Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:23])[CH:15]([NH:31][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:3]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)C(Br)c1ccccc1
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(NCc1ccccc1)c1ccccc1
Yield: 69.7 %

Procedure:
A solution of (±)-N-[2,6-bis(1-Methylethyl)phenyl]-α-bromobenzeneacetamide (4.3 g, 12 mmol), benzylamine (1.8 g, 18 mmol), and triethylamine (8.0 mL, 57 mmol) in toluene was refluxed (96 hours) then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), washed with water (2×100 mL), with saturated aqueous sodium bicarbonate (1×100 mL), with brine (1×100 mL), then dried (MgSO4) and concentrated to a solid. The solid was recrystallized from ethyl acetate/hexane to yield 3.35 g (72.8%) of the title compound as a white solid, mp 134°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]=[C:12]=[S:13])=[CH:5][CH:4]=1.[ClH:23]>C(OCC)C>[Cl:23][C:12]1[S:13][C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]=1
Reactant: Cl
Reactant: COc1ccc(C(=O)C(N=C=S)c2ccc(OC)cc2)cc1
Solvent: CCOCC
Product: COc1ccc(-c2nc(Cl)sc2-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
10 g of the 1,2-bis-(p-methoxyphenyl)-2-isothiocyanoethanone so obtained are suspended in 150 ml of diethyl ether and, while stirring, the suspension is cooled to 15°-20°. Gaseous hydrogen chloride is then introduced slowly at such a rate that the reaction temperature does not exceed 20°. After about 45 minutes a clear, yellowish solution is obtained. It is maintained at 15° and a little hydrogen chloride is introduced for a further 7 hours, the solution is left to stand overnight at 15°, poured onto 300 ml of ice, the diethyl ether is removed by distillation, and the crystalline precipitate is filtered with suction, then washed twice with water and sucked dry on a suction filter. The crude product is recrystallised from 100 ml of hexane. 2-Chloro-4,5-bis-(p-methoxyphenyl)-thiazole having a melting point of 92°-94° is obtained.
Reaction SMILES: [CH:1]([NH:3][CH:4](P(OCC)(OCC)=O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])=[S:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][C:33](=O)[CH3:34]>CC(C)=O>[CH3:32][C:33]1[CH2:34][S:2][CH:1]=[N:3][C:4]=1[C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)=[O:6]
Reactant: CCOP(=O)(OCC)C(NC=S)C(=O)OCc1ccc(OC)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C2=C(C)CSC=N2)cc1
Temperature: 25 °C
Yield: 83.7 %

Procedure:
A mixture of p-methoxybenzyl α-thioformamidodiethylphosphonoacetate (188 mg., 0.5 mmole), powdered potassium carbonate (1.52 mg., 1.1 mmole) and chloro-2-propanone (44μl., 0.55 mmole) in acetone (2.5 ml.) is stirred at room temperature and under a nitrogen atmosphere. After 22 hours stirring, the mixture is filtered and the salts washed with acetone. The combined filtrate and washings are evaporated in vacuo to a dark residue which is shaken with csrbon tetrachloride (3 × 2 ml.). The combined extracts are washed with water (2 × 2 ml.) and saturated brine (2 ml.), dried over magnesium sulfate and evaporated in vacuo to give p-methoxybenzyl 5-methyl-6H-1,3-thiazine-4-carboxylate (116 mg.) as an orange oil.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].IC>C1COCC1>[CH3:1][C:9]1[C:8]([F:14])=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisoproplylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrous THF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5 M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of TBF is added at a rate to keep the temperature below −65° C. The reaction is stirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of TBF is added to the reaction. The ice bath is removed and the reaction is allowed to warm to room temperature. After 2 hours the reaction is quenched with water and 1N HCl. The aqueous layer is extracted twice with ether. The combined organics are washed with brine and dried over Na2SO4. Removal of the solvent affords the desired product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:20]([C:28]4[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1>ClCCl.C1COCC1.[Pd]>[CH3:1][O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[C:14]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[C:20]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:19][C:15]=3[N:16]=[CH:17][N:18]=2)[CH:7]=1
Reactant: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccc(Br)cc4)c(-c4ccccc4)c23)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)COc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccccc4)c23)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 200 mg (0.377 mmol) of 3-{[6-(4-bromophenyl)-5-phenylfuro[2,3-d]pyrimidin-4-yl]amino}phenoxyacetic acid methyl ester in 5 ml of dichloromethane and 2 ml of THF and, under argon, add 40 mg of 10% palladium on activated carbon. Stir the mixture under a hydrogen atmosphere of 3 bar gauge at RT for 3 h, before filtering off the catalyst. Wash the catalyst residue with dichloromethane and methanol, concentrate the combined filtrates under reduced pressure and chromatograph the residue on silica gel (eluent: dichloromethane/ethyl acetate 10:1). 79.1 mg (45.5% of theory) of the target compound are obtained as a colourless solid.
Reaction SMILES: [CH:1]1([CH:7]([NH:25][C:26]2[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][CH:27]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH2:23][CH3:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:35][NH:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40]>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([N:36]([CH3:35])[CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:32])=[CH:33][CH:34]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:22])[F:20])=[CH:15][CH:14]=3)[S:10][C:9]=2[CH2:23][CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 46.1 %

Procedure:
An operation similar to that in Example 69 (9) was performed using 4-[(cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methyl)amino]benzoic acid (143 mg) synthesized in Example 71 (2) and ethyl 3-(methylamino)propanoate (45.9 mg) to give the title compound (77.4 mg, 46%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH:13](=[O:17])[CH:14]([CH3:16])[CH3:15]>>[CH3:15][CH:14]([CH3:16])[CH:13]([C:12]1[N:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[N:9]=[CH:10][CH:11]=1)[OH:17]
Reactant: CC(C)C=O
Reactant: Cc1ccc(-n2cccn2)cc1
Product: Cc1ccc(-n2nccc2C(O)C(C)C)cc1
Yield: 54 %

Procedure:
This compound was prepared from 1-(4-methylphenyl)-1H-pyrazole (Tetrahedron Lett. 39(19): 2941 (1998)) and isobutyraldehyde using the method described in example 10B and isolated as a clear oil in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:25][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH:13]2[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:25][CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH:13]3[CH2:12]2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cnc(Cl)nc1NC1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a solution of 2,4-dichloro-5-methyl-pyrimidine (2.00 g, 12.3 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (4.64 g, 20.5 mmol) in EtOH (25 mL) was added Et3N (2.62 g, 25.9 mmol). The reaction mixture was stirred at 50° C. overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the title compound as yellow oil (2.42 g, 55.9%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2c(F)cccc2F)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1c(F)cccc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 55.8 %

Procedure:
Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 6.27 mmol) was dissolved in MeOH (21 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.251 g, 6.27 mmol) dissolved in water (2.100 mL) was added over 8 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.384 mL, 6.27 mmol) was added over 6 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (32.3 mL, 193.76 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.232 g, 55.8%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.94-2.04 (m, 2H), 2.08-2.16 (m, 2H), 2.63-2.73 (m, 1H), 2.81-2.91 (m, 1H), 2.98-3.09 (m, 1H), 3.24-3.37 (m, 4H), 3.88-3.99 (m, 1H), 4.41-4.54 (m, 1H), 5.81 (s, 1H), 6.82-6.92 (m, 2H), 7.16-7.26 (m, 1H). MS m/z 353 (M+H)+
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH2:26][CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].[Br:30]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH:23]=[O:24])=[C:21]([Cl:25])[N:20]=[C:19]2[CH:26]([Br:30])[CH2:27][CH2:28][CH3:29])=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC(Br)c1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Yield: 40.4 %

Procedure:
A mixture of 1.12 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloroimidazole-5-carboxaldehyde and 0.49 g of N-bromosuccinimide in 40 mL of CCl4 was irradiated (UV-lamp, pyrex filter) for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo. Column chromatography (elution: ethyl acetate/benzene) afforded 0.54 g of 1-[(2'-carbomethoxybiphenyl-4-yl)-methyl]-2-(1-bromobutyl)-4-chloroimidazole-5-carboxaldehyde. NMR (200 MHz, CDCl3) δ9.87 (s, 1H); 7.86 (d, 1H); 7.54 (t, 1H); 7.46 (t, 1H); 7.30 (m, 3H); 7.11 (d, 2H); 6.16 (d, 1H); 5.32 (d, 1H); 4.79 (t, 1H); 3.65 (s, 3H); 2.32 (m, 2H); 1.34 (sext., 2H); 0.83 (t, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].O.[CH3:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>C(O)C>[CH3:20][C:21]1[CH:22]=[C:23]([NH:24][C:15](=[O:17])[CH2:14][C:9]2[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:8]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cccc(N)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(NC(=O)Cc2nc(N3CCOCC3)cc(=O)[nH]2)c1
Yield: 59.7 %

Procedure:
The product is prepared according to the procedure described in Example 19, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 and using a mixture of 1 ml of water and 9 ml of ethanol in place of the methanol and 214 mg of 3-methylaniline in place of the 3-(tert-butyl)aniline. 196 mg of N-(3-methylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8].CN(C=O)C>O>[N:1]([CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)[OH:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@@H](CCl)c1ccc(F)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NC[C@H](O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
Sodium azide (41.8 g, 642 mmol) was added to a solution consisting of (1R)-2-chloro-1-(4-fluoro-phenyl)-ethanol (37.4 g, 214 mmol) and DMF (214 mL) at rt. The reaction mixture was heated to 100° C. for 3 h, diluted with water (500 mL), and extracted with EtOAc (700 mL). The organic layer was washed with brine (500 mL), and the organic layer dried (MgSO4), filtered, and concentrated, giving the title compound as a yellow liquid, which was used without further purification (39 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2
Reactant: Cc1cccc2cc[nH]c12
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc2c1NCC2
Reaction time: 1 h
Yield: 111.5 %

Procedure:
To a stirred solution of 7-methylindole (10.27 g, 78.3 mmol) in glacial acetic acid (50 mL) is added sodium cyanoborohydride (6.33 g, 100.7 mmol) portionwise over a 5 minute period. The reaction solution is allowed to stir for 1 hour. The solution is diluted with water (500 mL) and basified with 50% sodium hydroxide solution. The basic solution is extracted with three 250 mL portions of diethyl ether. The organic fractions are combined, dried over anhydrous potassium carbonate, filtered and evaporated to give a pink oil. The oil is purified by silica gel column chromatography using 20% ethyl acetate/hexanes as eluent to give 11.63 g of 2,3-dihydro-7-methylindole as a colorless oil (94% yield).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[O:24]([CH2:23][CH2:22][CH2:21][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCCOc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCOc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of n-Boc-piperazine (1.08 g, 5.80 mmol) in dry DMF (10 mL) were added anhydrous potassium carbonate (4.01 g, 29.04 mmol) and compound 26 (1.5 g, 6.97 mmol). The reaction mixture was stirred at RT for 8 h. The potassium carbonate was removed by suction filtration and the solvent was removed under reduced pressure. The residue was dissolved with water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The crude product was purified by column chromatography using ethyl acetate:hexane (8:2) to give compound 28 (1.58 g, 85%). 1H NMR (400 MHz, CDCl3) δ 1.39 (s, 9H), 1.92 (s, 2H), 2.36 (s, 4H), 2.48 (s, 2H), 3.39 (s, 4), 3.95 (m, 2), 6.83 (m, 2H), 7.19 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[S:36])=[CH:30][CH:29]=1>C(#N)C>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:35]([NH:34][C:31]4[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=4)=[S:36])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: COc1ccc(N=C=S)cc1
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CC#N
Product: COc1ccc(NC(=S)Nc2cccc3cc4cccc5c4c(c23)C(=O)N(CCN(C)C)C5=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
300 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.90 mmole) are dissolved in 20 ml of acetonitrile. 250 μl (2 molar equivalents) of 4-methoxyphenyl isothiocyanate was added and the reaction mixture was maintained at room temperature for 16 hours. Two more equivalents of 4-methoxyphenyl isothiocyanate was added and the reaction mixture was stirred for 24 hours at room temperature. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 409 mg of UN the desired product (formula shown hereinabove) were isolated as a red powder (yield=91%) which was characterized as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH2:15])[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22][CH:23]=1)=O.[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[N:14]=[C:13]([NH:15][CH2:16][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[N:22][CH:23]=3)[NH:12][N:11]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc(CNc2nc(Nc3cc(Cl)cc(Cl)c3)n[nH]2)cn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A solution of N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (70 mg, 287 μmol) and tert-butyl (5-formylpyridine-2-yl)carbamate (159 mg, 717 μmol) in MeOH (3 ml) was stirred at 45° C. for overnight to give a suspension, cooled to −20° C. and was filtered to collect the solid. The solid was re-suspended in MeOH (5 ml), NaBH4 (163 mg, 4.3 mmol) was added in a few portions and the reaction was stirred for 1 hour. The solvent was removed, and the reaction mixture was redissolved in EtOAc (5 ml) and washed with water (2×4 ml), dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography (silica gel, 24 g, 3% to 6% MeOH in DCM) afforded a white solid as desired product (60.8 mg, 47% yield). MS +m/z: 450 (M+H)+
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19]>O>[CH:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[O:9]
Reactant: COC(=O)CCl
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)COc1ccccc1C=O
Temperature: 65 °C
Reaction time: 24 h

Procedure:
2. Approximately 509 g of the starting compound, salicylaldehyde (1) was introduced into a 4-liter Erlenmeyer flask with powdered potassium carbonate (569 g), dimethylformnamide (1,000 ml), and methyl chloroacetate (478 g) and mechanically stirred at 65° C. for about 24 hours. The stirring was stopped and the reaction mixture cooled to 25° C. The mixture was poured into cold water (0° C.) while stirring vigorously. An oil separated that suddenly solidified. Stirring was continued for 30 minutes and the solid isolated by filtration. The product was washed with water (2×1,000 ml) and pressed dry. The product can also be dried in vacuo at 25° C. A small sample (approx. 2 g) was purified by distillation. The boiling range of the pure product is 124-128° C. at 2 mm Hg and has a melting temperature range of about 50.2-50.6° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1Cl)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].[CH3:14][NH2:15]>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[NH:15][CH3:14])[C:7]([OH:9])=[O:8])([O-:3])=[O:2]
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: O
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
A mixture comprising 3-nitro-4-chlorobenzoic acid (1.3 g, 6.45 mmol), 10% methylamine and water (10 mL) in a sealed tube was heated at 100° C. for 11 hours, concentrated to 1 mL and then diluted with concentrated hydrochloric acid to give a yellow precipitate. The precipitate was isolated by filtration, washed with water and then diethyl ether and dried to provide 3-nitro-4-methylaminobenzoic acid (2.1 g, 86% yield); 1H-NMR (300 Mhz, CDCL3): 8.56 (d, 1H, J=2.1 Hz), 8.52 (q, 1H, J=8.6 Hz), 7.94 (dd, 1H, 9.3, 2.1 Hz), 7.00 (d, 1H, J=9.3 Hz), 2.97 (d, 3H, J=8.6 Hz).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[O:7])=[CH:2]1.S1C=CC(C(N2CCOCC2)C#N)=C1.[C:22]([O:26]CC)(=[O:25])[CH:23]=[CH2:24].[OH-].[K+]>C(O)C.O1CCCC1>[CH:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]([CH2:24][CH2:23][C:22]([OH:26])=[O:25])=[O:7]
Reactant: C=CC(=O)OCC
Reactant: O=Cc1ccsc1
Agent: N#CC(c1ccsc1)N1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCC(=O)c1ccsc1

Procedure:
As for Example 6, 99 g. of 3-thiophenecarboxaldehyde is converted to α-(3-thienyl)-4-morpholineacetonitrile (137 g.; m.p. 85°-87° C.). The preceding compound 50.5 g. is reacted with 100 ml. of ethyl acrylate in 500 ml. of tetrahydrofuran in the presence of 50 ml. of 30% potassium hydroxide in ethanol. The solvent is removed from the reaction mixture and the residue is heated with 6 N hydrochloric acid to give 3-(3-thenoyl)propionic acid. As for Example 1, the preceding compound is converted to the product of the Example to give a glass.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: C1CCNC1
Product: O=C(CCc1ccc(Br)cc1)N1CCCC1

Procedure:
The title compound was prepared from 3-(4-bromophenyl)propanoic acid and pyrrolidine using a similar procedure to that described for Description 8, but without chromatographic purification.