Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=1.[C:12]1([O:18][CH2:19][CH:20]2[O:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH2:23]>CS(C)=O>[OH:22][CH:20]([CH2:19][O:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:21][N:1]([CH2:19][CH:20]([OH:22])[CH2:21][O:23][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:2][CH2:3][C:4]1[S:8][C:7]([C:9]([NH2:11])=[O:10])=[CH:6][CH:5]=1
Reactant: NCCc1ccc(C(N)=O)s1
Reactant: O
Reactant: c1ccc(OCC2CO2)cc1
Solvent: CS(C)=O
Product: NC(=O)c1ccc(CCN(CC(O)COc2ccccc2)CC(O)COc2ccccc2)s1

Procedure:
3.4 g of 5-(2-aminoethyl)-2-thiophenecarboxamide and 2.7 ml of 2,3-epoxypropyl phenyl ether were heated to 90° in 30 ml of dimethylsulfoxide for 18 hours. The reaction mixture was poured into water and extracted with methylene chloride. The dried methylene chloride solutions were evaporated and the residue was chromatographed on silica gel with ether-methanol. There were obtained 1.5 g of 5-[2-[bis-[(RS)-2-hydroxy-3-phenoxypropyl]amino]ethyl]-2-thiophenecarboxamide, ε277 =12580.
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4].C[O:18][C:19]([CH3:21])=[CH2:20].CS(O)(=O)=O.CC([O-])=O.[Na+]>CCCCCCC>[CH3:15][C@H:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][C@H:2]([CH2:3][CH2:4][CH2:20][C:19]([CH3:21])=[O:18])[CH3:1]
Reactant: C=C(C)OC
Reactant: C#CC(C)(O)CCCC(C)CCCC(C)C
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [Na+]
Solvent: CCCCCCC
Product: CC(=O)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Temperature: 25 °C
Yield: 91 %

Procedure:
56.1 g 3,7,11-trimethyl-1-dodecin-3-ol, 27.0 g isopropenyl methyl ether and 100 mL n-heptane were initially introduced into a 500 ml flask. 14.5 mg methanesulfonic acid were added, while stirring. The reaction mixture was stirred under reflux for 7.5 hours. During this period of time, 36.5 g isopropenyl methyl ether and 21.6 mg methanesulfonic acid were added in each case in two portions. The mixture was cooled to room temperature, neutralized with 3 ml methanolic NaOAc solution (10 g/1) and evaporated. The crude was hydrogenated with 10% Pd/C in isopropanol. Phytone was obtained in a yield of 91%.
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([C:32]3([CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)O1>>[C:40]([O:39][C:38](=[O:44])[NH:37][CH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]4[C:4]5[CH:17]=[CH:16][S:15][C:5]=5[C:6](=[O:14])[NH:7][C:8]=4[CH:9]=[CH:10][C:11]=3[O:12][CH3:13])=[CH:31][CH:30]=2)[CH2:35][CH2:34][CH2:33]1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CC(C)(C)OC(=O)NCC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Product: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(C2(CNC(=O)OC(C)(C)C)CCC2)cc1
Yield: 51 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (1.9 g, 6.0 mmol) was reacted with tert-butyl (1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutyl)methylcarbamate (3.5 g, 9.0 mmol) to afford the desired product (1.5 g, 33%) as a light brown solid: ESI MS m/z 491 [C28H30N2O4S+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].C1C=C(Cl)C=C(C(OO)=[O:39])C=1>C(Cl)Cl>[N+:1]([C:4]1[C:5]([N:13]2[CH2:18][C@H:17]([C:19]([F:22])([F:21])[F:20])[CH2:16][C@H:15]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[CH2:14]2)=[C:6]2[CH2:12][CH2:11][CH2:10][C:7]2=[N+:8]([O-:39])[CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 13 h
Yield: 61.7 %

Procedure:
To a mixture of tert-butyl [(3S,5R)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (179.2 mg, 0.4163 mmol) and mCPBA (210.6 mg, 0.9397 mmol) was added DCM (2.00 mL). The reaction mixture was stirred at room temperature for 13 h. The mixture was diluted with DCM (30 mL), washed with 1 M NaOH aqueous solution. The separated aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound (114.7 mg, 62%). LCMS calc. for C19H26F3N4O5 (M+H)+: m/z=447.2. found 447.2.
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]([C:9]([CH3:12])([CH3:11])[CH3:10])=[N:5][N:4]=[C:3]1[S:13][CH3:14].O.[C:16]([OH:20])(=[O:19])[CH:17]=[O:18]>C(OCC)(=O)C>[CH3:14][S:13][C:3]1[N:2]([NH:1][CH:17]([OH:18])[C:16]([OH:20])=[O:19])[C:7](=[O:8])[C:6]([C:9]([CH3:11])([CH3:10])[CH3:12])=[N:5][N:4]=1
Reactant: CSc1nnc(C(C)(C)C)c(=O)n1N
Reactant: O=CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nnc(C(C)(C)C)c(=O)n1NC(O)C(=O)O
Reaction time: 3 h
Yield: 87.4 %

Procedure:
21.4 g (0.1 mol) of 4-amino-6-tert.-butyl-3-methylthio-1,2,4-triazin-5-one and 10.1 g (0.11 mol) of glyoxylic acid monohydrate were stirred in 250 ml of ethyl acetate for 12 hours at room temperature, whereby a clear solution was produced. The mixture was then left to stand; after about 3 hours, the product began to crystallize out. It was filtered off and the filtrate was concentrated, whereupon further material crystallized out. The combined filter residues were washed with ether and dried. 25.2 g (87.5% of theory) of N-(3-methylthio-6-tert.-butyl-1,2,4-triazin-5-on-4-yl)- α-hydroxy-glycine of melting point 161° C (decomposition) were obtained.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:31][CH:32]=1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NCC(O)c1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1ccc2ccccc2c1

Procedure:
A procedure similar to that described in Preparation 10, below, was followed, but using 520 mg of 2-amino-1-(2-naphthyl)ethanol [prepared as described in Preparation 8], 650 mg of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Preparation 9], 150 ml of benzene, 100 ml of absolute methanol and 1.25 g of sodium borohydride, to give the title compound in crude form. This crude product was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 490 mg of the title compound melting at between 115° C. and 145° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)=[O:33])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: COc1cccc(N=C=O)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cccc(NC(=O)NCc2ccc3c(c2)C(=O)N(C2CCC(=O)NC2=O)C3=O)c1
Temperature: 40 °C
Yield: 6.1 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3-methoxyphenylisocyanate (0.45 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The residue was triturated in Et2O (50 mL) for 3 h at rt, then refluxed in acetone (50 mL) for 1 h. The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(3-methoxy-phenyl)-urea as a white solid (0.08 g, 6% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.01 min (99.44%); mp: 323-325° C.; 1H NMR (DMSO-d6) δ 2.03-2.09 (m, 1H, CHH), 2.49-2.63 (m, 2H, CHH, CHH), 2.85-2.91 (m, 1H, CHH), 3.70 (s, 3H, CH3), 4.47 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 13.5 Hz, 1H, CH), 6.47-6.50 (m, 1H, Ar or NH), 6.82-6.91 (m, 2H, Ar or NH), 7.09-7.15 (m, 2H, Ar or NH), 7.78-7.91 (m, 3H, Ar or NH), 8.74 (s, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.90, 42.57, 48.96, 54.81, 103.52, 106.72, 110.14, 121.63, 123.47, 129.36, 129.65, 131.57, 133.17, 141.49, 143.07, 148.75, 155.16, 159.60, 167.02, 167.18, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6: C, 58.38; H, 4.85; N, 12.38. Found: C, 58.36; H, 4.45; N, 11.98.
Reaction SMILES: C[Si](C)(C)[N:3]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=1)[Si](C)(C)C.[CH:17]([N-]C(C)C)(C)C.[Li+].[C:25](=[O:27])=[O:26]>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[CH3:17][O:26][C:25](=[O:27])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([NH2:3])[N:9]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C=O
Reactant: Cc1cccc(N([Si](C)(C)C)[Si](C)(C)C)n1
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(N)n1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
1,1,1,3,3,3-Hexamethyl-2-(6-methyl-pyridin-2-yl)-disilazane (1.7 g) under an argon atmosphere in THF (20 mL) was cooled to −20° C. and treated dropwise at −20° C. with 6.73 mL of a 2 M solution of lithium diisopropylamide in THF/heptane/ethylbenzene (Fluka). The solution was stirred 1 h at −20° C., cooled to −70° C. and then treated with an access of dry ice. The mixture was allowed to warm to 0° C. and then quenched with trifluoro-acetic acid(0.57 ml) and concentrated in vacuo. The residue was taken up in MeOH and added dropwise to a solution of thionyl chloride (9.77 mL) in MeOH (30 ml) at 0° C. The reaction mixture was then heated to reflux for 24 h, cooled to RT and concentrated in vacuo. The residue was partitioned between aqueous diluted NaHCO3 and AcOEt, the layers were separated, the organic layer dried over Na2SO4, filtered, evaporated and the residue purified by flash chromatography (heptane/AcOEt 1:1) to give (6-amino-pyridin-2-yl)-acetic acid methyl ester as a crystalline off-white solid (0.429 g). MS (EI): 166.0 (M+).
Reaction SMILES: [Na].Cl[C:3]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[CH3:16][OH:17]>>[CH3:16][O:17][C:3]1[N:12]=[C:11]([CH3:13])[C:10]([CH2:14][CH3:15])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CO
Reactant: CCc1cc(C(=O)OC)c(Cl)nc1C
Agent: [Na]
Product: CCc1cc(C(=O)OC)c(OC)nc1C
Yield: 73 %

Procedure:
To a solution of sodium metal (0.55 g, 24 mmol) dissolved in anhydrous methanol (15 mL), under a nitrogen atmosphere, was added a solution of methyl 2-chloro-5-ethyl-6-methylnicotinate (3.18 g, 14.9 mmol) in dry methanol (5 mL). This solution was refluxed and monitored by tlc (thin layer chromatogram) until the starting material had been consumed (about 24 hours). The cooled mixture was diluted with diethyl ether (50 mL), washed with water, saturated aqueous NaHCO3, dried (Na2SO4), filtered and the solvent evaporated to yield 2.28 g (73%) of pure product as a light yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9](=[O:18])[N:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Na+].O.CN([CH:31]=[O:32])C>>[CH3:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([CH:31]=[O:32])[C:9](=[O:18])[N:8]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN(C)C=O
Reactant: Cn1c(-c2ccncc2)cc(=O)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccncc2)c(C=O)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a 25 ml round-bottom flask with stirbar was added N,N-dimethylformamide (10.0 ml, 130 mmol). The flask was cooled in an ice water bath, and phosphorous oxychloride (4.2 ml, 45 mmol) was added. The reaction was warmed to room temperature and stirred under nitrogen. After 50 minutes, this was transferred, first via syringe and then pipette, to a solution of 1-methyl-2-phenyl-5-(pyridin-4-yl)-1,2-dihydropyrazol-3-one (3.31 g, 13 mmol) in DMF (18 ml). The flask was placed in a preheated oil bath (120 C), stirred for 12 minutes, and then cooled to room temperature. The reaction was poured into a aqueous solution of 5 N NaOH (40 ml) and diluted with ice water (˜75 ml). More ice and water were added. The aqueous phase was extracted with chloroform and the organic extracts were dried over sodium sulfate, filtered, and concentrated. DMF present, so the crude material was diluted with chloroform and washed with water. The aqueous extractions were extracted with chloroform, and the organic layers were combined, dried over sodium sulfate, filtered, and concentrated to give the crude product. MS (ESI pos. ion) m/z: 280 (MH+). Calc'd exact mass for C16H13N3O2: 279. Material taken to next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[N+:18](C(C)(C)C)#[C-:19]>CO>[F:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[N:8]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[C:19]=2[NH2:18])=[CH:12][CH:11]=1
Reactant: Cc1ccc(N)nc1
Reactant: [C-]#[N+]C(C)(C)C
Reactant: O=Cc1ccc(F)cc1
Solvent: CO
Product: Cc1ccc2nc(-c3ccc(F)cc3)c(N)n2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-methylpyridin-2-amine (260 mg, 2.4 mmol) in 20 mL of MeOH was added 4-fluorobenzaldehyde (0.26 mL, 2.40 mmol), and followed by 1.0 N HClO4 in MeOH (0.20 mL, 0.20 mmol). The reaction mixture was stirred at room temperature for 0.5 hour which was followed by addition of 2-isocyano-2-methylpropane (0.23 mL, 2.0 mmol). The stirring was continued at room temperature overnight. HPLC/MS test showed that the desired product Reference Compound 76-1 was a major peak.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cc1cccc(OCOC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1cccc(OCOC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(3-(methoxymethoxy)phenyl)acetate (8.06 g, 35.9 mmol) in DMF (50 mL) was added NaH (1.74 g, 43.5 mmol) and iodomethane (6.37 g, 44.9 mmol) at 0° C. The reaction mixture was stirred for 1 hrs at 0° C. then diluted with H2O (250 mL) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:10) as eluant.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[Cl:18]C1C=CN=CC=1C1N=CN(CN2C(=O)C3C(=CC=CC=3)C2=O)C=1.NN>C(O)C>[Cl:18][C:4]1[CH:3]=[CH:2][N:7]=[CH:6][C:5]=1[C:8]1[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:11][CH:12]=1
Reactant: NCCCCc1nc(-c2ccc(Cl)nc2)c[nH]1
Reactant: O=C1c2ccccc2C(=O)N1Cn1cnc(-c2cnccc2Cl)c1
Agent: NN
Solvent: CCO
Product: NCCCCc1nc(-c2cnccc2Cl)c[nH]1
Temperature: 65 °C
Yield: 94 %

Procedure:
4-[4-(6-chloro-3-pyridyl)imidazolyl]butylamine. To a solution of 2-[4-(4-chloro-pyridin-3-yl)-imidazol-1-ylmethyl]-isoindole-1,3-dione (2.82 g, 7.42 mmoles) in ethanol (75 ml) was added hydrazine (0.58 ml, 18.6 mmoles). After heating the reaction mixture in a 65° C. oil bath for 15 hours, the solution was cooled, filtered, and concentrated. The resulting oil was taken up in dichloromethane (200 ml) and was washed with 1M NaOH (250 ml). The aqueous layer was extracted further with dichloromethane (2×200 ml), the combined organics were dried over MgSO4, filtered, and concentrated yielding 4-[4-(4-chloro-3-pyridyl)imidazolyl]butylamine (1.74 g, 94%). MH+(251)
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([SH:17])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18]([O-])([O-])=O.[Cs+].[Cs+].IC>CC#N>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([S:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nn(-c2ccccc2)c2cc(Br)ccc12
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: CSc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 6-bromo-1-phenyl-1H-indazole-3-thiol (24 g, 78.69 mmol, 1.00 equiv) in CH3CN (200 mL), Cs2CO3 (28.8 g, 88.34 mmol, 1.12 equiv). To the resulting mixture as then added iodomethane (12.6 g, 88.73 mmol, 1.13 equiv) dropwise with stirring at room temperature. The resulting solution was stirred for 60 min at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield 6-bromo-3-(methylthio)-1-phenyl-1H-indazole as a yellow solid. MS: 328 (MH+).
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19]>O1CCCC1>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[CH:4]([C:1](=[O:3])[CH2:2][C:17](=[O:23])[C:18]([OH:20])=[O:19])[CH2:5]1
Reactant: CC(=O)C1COc2ccccc2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)C1COc2ccccc2C1=O

Procedure:
A solution of 3-acetyl-4-chromanone (1.8 g, 9.5 mmoles, described in Example 5) in dry tetrahydrofuran (20 ml) is added dropwise to a suspension of 57% sodium hydride (1.17 g, 28.5 mmoles) in tetrahydrofuran (30 ml) and the mixture is heated at reflux temperature for 15 min. A solution of diethyl oxalate (1.39 g, 9.5 mmoles) is added dropwise under an atmosphere of nitrogen. The reaction mixture is heated at reflux temperature overnight and cooled to -40° C. A solution of 50% aqueous acetic acid (4 ml) is added and the reaction mixture evaporated. The residue is partitioned between chloroform and water, the organic phase is separated and the aqeuous phase is re-extracted with chloroform. The combined chloroform extracts are dried and evaporated. The residue is subjected to chromatography on silica gel. Elution with chloroform affords 4-(4-chromanon-3-yl)-2,4-dioxobutyric acid ethyl ester (VII; R1, R2, R3R4 and R17 = H, R19 = C2H5 and X = 0), which is crystallized from ether, m.p. 117°-119° C. b. Solid 3-acetyl-4-chromanone (0.570 g, 3 mmoles, described in Example 5) is added in portions at room temperature to a suspension of 57% sodium hydride (0.379 g, 9 mmoles) in dry tetrahydrofuran (10 ml). The mixture is heated within 15 min to 60° C and diethyl oxalate (0.438 g, 3 mmoles) in tetrahydrofuran (10 ml) is added. After heating at reflux temperature under an atmosphere of nitrogen for 17 hr., the solvent is removed under reduced pressure, the residue is dissolved in ice-water and extracted with ether. The aqeuous phase is acidified with 6N hydrochloric acid and extracted with chloroform. The organic phase is dried, evaporated, and the residue crystallized from methanol-chloroform to give 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid (VI; R1, R2, R3, R4 and R5 = H, and X = 0), νmaxnujol 1705, 1615 and 1560 cm-1. c. A solution of 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid ethyl ester [0.70 g, 2.4 mmoles, described above in (a)] in methanol is saturated with hydrogen chloride gas. The solution is heated at reflux temperature overnight and evaporated to dryness. The residue is chromatographed on silica gel using benzene-ethyl acetate (4:1). The eluate is evaporated and the residue is crystallized from chloroform-ether to give the title compound, m.p. 173°-174° C. d. In the same manner as described above in (c) but replacing 4(4-chromanone-3-yl)-2,4-dioxobutyric acid ethyl ester with an equivalent amount of the corresponding acid, 4-(4-chromanone-3-yl)-2,4-dioxobutric acid [described above in (b)], the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[N:25]=[CH:26][CH:27]=[N:28]2.[ClH:33]>>[ClH:33].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[N:25]=[CH:26][CH:27]=[N:28]4)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncccc2O)n1
Reactant: BrCc1cccc2nccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1csc(Nc2ncccc2OCc2cccc3nccnc23)n1
Yield: 31.5 %

Procedure:
2-(4-Methylthiazol-2-ylamino)pyridin-3-ol (prepared according to Example 3, Step A; 70 mg, 0.338 mmol), potassium carbonate (117 mg, 0.844 mmol) and 5-(bromomethyl)quinoxaline (75.3 mg, 0.338 mmol) [Hardie, M. J., Org. Biomol. Chem. (2004), 2(20), 2958] were reacted according to Example 3, Steps B and C, to provide N-(4-methylthiazol-2-yl)-3-(quinoxalin-5-ylmethoxy)pyridin-2-amine hydrochloride (41.1 mg, 31.5% yield) as a yellow solid after HCl salt formation. 1H NMR (d6-DMSO) δ 9.12 (d, 1H), 9.07 (d, 1H), 8.26 (d, 1H), 8.16 (d, 1H), 8.04 (d, 1H), 7.93 (t, 1H), 7.73 (d, 1H), 7.15 (dd, 1H), 6.85 (s, 1H), 5.88 (s, 2H), 2.33 (s, 3H). Mass spectrum (apci) m/z=350.0 (M+H-HCl).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCC)(OCC)OCC.C[O:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH:24]=O>>[OH:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: COc1cccc(C=O)c1
Reactant: BrCc1ccccc1
Agent: CCOP(OCC)OCC
Product: Oc1cccc(C=Cc2ccccc2)c1
Yield: 29.7 %

Procedure:
Analogously to Example 1, reaction of 20.0 g (0.12 mol) of benzyl bromide, 38.9 g (0.23 mol) of triethyl phosphite and 15.9 g (0.12 mol) of 3-methoxybenzaldehyde yields 7.0 g of 3-hydroxystilbene, corresponding to formula