmol) N,N-diisopropyl ethyl amine. The reaction was stirred at room temperature for 10 minutes. 1200 mg (5.5 mmol) di-tert.-butyl-dicarbonate was added and the reaction was stirred at room temperature over night. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed once with cold 1N aqueous HCl solution andonce with brine, dried over sodium sulphate, filtered and the solvent was evaporate under reduced pressure to yield 1240 mg (89percent) 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester as a colorless oil which solidified to give a white solid. 1H NMR (CDCl3, 250 MHz): delta (ppm)=4.35 (br m, 1H), 3.98 (br m, 2H), 3.62 (br m, 2H), 3.04 (br m, 1H), 2.44 (m, 2H), 1.51 (s, 9H).

References: [1]Patent: US2008/280948,2008,A1 .Location in patent: Page/Page column 18.

19
[ 626-34-6 ]
[ 188869-05-8 ]
[ 1075257-92-9 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate; at 80℃; for 24h;	Example 1 : 5-tert-butyl 3-ethyl 2-methyl-6,7-dihydro-lH-pyrrolo[3,2-c]pyridine-3,5(4H)- dicarboxylateA mixture of tert-butyl 3-bromo-4-oxopiperidine-l-carboxylate (3.0 g), (Z)- ethyl 3-aminobut-2-enoate (6.8 mL), and sodium bicarbonate (1.1 g) was heated to 80°C for 24 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate and concentrated.Excess (Z)-ethyl 3-aminobut-2-enoate was removed via distillation and the resulting residue was purified by column chromatography on silica gel (1 : 2 = ethyl acetate: hexanes) to obtain the title compound (0.73 g) having the following physical data. 1H NMR (CDCl3): delta 7.87 (bs, IH), 4.55 (s, 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.76-3.60 (m,2H), 2.66-2.54 (m, 2H), 2.51 (s, 3H), 1.47 (s, 9H), 1.34 (t, J = 7.2 Hz, 3H);Mass data (ESI, Pos.): m/z 331 (M + Na)+.

References: [1]Patent: WO2008/134354,2008,A1 .Location in patent: Page/Page column 59.

20
4-ethyl-piperazine-1-carbothioic acid amide [ No CAS ]
[ 188869-05-8 ]
C₁₇H₂₈N₄O₂S [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		A solution of thiourea 1b (0.687 g. 3.96 mmol), bromoketone 1c (0.5 g, 3.3 mmol) and MeCN (3 ml_) was sealed in a microwave vial, heated to 120 0C using microwave radiation and allowed to remain at this temperature for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between EtOAc (10 ml_) and saturated aqueous NaHCO3 solution (10 ml_). The organic phase was concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica gel (0-10percent MeOHZCH2Cb) to provide compound 8. MS: 353.1 (MH+)

References: [1]Patent: WO2010/71822,2010,A1 .Location in patent: Page/Page column 30.

21
[ 24424-99-5 ]
[ 17356-08-0 ]
[ 188869-05-8 ]
[ 365996-05-0 ]

Yield	Reaction Conditions	Operation in experiment
		Example 79 Synthesis of 2-[6-(lH-indazol-6-ylcarbamoyl)-lH-benzimidazol-2-ylamino]-6,7-dihydro-4H- thiazolo[5,4-c]pyridine-5-carboxylic acid tert-butyl esterTo a solution of l-Boc-4-piperidone (5 mmol) in dry THF (20 mL) was added solidBa2CC>3 (10 mmol). The resulting mixture was stirred vigorously. The reaction mixture was treated with pyrrolidone hydrotribromide (5.5 mmol) in portions at room temperature. After 3h, the contents were filtered and the solvent removed. The crude reaction mixture containing the product, 3-bromo-4-oxo-piperidine-l -carboxylic acid terf-butyl ester, was used for further transformation without further purification.To a solution of the bromo compound (5 mmol) , obtained as above, in acetone (20 mL) was added solid thiourea (6 mmol) and solid K2CO3 (10 mmol), and the reaction mixture was stirred at room temperature for 12h. To the reaction mixture was added BOC anhydride (5 mmol), and the reaction was stirred for 4h. The contents were then filtered, and the solvent was removed. The residue obtained was purified by silica gel chromatography using DCM/methanol as eluent. The product, 2-amino-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5- carboxylic acid tert-butyl ester, was obtained a light yellow solid. <n="66"/>The amine (0.5 mmol) from above was converted to corresponding isothiocyanate using general procedure A, which was then reacted with 334-diamino-N-(lH-indazol-6-yl)- benzamide (0.5 mmol; see Example 25) according to general procedure B to yield 2-[6-(1H- indazol-6-ylcarbamoyl)-lH-benzimidazol-2-ylamino]-6,7-dihydro-4H-thiazolo[5,4- cjpyridine-S-carboxylic acid tert-butyl ester. MS: m/z 531 (M+H)+.

References: [1]Patent: WO2007/95124,2007,A2 .Location in patent: Page/Page column 63-64.

22
[ 188869-05-8 ]
[ 365996-06-1 ]

References: [1]Patent: WO2012/29070,2012,A1 .
[2]Patent: WO2015/200677,2015,A2 .
[3]Patent: WO2015/193506,2015,A1 .

23
[ 188869-05-8 ]
[ 1363260-67-6 ]

References: [1]Patent: WO2012/29070,2012,A1 .

24
[ 188869-05-8 ]
[ 1363260-70-1 ]

References: [1]Patent: WO2012/29070,2012,A1 .

25
[ 188869-05-8 ]
[ 1363257-95-7 ]

References: [1]Patent: WO2012/29070,2012,A1 .

26
[ 188869-05-8 ]
[ 1363257-96-8 ]

References: [1]Patent: WO2012/29070,2012,A1 .

27
[ 84249-14-9 ]
[ 188869-05-8 ]
[ 1382805-22-2 ]

Yield	Reaction Conditions	Operation in experiment
62%	With sodium hydrogencarbonate; In isopropyl alcohol; at 80℃; for 90h;	To a 10 mL flask was added 2-amino-4-bromopyridine (20 mg, 0.12 mmol), tert-butyl 3-bromo-4-oxopiperidine- 1 -carboxylate (32 mg, 0.12 mmol) and sodium hydrogen carbonate (12 mg, 0.14 mmol) was weighed, 2-propanol (0.5 mL) was added, and the mixture was stirred at 80 ° C. for 90 hours. The crude product obtained by concentrating the reaction mixture was purified by flash silica gel column chromatography (chloroform only to chloroform / methanol = 98/2) to give tert-butyl 7-bromo-3,4-dihydroimidazo [1, 2-a: 5,4-c '] dipyridine-2 (1H) -carboxylate (hereinafter referred to as the compound of Reference Example 1) (25 mg, 72 mumol) as a white solid (yield 62percent).
32%	In toluene; at 105℃; for 16h;	2-Amino-4-bromopyridine (786 mg, 4.55 mmol) and <strong>[188869-05-8]tert-butyl 3-bromo-4-oxopiperidine-1-carboxylate</strong> (1.39 g, 5.00 mmol) were combined in toluene (20 mL) and heated at 105° C. for 16 h.The mixture was concentrated and purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100percent methylene chloride to 80percent methylene chloride over 30 min at 40 mL/min) to provide the title compound (512 mg, 32percent) as a white solid: 1H NMR (500 MHz, CDCl3) delta 7.93 (s, 1H), 7.46 (d, J=9.1 Hz, 1H), 7.22 (d, J=9.1 Hz, 1H), 4.69 (br s, 2H), 3.85 (br s, 2H), 2.93 (br s, 2H), 1.51 (s, 9H).

References: [1]Patent: JP2017/66078,2017,A .Location in patent: Paragraph 0035.
[2]Patent: US2012/157460,2012,A1 .Location in patent: Page/Page column 42-43.

28
C₈H₁₂NO₃^(1-)*Na⁽¹⁺⁾ [ No CAS ]
[ 188869-05-8 ]
[ 1380521-13-0 ]

Yield	Reaction Conditions	Operation in experiment
66%		General procedure: Enolate 4 (485 mg, 2.5 mmol) was stirred in EtOH (12 mL) with NH4OAc (578 mg, 7.5 mmol). After 5 min the solids had fully dissolved. At this point, chloroacetylaldehyde (50percent in H2O, 0.48 mL, 3.75 mmol) was added and the reaction was warmed to 80 °C for 1 h. Following cooling to room temperature, AcOH-H2O (4:1, 10 mL) was added and stirring was continued for 30 min. The volatiles were removed under vacuum and the residue was dissolved in CH2Cl2 and washed with H2O. The aqueous was extracted once with CH2Cl2, and the combined organics were dried over Na2SO4 and concentrated. The dark residue was purified by silica gel chromatography [heptane/EtOAc, 9:1-3:1] to give 2-formylpyrrole-3-carbonitrile (1) as an off-white solid, 153.5 mg, 51percent.

References: [1]Tetrahedron Letters,2012,vol. 53,p. 3056 - 3060.

29
[ 25984-63-8 ]
[ 188869-05-8 ]
[ 1174737-79-1 ]