Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].O[C:16]1(NC(=O)CCC)[C:25]2[C:20](=[CH:21][C:22]([CH3:26])=[CH:23][CH:24]=2)[N:19]=[CH:18][CH2:17]1.[N:33]1C=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:26][C:22]1[CH:23]=[CH:24][C:25]2[C:16]3[S:2][C:34]([CH2:35][CH2:36][CH3:37])=[N:33][C:17]=3[CH:18]=[N:19][C:20]=2[CH:21]=1
Reactant: c1ccncc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCCC(=O)NC1(O)CC=Nc2cc(C)ccc21
Product: CCCc1nc2cnc3cc(C)ccc3c2s1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, phosphorus pentasulfide (1.15 g, 2.6 mmol) was added to a mixture of N-(4-hydroxy-7-methylquinolin-4-yl)butyramide (630 mg, 2.6 mmol) in pyridine (20 mL). The reaction mixture was heated to reflux. The reaction mixture turned bright yellow and all of the solid went into solution. The reaction mixture was heated at reflux for about 2 hours and then allowed to cool to ambient temperature. The reaction mixture was extracted with water, aqueous sodium bicarbonate and dichloromethane. The organic layer was treated with saturated copper sulfate, dried with magnesium sulfate and then concentrated under vacuum to provide an oil. The oil was dried under high vacuum to provide 410 mg of 7-methyl-2-propylthiazolo[4,5-c]quinoline as an orange solid.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[S:22][C:23]3[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=3[C:25](=[O:27])[N:26]=2)[N:16]=1)(=O)=O.[C:32](OCC)(=O)C>CN(C=O)C.O>[N:5]1[CH:6]=[CH:7][C:2]([S:1][CH2:32][C:15]2[N:16]=[C:17]([C:21]3[S:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[C:25](=[O:27])[N:26]=3)[CH:18]=[CH:19][CH:20]=2)=[CH:3][CH:4]=1
Reactant: CS(=O)(=O)Oc1cccc(-c2nc(=O)c3ccccc3s2)n1
Reactant: Sc1ccncc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1nc(-c2cccc(CSc3ccncc3)n2)sc2ccccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 17 %

Procedure:
4-Mercaptopyridine (0.21 g, 1.89 mmol) and sodium hydride (60% in oil, 0.083 g, 2.06 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl methanesulfonate (0.60 g, 1.72 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.11 g, 17%) as pale yellow crystals.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[NH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][OH:26]>>[OH:26][CH2:25][C:24]([NH:23][C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2)([CH3:28])[CH3:27]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CC(C)(N)CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)CO
Temperature: 100 °C
Yield: 17 %

Procedure:
Prepared similarly to that described in Example 131 using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 48 mg, 0.162 mmol) and 2-amino-2-methylpropan-1-ol (31.1 μl, 0.324 mmol, Sigma-Aldrich), heating at 100° C. for 1.5 h. Purification by silica gel (100% DCM to 6% MeOH/DCM) provided 2-(3-((1-hydroxy-2-methylpropan-2-yl)amino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (17% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 (s, 6H) 2.56 (s, 3H) 2.88 (t, J=6.94 Hz, 2H) 3.45 (td, J=6.80, 2.45 Hz, 2H) 3.66 (d, J=5.28 Hz, 2H) 5.15 (t, J=5.58 Hz, 1H) 5.87 (s, 1H) 6.96 (br. s., 1H) 7.03 (d, J=2.15 Hz, 1H) 7.35 (t, J=7.82 Hz, 1H) 7.59 (dd, J=8.02, 1.37 Hz, 1H) 7.84 (dd, J=7.43, 1.37 Hz, 1H) 12.03 (br. s., 1H). MS (ESI, pos. ion) m/z: 366.0 (M+1).
Reaction SMILES: Cl.CO.[OH:4][C:5]1[CH:15]=[CH:14][C:8]2[C:9](=[O:13])[CH:10]=[CH:11][O:12][C:7]=2[CH:6]=1.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH:22]=O)[CH3:17]>O>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH:22]=[C:10]2[C:9](=[O:13])[C:8]3[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=3[O:12][CH2:11]2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:17]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: O=c1ccoc2cc(O)ccc12
Agent: Cl
Solvent: CO
Solvent: O
Product: CCOc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OCC
Reaction time: 72 h

Procedure:
After a saturated hydrogen chloride-methanol solution 20 ml was added to 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-diethoxybenzaldehyde 1.58 ml, the mixture was srtirred for 72 hours, water 100 ml was added, and the precipitated crystals were filtered. The crystals were added to methanol 60 ml of 55° C., and the mixture was stirred for 15 minutes and filtered. The resulting crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.762 g.
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:36])[C:18]([C:24]3[CH:35]=[CH:34][C:27]4[N:28]([CH3:33])[C:29](=[O:32])[N:30]([CH3:31])[C:26]=4[CH:25]=3)([OH:23])[C:19]([F:22])([F:21])[F:20])=[C:13]([Cl:37])[CH:12]=2)=[CH:6][C:5]=1[F:38].[Li+].[OH-].CO>C1COCC1>[Cl:37][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=1[CH:17]([CH3:36])[C:18]([C:24]1[CH:35]=[CH:34][C:27]2[N:28]([CH3:33])[C:29](=[O:32])[N:30]([CH3:31])[C:26]=2[CH:25]=1)([OH:23])[C:19]([F:21])([F:22])[F:20])[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[C:5]([F:38])[CH:6]=1
Reactant: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4c(c3)n(C)c(=O)n4C)C(F)(F)F)c(Cl)c2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(c1ccc(Oc2ccc(C(=O)O)c(F)c2)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
To 4-{3-chloro-4-[2-(1,3-dimethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-fluoro-benzoic acid methyl ester (400 mg) aqueous 1N LiOH (1.5 ml), MeOH (5 ml) and THF (10 ml) were added. The resulting solution was stirred for 1 h at room temperature. Volatile solvents were removed in vacuo. The residual aqueous solution was diluted with water (10 ml) and then acidified to pH 6 with 1 N aqueous HCl and extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4 and concentrated to give the title compound (300 mg) as a white foam. MS (m/e)=551.2 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([O:25]CC3C=CC=CC=3)=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1.[H][H]>O1CCCC1.[Pd]>[CH3:1][O:2][C:3](=[O:34])[C:4](=[O:33])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][O:14][C:15]2[C:24]([OH:25])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OCCOc2cc3ccccc3cc2O)cc1
Yield: 18.3 %

Procedure:
A mixture of alpha-oxo-4-[[2-[3-(phenylmethoxy)-2-naphthalenyloxy]ethyl]oxy]benzeneacetic acid methyl ester (0.456 g) in tetrahydrofuran (3 mL) was added to a flask containing 10% palladium on carbon catalyst and 5 mL of tetrahydrofuran in a hydrogen atmosphere. The mixture was stirred until one equivalent of hydrogen was absorbed and the reaction was filtered and the organic solvent was removed by evaporation. Chromatography on silica gel and elution with dichloromethane-hexane mixtures provided purified product. Crystallization from dichloromethane-diethyl ether gave 0.067 g of pure 4-[[2-(3-hydroxy-2-naphthalenyloxy)ethyl]oxy]-alphaoxobenzeneacetic acid methyl ester as a colorless solid, mp 177°-178° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][C:6](=[O:12])[CH2:5]2.[N:13]([O-])=O.[Na+].O.O.Cl[Sn]Cl.[C:22]([CH2:28][C:29]#[N:30])(=O)[C:23]([CH3:26])([CH3:25])[CH3:24]>Cl.C(O)C>[C:23]([C:22]1[CH:28]=[C:29]([NH2:30])[N:1]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH2:8][NH:7][C:6](=[O:12])[CH2:5]3)[N:13]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)CC(=O)NC2
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)CC(=O)NC3)n1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
To a suspension of 6-amino-1,2-dihydroisoquinolin-3(4H)-one (4.00 g, 20.1 mmol) in 2M HCl (40 mL) at −10° C. was added solid NaNO2 (1.39 g, 20.1 mmol) causing all solids to dissolve. The mixture was stirred at −10° C. for 30 min and then solid SnCl2.2H2O (9.09 g, 40.3 mmol) was added at −10° C. The mixture was allowed to warm to RT over a period of 30 min and then stirred for 2 h. Ethanol (160 mL) and pivaloylacetonitrile (2.52 g, 20.1 mmol) were added and the solution was heated at reflux overnight under Ar atm. The EtOH was removed under reduced pressure, H2O (200 mL) was added, and the mixture was extracted with CH2Cl2 (3×200 mL), dried (MgSO4), concentrated and purified via column chromatography to yield 6-(3-t-butyl-5-amino-1H-pyrazol-1-yl)-1,2-dihydroisoquinolin-3(4H)-one (1.98 g, 35% yield). 1H NMR (400 MHz, CDCl3): δ 7.82 (brs, 1H), 7.40 (brs, 1H), 7.35 (dd, J=8.4, and 2.4 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 5.52 (s, 1H), 3.67 (brs, 2H), 3.01 (t, J=7.8 Hz, 2H), 2.65 (t, J=7.4 Hz, 2H), 1.30 (s, 9H); MS (ESI) m/z: 285.2 (M+H+).
Reaction SMILES: [C:1]([O:11]C)(=O)[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1.C(O)(=O)C1NC(=O)NC(=O)C=1.S(Cl)([Cl:26])=O>N1C=CC=CC=1>[C:1]([Cl:26])(=[O:11])[C:2]1[NH:9][C:7](=[O:8])[NH:6][C:4](=[O:5])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(=O)[nH]c(=O)[nH]1
Agent: O=C(O)c1cc(=O)[nH]c(=O)[nH]1
Solvent: c1ccncc1
Product: O=C(Cl)c1cc(=O)[nH]c(=O)[nH]1

Procedure:
Org. Chem, 27, 3507 (1962) describes that methyl orotate can be synthesized by reacting orotic acid with thionyl chloride in the presence of a catalytic amount of pyridine to give orotyl chloride, which is then heated in methanol.
Reaction SMILES: O[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1
Reactant: CCOC(=O)c1c(O)nc2cc(C(F)(F)F)cnc2c1C
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)cnc2c1C
Temperature: 110 °C
Yield: 88 %

Procedure:
To ethyl 2-hydroxy-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (1.05 g, 3.50 mmol, 1 eq.) was added POCl3 (11 ml) at RT and the reaction mixture was heated to reflux at 110° C. for 3 h. Afterwards excess POCl3 was distilled off and the residue was diluted with EtOAc (50 ml). The mixture was washed with a sat. solution of NaHCO3 (50 ml), water (50 ml), brine (50 ml), dried over anhydrous Na2SO4 and evaporated to provide ethyl 2-chloro-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.98 g, 3.08 mmol, 88%), which was used in subsequent reactions without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]1[CH3:10].Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]N)=[CH:15][CH:14]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]2[N:19]([CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][CH:6]([CH3:9])[CH:5]3[CH3:10])[C:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][C:24]=3[C:15]=2[CH:14]=1
Reactant: CC1CCN(CCBr)C1C
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CC1CCN(CCn2c3c(c4cc(Cl)ccc42)CN(C)CC3)C1C

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-2,3-dimethylpyrrolidine, 4-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11](=[O:20])[NH:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([OH:19])[CH2:15][CH2:14]1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[C:6]([O:10][C:11]([NH:12][C@H:13]1[CH2:14][CH2:15][C@H:16]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:18]1)=[O:20])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (135 μl, 1.74 mmol) was added to a cooled (ice bath, 0-4° C.), stirred solution of trans-(4-hydroxycyclohexyl)carbamic acid tert-butyl ester (0.25 g, 1.16 mmol) and triethylamine (243 μl, 1.74 mmol) in dichloromethane (10 ml). Following the addition the reaction was stirred at this temperature for 30 minutes before being allowed to warm to ambient temperature. After stirring at ambient temperature for 2 hours, aqueous sodium hydrogen carbonate (10 ml) was added, followed by vigorous stirring for 30 minutes. The reaction was diluted with dichloromethane (20 ml) and aqueous sodium hydrogen carbonate (20 ml) and after partitioning the organic phase was washed with water (20 ml), dried (magnesium sulphate) and evaporated to dryness under reduced pressure to yield methanesulfonic acid trans-4-tert-butoxycarbonylaminocyclohexyl ester (340 mg, 100%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[C:6]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]([C:20]4[NH:24][C:23]5[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=5[N:21]=4)=[O:19])=[CH:14][CH:13]=3)=[N:7][CH:8]=[CH:9][N:10]=2)[CH2:2]1.C(N(CC)CC)C.N1([C:41](=[O:43])[CH3:42])C=CN=C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[NH:24]1[C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]=[C:20]1[C:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][C:6]2[C:5]([CH:3]3[CH2:4][N:1]([C:41](=[O:43])[CH3:42])[CH2:2]3)=[N:10][CH:9]=[CH:8][N:7]=2)=[CH:13][CH:14]=1)=[O:19]
Reactant: O=C(c1ccc(Oc2nccnc2C2CNC2)cc1)c1nc2ccccc2[nH]1
Reactant: CC(=O)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 36 %

Procedure:
To a solution of (4-(3-(azetidin-3-yl)pyrazin-2-yloxy)phenyl)(1H-benzo[d]imidazol-2-yl)methanone in DMF (1.0 mL) is added triethylamine (104 μL, 0.743 mmol) and 1-(1H-imidazol-1-yl)ethanone (60.0 mg, 0.545 mmol). The reaction was stirred at rt 7 h. The reaction mixture was added to saturated NaHCO3 (5 mL) and extracted with Teac (3×5 mL). The combined organic layers were washed with water (5 mL), saturated NaCl (5 mL), dried (MgSO4) and concentrated. Purification by RPHPLC gives 1-(3-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)azetidin-1-yl)ethanone (55.4 mg, 36.0% over 3 steps) as a white solid. MS (ESI, pos. ion) m/z: 414.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)=O.C(Cl)(=O)C([Cl:12])=O>C(OCC)C>[Cl-:12].[Cl:12][CH:1]=[N+:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: O=CN1CCOCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: ClC=[N+]1CCOCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 165.7 %

Procedure:
N-Formylmorpholine (7.58 g) dissolved in anhydrous ethyl ether (200 ml) is reacted with oxalyl chloride (8.02 g) under stirring at room temperature for 20 hours. The precipitate is filtered, washed with anhydrous ethyl ether and dried in vacuo at room temperature for 1 hour to yield 8.9 g of 4-chloromethylene-morpholinium chloride. This compound (5.47 g) is added portionwise at -15°60 C. to a stirred solution of 3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (3 g) in anhydrous tetrahydrofuran (130 ml) containing triethylamine (8.96 ml). The reaction mixture is kept under stirring at -15° C. for 2 hours and then at about 0° C. for 2 hours again. Finally it is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered, fired in vacuo at 50° C. and then purified over a SiO2 column using chloroform/methanol30% NH4OH 85/12/0.5 as eluent. The recovered product is crystallized from methanol to yield 1.4 g of 2-cyano-3(1,4-dihydro-8-morpholinomethyleneamino-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-3-oxo-N-phenyl-propanamide, m.p. 205°-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH2:17][CH2:18][N:19]4[C:23]([CH3:25])([CH3:24])[C:22](=[O:26])[NH:21][C:20]4=[O:27])[N:11]=3)=[CH:7][C:6]=2[CH:28]=1.[CH:29](=O)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:24][C:23]1([CH3:25])[N:19]([CH2:18][CH2:17][NH:16][C:12]2[N:11]=[C:10]([C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([NH:1][CH2:29][C:30]5[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=5)=[CH:28][C:6]=4[CH:7]=3)[CH:15]=[CH:14][N:13]=2)[C:20](=[O:27])[NH:21][C:22]1=[O:26]
Reactant: O=Cc1ccncc1
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(N)ccc3s2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)N1CCNc1nccc(-c2cc3cc(NCc4ccncc4)ccc3s2)n1
Temperature: 60 °C
Yield: 27.1 %

Procedure:
1-(2-(4-(5-aminobenzothiophen-2-yl)pyrimidin-2-ylamino)ethyl)-5,5-dimethyl imidazo-lidin-2,4-dione (300 mg, 0.758 mmol) was suspended in dichloromethane (10 mL). Isonicotinaldehyde (97.4 mg, 0.910 mmol), acetic acid (4-5 drops), and sodium triacetoxy-borohydride (321 mg, 1.516 mmol) were added, and the mixture was heated to 60° C. for 16 h. The reaction was cooled to room temperature, diluted with a saturated aqueous solution of sodium bicarbonate (15 mL), and extracted with dichloromethane (4×15 mL). The organic layers were combined and then washed in turn with a saturated aqueous solution of sodium bicarbonate (10 mL), deionized water (15 mL), and a saturated aqueous solution of sodium chloride (15 mL). The organic layer was separated, dried over sodium sulfate (200 mg), filtered through a coarse frit (to remove the sodium sulfate), and concentrated in vacuo to give a white solid (100 mg). The crude material was purified by flash chromatography (MeOH/DCM) to yield the title compound as a white powder (20 mg). MS (M+H)+ 488.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=3[C:5]=2[CH2:4]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>>[CH3:1][N:2]([CH3:17])[CH:3]1[CH2:16][CH2:15][C:6]2[O:7][C:8]3[CH:13]=[CH:12][C:11]([NH:14][C:18]([C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)=[O:25])=[CH:10][C:9]=3[C:5]=2[CH2:4]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Product: CN(C)C1CCc2oc3ccc(NC(=O)c4ccncc4)cc3c2C1
Yield: 42.4 %

Procedure:
Beginning with 0.132 gm (0.57 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine and 0.15 gm (0.84 mMol) of isonicotinoyl chloride, 0.081 gm (42%) of the title compound were obtained by the procedure described in Example 20.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:4].[Cl:13][CH2:14][O:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)C>[Cl-:13].[CH3:1][N:2]([CH3:12])[C:3]([O:5][C:6]1[CH:7]=[N+:8]([CH2:14][O:15][C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:23])[CH:9]=[CH:10][CH:11]=1)=[O:4]
Reactant: CN(C)C(=O)Oc1cccnc1
Reactant: O=C(OCCl)c1ccccc1
Solvent: CCOCC
Product: CN(C)C(=O)Oc1ccc[n+](COC(=O)c2ccccc2)c1
Product: [Cl-]
Reaction time: 4 h
Yield: 85.2 %

Procedure:
3-Dimethylcarbamoyloxypyridine (4.98 g) and chloromethylbenzoate (5.13 g) were heated to 70° C. with stirring for 4 hrs. The hot reaction mixture was poured into 100 ml of diethyl ether with vigorous stirring. The precipitated solids were filtered off and washed twice with anhydrous diethyl ether (100 ml×2). Recrystallization from acetone gave 8.6 g of 3-(dimethylcarbamoyloxy)-1-(phenylcarbonyloxymethyl)pyridinium chloride as prisms, m.p. 175°-176° C.
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][Br:22])=[CH:16][CH:15]=1>CC(C)=O>[BrH:22].[CH2:21]([NH:13][CH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[C:5]([O:6][CH3:7])[CH:4]=1)[CH2:20][C:17]1[CH:18]=[CH:19][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: BrCCc1ccccc1
Solvent: CC(C)=O
Product: Br
Product: COc1ccc(CCNCCc2ccccc2)cc1OC
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 44.5 %

Procedure:
A mixture of 10 g of homoveratrylamine and 12 g of β-phenethyl bromide was stirred for 15 minutes at 125° C. in a bath and after cooling the mixture to 60° C., 30 ml of acetone were added. The mixture was iced and vacuum filtered and the recovered precipitate was dissolved in 250 ml of methanol. The solution was concentrated to 50 ml and 400 ml of ethyl acetate were added thereto. The mixture was concentrated to 200 ml, was iced and vacuum filtered to obtain 12.5 g of raw product. The latter was crystallized from isopropanol to obtain 9 g of N-phenethyl-3,4-dimethoxyphenethylamine hydrobromide in the form of colorless crystals melting at 180° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCN1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CN1CCN(CC)CC1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
8.9 ml of ethylpiperazine are placed in 91.5 ml of toluene in a round-bottomed flask. A solution of 4.1 ml of ethyl bromoacetate in 11.6 ml of toluene is added dropwise. The mixture is refluxed at 110° C. for one hour, concentrated to a small volume and left in a refrigerator for 3 hours. A white precipitate forms, which is filtered off and washed with dichloromethane. The filtration liquors are evaporated; 7 g of expected product are obtained.