Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:10][C:9]([C:11]#[N:12])=[CH:8][C:7]=1[CH3:13].C(N(CC)CC)C.Cl.[NH2:22][OH:23]>C(O)C>[NH2:12][CH:11]([C:9]1[S:10][C:6]([CH:2]2[O:3][CH2:4][CH2:5][O:1]2)=[C:7]([CH3:13])[CH:8]=1)[NH:22][OH:23]
Reactant: NO
Reactant: Cc1cc(C#N)sc1C1OCCO1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(C(N)NO)sc1C1OCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.7 %

Procedure:
To a solution of 4-methyl-thiophene-2-carbonitrile (2.70 g, 21.9 mmol) in acetic acid (20 mL), bromine (5.25 g, 32.9 mmol) is added slowly. The mixture is stirred at rt for 1 h then at 40° C. for 3 h and again at rt for 16 h. The mixture is separated by prep. HPLC. The product containing fractions are carefully concentrated at 45° C. and 120 mbar before they are combined, and extracted with EA. The organic extract is dried over Na2SO4, filtered and carefully concentrated and dried to give 5-bromo-4-methyl-thiophene-2-carbonitrile (2.1 g) as a colourless liquid; 1H NMR (D6-DMSO): δ2.19 (s, 3H), 7.82 (s, 1H). b) A solution of 5-bromo-4-methyl-thiophene-2-carbonitrile (1.88 g, 9.30 mmol) in THF (75 mL) is cooled to −75° C. before n-butyl lithium (6.4 mL of a 1.6 m solution in THF, 10.2 mmol) is added. DMF (1.36 g, 18.6 mmol) is added and the mixture is stirred at −78° C. for 30 min and is then warmed to rt. Stirring is continued for 1 h at rt. The reaction is quenched by adding 2 N aq. HCl (10 mL). The solvent is evaporated and the residue is dissolved in EA (500 mL) and washed with sat. aq. NaHCO3 solution followed by water. The washings are extracted back with EA. The organic extracts are combined, dried over Na2SO4, filtered and concentrated. The crude product is purified by prep. HPLC. As above, the product containing fractions are carefully concentrated at 45° C. and 120 mbar before they are combined, and extracted with EA. The organic extract is dried over Na2SO4, filtered and carefully concentrated and dried to give 5-formyl-4-methyl-thiophene-2-carbonitrile (720 mg) as an almost colourless liquid; 1H NMR (D6-DMSO): δ 2.58 (s, 3H), 7.96 (s, 1H), 10.11 (s, 1H); 13C NMR (D6-DMSO): δ 14.10, 114.20, 114.53, 143.04, 143.10, 147.29, 184.82. c) A solution of 5-formyl-4-methyl-thiophene-2-carbonitrile (720 mg, 4.76 mmol), ethylene glycol (887 mg, 14.3 mmol) and p-toluene sulfonic acid monohydrate (16 mg, 0.095 mmol) in toluene (40 mL) is refluxed in a Dean-Stark apparatus for 2 h. The mixture is cooled to rt, diluted with EA and washed with water. The organic extract is dried over Na2SO4, filtered and concentrated to give 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carbonitrile (990 mg) as an almost colourless oil; 1H NMR (D6-DMSO): δ2.25 (s, 3H), 3.95-4.08 (m, 4H), 6.16 (s, 1H), 7.76 (s, 1H). d) To a solution of 5-[1,3]dioxolan-2-yl-4-methyl-thiophene-2-carbonitrile (990 mg, 5.07 mmol) in ethanol (50 mL), triethylamine (2.05 g, 20.3 mmol) followed by hydroxylamine hydrochloride (705 mg, 10.14 mmol) is added. The mixture is stirred at rt for 16 h. The solvent is evaporated, the residue is dissolved in water and is then separated by prep. HPLC (XBridge 50×50 +50×100 mm, eluting with a gradient of acetonitrile in water containing 0.5% of ammonia) to give N-[amino-(5-[1,3]dioxolan-2-yl-4-methyl-thiophen-2-yl)-methyl]-hydroxylamine (510 mg) as an off-white solid; LC-MS*: tR=0.60 min, [M+1]+=229.11. e) To a suspension of N-[amino-(5-[1,3]dioxolan-2-yl-4-methyl-thiophen-2-yl)-methyl]-hydroxylamine (510 mg, 2.23 mmol) in water (10 mL) and acetonitrile (10 mL), 1 N aq. HCl (1 mL) is added. The now clear solution is stirred at rt for 10 min before another portion of 1 N aq HCl (1 mL) is added. Stirring is continued for 10 min. The reaction mixture is basified by adding 25% aq. ammonia solution and is then separated by prep. HPLC (XBridge 50×50 +50×100 mm, eluting with a gradient of acetonitrile in water containing 0.5% of ammonia) to give the title compound (407 mg) as a yellow solid; LC-MS*: tR=0.55 min, [M+1]+=185.16; 1H NMR (D6-DMSO): δ2.53 (s, 3H), 6.06 (s br, 2H), 7.44 (s, 1H), 10.00 (s, 1H), 10.06 (s, 1H).