Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:5]([OH:7])=O)[CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][CH2:35][CH2:36][NH:37][CH3:38])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[Cl:8][C:9]1[CH:10]=[C:11]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:34][CH2:35][CH2:36][N:37]([CH3:38])[C:5]([C:2]3([OH:1])[CH2:4][CH2:3]3)=[O:7])[N:27]=[CH:26][N:25]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: O=C(O)C1(O)CC1
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)C1(O)CC1
Yield: 54 %

Procedure:
The procedure described in Example 1 was repeated using 1-hydroxycyclopropanecarboxylic acid and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound in 54% yield; NMR spectrum (DMSO-d6) 0.68-0.80 (m, 4H), 3.30 (s, 3H), 3.84-3.96 (m, 2H), 4.37-4.49 (m, 2H), 5.31 (s, 2H), 6.16-6.23 (m, 1H), 7.14-7.21 (m, 1H), 7.24 (d, 1H), 7.32-7.40 (m, 2H), 7.51-7.56 (m, 1H), 7.59 (d, 1H), 7.71-7.76 (m, 1H), 7.86-7.91 (m, 2H), 8.40-8.47 (m, 1H), 8.61 (d, 1H), 9.68-9.75 (m, 1H); Mass spectrum MH+ 520.
Reaction SMILES: C[O:2][C:3](=[O:17])[CH2:4][C:5]1[N:6]=[C:7]([C:11]2[S:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[O:8][C:9]=1[CH3:10].[OH-].[Na+]>CO>[CH3:10][C:9]1[O:8][C:7]([C:11]2[S:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[N:6][C:5]=1[CH2:4][C:3]([OH:17])=[O:2]
Reactant: COC(=O)Cc1nc(-c2ccc(C)s2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2nc(CC(=O)O)c(C)o2)s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
[5-Methyl-2-(5-methyl-thiophen-2-yl)-oxazol-4-yl]-acetic acid methyl ester (3.44 g, 13.7 mmol), in MeOH (45 mL) was treated with 5N NaOH (16 mL) and then the solution was warmed to 40° C. After 30 min, the reaction mixture was concentrated under reduced pressure, suspended in water, and then acidified to pH=1 with 5N HCl. The mixture was extracted with EtOAc (2×), dried (MgSO4), and concentrated to provide 2.47 g (76%) of the product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.43 (d, J=3.6 Hz, 1H), 6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.59 (s, 2H), 2.51 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1.[C:20](Cl)(=[O:24])[C:21]([Cl:23])=[O:22]>C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:20](=[O:24])[C:21]([Cl:23])=[O:22])=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Solvent: CCOCC
Product: Cn1c(COc2ccc(Cl)cc2)c(C(=O)C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-Methyl-2-(4-chlorophenoxymethyl)-1H-indole (1.00 g, 3.68 mmol), dissolved in 7.0 ml of diethyl ether in a round bottom flask under a nitrogen atmosphere. To the above solution was added oxalyl chloride (0.981 g, 7.73 mmol). The reaction mixture was stirred at room temperature for about 60 minutes. The progress of the reaction was monitored by thin layer chromatography.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]2[N:27]([C@@H:32]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:35][CH2:34][CH2:33]3)[CH:28]=[C:29]([C:30]#[N:31])[C:21]=12.CN(C)[CH:44]=[O:45]>O1CCCC1.O>[CH:44]([C:28]1[N:27]([C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][CH2:34][CH2:33]2)[C:22]2=[N:23][C:24]([CH3:26])=[CH:25][C:20]([CH3:19])=[C:21]2[C:29]=1[C:30]#[N:31])=[O:45]
Reactant: Cc1cc(C)c2c(C#N)cn([C@H]3CCCc4ccccc43)c2n1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2c(C#N)c(C=O)n([C@H]3CCCc4ccccc43)c2n1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diisopropylamine (2.36 ml, 18.0 mmol) in tetrahydrofuran (22 ml) was added a 1.6 N solution of butyllithium in hexane (11.3 ml, 18.0 mmol) at −78° C., and the mixture was stirred at −78° C. for 15 minutes. To the resultant solution was added dropwise a solution of 4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (3.61 g, 12.0 mmol) in THF (60 ml) at −78° C., and the mixture was stirred at 78° C. for 30 minutes. Dimethylformamide (3.41 ml, 36.0 mmol) was added thereto, and the mixture was stirred at room temperature for 1.5 hours, poured into iced water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the objective product as oily matter.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[C:4]2[CH:3]=[CH:2]1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([NH2:26])[N:20]=1.Cl.[OH-].[Na+]>O>[Cl:18][C:19]1[N:20]=[C:21]([NH2:26])[N:22]=[C:23]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([NH:10][C:9]3[CH:8]=[CH:7][N:6]=[C:5]4[NH:1][CH:2]=[CH:3][C:4]=34)=[CH:12][CH:13]=2)[CH:24]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Nc1ccc(Nc2ccnc3[nH]ccc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(Cl)cc(Nc2ccc(Nc3ccnc4[nH]ccc34)cc2)n1
Temperature: 100 °C

Procedure:
125 mg (0.56 mmol) of N-1H-pyrrolo[2,3-b]pyridin-4-ylbenzene-1,4-diamine and 118 mg (0.72 mmol) of 4,6-dichloropyrimidine-2-amine are suspended in 5 ml of water. 0.72 ml of 1 M hydrochloric acid are added, and the mixture is heated at 100° C. overnight. Using 1N aqueous sodium hydroxide solution, the suspension is then adjusted to pH 10, resulting in the precipitation of crystals. The solid is filtered off and washed with water. The crude product is purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7 M ammonia) 100:1 to 10:1).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>N1C=CC=CC=1.ClCCl>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:1][C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([O:9][CH3:10])=[O:8])(=[O:23])=[O:22])=[CH:17][CH:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1sccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 40 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
To a solution of methyl 3-aminothiophene-2-carboxylate (0.55 g; 3.5 mmol) in pyridine (2 mL) and dichloromethane (2 mL) was added 4-tert-butylbenzenesulfonyl chloride (0.98 g; 4.2 mmol). The resulting mixture was warmed to 40° C. to aid in solubility, then stirred at room temperature for 48 hours. The reaction mixture was diluted with dichloromethane and washed with aqueous hydrochloric acid (2N). The aqueous layer was separated and extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, decanted, and filtered through a and of silica. The silica was washed with dichloromethane. The eluant was combined with hexanes and allowed to stand. After 24 hours the resulting solid product was collected by filtration to give the desired product as a white solid (817 mg).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[OH:18].C(O)(=O)C>O>[OH:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[NH:8][C:5](=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc([N+](=O)[O-])cc1O
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Acetic anhydride (79.6 g, 0.76 mol, 1.46 equiv) was added over 1.5 hours to the mixture of 2-amino-5-nitrophenol (80 g, 0.52 mol, 1.00 equiv) and acetic acid (320 ml, 5.2 mol, 10 equiv) at 60° C. After 1 hour, additional acetic anhydride was added (7.4 g, 0.071 mol, 0.137 equiv). After another 1 hour, the mixture was cooled and diluted with 200 ml of water. Solid was formed and collected by filtration and washed with water and heptane. The solid was dried in a vacuum oven to give the title compound 94 g. MS (ESI) m/z: 197 (M+1).
Reaction SMILES: Br[C:2]1[C:14]([CH2:15][O:16]C2CCCCO2)=[CH:13][C:5]([O:6]C2CCCCO2)=[CH:4][C:3]=1[F:23].C([Li])CCC.[B:29](OC(C)C)(OC(C)C)[O:30]C(C)C.Cl>O>[F:23][C:3]1[C:2]2[B:29]([OH:30])[O:16][CH2:15][C:14]=2[CH:13]=[C:5]([OH:6])[CH:4]=1
Reactant: Fc1cc(OC2CCCCO2)cc(COC2CCCCO2)c1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Product: OB1OCc2cc(O)cc(F)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.7 %

Procedure:
To a solution of 2-(4-bromo-3-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)methyl)phenoxy)tetrahydro-2H-pyran (9.13 g, 23.5 mmol) was added n-butyllithium (1.6 M in hexanes, 16 mL, 26 mmol) dropwise at −78° C. After stirring 5 min, triisopropyl borate (8.7 mL, 38 mmol) was added, and the mixture was allowed to warm to room temperature and stirred for 2 h. 6 M HCl (10 mL) was added, and the mixture was stirred for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by silica gel chromatography (1:1 hexane/ethyl acetate) to give 7-fluorobenzo[c][1,2]oxaborole-1,5(3H)-diol (3.54 g, 90%). 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 4.86 (s, 2H), 6.40 (dd, J=9.9, 1.5 Hz, 1H), 6.59 (s, 1H), 8.92 (br s, 1H), 10.2 (s, 1H).
Reaction SMILES: [C:1]([NH:4][CH:5](OCC)[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].B(F)(F)F.CCOCC.[CH3:28][CH2:29][SH:30]>>[C:1]([NH:4][CH:5]([S:30][CH2:29][CH3:28])[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: CCS
Agent: FB(F)F
Solvent: CCOCC
Product: CCSC(NC(C)=O)C(=O)NCc1ccccc1

Procedure:
Using 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol), BF3.Et2O (2.72 g, 19.2 mmol) and EtSH (2.38 g, 38.4 mmol) gave an aqueous reaction mixture. The solution was extracted with CHCl3 (3×100 mL). The combined CHCl3 layers were dried (Na2SO4), and then concentrated in vacuo to give the desired product as white solid.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:13][N:14]1[C:18]([CH2:23][CH:24]([CH3:26])[CH3:25])([CH2:19][C:20](O)=[O:21])[C:17](=[O:27])[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15]1=[O:36].Cl.[CH2:38]([O:45][NH2:46])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.CN1CCOCC1>C(Cl)Cl>[CH2:38]([O:45][NH:46][C:20](=[O:21])[CH2:19][C:18]1([CH2:23][CH:24]([CH3:25])[CH3:26])[C:17](=[O:27])[N:16]([CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:15](=[O:36])[N:14]1[CH3:13])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)CC1(CC(=O)O)C(=O)N(CCc2ccccc2)C(=O)N1C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)CC1(CC(=O)NOCc2ccccc2)C(=O)N(CCc2ccccc2)C(=O)N1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
CDI (57.0 mg, 0.352 mmol) is added to a solution of 3-methyl-4-(2-methylpropyl)-2,5-dioxo-1-(2-phenylethyl)-4-imidazolidineacetic acid (113 mg, 0.340 mmol) and CH2Cl2 (2.5 mL). The solution is stirred for 1 hour at room temperature and then O-benzyl hydroxylaminehydrochloride (67.0 mg, 0.420 mmol) and N-methylmorpholine (46 μL, 0.42 mmol) are added. The solution is stirred for 60 hours at room temperature. Basic workup (CH2Cl2, NaHCO3, MgSO4) and purification by flash chromatography (1:1 hexane:EtOAc) provides 94.8 mg (64%) of the title compound as a white solid.
Reaction SMILES: [OH:1][C@@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][C:10](=[N:12][O:13][CH3:14])[CH2:9][N:8]1C(OC(C)(C)C)=O)=[O:6]>C(Cl)Cl>[OH:1][C@@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][NH:4][C:5]([C@@H:7]1[CH2:11][C:10](=[N:12][O:13][CH3:14])[CH2:9][NH:8]1)=[O:6]
Reactant: CON=C1C[C@@H](C(=O)NC[C@@H](O)c2ccccc2)N(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CON=C1CN[C@H](C(=O)NC[C@@H](O)c2ccccc2)C1
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
A solution was made containing the amide compounds from the previous step, e.g. tert-butyl (2S,4EZ)-2-({[(2S)-2-hydroxy-2-phenylethyl]amino}carbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (2.64 g, 7 mmol), in anhydrous DCM (35 ml). At 0° C., HCl gas was bubbled slowly through the reaction and the deprotection was followed by TLC. After approximately 20 minutes, the DCM was evaporated. The product was concentrated in vacuo from DCM (2–3 times) to remove the HCl. The desired product, e.g. (2S,4EZ)-N-[(2S)-2-hydroxy-2-phenylethyl]-4-(methoxyimino)-2-pyrrolidinecarboxamide (1.94 g, quant.) was isolated as a yellow solid and used without further purification.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:11][C:12]1[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=1.O>C1COCC1>[Cl:11][C:12]1[N:13]=[N:14][C:15]([O:3][CH2:4][CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)=[CH:16][CH:17]=1
Reactant: OCCN1CCCC1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(OCCN2CCCC2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
175 mg (4.01 mmol, 55%) NaH are added to a solution of 0.50 mL (4.04 mmol) N-(2-hydroxyethyl)pyrrolidine in 50 mL THF at 0° C. The reaction solution is stirred for 60 min and heated to RT. 500 mg (3.26 mmol) 3,6-dichloro-pyridazine are added. The solution is stirred for 5 h at RT. 50 mL water are added and the aqueous phase is extracted with 100 mL EtOAc. The organic phase is extracted once with saturated NaCl solution and dried over Na2SO4. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (gradient: EtOAc to EtOAc/MeOH/NH3 9:1:0.1).
Reaction SMILES: [S:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][NH:3]1.[OH-].[Na+].[C:11](O)(=O)C>O.IC>[CH3:11][S:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)O
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-thioxo-2,3-dihydropyrimidin-4(1H)-one (21 g) was added dropwise a solution of sodium hydroxide (13 g) in water (120 mL), iodomethane (11.5 mL) was added thereto, and the mixture was stirred overnight at room temperature. To the reaction mixture was added acetic acid (9.5 mL), and the resulting solid was collected by filtration. The obtained solid was washed with cold water to give the title compound (24 g).
Reaction SMILES: C[O-].[Na+].[NH:4]([CH2:11][CH2:12][C:13]#[N:14])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O[CH:16]([C:22]1[CH:23]=[C:24]([NH:34][CH3:35])[C:25]([CH3:33])=[C:26]([CH:32]=1)[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])CS(C)(=O)=O.CS(C)=O>O>[NH:4]([CH:11]=[C:12]([C:13]#[N:14])[CH2:16][C:22]1[CH:23]=[C:24]([NH:34][CH3:35])[C:25]([CH3:33])=[C:26]([CH:32]=1)[N:27]([CH3:31])[C:28](=[O:30])[CH3:29])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CNc1cc(C(O)CS(C)(=O)=O)cc(N(C)C(C)=O)c1C
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CNc1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C(C)=O)c1C

Procedure:
A mixture of 27 g. of sodium methylate, 41 g. of β-anilinopropionitrile and 79.5 g. of 5'-[1-hydroxy-2-(methylsulfonyl)ethyl]-N,2'-dimethyl-3'-methylaminoacetanilide in 350 ml. of absolute dimethylsulfoxide was stirred for 1 hour at 50°C., then diluted with 2 liters of water and extracted with 6 liters of ethyl acetate. The ethyl acetate extract was washed with 1 liter of water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on 2 kg. of silica gel with ethyl acetate/methylene chloride (1:1), there being obtained 5'-(3-anilino-2-cyanoallyl)-N,2'-dimethyl-3'-methylaminoacetanilide as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[Li]C(C)(C)C.[I:22]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)C.CCCCC>[I:22][C:4]1[C:3]([O:2][CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: CCCCC
Solvent: CCOCC
Product: COc1cccc(NC(=O)OC(C)(C)C)c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
To the solution of tert-butyl (3-methoxyphenyl)-carbamate (5 g, 22.4 mmol, 1 eq) in dry diethyl ether (50 mL) was added pentane solution of t-BuLi (35 mL, 49.3 mmol, 2.2 eq) at −20° C., and the mixture was stirred at 3 hours. To this mixed solution was added the solution of iodine (6.83 g, 26.9 mmol, 1.2 eq) in diethylether (60 mL) at −78° C., and after heating the whole solution to room temperature, the solution was stirred for 20 hours. After adding saturated aqueous solution of Na2S2O3 (100 mL), the mixture was extracted three times with diethyl ether (100 mL). The extract was washed with aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting concentrate was applied to silica gel (eluate: hexane-AcOEt=90-10) to give white solid of the title compound (5.755 g, yield 74%).
Reaction SMILES: N1C2C(=NC=CC=2)N(O[C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:34]=3[Cl:40])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])N=1.[NH2:43][CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]1>CC(N(C)C)=O>[C:52]([N:49]1[CH2:50][CH2:51][N:46]([CH2:45][CH2:44][NH:43][C:11]([C:13]2[C:17]([CH3:18])=[C:16](/[CH:19]=[C:20]3\[C:21](=[O:41])[NH:22][C:23]4[C:28]\3=[CH:27][C:26]([S:29]([CH2:32][C:33]3[C:34]([Cl:40])=[CH:35][CH:36]=[CH:37][C:38]=3[Cl:39])(=[O:31])=[O:30])=[CH:25][CH:24]=4)[NH:15][C:14]=2[CH3:42])=[O:12])[CH2:47][CH2:48]1)(=[O:54])[CH3:53]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)On1nnc2cccnc21
Reactant: CC(=O)N1CCN(CCN)CC1
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(CCNC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(S(=O)(=O)Cc5c(Cl)cccc5Cl)cc43)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1,2,3]triazolo[4,5-b]pyridin-3-yl ester (100 mg, 0.162 mmol) in DMA (2 mL) was added 1-[4-(2-amino-ethyl)-piperazin-1-yl]-ethanone (55 mg, 2 eq.). The mixture was stirred at rt for 2 hours. The reaction was concentrated, diluted with DCM, washed with sat.NaHCO3, water, concentrated and triturated with methanol to give the titled compound as a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([C:12](O)([CH3:14])[CH3:13])[CH2:8][CH:7]=1)(=[O:3])[CH3:2]>CS(C)=O>[CH3:14][C:12]([CH:9]1[CH2:8][CH:7]=[C:6]([CH2:5][O:4][C:1]([CH3:2])=[O:3])[CH2:11][CH2:10]1)=[CH2:13]
Reactant: CC(=O)OCC1=CCC(C(C)(C)O)CC1
Solvent: CS(C)=O
Product: C=C(C)C1CC=C(COC(C)=O)CC1

Procedure:
Heated solutions of dimethyl sulfoxide (DMSO) can dehydrate secondary or tertiary alcohols. Heating 65 grams of alcohol (E) (0.30 moles) in 65 ml of DMSO at 190° C. for ninety minutes resulted in the rapid formation of acetates (B) and (G). The reaction mixture was cooled to 0° C. and then poured into an equal volume of water. The resulting mixture was then extracted with three 200 ml portions of tert-butyl methyl ether. The combined ethereal extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to afford 52 grams of a crude oil. NMR analysis indicated this oil to consist of a 5:1 mixture of (B) to (G) respectively. Although the dehydration yield was consistently greater than 85%, hot DMSO generated various foul smelling vapors that could not be identified nor prevented. The addition of inorganic bases such as barium or calcium oxide suppressed the decomposition of dimethyl sulfoxide but also retarded the rate of dehydration. This reaction is amenable to a large scale process that is in quantities greater than 250 grams.
Reaction SMILES: [OH-].[Na+].[CH2:3](Cl)Cl.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:17](=[O:18])[C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)=[C:15]([NH2:26])[O:14]1.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]1[C:17](=[O:18])[C:16]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][N:20]=2)=[C:15]([NH:26][CH3:3])[O:14]1
Reactant: ClCCl
Reactant: Cc1ccnc(C2=C(N)OC(c3ccccc3Cl)C2=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CNC1=C(c2cc(C)ccn2)C(=O)C(c2ccccc2Cl)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Solid sodium hydroxide(180 mg, 4.50 mmol) was dissolved in a small amount of water and then added to methylene chloride (8.6 ml) containing 2-(o-chlorophenyl)-3-oxo-4-(4-methylpyridyl)-5-amino-2,3-dihydrofuran(400 mg, 1.3 mmol). Tetrabutylammonium bromide (50.0 mg, 1.37 mmol) was added and then a mixture containing dimethyl sulfate (164 mg, 1.30 mmol) was slowly added at room temperature. The mixture was stirred at room temperature for one hour and then washed twice with water, dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo to yield a crude product, which was separated by column-chromatography over silica gel to obtain the desired product (370 mg, yield=88%) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:21].[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.C(O)C>CN(C)C=O>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][N:4]3[C:13](=[O:14])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:5]3=[O:21])[CH2:33][CH2:32]2)=[O:30])=[CH:27][CH:28]=1
Reactant: O=c1c2ccccc2n(-c2ccccc2)c(=O)n1CCCl
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)c3ccccc3n(-c3ccccc3)c2=O)CC1
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 6 parts of 3-(2-chloroethyl)-1-phenyl-2,4(1H,3H)-quinazolinedione, 8.3 parts of (4-fluorophenyl)(4-piperidinyl)methanone and 48 parts of ethanol is stirred and refluxed. N,N-dimethylformamide is added at reflux temperature till all solid enters solution. Stirring is continued overnight at reflux. The reaction mixture is evaporated. The residue is purified twice by column-chromatography over silica gel using first a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol, yielding 2.2 parts (23%) of 3-[2-[4-(4 fluorobenzoyl)-1-piperidinyl]-ethyl]-1-phenyl-2,4(1H,3H)-quinazolinedione; mp. 166.1° C.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].N>>[NH2:2][CH:3]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C=CC(=CN(C)C)C(=O)OCC
Agent: N
Product: CCOC(=O)C=CC(=CN)C(=O)OCC

Procedure:
If diethyl 1-dimethylamino-1,3-butadiene-2,4-dicarboxylate and ammonia are used as starting substances for the process according to the invention in variant (b), the diethyl 1-amino-1,3-butadiene-2,4-dicarboxylate formed is isolated and this ester is reacted further with sodium ethylate, the reaction sequence can be outlined by the following equation: ##STR6##