Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1.[CH3:9][C:10]([CH3:12])=O>O>[CH2:9]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][CH:3]=1)[C:10]1[CH:12]=[CH:6][CH:7]=[CH:2][CH:3]=1
Reactant: CC(C)=O
Reactant: O=c1ccocc1O
Solvent: O
Product: O=c1ccocc1OCc1ccccc1
Yield: 34 %

Procedure:
3-Benzyloxy-4-pyrone is prepared from 3-hydroxy-4-pyrone as described by Spenser et al, Canadian Journal of Chemistry, 1962, 40, 1377 and has m.p. 82°-85° C. A mixture of this compound (1 g) and ethylenediamime (0.37 g) in water (12 ml) is heated under reflux for 1 hour. The reaction mixture is evaporated to dryness and the residue is treated with concentrated hydrochloric acid (12 ml) and the mixture is heated on a steam bath for 30 minutes. The excess acid and water are evaporated under reduced pressure to give a solid brown residue. This is slurried in acetone, then filtered off and recrystallised from ethanol containing a little concentrated hydrochloric acid to give 1-(2'-aminoethyl-3-hydroxypyrid-4-one in 34% yield as colourless needles, m.p. 264°-266° C., νmax (nujol) 1050, 1540, 1600, 1635 cm-1, δ(d6DMSO), 2.85 (t, 2H), 4.35 (t, 2H), 7.1 (d, 1H), 8.1 (m, 2H).
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[F:7][C:8]1[CH:9]=[C:10]([S:15][C:16]2[CH:17]=[C:18]3[C:24]([NH2:25])=[N:23][NH:22][C:19]3=[N:20][CH:21]=2)[CH:11]=[C:12]([F:14])[CH:13]=1.O1CCCC1.CO.[OH2:33]>>[F:7][C:8]1[CH:9]=[C:10]([S:15]([C:16]2[CH:17]=[C:18]3[C:24]([NH2:25])=[N:23][NH:22][C:19]3=[N:20][CH:21]=2)(=[O:1])=[O:33])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12
Reactant: O=S([O-])OO
Reactant: O
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1n[nH]c2ncc(S(=O)(=O)c3cc(F)cc(F)c3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 81 %

Procedure:
A solution of 663 mg (1.078 mmol) of oxone in 1.1 ml of water is added to a solution of 300 mg (1.078 mmol) of 5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-amine in 10 ml of a 1:1 mixture of tetrahydrofuran and methanol at 0° C. The reaction mixture is stirred at room temperature for 16 hours. An additional portion of 663 mg of oxone at 0° C. is then added and the reaction medium stirred at room temperature for 24 hours. The solvents are evaporated and the reaction medium is diluted with sodium bicarbonate solution, extracted with ethyl acetate, dried on MgSO4 and then concentrated to yield 340 mg (81%) of 5-(3,5-difluorophenylsulfonyl)-1H-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow solid.
Reaction SMILES: [C:1]1([CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].[F:22]N(CC(C)(C)C)S(C1C=CC(C)=CC=1)(=O)=O>O1CCCC1.CCOCC>[F:22][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)N(F)CC(C)(C)C)cc1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(F)(C(=O)OCC)c1ccccc1
Reaction time: 0.25 h
Yield: 80.6 %

Procedure:
Diethyl phenylmalonate (472 mg, 431 μL, 2 mmole) was dissolved in anhydrous tetrahydrofuran (10 mL) under nitrogen. Sodium hydride (96 mg as a 60% oil dispersion, 2.4 mmole) was added and the mixture was stirred until hydrogen evolution ceased (about 15 minutes). The solution was then cooled to -50° under nitrogen and N-fluoro-N-neopentyl-p-toluenesulfonamide (518 mg, 2 mmole, as prepared in Example 1) was added and the mixture was stirred at -50° for 15 minutes. The solution was stirred at -20° for 15 minutes, 0° for 15 minutes, and room temperature for 15 minutes before being diluted with ether (100 mL). The ether solution was washed with aqueous 1N oxalic acid (30 mL), 10% aqueous potassium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL) solutions, and then dried over anhydrous magnesium sulfate. Filtration, removal of solvent under reduced pressure, and purification by flash column chromatography (silica, 30% methylene chloride in hexane) yielded diethyl 2-fluoro-2-phenylmalonate (410 mg, 81% yield) as a colorless oil. This material, and additional samples prepared by this procedure, were analyzed and provided the following results: IR (liquid film) γmax (cm-1) 2800 (m), 1760 (s, ester), 1420 (m), 1350 (m), 1250 (s); 1H NMR (80 MHz, CDCl3) δ1.32 (t, J=8.0 Hz, 6H, CH3), 4.33 (q, J=8 Hz, 4H, CH2), 7.50 (m, 5H); 19F NMR (94.1 MHz, CDCl3) -162.23; HRMS calcd. for C13H15O4F: 254.0954; found: 254.0947.
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].CS(C)=O.[CH3:20][C:21]1[O:25][N:24]=[C:23]([OH:26])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][C:21]1[O:25][N:24]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[C:23](=[O:26])[CH:22]=1
Reactant: Cc1cc(O)no1
Reactant: CCOC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2oc(C)cc2=O)c([N+](=O)[O-])c1
Reaction time: 10 h
Yield: 58.9 %

Procedure:
After mixing 400 g of ethyl 4-chloro-3-nitrobenzoate, 1.2 liters of dimethyl sulfoxide, 270 g of 5-methyl-3-hydroxyisoxazole, and 292 g of potassium carbonate, the reaction was performed for 10 hours at 60° C. After the reaction was over, the reaction mixture was poured into water and crystals thus deposited were recovered by filtration and recrystallized from ethyl acetate to provide 300.1 g of the desired compound with a yield of 59.0%. The melting point thereof was 122° C. to 123° C.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:32][CH2:31]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:6][C:5]=1[Cl:33].C1COCC1.[OH-].[Li+].Cl>O.CO>[Cl:33][C:5]1[CH:6]=[C:7]([O:11][C:12]2[C:17]([C:18]([N:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]([CH:30]4[CH2:31][CH2:32]4)[CH2:22][CH2:21]3)=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([OH:34])=[O:2]
Reactant: COC(=O)c1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)c(Oc2ncccc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a solution of 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-2-yloxy]-benzoic acid methyl ester (50 mg, 0.10 mmol, 1.0 equiv; Example 182) in a 2:2:1 mixture of THF, methanol and water (2 mL) was added lithium hydroxide (4.8 mg, 0.20 mmol, 2.0 equiv; [CAS RN 1310-65-2]) and the reaction mixture stirred at rt over night. The crude reaction product was taken up in water (50 mL), acidified to pH 1 by addition of a solution of 1 M HCl and extracted with ethyl acetate (3×40 mL). The combined organic phases were dried over MgSO4 and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to give 40 mg (82%) of the title compound as a light yellow solid. MS (ISN): 482.0 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10])(=[O:5])=[O:4].[BH4-].[Na+]>C1COCC1>[CH3:1][N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:9][OH:10])(=[O:4])=[O:5]
Reactant: COc1ccc(C=O)cc1S(=O)(=O)N(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 62.7 %

Procedure:
To a solution of OBS02049 (5.5 g, 21.21 mmol) in anhydrous THF (50 mL) was added sodium borohydride (0.88 g, 23.33 mmol). The mixture was stirred at room temperature for 4 h, quenched with water (CARE!!) and filtered through a Celite pad. The filtrate was concentrated in vacuo and re-dissolved in DCM (200 mL). The organic layer was washed with brine (2×200 mL), dried (Na2SO4) and filtered. Concentration in vacuo of the combined filtrates gave OBS02053 as a golden-yellow oil (3.26 g, 59%). TLC [SiO2, EtOAc-n-hexane (1:1)] Rf=0.36; 1H-NMR (270 MHz, CDCl3)=1.73 (1H, bs, OH), 2.97 (6H, s), 3.88 (3H, s), 4.62 (2H, s), 6.95 (1H, d, J=8.4), 7.23 (1H, dd, J=2.2, 8.4), 7.36 (1H, d, J=2.2).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19])=O.[CH3:20][S:21]([CH2:24][C:25](=O)[CH3:26])(=[O:23])=[O:22].[Na]>CC(O)C>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:25]([CH3:26])[C:24]([S:21]([CH3:20])(=[O:23])=[O:22])=[C:9]2[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[F:19]
Reactant: Nc1ccc(Br)cc1C(=O)c1cc(F)c(F)cc1F
Reactant: CC(=O)CS(C)(=O)=O
Agent: [Na]
Solvent: CC(C)O
Product: Cc1nc2ccc(Br)cc2c(-c2cc(F)c(F)cc2F)c1S(C)(=O)=O
Yield: 20.4 %

Procedure:
(2-Amino-5-bromo-phenyl)-(2,4,5-trifluoro-phenyl)-methanone (compound of example A.4) (1.9 g, 5.7 mmol), methanesulfonylacetone (1.18 g, 8.6 mmol) and sodium tetrachloroaureate(III) dihydrate (0.12 g, 0.28 mmol) were heated at reflux in 2-propanol (50 ml) for 4 days. The resulting mixture was evaporated to dryness and the residue extracted with dichloromethane (2×), NaOH (2×) and NaCl (1×). The crude product was purified by chromatography on silica gel with a heptane/ethyl acetate gradient from 100:0 to 90:10. One obtained a light yellow solid (0.5 g, 20%). MS: m/z=430 (M).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1.[CH3:18][N:19](C)C=O.[C-]#N.[Na+]>O>[C:18]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:15][C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[C:8](=[O:16])[C:7]=2[CH:17]=1)#[N:19]
Reactant: O=c1c2cc(CBr)ccc2oc2ncccc12
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc2oc3ncccc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 25 g of 7-bromomethyl-5-oxo-5H-[1]benzopyrano-[2,3-b]pyridine and 175 ml of dimethylformamide is added 5.1 g of sodium cyanide under ice cooling. The mixture is stirred at room temperature for 2 hours, and then 300 ml of water is added to the reaction mixture. The resulting crystalline precipitate is filtered off, washed with water, and recrystallized from dioxane to give 17 g of 7-cyanomethyl-5-oxo-5H-[1]-benzopyrano[2,3-b]pyridine melting at 198°-201°C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:12]1)=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)C1
Reactant: BrCc1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)OCc2ccccc2)C1
Reaction time: 12 h

Procedure:
To a solution of 1.00 g Boc-1-pyrrolidine-3-carboxylic acid in 10 ml toluene were added 0.61 ml benzyl bromide and 0.76 ml DBU. After stirring for 12 h the reaction mixture was washed with water and the crude product obtained after evaporation of the solvent was purified by flash chromatography on silica using ethyl acetate/heptane 1:3 as eluent.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[O-]CC.[Na+].Cl[C:14]1[C:15](=[O:26])[C:16]2[C:21]([C:22](=[O:25])[C:23]=1Cl)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl>C(O)C>[OH:2][C:1]1[CH:8]=[CH:7][C:6]2[C:23]3[C:22](=[O:25])[C:21]4[C:16]([C:15](=[O:26])[C:14]=3[O:5][C:4]=2[CH:3]=1)=[CH:17][CH:18]=[CH:19][CH:20]=4
Reactant: Oc1cccc(O)c1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1c2ccccc2C(=O)c2c1oc1cc(O)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
Resorcinol (6.6 g, 60 mmol) in ethanol (80 mL) was added dropwise to a stirred ethanolic sodium ethoxide solution (prepared by dissolving 3.8 g of sodium metal in 120 mL of absolute ethanol) containing 2,3-dichloro-1,4-naphthoquinone (6.9 g, 30 mmol) at 0° C. After stirring at room temperature overnight, the black reaction mixture was acidified with 5N HCl at 0° C. The yellow solid that precipitated was collected by filtration, washed successively with water, methanol, diethyl ether and air-dried to give crude 12 as a deep yellow solid (7.1 g, 88%); mp>310° C. (lit.>300° C.);Cheng 1993 JMC TLC (chloroform/acetone, 8:1): Rf 0.47; νmax (KBr) 3400 (OH), 1670 and 1620 (C═O) cm−1; δH (400 MHz, DMSO-d6) 7.05 (1H, d, JC-5-H, C-4-H=8.54 Hz, C-4-H), 7.16 (1H, s, C-2-H), 7.2–7.7 (2H, m, C-8-H and C-9-H), 7.95 (1H, d, JC-4-H, C-5-H=8.5 Hz, C-5-H), 8.2–8.7 (2H, m, C-7-H and C-10-H) and 10.53 (1H, br s, exchanged with D2O, C-3-OH); MS m/z (FAB+) 265.1 [70, (M+H)+], 255.3 (75), 243.2 (30), 173.2 (100); MS m/z (FAB−) 263.1 [100, (M-H)−], 242.1 (20), 210.1 (25), 198.1 (45), 181.1 (35); Acc. MS (FAB+) 265.0502 C16H9O4 requires 265.0501.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:15][C:16]3[C:21]([CH:22]=2)=[CH:20][C:19]([C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].BrC[O:30][C:31](=O)[CH3:32].[CH3:34]N(C=O)C>>[CH3:34][CH2:32][C:31]([NH:25][C:23]([C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:13][CH2:12]1)=[CH:22]2)=[O:24])=[O:30]
Reactant: CC(=O)OCBr
Reactant: CN(C)C=O
Reactant: NC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Agent: [H-]
Agent: [Na+]
Product: CCC(=O)NC(=O)c1ccc2[nH]c(N3CCC(Cc4ccccc4)CC3)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
1.95 g (6.13 mmol) of 4-benzylpiperidinyl indole-5-carboxamide was dissolved in 30 mL dry DMF and was treated with 320 mg (8 mmol, 60% suspension in oil) sodium hydride for 30 minutes. The reaction mixture was cooled to 0° C. and 1.225 g (8 mmol) bromomethylacetate was added and stirring continued for 1 h at 0° C. The ice-bath was removed and stirring continued for another 6 h at room temperature. The reaction was quenched by the addition of sat. ammonium chloride solution, diluted with water and extracted with dichloromethane. The extract was dried, evaporated and the residue purified by column chromatography on silica gel eluting with ethylacetate-hexane (25–35% ethylacetate) to yield 2.2 g (92%) of the desired product. MS: M+, 390; M+−1, 389. 1HNMR (CDCl3): □ 7.7 (s, 1H); 7.35–7.1 (m, 8H); 6.6 (s, 1H); 5.1 (s, 2H); 3.75 (s, 3H); 3.0–2.7 (br, m, 4H); 2.6 (d, 2H); 1.9–1.2 9m, 5H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.[CH2:13]([O:20][C:21](Cl)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O.O.CC(C)=O>[CH2:13]([O:20][C:21]([N:10]1[CH2:9][CH2:8][N:7]2[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]2[CH2:11]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCC2CNCCN2C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1)N1CCN2CC(CO)CCC2C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.6 %

Procedure:
To a solution of the title product of Example 6 (640 mg, 3.76 mmol)in acetone/water (6.3 ml and 2.2 ml, respectively), a solution of benzylchloroformate (0.61 ml, 729 mg, 4.27 mmol) in acetone (2,0 ml) was added dropwise over several minutes while maintaining the pH of the mixture at 9.5 by intermittent dropwise addition of saturated aqueous sodium carbonate. After completing the addition, the reaction was stirred for 5 minutes at ambient temperature. The acetone solvent was removed in vacuo, ethyl acetate (60 ml) and water (30 ml) were added, and the pH of the well-stirred mixture was adjusted to 9.5 (sodium carbonate). The separated organic phase was dried (anhydrous sodium sulfate)and concentrated in vacuo to an oil (940 mg). Rash chromatography of the entire sample [10 g, silica gel, 32-63 mesh, eluting initially with ethyl acetate (100 mg), followed by ethyl acetate/methanol (100 ml, 97:3 in volume) and finally ethyl acetate/methanol (200 ml, 90:10 in volume)]afforded the present title compound as a colorless oil, 350 mg (30.6% yield). TLC Rf (ethyl acetate/methanol/concentrated aqueous ammonia=9:2:0.2 in volume): 0.63.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:7]([C:21]#[N:22])[CH2:6]1)=[O:4].Cl.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C=O.[C:32](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:19][C@H:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][C:11]=3[CH2:32][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:7]([C:21]#[N:22])[CH2:6]1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]2N(C#N)C1
Reactant: C1COCCN1
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H]2c3cccc4[nH]c(CN5CCOCC5)c(c34)C[C@H]2N(C#N)C1
Yield: 50 %

Procedure:
3.54 g of 6-cyano-8beta-ergoline-carboxylic acid methyl ester (12 mmol), 9.46 g of morpholine hydrochloride (77 mmol) and 1.77 g of paraformaldehyde (59 mmol) are heated in 90 ml of dimethylformamide for 30 minutes at 100° C. After cooling, the mixture is poured on ice, made alkaline with sodium carbonate solution and shaken out five times with toluene. The organic phases are washed with water, dried with sodium sulfate and concentrated by evaporation. The precipitated crystals are suctioned off, yield 4.71 g (quantitative). The substance is chromatographed on silica gel with dichloromethane/methanol (98:1 and 9:1), 3.05 g (64% of theory) is isolated. The substance can be crystallized from dichloromethane/diisopropylether, the pure substance is obtained in 50% yield. [α]D =+33.4° (0.5% in chloroform).
Reaction SMILES: [N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][C:10]([NH2:14])=[CH:9][C:8]=3[C:7]3([O:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:6]=12.N1C=CC=CC=1.C(Cl)Cl.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O>[N:1]1[CH2:2][CH2:3][CH2:4][N:5]2[C:13]3[CH:12]=[CH:11][C:10]([NH:14][C:29](=[O:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:9][C:8]=3[C:7]3([O:19][CH2:18][CH2:17][CH2:16][O:15]3)[C:6]=12
Reactant: Nc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc2c(c1)C1(OCCCO1)C1=NCCCN12)c1ccccc1
Reaction time: 2 h
Yield: 15.1 %

Procedure:
To a cold solution of 3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-amine (0.290 g, 1.44 mmol) and pyridine (0.349 mL, 4.32 mmol, 3 eq) in anhyd. CH2Cl2 (14.4 mL) was added benzoyl chloride (0.200 mL, 1.73 mmol, 1.2 eq) drop-wise with cooling in an ice bath under a dry N2 atmosphere. After stirring 2 hr. at room temperature the reaction was added to water. The reaction mixture was washed with Et2O (3×), basified with 2.5N NaOH and extracted with EtOAc (4×). The combined organic extracts were concentrated. The crude product was purified on Biotage KP silica gel eluting with CH2Cl2/CH3O H/NH4OH (98/1/1) to give the title compound as a yellow solid (0.079 g, 15% yield). NM (300 Mz, DMSO-d6): consistent.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].CO[CH:15](OC)[N:16]([CH3:18])[CH3:17].N1CC[CH2:23][CH2:22]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH:12]=[CH:18][N:16]1[CH2:15][CH2:23][CH2:22][CH2:17]1
Reactant: COC(OC)N(C)C
Reactant: C1CCNC1
Reactant: Cc1c(Br)cc(F)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc(Br)c1C=CN1CCCC1
Temperature: 110 °C

Procedure:
To a solution of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (1.78 g) in dimethylformamide (15 ml) was added dimethylformamide dimethyl acetal (3.0 ml) followed by pyrrolidine (0.63 ml) and heated to 110° C. After 24 hours the cooled reaction mixture was diluted with ethyl acetate, washed with water, brine, dried (MgSO4) and the solvent removed in vacuo to yield crude 1-[2-(2-bromo-4-fluoro-6-nitro-phenyl)-vinyl]-pyrrolidine.
Reaction SMILES: [NH2:1][OH:2].[CH2:3]([C:5]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=2)[N:6]=1)[CH3:4]>CO>[CH2:3]([C:5]1[C:9]([C:10](=[N:1][OH:2])[NH2:11])=[C:8]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])[N:7]([C:18]2[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=2)[N:6]=1)[CH3:4]
Reactant: CCc1nn(-c2ccc(O)cc2)c(-c2occc2C)c1C#N
Reactant: NO
Solvent: CO
Product: CCc1nn(-c2ccc(O)cc2)c(-c2occc2C)c1C(N)=NO
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 51.2 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.3 mL, 4.8 mmol) was added to 3-ethyl-1-(4-hydroxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carbonitrile (5 mg, 0.02 mmol) in MeOH (0.6 mL) and the reaction was stirred at 150° C. for 20 min in the microwave reactor. The crude reaction was purified on preparative HPLC to give 3-ethyl-N′-hydroxy-1-(4-hydroxyphenyl)-5-(3-methylfuran-2-yl)-1H-pyrazole-4-carboximidamide (3.34 mg, 63%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 327.1 (M+H), 325.23 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.13 (s, 1H), 7.53 (d, 1H, J=1.9 Hz), 7.05 (m, 2H), 6.80 (m, 2H), 6.36 (d, 2H, J=1.9 Hz), 2.83 (q, 2H, J=7.6 Hz), 1.76 (s, 3H), and 1.26 (t, 3H, J=7.6 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([NH:13][C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[C:16]([CH:31]3[CH2:33][CH2:32]3)=[N:17][N:18]4[CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.[OH-].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][OH:45])[CH2:39][CH2:38]1>O.CS(C)=O.C1COCC1>[CH:31]1([C:16]2[C:15]3[C:19](=[CH:20][CH:21]=[CH:22][C:14]=3[NH:13][C:11]([C:8]3[N:5]4[CH:6]=[CH:7][C:2]([O:45][CH2:44][CH2:43][N:40]5[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]5)=[CH:3][C:4]4=[N:10][CH:9]=3)=[O:12])[N:18]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=3)[N:17]=2)[CH2:32][CH2:33]1
Reactant: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(Cl)ccn45)cccc32)n1
Reactant: CN1CCN(CCO)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(Cn2nc(C3CC3)c3c(NC(=O)c4cnc5cc(OCCN6CCN(C)CC6)ccn45)cccc32)n1
Temperature: 95 °C
Reaction time: 3 h
Yield: 73.8 %

Procedure:
7-Chloro-N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide (5.0 g, 10.9 mmol), potassium hydroxide (3.38 g, 60.2 mmol), DMSO (50 mL), and 2-(4-methylpiperazin-1-yl)ethanol (3.16 g, 21.9 mmol) were combined under nitrogen and heated to 95° C. for 16 hours. The mixture was cooled to ambient temperature and THF (300 mL) was added. The slurry was stirred at ambient temperature for 3 hours. The solids were filtered off and the THF removed from the filtrates under vacuum to give a DMSO solution of the product. The DMSO solution was heated to 60° C. and water (100 mL) was added to precipitate out the product. The slurry was cooled to ambient temperature and stirred for 18 hours. The solids were collected by filtration and washed with water (100 mL) and MTBE (50 mL). The material was dried under vacuum at 40° C. to give N-(3-cyclopropyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxamide (4.54 g). MS (ES+APCI) m/z=565.1 (M+H).