Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH2:17])[CH2:14][O:15][CH3:16])[CH2:8]2)=[CH:4][CH:3]=1.C1([O:26][C:27](=O)[NH:28][C:29]2[N:30]([CH3:36])[N:31]=[C:32]([CH2:34][CH3:35])[CH:33]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:10][N:9]([CH2:11][CH2:12][C@H:13]([NH:17][C:27]([NH:28][C:29]3[N:30]([CH3:36])[N:31]=[C:32]([CH2:34][CH3:35])[CH:33]=3)=[O:26])[CH2:14][O:15][CH3:16])[CH2:8]2)=[CH:18][CH:19]=1
Reactant: COC[C@@H](N)CCN1CC(Oc2ccc(Cl)cc2)C1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)n(C)n1
Solvent: CS(C)=O
Product: CCc1cc(NC(=O)N[C@@H](CCN2CC(Oc3ccc(Cl)cc3)C2)COC)n(C)n1

Procedure:
A solution of (S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propylamine (1.6 g, 5.6 mmol) and (5-Ethyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid phenyl ester (1.65 g, 6.7 mmol, see preparation below) in DMSO (7 ml) is stirred at ambient temperature for 4 hours, then partitioned between water and ethylacetate. The organic phase is washed again with water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 5:95 methanol/dichloromethane) to afford 1-{(S)-3-[3-(4-Chloro-phenoxy)-azetidin-1-yl]-1-methoxymethyl-propyl}-3-(5-ethyl-2-methyl-2H-pyrazol-3-yl)-urea. [M+H] 436.37.
Reaction SMILES: NCC(O)=O.C(=O)([O-])[O-].[Na+].[Na+].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[O:22]>O>[CH:12](=[C:26]1[NH:20][C:21](=[O:22])[NH:23][C:24]1=[O:25])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CNC(=O)N1
Reactant: O=Cc1ccccc1
Agent: NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1NC(=O)C(=Cc2ccccc2)N1
Yield: 88.3 %

Procedure:
A 37.5 g amount of glycine and 26.5 g of sodium carbonate were dissolved in 200 ml of water in the flask. Then, 53.0 g of benzaldehyde and 50.0 g of hydantoin were added to the resultant solution. The mixture was allowed to react at a temperature of 100° C. for 1 hour while stirring. During the reaction, the pH of the reaction mixture was 9.7 to 9.4. After cooling, the precipitated 5-benzylidene hydantoin was separated and recovered from the reaction mixture. Thus, 83.0 g of 5-benzylidene hydantoin was obtained. The yield was 88% based on the hydantoin.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2[CH2:16][C:17]#[N:18].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1.C(OCC)C>C(O)C.ClCCl>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([CH3:15])=[C:9]2/[C:16](=[CH:25]/[C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)/[C:17]#[N:18]
Reactant: O=Cc1cccnc1
Reactant: COc1ccc2[nH]c(C)c(CC#N)c2c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc2[nH]c(C)c(/C(C#N)=C/c3cccnc3)c2c1
Temperature: 50 °C

Procedure:
To a solution of sodium methanolate (162 mg, 3.0 mmol, 2.0 eq.) in anhydrous ethanol (20 mL) were added, under an argon atmosphere, (5-methoxy-2-methyl-1H-indol-3-yl)-acetonitrile (300 mg, 1.5 mmol, 1.0 eq.) and, after 30 minutes stirring, pyridine-3-carbaldehyde (352 μL, 3.8 mmol, 2.5 eq.). The reaction apparatus was protected from light and the mixture heated at 50° C. for 12 hours. The reaction was allowed to cool to room temperature and then, the solvent was removed under reduced pressure and the crude taken up in ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4 and then, evaporated. The residue was purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 40/60) to afford, after trituration with diethyl ether and dichloromethane, the compound (35) as a yellow solid (250 mg, 58%). IR □max (cm−1): 2212 (νCN); 1H NMR (DMSO, 300 MHz) δ (ppm): 2.54 (3H, s, 2′-methyl), 3.77 (3H, s, 5′-methoxy), 6.78 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.4 Hz, H6′), 7.18 (1H, d, J4′-6′=2.4 Hz, H4′), 7.27 (1H, d, J7′-6′=8.9 Hz, H7′), 7.50 (1H, s, H3), 7.55 (1H, dd, J5″-4″=8.1 Hz, J5″-6″=4.8 Hz, H5″), 7.74 (1H, s, H3), 8.35 (1H, d, J4″-5″=8.1 Hz, H4″), 8.61 (1H, d, J6″-5″=4.8 Hz, H6″), 8.97 (1H, s, H2″), 11.45 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz) δ (ppm): 12.6 (2′-methyl), 55.3 (5′-methoxy), 100.4 (C4′), 106.1 (C2), 106.9 (C3′), 110.9 (C6′), 111.9 (C7′), 118.0 (C1), 123.7 (C5″), 126.2 (C3a′), 129.9 (C2′), 130.5 (C3″), 134.6 (C3), 136.3 (C7a′), 137.6 (C4″), 149.8 (C6″), 150.0 (C2″), 154.1 (C5′); ESI-MS: m/z 290.1 ([M+H]+), 312.1 ([M+Na]+); HRESI-MS: m/z 290.1299 (calcd for C18H16N3O+, 290.1293).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][N:14]([CH3:18])[CH2:15][C:16]#[CH:17]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:5][C:4]1[CH:3]=[C:2]([CH2:17][C:16]#[C:15][N:14]([CH3:18])[CH3:13])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Reactant: C#CCN(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CN(C)C#CCc1cc(N)cc(C(F)(F)F)c1
Temperature: 100 °C

Procedure:
A mixture of 3-bromo-5-trifluoromethylaniline (1.4 g, 5.9 mmol), 1-dimethylamino-2-propyne (1.3 mL, 0.76 mmol), PdCl2(PPh3)2 (0.26 g, 0.29 mmol) and CuI (114 mg, 0.60 mmol) in 10 mL of TEA was heated at 100° C. in a sealed tube for 3 h. The resulting mixture was filtered over Celite®. The filtrate was concentrated, and the residue was purified by prep-HPLC (reverse phase) to give the aniline. MS (ES+): 243 (M+H)+; (ES−) : 241 (M−H)−. Calc'd C12H13F3N2−242.24.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]([NH2:13])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:23])=CC=1>C1COCC1>[Br:1][C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11](=[S:23])[NH2:13]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)n1ncc(C(N)=O)c1Br
Solvent: C1CCOC1
Product: CC(C)(C)n1ncc(C(N)=S)c1Br
Yield: 81.3 %

Procedure:
A solution of the compound (3.59 g, 14.59 mmol) obtained in step 4 and Lawesson's reagent (5.31 g, 13.13 mmol) in THF (60 mL) was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH-silica gel column chromatography (solvent gradient; 2→50% ethyl acetate/hexane) to give 5-bromo-1-tert-butyl-1H-pyrazole-4-carbothioamide (2.8 g, 10.68 mmol, 73%) as a pale-yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[N:17]=[C:18]([CH3:22])[S:19][C:20]=2[CH3:21])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[N:17]=[C:18]([CH3:22])[S:19][C:20]=1[CH3:21]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(-c2c(-c3ccc(Cl)cc3)c(C)n[nH]c2=O)c(C)s1
Product: Cc1nc(-c2c(Cl)nnc(C)c2-c2ccc(Cl)cc2)c(C)s1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
0.40 g of 5-(4-chlorophenyl)-4-(2,5-dimethyl-4-thiazolyl)-6-methyl-2H-pyridazin-3-one and 2 ml of phosphorus oxychloride were mixed. The mixture was stirred for 1 hour on an oil bath of 110° C. The reaction mixture was allowed to cool to room temperature, then, concentrated under reduced pressure. To the resultant residue was added ethyl acetate and ice water. The mixture was stirred for about 5 minutes at room temperature, then, liquid-partitioned. The organic layer was washed with brine three times, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 0.40 g 3-chloro-5-(4-chlorophenyl)-4-(2,5-dimethyl-4-thiazolyl)-6-m ethylpyridazine (hereinafter, described as compound (1) of the present invention.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][CH2:18]Cl>CC(C)=O>[CH3:16][O:17][CH2:18][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: COCCl
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCOc1cccc(C=O)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (5.0 g) in acetone (120 mL), potassium carbonate (8.5 g) and methoxymethyl chloride (4.0 g) were added, followed by stirring at 50° C. for 6 hours. The reaction mixture was concentrated and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried and concentrated. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to thereby give the title compound (6.0 g) having the following physical properties.
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13](=[O:21])[CH2:14][S:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:34])C=1.S(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([C:5]1[CH:25]=[CH:24][CH:23]=[CH:22][C:6]=1[O:7][CH2:8][CH:9]1[CH2:12][N:11]([C:13](=[O:21])[CH2:14][S:15]([C:16]2[N:20]=[CH:19][NH:18][N:17]=2)=[O:34])[CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1OCC1CN(C(=O)CSc2nc[nH]n2)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1OCC1CN(C(=O)CS(=O)c2nc[nH]n2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A solution of 3-[(2-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl]-2-oxoethyl)sulfanyl}-1H-1,2,4-triazole (112 mg, 0.31 mmol) obtained in Example 243 and m-chloroperbenzoic acid (122 mg, 0.50 mmol) in ethyl acetate (6.2 mL) was stirred at 0° C. for 3 hr. Saturated aqueous sodium bisulfite solution (5 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative HPLC (device: Gilson Inc., High Throughput Purification system; column: YMC Combiprep ODS-A, S-5 μm, 50×20 mm; solvent: SOLUTION A; 0.1% trifluoroacetic acid-containing water, SOLUTION B; 0.1% trifluoroacetic acid-containing acetonitrile; gradient cycle: 0.00 min (SOLUTION A/SOLUTION B=90/10), 1.00 min (SOLUTION A/SOLUTION B=90/10), 4.20 min (SOLUTION A/SOLUTION B=10/90), 5.40 min (SOLUTION A/SOLUTION B=10/90), 5.50 min (SOLUTION A/SOLUTION B=90/10), 5.60 min (SOLUTION A/SOLUTION B=90/10); flow rate: 25 mL/min; detection method: UV 220 nm) to give 3-[(2-{3-[(2-tert-butylphenoxy)methyl]azetidin-1-yl}-2-oxoethyl)sulfinyl]-1H-1,2,4-triazole (61 mg, 53%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]([CH:11]=1)[C:7]([NH:9][CH3:10])=[O:8].[H][H]>[Pd].CO>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:11][C:6]=1[C:7]([NH:9][CH3:10])=[O:8]
Reactant: [H][H]
Reactant: CNC(=O)c1cc(F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1cc(F)ccc1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Pd/C (10% wt, 860 mg) was added to 5-Fluoro-N-methyl-2-nitrobenzamide (4.58 g, 23.4 mmol) under argon. Methanol was added (50 mL) and the argon balloon was replaced with a hydrogen balloon. The mixture was stirred for 24 h at room temperature. It was filtered through a celite pad and the solvent was removed to yield the title compound as a pale yellow solid in quantitative yield.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[CH:6]=[N:5]1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]([CH:22]=1)[C:20]#[N:21].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:20]([C:19]1[CH:22]=[C:15]([NH:14][C:9]([C:7]2[CH:6]=[N:5][N:4]([CH2:3][C:2]([F:1])([F:13])[F:12])[CH:8]=2)=[O:11])[CH:16]=[CH:17][C:18]=1[O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])#[N:21]
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Reactant: O=C(O)c1cnn(CC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(NC(=O)c2cnn(CC(F)(F)F)c2)cc1C#N
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 41.8 %

Procedure:
1-(2,2,2-Trifluoroethyl)pyrazole-4-carboxylic acid (2.2 g), 5-amino-2-neopentyloxybenzonitrile (2.5 g), 1-hydroxybenzotriazole (1.8 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (2.6 g) were added to dimethylformamide (20 ml) and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was treated with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from ethyl acetate to give the title compound (1.8 g), melting point 159–160° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]2[S:14][C:15]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[N:16][C:12]=2[C:11]([F:25])=[CH:10][N:9]=1)(C)(C)C>Cl>[Cl:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[C:15]1[S:14][C:13]2[C:8]([NH2:7])=[N:9][CH:10]=[C:11]([F:25])[C:12]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(F)c2nc(-c3c(F)cccc3Cl)sc12
Agent: Cl
Product: Nc1ncc(F)c2nc(-c3c(F)cccc3Cl)sc12
Temperature: 50 °C
Yield: 103.1 %

Procedure:
HCl (4N in dioxane, 10 mL) was added to [2-(2-chloro-6-fluorophenyl)-7-fluorothiazolo[5,4-c]pyridin-4-yl]-carbamic acid tert-butyl ester (0.350 g, 0.88 mmol) and the reaction mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the volatiles were removed under reduced pressure to afford the title compound as an off-white solid (270 mg, quantitative). 1H NMR (400 MHz, CDCl3): δ 7.84 (s, 1H), 7.61-7.49 (m, 1H), 7.44 (d, J=8.1 Hz, 1H), 7.25 (t, J=8.7 Hz, 1H), 2.90 (br s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7](C(C2C(O)=CC3C(C)(C)CCC(C)(C)C=3C=2)=O)=[CH:6][CH:5]=1.[OH-].[K+].BrCCCCCC>CS(C)=O>[C:3]([OH:27])(=[O:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2cc3c(cc2O)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCCCCCBr
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of the 4-[(3-hydroxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid methyl ester (from Example 7, 433 mg, 1.18 mmol) in DMSO (2 mL) was treated with KOH (1.5 mmol) at 0° C. and allowed to warm to ambient temperature over 1 h. The yellow solution was cooled again to 0° C. and treated with a solution of bromohexane (156 mL, 1.30 mmol) in DMSO (1 mL) and allowed to warm to ambient temperature and stirred for 10 h. The reaction was quenched with saturated aqueous NH4Cl. The aqueous solution was adjusted to pH=3 with 1M HCl and extracted with EtOAc, 3×. The organic layers were combined and washed with water (2×) and brine. The organic solution was dried (NaSO4), filtered, and concentrated. Purification by silica gel radial chromatography (20:1=hexane:Et2O) gave 4-[2-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid, 317 mg (62%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ8.14 (½ABq, J=8.4 Hz, 2H, ArH), 7.84 (½ABq, J=8.4 Hz, 2H, ArH), 7.47 (s, 1H, ArH), 6.81 (s, 1H, ArH), 3.80 (t, J=6.2 Hz, 2H, OCH2), 1.17 (m, 4H, 2CH2), 1.34 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.28 (s, 6H, 2CH3), 1.11 (m, 4H, 2CH2), 0.95 (m, 2H, CH2), 0.80 (t, J=7.1 Hz, 3H, CH3). The hexyloxyketo acid (87 mg, 0.19 mmol) in EtOH (2 mL) was converted into the oxime derivative as described in Example 4 to provide, after recrysallization (CH2Cl2/hexanes), 4-[(3-hexyloxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carbonyl]benzoic acid oxime (114), 312 mg (60%) as a white solid: mp 197-199° C. (d); 1H NMR (400 MHz, CDCl3) δ8.14 (½ABq, J=8.5 Hz, 2H, ArH), 7.57 (½ABq, J=8.5 Hz, 2H, ArH), 7.22 (s, 1H, ArH), 6.85 (s, 1H, ArH), 3.82 (t, J=6.3 Hz, 2H, OCH2), 1.70 (m, 4H, 2CH2), 1.45 (m, 2H, CH2), 1.32 (s, 6H, 2CH3), 1.25 (s, 6H, 2CH3), 1.13 (m, 6H, 3CH2), 0.80 (t, J=6.8 Hz, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ155.7, 153.8, 147.8, 141.1, 137.0, 130.3, 129.9, 128.4, 127.0, 118.5, 110.0, 68.3, 35.3, 35.0, 34.8, 33.8, 31.9, 31.8, 31.4, 29.0, 25.4, 22.5, 13.9.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[CH:5]=[CH:6][CH:7]=O.[C:13]([CH2:15][C:16]([N-:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[O:17])#[N:14].N1CCCCC1.Cl>C(O)C.O>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][NH:18][C:16](/[C:15](=[CH:7]/[CH:6]=[CH:5]/[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1)/[C:13]#[N:14])=[O:17]
Reactant: COc1ccc(C[N-]C(=O)CC#N)cc1OC
Reactant: O=CC=Cc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(CNC(=O)/C(C#N)=C/C=C/c2ccc(O)c(O)c2)cc1OC
Reaction time: 1 h
Yield: 68.4 %

Procedure:
To 3,4-dihydroxycinnamaldehyde (32 mg, 0.2 mmol) and N-(cyanoacetyl)3,4-dimethoxybenzylamide (47 mg, 0.2 mmol) in 8 mL of ethanol 40 μl of piperidine was added and the mixture was kept at room temperature for 1 h. 2N HCl and water were added and the precipitated solid was recrystallized from ethanol-water to give 52 mg (68%) of an orange solid. The product gave the following analytical data:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].C(N(CC)CC)C.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38].O>O1CCCC1>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[C:2]([NH:1][C:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)=[O:38])[CH:7]=1
Reactant: Nc1cc(Cl)ccc1N1C(=O)c2ccccc2C1=O
Reactant: O=C(Cl)c1ccc2ccccc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(Cl)ccc1N1C(=O)c2ccccc2C1=O)c1ccc2ccccc2c1
Yield: 44.7 %

Procedure:
A reaction solution of N-(2-amino-4-chlorophenyl)phthalimide (0.5 g), triethylamine (0.28 g) and 2-naphthoyl chloride (0.35 g) in anhydrous tetrahydrofuran (50 ml) was heated at reflux temperature for 6 hr under nitrogen atmosphere. The resulting mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed and the residue was purified by column chromatography on silica gel using ethyl acetate-hexane (1:5) to give the title compound (0.35 g) as a yellow solid.
Reaction SMILES: [N:1]1([CH2:7][CH:8]2[N:13](N)[C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:34])[CH2:29][C:30](=O)[CH2:31][CH3:32])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.O>[N:1]1([CH2:7][CH:8]2[N:13]3[C:30]([CH2:31][CH3:32])=[C:29]([C:28](=[O:34])[C:25]4[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[C:15]4[CH:16]=[CH:17][CH:18]=[C:11]([C:12]=43)[O:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCC(=O)CC(=O)c1ccc(OC)cc1
Reactant: NN1c2ccccc2OCC1CN1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1c(C(=O)c2ccc(OC)cc2)c2cccc3c2n1C(CN1CCOCC1)CO3

Procedure:
A solution of 22.2 g (0.089 mole) of 3-(4-morpholinylmethyl)-4-amino-3,4-dihydro-2H-1,4-benzoxazine and 18.3 g (0.08 mole) of the sodium salt of 5-(4-methoxyphenyl)-3,5-pentanedione in 250 ml of glacial acetic acid was heated under reflux for four hours, then cooled and poured into 1500 ml of water and 600 ml of ethyl acetate. The mixture was neutralized by the addition of solid sodium carbonate and solid sodium bicarbonate with stirring, the organic layer was separated from the aqueous layer and dried over magnesium sulfate, filtered and taken to dryness. The crude product was purified by chromatography on silica gel, eluting with 4:1 hexane/ethyl acetate, the first 700 ml of eluate being discarded, and the next 800 ml, containing the product, being retained. Evaporation of the latter to dryness and recrystallization of the residue from ethyl acetate afforded 3.9 g of 3-(4-morpholinylmethyl)-5-ethyl-6-(4-methoxybenzoyl)-2,3-dihydropyrrolo[1,2,3-de]-1,4-benzoxazine, m.p. 185.5°- 187.0° C.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([C:10]#[N:11])[C:5](=[CH:8][CH:9]=1)[C:6]#[N:7].C(=O)([O-])[O-].[K+].[K+].ClCC[Si](C)(C)C.Cl>CN(C)C=O>[C:10](#[N:11])[C:4]1[C:5](=[CH:8][CH:9]=[CH:2][CH:3]=1)[C:6]#[N:7]
Reactant: N#Cc1ccc(O)cc1C#N
Agent: C[Si](C)(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 138.4 %

Procedure:
In 200 ml of N,N-dimethylformamide were dissolved with heating 20 g of 4-hydroxyphthalonitrile and 10.55 g of potassium carbonate, to which 20 g of chloroethyl-trimethylsilane were added dropwise at 40° C. in the atmosphere of argon. Immediately after the addition, the mixture was stirred for 18 hours while maintaining the reaction temperature at 85°-105° C. The reaction vessel was then cooled to room temperature and 250 ml of dilute hydrochloric acid was added. The mixture was extracted with 1.2 liters of toluene. The organic layer was washed well with water and water was removed with magnesium sulfate. Thereafter, toluene was removed by distillation and the residue was purified with a toluene/silica gel column to obtain 24.6 g (yield: 77.0%) of a compound having the formula (XVII) below. ##STR39##
Reaction SMILES: C(OC([N:7]1[C@H:11]([CH2:12][C:13]2[N:14]3[CH:20]=[N:19][CH:18]=[C:15]3[S:16][CH:17]=2)[CH2:10][C@H:9]([S:21][C:22]2[C@H:23]([CH3:39])[C@@H:24]3[C@@H:34]([C@H:35]([OH:37])[CH3:36])[C:33](=[O:38])[N:25]3[C:26]=2[C:27]([O:29]CC=C)=[O:28])[CH2:8]1)=O)C=C.CNC1C=CC=CC=1.O.C(OCC)(=O)C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:37][C@@H:35]([C@H:34]1[C:33](=[O:38])[N:25]2[C:26]([C:27]([OH:29])=[O:28])=[C:22]([S:21][C@H:9]3[CH2:10][C@@H:11]([CH2:12][C:13]4[N:14]5[CH:20]=[N:19][CH:18]=[C:15]5[S:16][CH:17]=4)[NH:7][CH2:8]3)[C@H:23]([CH3:39])[C@H:24]12)[CH3:36]
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](Cc3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CNc1ccccc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](Cc4csc5cncn45)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 11 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (14.3 mg) is added to a solution of 71 mg of allyl(1R,5S,6S)-2-[(3S,5R)-1-allyloxycarbonyl-5-(imidazo[5,1-b]thiazol-3-yl)methylpyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate and 0.08 ml of N-methylaniline in 1.0 ml of dry dichloromethane, and the mixture is stirred in an argon atmosphere at room temperature for 40 min. Distilled water (3 ml) and 5 ml of ethyl acetate are added thereto to remove insolubles, followed by washing twice with 5 ml of ethyl acetate and concentration under reduced pressure. The concentrate is then freeze dried to give a colorless flocculent material. This material is then purified by column chromatography on Cosmosil 40C18-PREP (water:methanol) to give 6.12 mg of the title compound as a colorless flocculent material.