Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[C:10](=[CH:15][N:16]([CH3:18])C)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][N:26]2C(N)=[CH:29][CH:28]=[N:27]2)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:33]=[CH:32][C:24]([CH2:25][N:26]2[C:18]3[N:16]=[CH:15][C:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][C:11]=4[C:29]=3[CH:28]=[N:27]2)=[CH:23][CH:22]=1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: COc1ccc(Cn2nccc2N)cc1
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)OC(C)(C)C)CC4)cc1
Temperature: 130 °C

Procedure:
A mixture of tert-butyl-3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (10.2 g, 40.15 mmol) and 1-(4-methoxybenzyl)-1H-pyrazol-5-amine (8.55 g, 42.16 mmol) were heated at 130° C. for 48 hours. The reaction mixture was cooled and the crude product was purified by flash column chromatography (SiO2, gradient from 100% CH2Cl2 to 5% MeOH in CH2Cl2) to give the desired product tert-butyl 3-(4-methoxybenzyl)-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxylate as an off white solid (3.5 g, 22%). 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.99 (s, 1H), 7.14 (d, J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 2H), 5.62 (s, 2H), 4.71 (s, 2H), 3.82-3.74 (m, 5H), 3.07 (t, J=6.0 Hz, 2H), 1.44 (s, 9H). LCMS [M+H]: 395.
Reaction SMILES: Br[C:2]1[C:3]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:3]2[C:2]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(-c2ncc([N+](=O)[O-])cc2Br)c1
Reactant: OB(O)c1ccccc1
Product: COc1cccc(-c2ncc([N+](=O)[O-])cc2-c2ccccc2)c1

Procedure:
Obtained (0.257 g, 87% of yield) following the procedure described in Intermediate 2 (step A) starting with 3-bromo-2-(3-methoxyphenyl)-5-nitropyridine (0.97 mmol, 0.300 g) and phenylboronic acid (1.07 mmol, 0.130 g).
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=O)[CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Sodium hydride (60%, 202 mg, 5.06 mmol) was suspended in anhydrous THF (15 mL) and cooled in an ice bath. Ethyl 2-(diethoxyphosphoryl)propanoate (1.2 g, 5.06 mmol) was added dropwise under nitrogen and the mixture was stirred in an ice bath for 1 h. 1-(Diphenylmethyl)azetidin-3-one (1 g, 4.21 mmol) was added in portions as a solid and the mixture was stirred at room temperature for 1 h, then left to stir at room temperature overnight. Water (50 mL) was added and the mixture was extracted with DCM (3×50 mL). Brine was added, and the aqueous and organic layers were separated. The organic layer was dried over sodium sulfate and concentrated. The resulting crude yellow oil was purified by FCC, eluting with 0-50% EtOAc, to afford a clear oil which crystallised upon standing. The solids were sonicated with heptane and the remaining solid was collected by filtration. The filtrate was concentrated and sonicated with heptane to afford a second crop of solid. The filtrate was concentrated and the residue was sonicated with heptane to afford a further crop of solid material. The resultant solids were collected and combined to afford the title compound (892 mg, 66%) as a white solid. δH (250 MHz, CDCl3) 7.56-7.39 (m, 4H), 7.38-7.15 (m, 6H), 4.63-4.45 (m, 1H), 4.24-4.01 (m, 4H), 3.96-3.76 (m, 2H), 1.72-1.58 (m, 3H), 1.27-1.14 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][C:22]1[CH:26]=[C:25]([NH2:27])[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:20][C:5]1[C:6]([NH:8][C:9]2[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([NH:13][O:14][CH3:15])=[O:12])=[CH:7][C:2]([NH:27][C:25]2[N:24]([CH:28]([CH3:30])[CH3:29])[N:23]=[C:22]([CH3:21])[CH:26]=2)=[N:3][CH:4]=1
Reactant: Cc1cc(N)n(C(C)C)n1
Reactant: CONC(=O)c1ccccc1Nc1cc(Cl)ncc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2C(C)C)ncc1Cl
Temperature: 160 °C
Yield: 16.1 %

Procedure:
A microwave tube was charged with 2-[(2,5-dichloro-4-pyridinyl)amino]-N-(methyloxy)benzamide (70 mg, 0.224 mmol), 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (70 mg, 0.503 mmol) and cesium carbonate (230 mg, 0.706 mmol). The reaction mixture was degassed with nitrogen for 10 min. At same time, BINAP (50 mg, 0.080 mmol) and palladium(II) acetate (10 mg, 0.045 mmol) were added. The reaction mixture was heated in a microwave at 160° C. for 40 min. The crude material was purified on reverse-phase HPLC (Gilson) eluting with CH3CN/H2O with 0.1% formic acid which gave a title compound (15 mg, 15%); MS: M(C20H23ClN6O2)=414.89, (M+H)+=415, 416; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.42 (br. s., 1 H) 8.71 (br. s., 1 H) 8.02 (s, 1 H) 7.54 (br. s., 1H) 7.06 (t, J=7.5 Hz, 1 H) 6.48 (s, 1 H) 6.32 (br. s., 1 H) 5.86 (s, 1 H) 4.47 (dt, J=13.4, 6.7 Hz, 1 H) 3.92 (s, 3 H) 2.26 (s, 3H) 1.41-1.43 (d, J=6.6 Hz, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.[CH3:19][O:20][CH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[NH2:27]>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[N:6][CH:7]=[C:8]([CH:12]=2)[C:9]([NH:27][N:23]2[CH2:24][CH2:25][CH2:26][C@H:22]2[CH2:21][O:20][CH3:19])=[O:11])[CH2:2][CH2:3]1
Reactant: COC[C@@H]1CCCN1N
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CC2)c1
Product: COC[C@@H]1CCCN1NC(=O)c1cnc(OCC(F)(F)F)c(C2CC2)c1

Procedure:
The title compound was synthesized in analogy to the procedure described in Example 34 c), using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (example 34b) and (S)-2-methoxymethyl-pyrrolidin-1-yl amine as starting materials (CAN 59983-39-0); MS (ESI) 396.4 (M+Na)+.
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].C([O:9][C:10](=O)[CH:11]([C:20]#[N:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[Cl:19])C>C(O)C>[NH2:5][C:4]1[N:6]=[C:20]([NH2:21])[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[C:10]([OH:9])[N:3]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C(C#N)c1cccc(Cl)c1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Nc1nc(N)c(-c2cccc(Cl)c2Cl)c(O)n1

Procedure:
Sodium (1.2 g, 0.052 mol) was added in portions to absolute ethanol (50 ml) with stirring. After the sodium had dissolved guanidine hydrochloride (3.69 g, 0.039 mol) was added followed by ethyl-2-cyano-2-(2,3-dichlorophenyl)acetate (5 g, 0.0195 mol). The mixture was refluxed for 8 hours, EtOH was removed under reduced pressure and the residue was partitioned between EtOAc and water. The EtOAc layer was extracted with 2N NaOH and the extract was neutralised with 2N HCl with cooling. The precipitated solid was filtered and dried to give the title compound. (0.22 g), mp. 275° C. (decomp). Microanalysis:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C=O)C>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[O:19][CH2:18][CH2:17][O:13][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:12][CH:11]=1
Reactant: Oc1ccc(N2CCOCC2)cc1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(N2CCOCC2)ccc1OCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.1 %

Procedure:
4-morpholinophenol (0.358 g, 2 mmol) in DMF (5 mL) was cooled to 0° C. To this solution was added 60% NaH (0.192 g, 4.8 mmol). After the bubbling ceased, 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.501 g, 2.4 mmol) in DMF (2 mL) was added to the above solution. The solution was stirred at room temperature for 2 hours, and partitioned between EtOAc and water. The aqueous layer was extracted with additional EtOAc, and the combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 7:3 hexanes/EtOAc to give 0.48 g of the title compound (78%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:28][O:29][NH:30][CH3:31]>ClCCl>[CH3:28][O:29][N:30]([CH3:31])[C:12](=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)CCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
While under an atmosphere of argon, a room temperature solution of 4-(tert-butoxycarbonylamino) butanoic acid (20 g, 0.098 mol) in dichloromethane (280 mL, 0.35 M) was treated with CDI (17.6 g, 0.108 mol). After 1.5 hr, O,N-dimethylhydroxylamine hydrochloride (10.6 g; 0.108 mol) was added, and the resulting solution was stirred overnight. The mixture was added to a separatory funnel, diluted with dichloromethane (220 mL) and washed successively with 2 M HCl (2×), 1 M NaOH and sat'd aq sodium chloride, dried over MgSO4, filtered and concentrated to give tert-butyl 4-(methoxy(methyl)amino)-4-oxobutylcarbamate (23.8 g, 98%). ESI MS found for C11H22N2O4 m/z [269.4 (M+Na+)].
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C([Li])CCC.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.O>CCOCC.CCCCCC>[CH3:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[B:18]([OH:19])[OH:17]
Reactant: Cc1ccncc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccncc1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-4-methylpyridine (5.96 g) in ether (20 ml) was added dropwise to n-butyl lithium in hexane (1.57M;22 ml) in ether (100 ml) at -78° under nitrogen. After 10 min stirring at -78° triisopropylborate (10.2 ml) was added during 2 min. The mixture was stirred at -78° for 30min and allowed to warm to room temperature during 2 h. Water (30 ml) was added and the organic layer was extracted with aqueous sodium hydroxide (0.5N; 33 ml). The combined aqueous layers were washed with ether (30 ml) and then acidified to pH6 with hydrochloric acid (2N). The mixture was stirred until the resulting gum had solidified. Filtration gave the title compound as a white solid (1.5 g).
Reaction SMILES: [Br:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3](O)=[O:4].S(Cl)([Cl:12])=O>>[Br:1][CH:2]([C:6]([F:9])([F:8])[F:7])[C:3]([Cl:12])=[O:4]
Reactant: O=C(O)C(Br)C(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Br)C(F)(F)F

Procedure:
A solution of 2-bromo-3,3,3-trifluoropropanoic acid (5 g.) in thionyl chloride (5 ml.) is refluxed in the steam bath for two hours. The excess thionyl chloride is removed in vacuo, and the residue distilled under reduced pressure to yield 2-bromo-3,3,3-trifluoropropanoic acid chloride.
Reaction SMILES: S1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([CH2:17][N:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1.O[O:32][S:33]([O-:35])=O.[K+]>CO.O.C([O-])([O-])=O.[Na+].[Na+]>[O:32]=[S:33]1(=[O:35])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([CH2:17][N:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: c1cncc(N(Cc2cccnc2N2CCSc3ccccc32)c2cccnc2)c1
Reactant: O=S([O-])OO
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S1(=O)CCN(c2ncccc2CN(c2cccnc2)c2cccnc2)c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of: N-{[2-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)pyridine-3-yl]methyl}-N-pyridin-3-ylpyridin-3-amine (52 mg, 0.126 mmol) in methanol (1.5 mL) and water (1 mL) was added Oxone™ (97 mg, 0.157 mmol). The reaction progress was monitored by LC/MS and after 2 hours the reaction was diluted with water and Na2CO3 solution and the product was extracted into ethyl acetate, the solution dried, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-100% acetone/hexane gradient to give the title compound as a coloress glass. 1H-NMR (500 MHz, CDCl3): δ 8.51 (1H, d, J=3.6 Hz), 8.29 (2H, s), 8.26 (2H, d, J=3.9 Hz), 7.88 (2H, t, J=9.0 Hz), 7.26-7.31 (4H, m), 7.18-7.21 (2H, m), 7.00 (1H, t, J=7.3 Hz), 6.22 (1H, d, J=8.3 Hz), 4.76 (2H, s), 4.38 (2H, br s), 3.57 (2H, t, J=5.8 Hz). m/e (m+1): 444.2.
Reaction SMILES: Br.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27]C)[N:21]=2)[CH2:13][C@@H:14]2[NH:18][C:17](=[O:19])[CH2:16][CH2:15]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3]>O1CCOCC1>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([CH:12]([C:20]2[NH:21][C:22](=[O:27])[C:23]([Cl:26])=[CH:24][CH:25]=2)[CH2:13][C@H:14]2[CH2:15][CH2:16][C:17](=[O:19])[NH:18]2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COc1nc(C(C[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Cl
Agent: Br
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(C(C[C@H]2CCC(=O)N2)c2ccc(Cl)c(=O)[nH]2)cc1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
48% hydrobromic acid (1 mL) was added to a solution of (5R)-5-[2-(4-tert-butylphenyl)-2-(5-chloro-6-methoxypyridin-2-yl)ethyl]pyrrolidin-2-one (100 mg) in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 30 minutes and at 65° C. for 30 minutes. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The resulting residue was purified by preparative TLC (chloroform:methanol=10:1) to give 6-{1-(4-tert-butylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]ethyl}-3-chloropyridin-2(1H)-one, which was separated by preparative HPLC (Inertsil ODS-3 (20 mm i.d.×250 mm L, GL Sciences Inc.), 40° C., flow rate: 10 mL/min, acetonitrile:water=40:60). The fraction containing a single diastereomer eluted with a retention time of 43 minutes was concentrated to give the title compound as a white solid (18 mg, 19%) (Example 4-69).
Reaction SMILES: [NH2:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13](=[O:17])[CH2:14][C:15]#[N:16])=[O:11])=[O:3].O1CCOCC1.[N:24]([O-])=[O:25].[Na+].S(=O)(=O)(O)O>O.C(OCC)(=O)C.C(O)(=O)C>[NH2:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13](=[O:17])[C:14]([C:15]#[N:16])=[N:24][OH:25])=[O:11])=[O:3]
Reactant: N#CCC(=O)NC(=O)NCCCCCC(N)=O
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: N#CC(=NO)C(=O)NC(=O)NCCCCCC(N)=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
A mixture of 72 g of 1-(5-aminocarbonyl-pentyl)-3-(2-cyanoacetyl)-urea, 125 ml of water, 125 ml of dioxane, 23.2 g of sodium nitrite and 1 ml of acetic acid was adjusted to pH 4.5 to 5 at 50° C. by slowly adding 15% strength sulphuric acid dropwise. The reaction mixture was stirred at 50° C. for 2 hours, diluted with 600 ml of water and 600 ml of ethyl acetate, then cooled at 20° C. and adjusted to a pH value of 2. The crystals were separated off, washed with water and dried in vacuo. 61.3 g of 1-(5-aminocarbonyl-pentyl)-3-(2-cyano-2-oximinoacetyl)-urea of melting point 187°-189° C. were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20]C4C=C5C(CCN(C)C5=O)=CC=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.[Cl:33]CCCCO[C:39]1[CH:48]=[C:47]2[C:42]([CH2:43][CH2:44][N:45]([CH3:50])[C:46]2=[O:49])=[CH:41][CH:40]=1.CO.Cl>CO>[ClH:33].[S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:44]4[CH2:43][C:42]5[C:47](=[CH:48][CH:39]=[CH:40][CH:41]=5)[C:46](=[O:49])[N:45]4[CH3:50])[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CN1CCc2ccc(OCCCCCl)cc2C1=O
Reactant: CN1CCc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2C1=O
Agent: Cl
Solvent: CO
Product: CN1C(=O)c2ccccc2CC1OCCCCN1CCN(c2cccc3sccc23)CC1

Procedure:
By a similar method as in Example 1, 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one was prepared from 7-(4-chlorobutoxy)-2-methyl-3,4-dihydro-2H-isoquinolin-1-one, and after it was made into a methanol solution, 0.5N hydrochloric acid methanol solution was added thereto, precipitated crystals were separated by filtration, recrystallized from a mixed solvent of methanol-ethyl acetate and thereby 7-[(4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)butoxy]-2-methyl-3,4-dihydro-2H-isoquinolin-1-one hydrochloride was obtained in the form of a white powder.
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5](=[O:18])[CH:6]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:16]O)[CH3:7]>>[Br:1][CH2:16][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:9]=1[O:8][CH:6]([CH3:7])[C:5]([O:4][CH3:3])=[O:18]
Reactant: COC(=O)C(C)Oc1c(C)cccc1CO
Reactant: BrBr
Product: COC(=O)C(C)Oc1c(C)cccc1CBr

Procedure:
MS (EI) 286 (M)+, bromine pattern. Prepared from methyl 2-(2-hydroxymethyl-6-methyl-phenoxy)-propionate (example 23c).
Reaction SMILES: Cl.C1COO[C:5]([O:16][CH3:17])([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)[O:4]O1>O1CCCC1>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][C:5]([O:16][CH3:17])=[O:4])=[CH:9][CH:10]=1)=[O:15]
Reactant: COC1(CCc2ccc(C=O)cc2)OOCCOO1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
1M Hydrochloric acid (182 ml) was added to a stirred solution of methyl 3-(4-formylphenyl)propanoate ethylenedioxy acetal (16 g, 68 mmole, from example 33) in tetrahydrofuran (1100 ml) at 0° C. and the mixture stirred overnight at room temperature. The acid was neutralised and the product was extracted into ether. Evaporation of the dried (MgSO4) extracts gave 10.54 g (81%) of the title compound as an oil, νmax (film) 1735, 1700, 1605 cm-1, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:12]=2)[NH:5][C:6](=[O:10])[C:7]=1[N:8]=O.C(N(CC)CC)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:12]=2)[NH:5][C:6](=[O:10])[C:7]=1[NH2:8]
Reactant: Nc1nc(-c2cccc(Cc3ccccc3)c2)[nH]c(=O)c1N=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(-c2cccc(Cc3ccccc3)c2)[nH]c(=O)c1N
Temperature: 60 °C
Yield: 97.3 %

Procedure:
4-Amino-2-(3-benzylphenyl)-5-nitrosopyrimid-6-one (11.95 g.) was suspended in water (250 ml.), and triethylamine (20 ml.) was added, giving a purple-red solution. Sodium dithionite (12 g.) was added in portions during 30 minutes with shaking and heating at 60° C. After cooling, the mixture was extracted three times with chloroform, and the combined extracts were dried over magnesium sulphate and evaporated to give crude 4,5-diamino-2-(3-benzylphenyl)pyrimid-6-one (11.1 g.), sufficiently pure to use in the above preparation of 8-aza-2-(3-benzylphenyl)purin-6-one.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1.[I-].[Na+]>C1(C)C=CC=CC=1>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:35][CH2:34]2)=[CH:31][CH:32]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Yield: 36.1 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (5.3 g), triethylamine (2.6 cc), 4-(4-chlorophenyl) piperazine (5 g) and sodium iodide (2.8 g) in toluene (50 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After recrystallization, firstly from boiling acetonitrile 6 hours and secondly from boiling methyl ethyl ketone (15 cc), 2-{3-[4-(4-chlorophenyl)-1-piperazinyl ]propyl}naptho[1,8-cd]isothiazole 1,1-dioxide (3 g) is obtained, m.p. 120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[S:22])OC2C=CC=CC=2)=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:34]2[CH2:33][CH2:32][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:36][CH2:35]2)=[S:22])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: COc1nc2ccccc2cc1NC(=S)Oc1ccccc1
Product: COc1cccc(N2CCN(C(=S)Nc3cc4ccccc4nc3OC)CC2)c1
Yield: 81 %

Procedure:
Phenyl N-(2-methoxyquinolin-3-yl)thiocarbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 109 to obtain the titled compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH:5]([CH3:6])[CH3:4])[C:2]=1[NH2:1])([CH3:7])[CH3:3]
Reactant: Nc1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1N

Procedure:
The coupling reaction was carried out in toluene using Pd2(dba)3 as the catalyst precursor and the desired aniline at 90° C. overnight. After the reaction was completed the solution turned dark with an intense yellow coloration. Both compounds were isolated as yellow solids. 2-Ph-H was synthesized in good yield (76%), but when 2,6-diisopropylaniline was used to produce 2-Dipp-H, the yield decreased considerably (46%). Even over increased periods of time, no significant change in the yield was observed. This result is most likely a consequence of the steric hindrance afforded by the bulky 2,6-diisopropyl groups, diminishing the coordination of the amine to the palladium center. Neither 2-Ph-H nor 2-Dipp-H displayed fluorescence upon irradiation with UV light (254 nm). For 2-Dipp-H the 1H NMR displayed the characteristic resonance for the 2,6-diisopropyl groups and both ligands showed the amine proton shifted down field. The aromatic region of the 1H NMR spectrum was complicated by the overlap of some signals; nevertheless it was fully assigned using 2D experiments.