Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[CH2:9]([O:11][C:12](=[O:19])[CH:13]([CH:17]=O)[C:14](=O)[CH3:15])[CH3:10].N1C=CC=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[C:14]([CH3:15])=[N:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:17]=1)=[O:19])[CH3:10]
Reactant: NNc1ccccn1
Reactant: CCOC(=O)C(C=O)C(C)=O
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C

Procedure:
Similar to Example 1, equimolar amounts of 2-pyridylhydrazine and 2-formyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was determined to be the named product (m.p. 49° C.–50° C.).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[H-].[Na+].Cl.[CH3:15][N:16]([CH2:18][CH2:19]Cl)[CH3:17]>C(#N)C>[CH3:15][N:16]([CH2:18][CH2:19][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])[CH3:17]
Reactant: COC(=O)c1ccccc1O
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1ccccc1OCCN(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
15.2 g of methyl salicylate are dissolved in 200 ml of anhydrous acetonitrile and stirred with 4.4 g of 60% sodium hydride suspension in oil at ambient temperature for 60 minutes. To this solution is added 200 ml of absolute acetonitrile, then it is mixed with 17.4 g of 2-(N,N-dimethylamino)ethylchloride hydrochloride and 5.2 g of 60% sodium hydride suspension in oil. This solution is also stirred for 60 minutes at ambient temperature. The combined solutions are refluxed for 1 hour and then evaporated down in vacuo. The residue is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is distilled off in vacuo and the residue is chromatographed on silica gel with ethyl acetate/methanol (1:1). In this way, 14.6 g of a yellow oil are obtained (65% of theory).
Reaction SMILES: [CH2:1]([NH:5][CH3:6])[CH2:2][CH2:3][CH3:4].[CH:7]1([N:13]=[C:14]=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.NC(N)=N>>[CH2:1]([N:5]([CH3:6])[C:14]([NH:13][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:2][CH2:3][CH3:4]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CCCCNC
Agent: N=C(N)N
Product: CCCCN(C)C(=NC1CCCCC1)NC1CCCCC1

Procedure:
A mixture of 17.78 g of N-butyl-N-methylamine (0.204 mol) and 21.05 g of dicyclohexylcarbodiimide (0.102 mol) is refluxed for 3 h. GC analysis then shows a conversion of greater than 99.50 of the dicyclohexylcarbodiimide. The colorless final mixture is concentrated at 60° C. under 1 mbar for 2 h so as to give 29.9 g of a colorless and virtually odorless liquid of medium viscosity, corresponding to the expected guanidine (yield 99.70).
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[CH3:48][C:49]1[S:53][C:52]([CH2:54][NH2:55])=[CH:51][CH:50]=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:55][CH2:54][C:52]4[S:53][C:49]([CH3:48])=[CH:50][CH:51]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1ccc(CN)s1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1ccc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)s1
Yield: 41 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (5-methylthiophen-2-yl)methanamine, the title compound was obtained as a colorless solid in 41% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.98 (m, 2H), 6.78 (d, J=3.2 Hz, 1H), 6.58 (d, J=3.2 Hz, 1 H), 6.09 (s, 1H), 5.94 (t, J=5.1 Hz, 1H), 4.64 (d, J=5.1 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.39 (m, 2H), 2.49 (s, 3H), 2.44 (s, 3H); MS (ES+) m/z 466.2 (M+23).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[O:27]1[CH2:31][CH2:30][CH2:29][C@H:28]1[CH2:32][C:33](O)=[O:34]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:33](=[O:34])[CH2:32][C@@H:28]5[CH2:29][CH2:30][CH2:31][O:27]5)[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C[C@@H]1CCCO1
Agent: Cl
Product: O=C(C[C@@H]1CCCO1)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (72 mg, 65%), MS (ISP) m/z=441.4 [(M+H)+], mp 192° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and (S)-2-(tetrahydro-furan-2-yl)-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].CC(C)([O-])C.[K+].I[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[N:25]=2)[N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cl-].[Na+].O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][C:17]1[CH:18]=[CH:19][C:20]2[N:21]([CH:23]=[C:24]([NH:26][C:27](=[O:29])[CH3:28])[N:25]=2)[N:22]=1
Reactant: Cc1ccc(O)cc1N
Reactant: CC(=O)Nc1cn2nc(I)ccc2n1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1cn2nc(Oc3ccc(C)c(N)c3)ccc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
To a solution of 3-amino-4-methylphenol (1.22 g, 9.93 mmol) in N,N-dimethylformamide (25.0 mL) was added potassium tert-butoxide (1.16 g, 10.3 mmol), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture were added N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (2.5 g, 8.28 mmol) and potassium carbonate (0.57 g, 4.14 mmol), and the mixture was stirred at 140° C. for 16 hr. Saturated brine was added to the reaction mixture, and the mixture was extracted with ethyl acetate/tetrahydrofuran, washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate alone) and the obtained residue was washed with hexane/ethyl acetate, and filtrated to give the title compound (1.04 g, 42%) as a brown powder.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH2:11]1[O:21][C:20]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=2[O:12]1.[OH-].[Na+]>CO>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:2](=[O:3])[CH:1]=[CH:16][C:15]1[CH:18]=[CH:19][C:20]2[O:21][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(=O)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1

Procedure:
3-Hydroxy acetophenone, 2 (2.7 g, 20 mmol), 3,4-methylenedioxy benzaldehyde, 6 (3 g, 20 mmol) and 50% aqueous sodium hydroxide (5 mL) in methanol (40 mL) were reacted under reflux as in 7 to yield 12. Yield 4.1 g (76%); mp 188-189° C.; MS (FAB) 269 (M++1); IR (KBr) 3389, 1659; 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.73 (d, J=15.6 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.63 (s, 1H), 7.62 (d, J=5.4 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.05 (dd, J=7.9 Hz, 2.4 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.09 (s, 2H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([CH2:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:16])[CH:2]=[CH2:3]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:4]1[C:9]([O:10][CH2:11][C:12]([CH2:14][CH3:15])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:16])[CH2:2][CH3:3]
Reactant: C=CCc1c(O)cccc1OCC(=O)CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)cccc1OCC(=O)CC
Reaction time: 2 h

Procedure:
A solution of 2-allyl-3-(2-ethyl-2-oxoethoxy)phenol (480 mg) in ethyl acetate (25 mL) was treated with 10% palladium (75 mg) on carbon catalyst. The mixture was shaken under a hydrogen atmosphere (40 psi) for two hours. The mixture was filtered through Celite and concentrated to get the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1.C(N(CC)CC)C.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH:10][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[C:19]([F:18])([F:29])[F:30])=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NCCc1ncc(Br)cn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCc1ncc(Br)cn1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To 0.06 g of 2-(5-bromopyrimidin-2-yl)ethanamine (3.0 mmol) and triethylamine (0.03 g, 1.0 equivalent) in THF (5 ml), at room temperature whilst stirring, was added the 2-trifluoromethyl benzoyl chloride (0.062 g, 1.0 equivalent) and the mixture was left to stir at room temperature overnight. The solvent was removed by evaporation in vacuo and saturated sodium bicarbonate (10 mls) was added. The mixture was extracted with dichloromethane and the organic phase was collected, dried over MgSO4, and evaporated in vacuo to give the crude product which was purified by chromatography on silica using 1:1 heptane/ethyl acetate to yield to 0.036 g of N-[2-(5-bromopyrimidin-2-yl)ethyl]-2-(trifluoromethyl)benzamide (Compound A-1) (32%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4](O)=[O:5].C1C=C2N=NN(O)C2=CC=1.O.CCN=C=[N:37][CH2:38][CH2:39][CH2:40][N:41]([CH3:43])C.Cl.Cl.N1CC(C#N)C1.CN1CCOCC1>CN(C=O)C>[CH3:21][C:2]([CH3:1])([CH3:20])[C@@H:3]([N:7]1[C:16](=[O:17])[C:15]2=[CH:18][NH:19][C:13]3[C:14]2=[C:9]([CH:10]=[CH:11][N:12]=3)[CH2:8]1)[C:4]([N:41]1[CH2:40][CH:39]([C:38]#[N:37])[CH2:43]1)=[O:5]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)[C@H](C(=O)O)N1Cc2ccnc3[nH]cc(c23)C1=O
Agent: Cl
Agent: N#CC1CNC1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](C(=O)N1CC(C#N)C1)N1Cc2ccnc3[nH]cc(c23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.9 %

Procedure:
(R)-3,3-Dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoic acid (80 mg, 0.278 mmol), HOBt hydrate (51.2 mg, 0.334 mmol), and EDC hydrochloride (80 mg, 0.418 mmol) were combined in DMF (2 mL). Azetidine-3-carbonitrile hydrochloride (49.5 mg, 0.418 mmol) and 4-methylmorpholine (0.124 mL, 1.114 mmol) were added, and the reaction mixture was stirred at room temperature for 2 h. The product was purified by preparative HPLC (10-50% AcCN/H2O with 0.035% TFA), concentrated in vacuo, and purified by flash column chromatography (8% MeOH/DCM) to afford the title compound (38 mg, 39%). 1H NMR (500 MHz, CD3OD) δ 1.17 (s, 9H), 3.58-3.72 (m, 1H), 4.13-4.65 (m, 4H), 5.35-5.45 (m, 3H), 7.28-7.38 (m, 1H), 7.95 (d, J=15.5 Hz, 1H), 8.33-8.40 (m, 1H). [M+H] calc'd for C19H21N5O2, 352; found, 352.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH3:11])=[O:7])=[C:4]([F:26])[CH:3]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCCC1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:25]=[CH:24][C:5]([C:6]([NH:8][CH2:9][CH:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[CH3:11])=[O:7])=[C:4]([F:26])[CH:3]=2)=[CH:30][CH:29]=1
Reactant: CC(CNC(=O)c1ccc(Br)cc1F)c1ccc(CN2CCCC2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CNC(=O)c1ccc(-c2ccc(Cl)cc2)cc1F)c1ccc(CN2CCCC2)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
To a solution (7 ml) of 4-bromo-2-fluoro-N-{2-[4-(1-pyrrolidinylmethyl)phenyl]propyl}benzamide (300 mg, 0.715 mmol) obtained in Example 5, 4-chlorophenylboronic acid (224 mg, 1.43 mmol) and 2N aqueous sodium carbonate solution (0.715 ml) in tetrahydrofuran was added tetrakistriphenylphosphine palladium (24.8 mg, 21.5 mmol) under a nitrogen atmosphere. This was stirred at 90° C. for 16 hrs, and allowed to cool to room temperature. Ethyl acetate was added to the reaction mixture, and the mixture was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by NH-silica gel column chromatography (developing solvent; ethyl acetate), and powderized with isopropyl ether to give the title compound (142 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[CH2:12]([N:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[NH:22][CH:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:26]2[CH2:27][CH2:28][C:23]3([N:19]([CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:20](=[O:36])[CH:21]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[NH:22]3)[CH2:24][CH2:25]2)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)N2CCC3(CC2)NC(Cc2ccccc2)C(=O)N3Cc2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-Methoxyphenyl isocyanate (221 mg, 1.49 mmol) was added to a solution of 1,3-di-benzyl-1,4,8-triazaspiro[4,5]decan-2-one (499 mg, 1.49 mmol) in toluene (12.3 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred at 115° C. for 4 h. After removal of the solvent, the desired product 11,3-dibenzyl-2-oxo-1,4,8-triazaspiro[4,5]decane-8-carboxylic acid (4-methoxyphenyl)amide was obtained by means of preparative HPLC.
Reaction SMILES: [C:1]1([C:11]2[CH:25]=[C:14]3[NH:15][CH:16]=[C:17]([C:20]([O:22]CC)=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(O)C.[Cl-].[NH4+]>[OH-].[Na+].O>[C:1]1([C:11]2[CH:25]=[C:14]3[NH:15][CH:16]=[C:17]([C:20]([OH:22])=[O:21])[C:18](=[O:19])[N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c[nH]c2cc(-c3cccc4ccccc34)nn2c1=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c2cc(-c3cccc4ccccc34)nn2c1=O
Yield: 97.1 %

Procedure:
Ethyl 2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylate (163 mg, 0.489 mmol) is stirred in 4 M NaOH (2.4 mL) and ethanol (1.2 mL) at 100° C. in a sealed vial for 5 hr during which time a precipitate forms. The reaction mixture is diluted with water and a saturated solution of ammonium chloride to bring the pH to about 4. The precipitate is collected in a Buchner funnel to provide 2-(1-naphthyl)-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidine-6-carboxylic acid (145 mg, yield 97%). 1H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.72-8.64 (m, 1H), 8.03 (dd, J=11.4, 5.4 Hz, 2H), 7.86 (d, J=6.3 Hz, 1H), 7.69-7.52 (m, 3H), 6.80 (s, 1H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH2:6]=[CH:7][CH:8]1[O:10][CH2:9]1.[Cl-].[NH4+]>O1CCCC1>[CH:7]([CH:8]([C:4]#[C:3][C:2]1[CH:1]=[CH:4][CH:3]=[CH:2][CH:1]=1)[CH2:9][OH:10])=[CH2:6]
Reactant: C=CC1CO1
Reactant: [Li]CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(C#Cc1ccccc1)CO
Reaction time: 0.5 h

Procedure:
40 ml of dry tetrahydrofuran and 20 ml of a 1.6 M n-butyl lithium solution were added to a nitrogen-substituted flask at −78° C., and the obtained mixture was then stirred for 30 minutes. Thereafter, 3.5 ml of a trifluoroborane tetrahydrofuran complex was slowly added dropwise to the reaction solution. The obtained solution was further stirred at −78° C. for 15 minutes, and 2.00 g of 1,3-butadiene monoepoxide was slowly added dropwise thereto. The thus obtained mixture was further stirred at −78° C. for 3 hours. Thereafter, 50 ml of a saturated ammonium chloride aqueous solution was added to the reaction solution, and the obtained solution was extracted with 100 ml of ethyl acetate once and was then dried over sodium sulfate. The sodium sulfate was filtrated, and the organic layer was then concentrated. The residue was purified by flash chromatography (manufactured by Biotage AB; Isolera™), so as to obtain 1.80 g of 2-vinyl-4-phenyl-3-butyn-ol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[C:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2.CN(C)C=O>[Pd].C(O)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[C:19]2[N:18]3[CH:20]=[CH:21][N:22]=[C:17]3[C:16](=[O:23])[NH:15][C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]1=2
Reactant: O=c1[nH]c2c3ccccc3c(=Cc3ncc[nH]3)c2n2ccnc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1[nH]c2c(n3ccnc13)C(Cc1ncc[nH]1)c1ccccc1-2
Yield: 30.1 %

Procedure:
The procedure is performed as in Example 21, but starting with 1.65 g of 10-(2-imidazolylmethylene)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one, 300 ml of dimethylformamide, 5 ml of acetic acid and 0.17 g of 10% palladium on charcoal. 0.5 g of 10-(2-imidazolylmethyl)-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is obtained, in the form of a pale yellow solid melting above 260° C. (Analysis % calculated C: 67.32, H: 4.32, N: 23.09, O: 5.27, % found C: 67.2, H: 4.3, N: 23.0).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Mg].II.[CH2:15]=[C:16]([CH2:19]Cl)[CH2:17][Cl:18].Cl>C(OCC)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH2:19][C:16](=[CH2:15])[CH2:17][Cl:18])=[CH:3][CH:4]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(Br)cc1
Reactant: C=C(CCl)CCl
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: C=C(CCl)Cc1ccc(C(C)(C)C)cc1
Yield: 44.9 %

Procedure:
A solution of p-bromo-(t-butyl)benzene (21.3 g., 0.10 mole) in dry diethyl ether (100 ml.) was added dropwise to a mixture of magnesium turnings (2.4 g.), a single iodine crystal and dry diethyl ether (50 ml.). The mixture was allowed to react at ambient temperature for two hours. The resultant Grignard solution was transferred to a dry dropping funnel and added dropwise to a solution of methallyl dichloride (13 8 g., 0.11 mole) in dry diethyl ether (50 ml.). After complete addition of the Grignard solution, the mixture was refluxed for three hours and thereafter cooled with an ice-water bath while 15% hydrochloric acid (150 ml.) was added thereto. The mixture was extracted with diethyl ether and the organic phase dried over sodium sulfate, filtered and evaporated to yield a liquid. The liquid was distilled to provide 10 grams of 2-[(p-t-butylphenyl)methyl]-2-propenyl chloride. This product was characterized by a boiling point of 105° C. to 111° C. at a pressure of 0.25 mm Hg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([CH3:28])=[C:15]([CH2:17][O:18][C:19]3[CH:23]=[C:22]([C:24](OC)=[O:25])[O:21][N:20]=3)[N:16]=2)=[CH:8][CH:7]=1)[CH3:2].[BH4-].[Na+].O>CO>[OH:25][CH2:24][C:22]1[O:21][N:20]=[C:19]([O:18][CH2:17][C:15]2[N:16]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:29])=[CH:7][CH:8]=3)[O:13][C:14]=2[CH3:28])[CH:23]=1
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3cc(C(=O)OC)on3)c(C)o2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3cc(CO)on3)c(C)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.6 %

Procedure:
To a solution of methyl 3-({2-[4-(2-ethoxy-2-oxoethyl)phenyl]-5-methyl-1,3-oxazol-4-yl}methoxy)isoxazole-5-carboxylate (2.02 g) in methanol (25 mL) was gradually added sodium borohydride (250 mg) at 0° C. After stirring at room temperature for 16 hrs, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9-1:1, v/v) to give ethyl (4-[4-({[5-(hydroxymethyl)isoxazol-3-yl]oxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl)acetate as colorless crystals (0.95 g, yield 46%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 116-117° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[C:12](Cl)(Cl)=[S:13].C(OCC)(=O)C>C(Cl)Cl.CCCCCC>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([N:6]=[C:12]=[S:13])[CH:7]=[CH:8][CH:9]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: FC(F)(F)c1cccc(N=C=S)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
To a stirred solution of 3-(trifluoromethyl)aniline (20 g, 124.2 mmol) in DCM (100 mL) was added thiophosgene (21.24 g, 186.4 mmol) at 5-10° C. and the reaction mixture was stirred at room temperature for 1-2 h. The reaction was monitored by TLC (mobile phase-40% ethyl acetate in n-Hexane, Rf. S.M.—0.25, product—0.5). Upon disappearance of the starting material, the reaction mass was diluted with DCM, the organic layer was washed with 10% NaHCO3, water and brine. The organic layer was dried and concentrated in vacuo at a temperature lower than 45° C. to afford the product as a yellow oil (Yield: 19.2 g, 76.19% of theoretical).
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[C:13](=[O:36])[N:14]([CH2:33][CH2:34][CH3:35])[C:15](=[O:32])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:17]=1[NH2:18]>>[CH2:7]([C:8]1[NH:11][C:12]2[C:13](=[O:36])[N:14]([CH2:33][CH2:34][CH3:35])[C:15](=[O:32])[N:16]([CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=3)[C:17]=2[N:18]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCn1c(=O)c(N)c(N)n(CCCCc2ccc([N+](=O)[O-])cc2)c1=O
Reactant: O=C(O)Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(Cc3ccccc3)nc2n(CCCCc2ccc([N+](=O)[O-])cc2)c1=O

Procedure:
By the method of Example 2, phenylacetic acid is reacted with 5,6-diamino-1-[4-(4-nitrophenyl)butyl]-3-propyluracil to yield 8-benzyl-1-propyl-3-[4-(4-nitrophenyl)butyl]xanthine. In turn, 5,6-diamino-3-propyl-1-[4-(4-nitroyphenyl)butyl]-3-uracil is made by the synthetic methods of Example 1, starting with n-propyl isocyanate and 4-(4-nitrophenyl)butylamine. By the methods of Example 3 and Example 4,8-benzyl-3-[4-(4-nitrophenyl)butyl]-1-propylxanthine is alkylated with a mixture of 1,2-dichloroethane and 2-(ethylamino)ethanol, to afford 8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-3-[4-(4-nitrophenyl)butyl]-1-propylxanthine, which, in turn, is reduced with hydrazine hydrate or hydrogen gas in the presence of a palladium catalyst to yield 3-[4-(4-aminophenyl)butyl]-8-benzyl-7-[2-ethyl(2-hydroxyethyl)amino]ethyl-1-propylxanthine free base. The corresponding dihydrochloride salt is then made on exposure to an excess of hydrogen chloride in solution.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2.[Cl:12][CH2:13][C:14](Cl)=[O:15]>>[Cl:12][CH2:13][C:14]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[O:11])[NH:6]2)=[O:15]
Reactant: Nc1cccc2c1CC(=O)N2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1cccc2c1CC(=O)N2

Procedure:
The subtitle compound was prepared from 4-amino-oxindole (0.19 g) (J. Org. Chem., 1983, 48 (15), 2468-72) and chloroacetyl chloride (0.1 ml) by the method of Example 15 step (i). Yield: 0.25 g