Name: 861340-10-5|1H-Indazole-4-carbonitrile|98%
Brand: Ambeed
SKU: A266626
Price: 23.0 USD
Availability: InStock
Rating: 90 (25 reviews)

1
[ 41748-71-4 ]
[ 861340-10-5 ]

Reference： [1]Chemische Berichte,1920,vol. 53,p. 1213,1216, 1227

2
[ 2942-40-7 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: iron (II)-sulfate; aqueous-alcoholic ammonia 2: concentrated sulfuric acid / Diazotization_.und Eintragen der Reaktionsloesung in heisse Kupfer(I)-cyanid-Loesung

Reference： [1]v. Auwers; Schwegler [Chemische Berichte, 1920, vol. 53, p. 1213,1216, 1227]

3
[ 557-21-1 ]
[ 186407-74-9 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one at 85℃;	11.1 Example 11 1-(3- Methylamino-l-phenyl-propyl)-lH -indazole-4-carbonitrile The synthetic procedure of Example 11 is outlined in Scheme J below. SCHEME Step; 4-Bromoindazole (1.0 g, Judldns et al. , WO 9641803) and zinc cyanide (0.6 g) were added to N-methylpyrrolidinone (12.5 ml) and placed under an argon atmosphere. To this mixture was added tetralus(triphenylphosphine)palladium(0) (0.88 g) and the reaction was heated to 85 °C over night. The reaction mixture was cooled and partitioned between ethyl acetate and water, the organic layer was washed with brine, dried (MgS04), and evaporated to dryness. The product was purified by chromatography on silica gel using ethyl acetate - dichloromethane (5 : 95) as the eluting solvent to afford 0.581 g pure 4-cyanoindazole.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2005/118539, 2005, A1 Location in patent: Page/Page column 102-103

4
[ 539-74-2 ]
[ 861340-10-5 ]
[ 1072947-73-9 ]
[ 1072947-74-0 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 1.5h;	D.48 A mixture of ethyl 4-bromobutanoate (0.390 g, 1.998 mmol), 1 H-indazole-4- carbonitrile (0.143 g, 0.999 mmol) and cesium carbonate (0.976 g, 3.00 mmol) in N,N-dimethylformamide (4 ml) was stirred and heated at 80 0C for 90 mins. Cooled, diluted with ethyl acetate/water (30ml of each) and the organic washed with 3x15ml of water, dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 1 :2 ethyl acetate/hexane to give partial separation of the two isomers which after characterisation were recombined to give the title mixture of isomers (249 mg). δH (CDCI3, 400MHz) for 1-isomer: 1.24 (3H, t), 2.29 (4H, m), 4.12, (2H, q), 4.53 (2H, t), 7.45 (1 H, dd), 7.54 (1 H, dd), 7.71 (1 H, dd), 8.19 (1 H, d). δH (CDCI3, 400MHz) for 2-isomer 1.25 (3H, t), 2.35 (4H, m), 4.14, (2H, q), 4.58 (2H, t), 7.33 (1 H, dd), 7.54 (1 H, dd), 7.96 (1 H, dd), 8.15 (1 H, d).; A mixture of ethyl 4-(4-cyano-2H-indazol-2-yl)butanoate & ethyl 4-(4-cyano-1 H- indazol-1-yl)butanoate (D48) A mixture of ethyl 4-bromobutanoate (5.36 ml, 37.4 mmol), 1 H-indazole-4-carbonitrile (2.68 g, 18.72 mmol) and cesium carbonate (18.30 g, 56.2 mmol) in N, N- dimethylformamide (50 ml) was heated at 80 0C for 90 mins. Cooled, diluted with EtOAc/water and the organic washed with 3x30ml of water, dried (magnesium sulphate) and evaporated. Purified by flash chromatography eluting with EtOAc/hexane 1 :3 to give the title mixture of isomers (4.7g) as a yellow oil. MS (ES+): C14H15N3O2 requires 257; found (MH+) 258.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/128951, 2008, A1 Location in patent: Page/Page column 66-67

5
[ 539-74-2 ]
[ 861340-10-5 ]
[ 1072947-75-1 ]
[ 1072947-76-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 2h;	D.49 A mixture of ethyl 3-bromopropanoate (1.808 g, 9.99 mmol), 1 H-indazole-4- carbonitrile (0.715 g, 4.99 mmol) and cesium carbonate (4.88 g, 14.98 mmol) in N, N- dimethylformamide (DMF) (10 ml) was stirred and heated at 80 0C for 2 hours. Cooled, diluted with ethyl acetate (40ml) and water (40ml) and the organic washed with 3x15ml of water, dried (magnesium sulphate), evaporated and purified by flash chromatography eluting with 3:7 ethyl acetate/hexane to give 1.19g of colourless oil which slowly crystallised to a white solid. NMR and LC/MS showed this to be a -3:1 mix of isomers.. MS (ES): C13H13N3O2 requires 243 found (MH+) 244.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/128951, 2008, A1 Location in patent: Page/Page column 67

6
[ 539-74-2 ]
[ 861340-10-5 ]
[ 1072947-75-1 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate In N,N-dimethyl-formamide at 90℃; for 1.33333h;	D.96 1 H-indazole-4-carbonitrile (0.716 g, 5 mmol), ethyl 3-bromopropanoate (1.276 ml, 10.00 mmol) and caesium carbonate (4.90 g, 15.00 mmol) were added to N, N- dimethylformamide (DMF) (20 ml) and the mixture was was heated to 9O0C for 80 minutes. The mixture was cooled before being extracted in a mixture of ethyl acetate and water. The organic fraction was washed with 3x30ml portions of water, dried (MgSC>4), filtered and evaporated. The crude product mixture was added to a Biotage column and was eluted with ethyl acetate/petrol 1 :3 to give 0.95g of the title compound. δH (CDCI3, 400MHz) 1.17 (3H, t), 3.01 (2H, t), 4.08 (2H, q), 4.71 (2H, t), 7.46 (1 H, dd), 7.54 (1 H, dd), 7.81 (1 H, d), 8.21 (1 H, d).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/128951, 2008, A1 Location in patent: Page/Page column 87

7
[ 2843-18-7 ]
[ 861340-10-5 ]
[ 1072948-33-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: 1H-indazole-4-carbonitrile With sodium hydride In N,N-dimethyl-formamide Stage #2: 3-bromo-2,2-dimethylpropionic acid ethyl ester In N,N-dimethyl-formamide at 80℃;	D.102 I H-indazole-4-carbonitrile (commercially available from Insight Chemical Solutions Ltd., 298 mg, 1.957 mmol) in dry N,N-Dimethylformamide (DMF) (1 ml), under nitrogen was treated with NaH (94 mg, 2.348 mmol). A solution of ethyl 3-bromo-2,2- dimethylpropanoate (D98) (450 mg, 2.153 mmol), in DMF (2ml), was then added to the dark brown mixture. The reaction mixture was heated to 8O0C overnight then concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water then brine, dried and concentrated to give a brown gum. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (217 mg, 86%) as a yellow oil. MS (ES) C15H15N3O2 requires 271 , found 272 [M+H]+
37%	With caesium carbonate In N,N-dimethyl-formamide at 80℃;	D.102 1 H-lndazole-4-carbonitrile (commercially available from Insight Chemical Solutions Ltd.) (500 mg, 3.49 mmol), ethyl 3-bromo-2,2-dimethylpropanoate (D98) (803 mg, 3.84 mmol) and Cs2CO3 (1.36 g, 4.19 mmol) in dry DMF (3 ml) was heated to 8O0C overnight and then for a further 7 hours. The reaction mixture was then partitioned between EtOAc and H2O. The two layers were separated and the organic phase was washed with more H2O, brine, dried and concentrated a yellow oil. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (356 mg, 37%) as a crystalline material. MS (ES) Ci5H17N3O2 requires 271 , found 272 [M+H]+

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/128951, 2008, A1 Location in patent: Page/Page column 91
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2008/128951, 2008, A1 Location in patent: Page/Page column 90

8
[ 871351-43-8 ]
[ 861340-10-5 ]
[ 871351-37-0 ]

Yield	Reaction Conditions	Operation in experiment
	Stage #1: 1H-indazole-4-carbonitrile With sodium hydride In 1-methyl-pyrrolidin-2-one at 20℃; for 0.5h; Stage #2: methanesulfonic acid 3-chloro-1-phenyl-propyl ester In 1-methyl-pyrrolidin-2-one at 20℃; for 6h;	11.2 Step l-(3-Chloro-l-phenyl-propyl)-lH-indazole-4-carbonitrile; Sodium hydride (0.092 g , 60% in oil) was added to a solution of 4-cyanoindazole (0.300 g) in N-methylpyrrolidinone and the reaction mixture was stirred at room temperature for 30 minutes. Solid methanesulfonic acid 3-chloro-l-phenyl-propyl ester (0.573 g) was added followed by 3 ml more of N-methylpyrrolidinone. The reaction mixture was stirred for an additional 6 hours at room temperature. The reaction mixture was partitioned between water and ethyl acetate, and the organic layer was washed with water, then with brine, and dried (MgS04). Evaporation to dryness gave a residue which was purified by column chromatography on silica gel using ethyl acetate - hexane (1:9) to give 1-(3-chloro-l-phenyl-propyl)-lH-indazole-4-carbonitrile (0.228 g) as a foam, (M+H = 297).

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2005/118539, 2005, A1 Location in patent: Page/Page column 103

9
[ 108-24-7 ]
[ 861340-10-5 ]
[ 1312008-64-2 ]

Yield	Reaction Conditions	Operation in experiment
	With pyridine In tetrahydrofuran at 20℃; for 2.5h;	5; 30 1H-indazole-4-carbonitriie (10 g, 70 mmol) was added to a solution of pyridine (5.75 g, 73 mmol), acetic anhydride (7.85 g, 77 mmol) and 4-dimethylaminopyridine (0.9 g, 7 mmol) in THF (120 mL) and the mixture stirred at RT for 2.5 h. The mixture was then concentrated in vacuo and DCM added. This mixture was washed with 1 M aqueous hydrochloric acid solution (x2) and then concentrated to afford the title compound as a solid (11 g). LCMS m/z: 186 [M+1]+, Rt 1.435 min
	With pyridine In tetrahydrofuran at 20℃; for 2.5h;	30 Description 30:1-Acetyl-1H-indazole-4-carbonitrile 1H-indazole-4-carbonitrile (10 g, 70 mmol) was added to a solution of pyridine (5.75 g, 73 mmol), acetic anhydride (7.85 g, 77 mmol) and 4-dimethylaminopyridine (0.9 g, 7 mmol) in THF (120 mL) and the mixture stirred at RT for 2.5 h. The mixture was then concentrated in vacuo and DCM added. This mixture was washed with 1M aqueous hydrochloric acid solution (*2) and then concentrated to afford the title compound as a solid (11 g). LCMS m/z: 186 [M+1]+, Rt 1.435 min.

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1 Location in patent: Page/Page column 17-18; 40-41
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1 Location in patent: Page/Page column 23

10
[ 24424-99-5 ]
[ 861340-10-5 ]
[ 1312008-78-8 ]
[ 1312008-77-7 ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine In dichloromethane at 20℃; for 1h;	5; 46 A mixture of 1 H-indazole-4-carbonitrile (0.143 g, 0.999 mmol), triethylamine (0.153 mL, 1.099 mmol), 4-dimethylaminopyridine (1.220 mg, 9.99 μϖηοΙ) and di-tert-butyl dicarbonate (0.464 mL, 1.998 mmol) in DCM (4 mL) was stirred at RT for 1 h. The mixture was then diluted with ethyl acetate (30 mL) and washed with 2M aqueous hydrochloric acid solution (10 mL). The organic layer was then dried over magnesium sulfate, reduced and purified by chromatography on silica gel, eluting with 20% ethyl acetate in hexane to afford the title compound as a white solid (86 mg). 1H NMR (CDCI3j 400MHz) δ ppm: 1.75 (9H, s), 7.63 (1 H, m), 7.70 (1 H, m), 8.37 (1 H, d, J 1.0 Hz), 8.50 (1 H, d, J 8.5 Hz). In addition, 1 ,1-dimethylethyl 4-cyano-2H-indazole-2- carboxylate (91 mg) was also isolated. 1H NMR (CDCI3, 400MHz) δ ppm: 1.75 (9H, s), 7.39 (1 H, dd, J 9.0, 7.0 Hz), 7.59 (1 H, dd, J 7.0, 1 Hz), 8.03 (1 H, dt, J 9.0, 1 Hz), 8.82 (1 H, d, J 1.0 Hz).
	With triethylamine In dichloromethane at 20℃; for 1h;	46 Description 46: 1,1-Dimethylethyl 4-cyano-1H-indazole-1-carboxylate A mixture of 1H-indazole-4-carbonitrile (0.143 g, 0.999 mmol), triethylamine (0.153 mL, 1.099 mmol), 4-dimethylaminopyridine (1.220 mg, 9.99 μmol) and di-tert-butyl dicarbonate (0.464 mL, 1.998 mmol) in DCM (4 mL) was stirred at RT for 1 h. The mixture was then diluted with ethyl acetate (30 mL) and washed with 2M aqueous hydrochloric acid solution (10 mL). The organic layer was then dried over magnesium sulfate, reduced and purified by chromatography on silica gel, eluting with 20% ethyl acetate in hexane to afford the title compound as a white solid (86 mg). 1H NMR (CDCl3, 400 MHz) δ ppm: 1.75 (9H, s), 7.63 (1H, m), 7.70 (1H, m), 8.37 (1H, d, J 1.0 Hz), 8.50 (1H, d, J=8.5 Hz). In addition, 1,1-dimethylethyl 4-cyano-2H-indazole-2-carboxylate (91 mg) was also isolated. 1H NMR (CDCl3, 400 MHz) δ ppm: 1.75 (9H, s), 7.39 (1H, dd, J 9.0, 7.0 Hz), 7.59 (1H, dd, J 7.0, 1 Hz), 8.03 (1H, dt, J 9.0, 1 Hz), 8.82 (1H, d, J=1.0 Hz).

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1 Location in patent: Page/Page column 17-18; 50-51
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1 Location in patent: Page/Page column 27

11
[ 861340-10-5 ]
[ 1312008-84-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol at 65℃; Inert atmosphere;	5; 54 A solution of 1H-indazole-4-carbonitrile (837 mg, 5,85 mmol) in methanol (40 mL) was added to hydroxylamine hydrochloride (1.625 g, 23.38 mmol) and sodium bicarbonate (2.456 g, 29.2 mmol). The reaction mixture was then evacuated, purged with nitrogen and heated at 65 °C for the weekend. The reaction mixture was allowed to cool to RT, filtered and washed with methanol and the filtrate reduced to give an off white solid. Careful trituration with DCM was followed by filtration and evaporation of the colourless filtrate to give a cream solid. The solid and filtrate were therefore recombined and used directly in the next reaction. 1H NMR (CD3OD, 400MHz) δ ppm: 7.37 - 7.43 {2H, m), 7.54 - 7.61 (1 H, m), 8.34 (1 H, d, J 1.0 Hz)
	Multi-step reaction with 2 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1 Location in patent: Page/Page column 17-18; 55-56
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1

12
[ 861340-10-5 ]
[ 1312008-85-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1

13
[ 861340-10-5 ]
[ 1312008-98-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C
	Multi-step reaction with 2 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux

	Multi-step reaction with 3 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C
	Multi-step reaction with 3 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux
	Multi-step reaction with 3 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C
	Multi-step reaction with 3 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

14
[ 861340-10-5 ]
[ 1312008-97-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

15
[ 861340-10-5 ]
[ 1312008-99-3 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

16
[ 861340-10-5 ]
[ 1312009-00-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

17
[ 861340-10-5 ]
[ 1312009-01-0 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere

	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere
	Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 8 h / 70 - 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 8 h / 70 - 80 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 8 h / 70 - 80 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

18
[ 861340-10-5 ]
[ 1312009-30-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C 3.2: 80 °C
	Multi-step reaction with 2 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 0.5 h / 20 °C 2.2: 80 °C
	Multi-step reaction with 2 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 2.5 h / 20 - 80 °C

Multi-step reaction with 3 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 2.5 h / 20 - 80 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

19
[ 861340-10-5 ]
[ 1312009-32-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere 5.2: 1 h / Sonographic reaction
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere 4.2: 1 h / Sonographic reaction
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere 4.2: 1 h / Sonographic reaction

	Multi-step reaction with 5 steps 1.1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere 5.2: 1 h / Sonographic reaction
	Multi-step reaction with 5 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4.1: caesium carbonate / N,N-dimethyl-formamide / 20 - 80 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere 5.2: 1 h / Sonographic reaction
	Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 5: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: caesium carbonate / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 5: sodium hydroxide; water / ethanol / 85 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

20
[ 861340-10-5 ]
[ 1312009-34-9 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere 5.2: Acidic conditions
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere 4.2: Acidic conditions
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere 4.2: Acidic conditions

	Multi-step reaction with 5 steps 1.1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3.1: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere 5.2: Acidic conditions
	Multi-step reaction with 5 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere 5.2: Acidic conditions
	Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 4: sodium hydroxide / ethanol / 6 h / 65 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 6 h / 65 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 6 h / 65 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

21
[ 861340-10-5 ]
[ 1312009-36-1 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere

	Multi-step reaction with 5 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5: sodium hydroxide; water / ethanol / 6 h / 65 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 4: sodium hydroxide / ethanol / 6 h / 65 °C / Inet atmosphere
	Multi-step reaction with 5 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 6 h / 65 °C / Inet atmosphere
	Multi-step reaction with 5 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: potassium carbonate / N,N-dimethyl-formamide / 70 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 6 h / 65 °C / Inet atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

22
[ 861340-10-5 ]
[ 1312009-37-2 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 5 steps 1.1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2.1: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 3.2: 20 °C 3.3: 72 h / 80 °C 4.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere 5.1: sodium hydroxide; water / ethanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2.1: triethylamine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / tetrahydrofuran / 0.5 h / 20 °C 2.2: 20 °C 2.3: 72 h / 80 °C 3.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere 4.1: sodium hydroxide; water / ethanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere 4: sodium hydroxide; water / ethanol / 4 h / 65 °C / Inert atmosphere

	Multi-step reaction with 5 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 50 °C 3: 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; benzotriazol-1-ol / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere 5: sodium hydroxide; water / ethanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; ethanol; sodium carbonate / 6 h / Reflux 3: triethylamine / acetonitrile / 0 °C / Inert atmosphere; Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 20 - 80 °C / Inert atmosphere 5: sodium hydroxide; water / ethanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride; sodium hydrogencarbonate / methanol / 65 °C / Inert atmosphere 2: triethylamine / acetonitrile / 0 - 80 °C / Reflux 3: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 8 h / 70 - 80 °C / Inert atmosphere 4: sodium hydroxide / ethanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C 3: benzotriazol-1-ol; 1,2-dichloro-ethane / N,N-dimethyl-formamide / 8 h / 80 - 120 °C 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 8 h / 70 - 80 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 4 h / 65 °C / Inert atmosphere
	Multi-step reaction with 5 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux 3: triethylamine / acetonitrile / 0 - 80 °C / Reflux 4: 1,8-diazabicyclo[5.4.0]undec-7-ene / acetonitrile / 8 h / 70 - 80 °C / Inert atmosphere 5: sodium hydroxide / ethanol / 4 h / 65 °C / Inert atmosphere

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[4]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[5]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2011/72488, 2011, A1
[6]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[7]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1
[8]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

23
[ 1022158-35-5 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / N,N-dimethyl-formamide; water / 0.67 h / 150 °C / Inert atmosphere; Microwave irradiation 2: hydrogenchloride / ethanol / 20 °C

Reference： [1]Lohou, Elodie; Sopkova-De Oliveira Santos, Jana; Schumann-Bard, Pascale; Boulouard, Michel; Stiebing, Silvia; Rault, Sylvain; Collot, Valerie [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5296 - 5304]

24
[ 1337880-47-3 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
76%	With hydrogenchloride In ethanol at 20℃;	1 General procedure for the synthesis of 1H-indazole-4 and 5-carbonitriles (9a-b) General procedure: Indazole 8a or 8b was introduced in ethanolic HCl (5-15 mL) and the preparation was stirred for 3-6 h at room temperature. Then, the acidic mixture was neutralized thanks to a 2 N sodium hydroxide solution and ethanol was evaporated in vacuo. After addition of EtOAc (20 mL) to the residue, the organic layer was washed with brine (3 × 10 mL), dried over MgSO4, filtered and evaporated in vacuo. Finally, the expected unprotected indazole-carbonitriles 9a-b were in this case directly isolated.

Reference： [1]Lohou, Elodie; Sopkova-De Oliveira Santos, Jana; Schumann-Bard, Pascale; Boulouard, Michel; Stiebing, Silvia; Rault, Sylvain; Collot, Valerie [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5296 - 5304]

25
[ 55289-36-6 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 4 steps 1.1: tetrafluoroboric acid; sodium nitrite / water / 3 h / 0 - 20 °C 1.2: 2 h / 20 °C 2.1: trifluoroacetic acid / ethyl acetate / 6 h / Reflux 3.1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / N,N-dimethyl-formamide; water / 0.67 h / 150 °C / Inert atmosphere; Microwave irradiation 4.1: hydrogenchloride / ethanol / 20 °C

Reference： [1]Lohou, Elodie; Sopkova-De Oliveira Santos, Jana; Schumann-Bard, Pascale; Boulouard, Michel; Stiebing, Silvia; Rault, Sylvain; Collot, Valerie [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5296 - 5304]

26
[ 186407-74-9 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 3 steps 1: trifluoroacetic acid / ethyl acetate / 6 h / Reflux 2: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane / N,N-dimethyl-formamide; water / 0.67 h / 150 °C / Inert atmosphere; Microwave irradiation 3: hydrogenchloride / ethanol / 20 °C

Reference： [1]Lohou, Elodie; Sopkova-De Oliveira Santos, Jana; Schumann-Bard, Pascale; Boulouard, Michel; Stiebing, Silvia; Rault, Sylvain; Collot, Valerie [Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5296 - 5304]

27
[ 861340-10-5 ]
[ 1312008-85-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: triethylamine / dmap / dichloromethane / 1 h / 20 °C 2: hydroxylamine hydrochloride; sodium hydrogencarbonate / ethanol / 3 h / 50 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

28
[ 861340-10-5 ]
[ 1312008-84-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium hydrogencarbonate In methanol at 65℃; Inert atmosphere;	54 Description 54: N-Hydroxy-1H-indazole-4-carboximidamide A solution of 1H-indazole-4-carbonitrile (837 mg, 5.85 mmol) in methanol (40 mL) was added to hydroxylamine hydrochloride (1.625 g, 23.38 mmol) and sodium bicarbonate (2.456 g, 29.2 mmol). The reaction mixture was then evacuated, purged with nitrogen and heated at 65° C. for the weekend. The reaction mixture was allowed to cool to RT, filtered and washed with methanol and the filtrate reduced to give an off white solid. Careful trituration with DCM was followed by filtration and evaporation of the colourless filtrate to give a cream solid. The solid and filtrate were therefore recombined and used directly in the next reaction. 1H NMR (CD3OD, 400 MHz) δ ppm: 7.37-7.43 (2H, m), 7.54 7.61 (1H, m), 8.34 (1H, d, J=1.0 Hz)
	Multi-step reaction with 2 steps 1: pyridine / dmap / tetrahydrofuran / 2.5 h / 20 °C 2: hydroxylamine hydrochloride; sodium carbonate / ethanol / 6 h / Reflux

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1 Location in patent: Page/Page column 29
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - US2012/283297, 2012, A1

29
[ 861340-10-5 ]
[ 944898-93-5 ]

Yield	Reaction Conditions	Operation in experiment
64.7%	With iodine; potassium hydroxide In N,N-dimethyl-formamide at 20℃;	17.2 step 2: A mixture of lH-indazole-4-carbonitrile (1.65g, 11.1 mmol), KOH (1.86 g, 33.3 mmol), and (5.6 g, 22.2 mmol) in DMF (30 mL) was stirred at RT overnight. The reaction mixture was filtered. The filtrate was diluted with water (100 mL) and extracted with EtOAc (200 mL). The organic layer was concentrated in vacuo to afford 3-iodo-lH-indazole-4-carbonitrile as white solid (2.01 g, 64.7%). MS (ESI): w/z = 270 [M+l]+.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/26914, 2013, A1 Location in patent: Page/Page column 112

30
zinc cyanide [ No CAS ]
[ 186407-74-9 ]
[ 861340-10-5 ]

Yield	Reaction Conditions	Operation in experiment
52.5%	With tetrakis(triphenylphosphine) palladium⁽⁰⁾ In 1-methyl-pyrrolidin-2-one at 110℃; for 16h; Inert atmosphere;	17.1 Referential Example 17 N-Methyl- 1 -(3 -methyl- 1 H-indazol-4-yl)methanamine (109) step 1 : A mixture of 4-bromo-lH-indole (10 g, 50.7 mmol), Pd(PPh3)4 (8.78 g, 7.6 mmol), Zn(CN)2 (9.22 g 101.4 mmol) in NMP (150 mL) under nitrogen was heated at 110 °C for 16 h. The reaction mixture was cooled, filtered and the filtrate diluted with water and extracted with EtOAc (100 mL x 5). The combined extracts were washed with brine (300 mL), dried (MgSO i), filtered, and concentrated in vacuo to afford lH-indazole-4-carbonitrile (3.76 g, 52.5%) as white solid, which went to next step without further purification.

Reference： [1]Current Patent Assignee: ROCHE HOLDING AG - WO2013/26914, 2013, A1 Location in patent: Page/Page column 111

31
[ 861340-10-5 ]
[ 1425932-33-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: potassium hydroxide; iodine / N,N-dimethyl-formamide / 20 °C 2: toluene-4-sulfonic acid / tetrahydrofuran / 85 °C / Inert atmosphere