Azzindani/Open_Reaction_Data huggingface dataset:
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.Cl.[NH2:49][CH2:50][C:51]1[O:55][C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:53][CH:52]=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:49][CH2:50][C:51]4[O:55][C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])=[CH:53][CH:52]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: CCOC(=O)c1ccc(CN)o1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: Cl
Product: CCOC(=O)c1ccc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)o1
Yield: 59 %

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 ethyl 5-(aminomethyl)furan-2-carboxylate hydrochloride, the title compound was obtained as a colorless solid in 59% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.11 (d, J=3.4 Hz, 1H), 7.07-6.99 (m, 2H), 6.41 (d, J=3.4 Hz, 1H), 6.10 (br s, 2H), 4.62 (d, J=5.7 Hz, 2H), 4.43 (s, 2H), 4.36 (q, J=7.1 Hz, 2H), 3.83-3.75 (m, 2H), 3.47-3.40 (m, 2H), 2.48 (s, 3H), 1.38 (t, J=7.1 Hz, 3H); MS (ES+) m/z 508.15 (M+23).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([CH:11]1[C:16](=[O:17])[O:15][C:14]([CH3:19])(C)O[C:12]1=O)=[O:10])=[N+:2]=[N-:3].OCC[C:24]#[N:25].C(=O)=O.[N+:29]([C:32]1[CH:39]=[CH:38][C:35](C=O)=[CH:34][CH:33]=1)([O-:31])=[O:30].N1CCCCC1.C(O)(=O)C>CC(O)C>[C:24]([CH2:19][CH2:14][O:15][C:16](=[O:17])[C:11](=[CH:12][C:35]1[CH:38]=[CH:39][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=1)[C:9](=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])#[N:25]
Reactant: N#CCCO
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC(=O)C(C(=O)CCCCCN=[N+]=[N-])C(=O)O1
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: N#CCCOC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)CCCCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5-(6-Azidohexanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was heated with 3-hydroxypropionitrile (8.90 g, 125 mmol) at 80° C. until no more CO2 was released. The reaction mixture was diluted with 150 ml of 2-propanol and 4-nitrobenzaldehyde (6.30 g, 41.7 mmol), piperidine (178 mg, 2.10 mmol) and acetic acid (125 mg, 2.10 mmol) were added. The mixture was stirred at room temperature for 48 hrs. After the solvent was evaporated, the residue was dissolved into CHCl3 (200 ml), washed with water (150 ml) and brine (150 ml). After drying (Na2SO4) and evaporation of solvent, 8-azido-2-[ (4-nitrophenyl)methylene]-3-oxooctanoic acid 2-cyanoethyl ester was obtained as a brownish oil (17.0 g, 100%).
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11](C(OC(C)(C)C)=O)=[CH:10][CH:9]=2)[CH:4]=[CH:3]1.O[CH2:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=[O:57]>C1COCC1>[OH:57][C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:1])[N:7]([CH2:22][C:23]3[CH:24]=[C:25]([NH:29][C:30](=[O:34])[O:31][CH2:32][CH3:33])[CH:26]=[CH:27][CH:28]=3)[N:6]=2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)Nc1cccc(CO)c1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(=O)[nH]n2)cc1
Reactant: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(O)cc3)ccc2=O)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
5 g (17.3 mmol) of tert-butyl 4-(6-oxo-1,6-dihydropyridazin-3-yl)phenylcarboxylate, 5.08 g (26 mmol) of ethyl (3-hydroxymethylphenyl)carbamate and 6.8 g (26 mmol) of triphenylphosphine are dissolved in 400 ml of THF. Under a nitrogen atmosphere, the yellow solution is cooled to 0° C., 4.1 ml (26 mmol) of diethyl azodicarboxylate are slowly added dropwise, and the reaction mixture is stirred at room temperature for 20 h. The yellow suspension is evaporated to dryness. The residue is dissolved in 300 ml of dichloromethane, and 40 ml of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 20 h, evaporated to dryness, and 100 ml of water, 200 ml of 1N NaOH and 100 ml of ethyl acetate are added to the viscous oil. A precipitate forms in the process, which is filtered off with suction, washed with water and dried in vacuo.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([OH:18])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].[N+:21]([C:24]1[CH:29]=[C:28]([S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])[CH:27]=[CH:26][C:25]=1Cl)([O-:23])=[O:22]>C1COCC1>[CH2:16]([O:15][C:13](=[O:14])[C:11]1[CH:12]=[C:2]([O:1][C:25]2[CH:26]=[CH:27][C:28]([S:30]([C:33]([F:35])([F:36])[F:34])(=[O:32])=[O:31])=[CH:29][C:24]=2[N+:21]([O-:23])=[O:22])[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:9][C:10]=1[OH:18])[CH3:17]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: CCOC(=O)c1cc(O)c(C(=O)OCC)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])c(C(=O)OCC)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of diethyl 2,5-dihydroxyterephthalate (100 mg, 0.393 mmol) in THF was added sodium hydride (32 mg of 60% dispersion in mineral oil) followed by 2-nitro-4-(trifluoromethylsulfonyl)chlorobenzene (228 mg, 0.787 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, the organic layer was washed with water and brine, dried, concentrated and purified to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.77 (br s, 1H, OH), 8.78 (d, J=2.3 Hz, 1H), 8.22 (dd, J=2.3 & 9.0 Hz, 1H), 7.82(s, 1H), 7.56 (s, 1H), 7.19 (d, J=9.0 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H, OCH2CH3), 4.09 (q, J=7.2 Hz, 2H, OCH2CH3), 1.3 (t, J=7.2 Hz, 3H, OCH2CH3), 0.92 (t, J=7.2 Hz, 3H, OCH2CH3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45](B(O)O)=[CH:44][N:43]=1>>[CH3:40][O:41][C:42]1[N:47]=[CH:46][C:45]([C:2]2[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=2)[CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=4)=[CH:14][C:9]=3[N:8]=[C:7]2[C@@H:27]2[C@H:29]([C:30]([OH:32])=[O:31])[C:28]2([CH3:36])[CH3:35])=[CH:44][N:43]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Product: COc1ncc(-c2cccc(Cn3c([C@@H]4[C@H](C(=O)O)C4(C)C)nc4cc(OCc5ccc6ccccc6n5)ccc43)c2)cn1

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 2-methoxypyrimidine-5-boronic acid in Step A. MS (ESI): mass calcd. for C35H31N5O4, 585.24; m/z found, 586.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.63 (s, 2H), 8.23 (d, J=8.3, 1H), 8.11 (d, J=8.8, 1H), 7.85 (d, J=8.3, 1H), 7.78-7.74 (m, 1H), 7.70 (d, J=8.5, 1H), 7.60-7.55 (m, 1H), 7.51-7.45 (m, 2H), 7.35-7.32 (m, 1H), 7.27-7.25 (m, 1H), 7.25-7.23 (m, 1H), 7.15-7.11 (m, 1H), 7.07-7.04 (m, 1H), 5.52-5.46 (m, 1H), 5.44 (s, 2H), 5.43-5.38 (m, 1H), 4.06 (s, 3H), 2.32-2.29 (m, 1H), 2.11-2.08 (m, 1H), 1.20 (s, 3H), 0.99 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][CH:7]=1.[I:21]I>ClCCl.FC(F)(F)C([O-])=O.[Ag+]>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[N:15]3)[O:10][C:9]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:21]
Reactant: Cc1cn(C[C@H]2CN(c3cccc(F)c3)C(=O)O2)nn1
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Reaction time: 8 h
Yield: 42.6 %

Procedure:
Silver trifluoroacetate (0.52 g, 2.35 mmol) was added to a solution of (5R)-3-(3-fluorophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 1, 0.50 g, 1.81 mmol) in dichloromethane (15 ml). Iodine (0.55 g, 2.17 mmol) was added over 1.5 h, and the reaction mixture was stirred overnight. After 16 h, the solids were removed by filtration and additional silver trifluoroacetate (0.38 g, 1.72 mmol) and iodine (0.27 g, 1.06 mmol) were added. After an additional 24 h, the reaction mixture was filtered. The filter cake was washed with methanol. The methanol filtrate was concentrated under vacuum to give 0.31 g of the title product.
Reaction SMILES: Cl.[O:2]([CH2:6][CH2:7][NH2:8])[N+:3]([O-:5])=[O:4].C[O-].[Na+].[C:12]([N:14]=[C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:25]=1)OCCC)#[N:13]>CN(C=O)C>[C:12]([NH:14][C:15]([C:20]1[CH:21]=[N:22][CH:23]=[C:24]([NH:26][CH:27]([CH3:29])[CH3:28])[CH:25]=1)=[N:8][CH2:7][CH2:6][O:2][N+:3]([O-:5])=[O:4])#[N:13]
Reactant: CCCOC(=NC#N)c1cncc(NC(C)C)c1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Nc1cncc(C(=NCCO[N+](=O)[O-])NC#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
To a solution of 2-nitroxyethylamine hydrochloride (95 mg, 0.67 mmol) in DMF (1 ml) was added sodium methoxide (25 mg, 0.46 mmol) followed by a solution of propyl N-cyano-5-isopropylamino-3-pyridinecarboximidate (80 mg, 0.33 mmol) described in Example 11 of Experimental Example 1 in DMF (1 ml), and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure. The residue was suspended in water and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography with a mixed solvent of methanol and chloroform as an eluent to give the title compound (26 mg, yield 27%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[S:26][C:25]([NH:27]C(=O)OC(C)(C)C)=[N:24][C:23]=2[CH3:35])=[C:20]2[C:15]([N:16]([CH2:39][CH:40]3[CH2:42][CH2:41]3)[C:17](=[O:38])[N:18]([CH3:37])[C:19]2=[O:36])=[N:14]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:27][C:25]1[S:26][C:22]([C:21]2[N:13]([CH2:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)[N:14]=[C:15]3[C:20]=2[C:19](=[O:36])[N:18]([CH3:37])[C:17](=[O:38])[N:16]3[CH2:39][CH:40]2[CH2:42][CH2:41]2)=[C:23]([CH3:35])[N:24]=1
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)sc1-c1c2c(=O)n(C)c(=O)n(CC3CC3)c2nn1Cc1ccnc2ccc(Cl)cc12

Procedure:
This compound was synthesized by treating tert-butyl 5-[2-[(6-chloroquinolin-4-yl)methyl]-7-(cyclopropylmethyl)-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl]4-methyl-1,3-thiazol-2-ylcarbamate with 10% TFA in dichloromethane at room temperature for 5 hours. Mass: 508.13 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH2:11]([CH2:13][NH2:14])O.C(Cl)(Cl)Cl.S(Cl)(Cl)=O>C(OCC)(=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:8][CH2:11][CH2:13][N:14]=2)=[CH:9][CH:10]=1
Reactant: NCCO
Reactant: O=C(O)c1ccc(O)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Oc1ccc(C2=NCCO2)cc1
Temperature: 60 °C
Reaction time: 1.8 h

Procedure:
Phenyl ester of 4-hydroxybenzoic acid (19.28 grams, 0.09 mole) and monoethanolamine (5.55 grams, 0.0909 mole) are added to a reactor and stirred as a powder under a nitrogen atmosphere. Heating commences and fourteen minutes later, a temperature of 150° C. is achieved. After 108 minutes at 150° C., the reactor is cooled to 60° C., then chloroform (100 milliliters) is added. After boiling for 5 minutes, the chloroform is decanted off, and a second portion (100 milliliters) of chloroform is added. After boiling for 5 minutes, the chloroform is again removed by decantation. A third portion (100 milliliters) of chloroform is added followed by boiling for 5 minutes and decantation. Ethyl acetate (100 grams) is added to the powder product remaining in the reactor and stirring under a nitrogen atmosphere commences to provide a fine slurry. Thionyl chloride (21.41 grams, 0.18 mole) dissolved in ethyl acetate (50 grams) is added to the reactor inducing an exotherm to 29° C. three minutes later. The reactor is allowed to cool to 25° C. and maintained therein for 237 minutes. The product is filtered off and the product recovered on the filter is washed with two portions (50 milliliters) of ethyl acetate. The filter cake of N-(2-chloroethyl)-4-hydroxybenzamide slightly damp with ethyl acetate is added to a beaker containing deionized water (300 milliliters) and stirred to a solution. Five percent aqueous sodium hydroxide solution is added dropwise to the solution until the pH reached 7. At this time, a white slurry of crystalline product is formed and is stirred for an additional ten minutes before filtration. The product is washed on the filter with two portions (50 milliliters) of deionized water, removed, added to a porcelain dish and then dried in a vacuum oven at 50° C. and 1 mm Hg for two hours. After this time, the product is removed and boiled in acetone (300 milliliters). After cooling to 25° C., 200 milliliters of the acetone is removed by rotary evaporation. The resulting product is recovered by filtration, washed on the filter with cold acetone (25 milliliters), removed, added to a porcelain dish and then dried in a vacuum oven at 50° C. and 1 mm Hg to a constant weight of 9.02 grams of crystalline white powder. Fourier transform infrared spectrophotometric analysis of a potassium bromide pellet of the product reveals the presence of the expected oxazoline >C=N-- absorbance at 1636 cm-1, the hydroxyl group O--H stretching at 3442 cm-1 and the out-of-plane C--H bending vibration at 839 cm-1 indicative of para-disubstitution. An absorption characteristic of the oxazoline ring is observed at 945 cm-1. Proton magnetic resonance spectroscopy (250 MHz) further confirms the product structure as the 2-(4-hydroxyphenyl)oxazoline.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([OH:16])=O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:19][C@@H:20]1[CH2:25][C@@H:24]2[CH2:26][C@@H:22]([C:23]2([CH3:28])[CH3:27])[C@H:21]1[CH3:29].[N:30]1(C(N2C=CN=C2)=O)C=CN=C1.N.O>CN(C)C=O>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH:13]([CH2:17][CH3:18])[C:14]([NH2:30])=[O:16])=[O:11])[N:5]=[CH:4][C:3]=1[NH:19][C@@H:20]1[CH2:25][C@@H:24]2[CH2:26][C@@H:22]([C:23]2([CH3:27])[CH3:28])[C@H:21]1[CH3:29]
Reactant: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CCC(NC(=O)Cn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Cl)c1=O)C(N)=O
Yield: 29.2 %

Procedure:
2-({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyric acid (48 mg, 0.113 mmol) in N,N-dimethylformamide (2 mL) was stirred with di-1H-imidazolylmethanone (55 mg, 0.340 mmol) at room temperature for 2 days and then with 30% aqueous ammonia (0.2 mL) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (14 mg, 29% yield).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][C:29]([O:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]([CH2:10][CH:4]([O:3][CH2:1][CH3:2])[C:5]([OH:7])=[O:6])[CH:16]=[CH:15][CH:14]=1)=[O:30]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Product: CCOC(Cc1cccc(CCOC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([CH:17]=1)=[C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[O:9][N:10]=2.[C-:18]#[N:19].[K+].O.O1CCOCC1>C(Cl)Cl>[C:11]1([C:8]2[O:9][N:10]=[C:6]3[CH:5]=[CH:4][C:3]([CH2:2][C:18]#[N:19])=[CH:17][C:7]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccc2noc(-c3ccccc3)c2c1
Reactant: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: N#CCc1ccc2noc(-c3ccccc3)c2c1
Yield: 114.7 %

Procedure:
A mixture of 9.1 g (0.032 mole) of 5-(bromomethyl)-3-phenyl-2,1-benzisoxazole, 9.8 g (0.15 mole) of potassium cyanide, 50 ml of water and 80 ml of dioxane was heated at reflux under nitrogen for 2.5 hr. The solution was cooled and diluted with 200 ml of methylene chloride. The layers were separated and the organic layer was washed twice with water (emulsion), dried over sodium sulfate and concentrated to give 8.6 g of a dark solid as residue. The solid was chromatographed on 180 g of silica gel eluting with 2% acetone in benzene and 5.8 g (80%) of solid was obtained from the eluant. An analytical sample, m.p. 107°-109° C. was prepared by recrystallizing with 2-propanol.
Reaction SMILES: CC1(C)OC(=O)CC(=O)O1.C1(N=C=O)C=CC=CC=1.Cl.[NH:21]([C:28]([OH:39])=[C:29]1[C:34](=[O:35])OC(C)(C)OC1=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[CH3:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH2:44]>CN(C=O)C>[CH3:40][O:41][C:42]1[CH:48]=[CH:47][CH:46]=[CH:45][C:43]=1[NH:44][C:34](=[O:35])[CH2:29][C:28]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: COc1ccccc1N
Reactant: CC1(C)OC(=O)C(=C(O)Nc2ccccc2)C(=O)O1
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccccc1NC(=O)CC(=O)Nc1ccccc1
Reaction time: 0.08 h

Procedure:
Meldrum's Acid (5.0 g, 34.7 mmol) was added to a flask along with DMF (40 ml) and TEA (10 ml, 70 mmol). The mixture was allowed to stir for 5 minutes and phenyl isocyanate (4.13 g, 34.7 mmol) was added. The contents of the flask were allowed to stir for 30 minutes. The mixture was poured into a flask containing HCl (200 ml) and ice. The solid was filtered and dried in vacuo overnight to afford product as a white solid. 5-[anilino(hydroxy)methylene]-2,2-dimethyl-1,3-dioxane-4,6-dione (100 mg, 0.380 mmol) was added to a microwave vial along with o-methoxyaniline (51 mg, 0.418 mmol) and 1 ml of DMF. The vial was capped and microwaved at 165° C. for 10 minutes. The contents of the vial were concentrated and purified by trituration with DCM to afford the product, N-(2-methoxyphenyl)-N′-phenylmalonamide as an off-white solid. ESIMS calcd 285.2 (M++H), found 285.3 (M++H)
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:36]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1>>[N:36]1([C:41]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:42])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: O=C(Cl)N1CCCC1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)N5CCCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available 1-pyrrolidinecarbonyl chloride (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=575 by positive ion CI.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:33])[CH3:32])[C:26]=1[N:34]=[C:35]=[O:36])([CH3:24])[CH3:23]>CCOCC>[CH3:24][CH:22]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]([CH3:32])[CH3:33])[C:26]=1[NH:34][C:35](=[O:36])[CH2:14][C:13](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CC(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
To a cooled (-78° C.) solution of diisopropylamine (2.48 g, 0.024 mol) in 100 mL ether, n-BuLi (0.024 mol) was added dropwise followed by 50 mL ether. After stirring for 5 minutes at -78° C. under a nitrogen atmosphere, a solution of acetophenone (2.95 g, 0.024 mol) in 25 mL ether was added dropwise and the resulting solution was stirred for 20 minutes at -78° C. A solution of 2,6-diisopropylphenyl isocyanate in 25 ML Et2O was then added dropwise and the reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours under a nitrogen atmosphere (J. F. Wolfe, et al, Synthetic Communications 17, 13 (1987)). The reaction mixture was then quenched with a saturated solution of ammonium chloride and extracted with methylene chloride. The layers were separated and the organic layer was washed two times with water, dried (Na2SO4) and concentrated in vacuo (30° C.) to afford a yellow residue. This residue was washed with hexane, filtered, and oven-dried (40° C.) to yield a pale yellow solid, 4.3 g (0.013 mol, 54%) of the title compound, mp 124°-126° C.