Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:32][C@H:31]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@@H:30]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[O:29]3)[CH2:27]2)[C:13](=O)[CH2:14][CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C([O-])(=O)C.[NH4+:51].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([C:13]2[NH:51][C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:15][CH:14]=2)[CH2:25][C@H:26]2[CH2:46][CH2:45][C:28]3([O:29][C@H:30]([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C@@H:31]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:32]3)[CH2:27]2)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2ccccn2)cc1Cl
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(-c3ccccn3)[nH]2)cc1Cl
Temperature: 110 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
To a solution of 5-[3-chloro-4-(methylsulfonyl)phenyl]-6-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(pyridin-2-yl)hexane-1,4-dione (698 mg) in acetic acid (5 mL) was added ammonium acetate (1.31 g), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (580 mg, yield 85%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C(O[C:4](=[O:14])[C:5]([NH:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:6])C.[CH3:15][O:16][CH:17]([O:20][CH3:21])[CH2:18][NH2:19]>CC(O)C>[CH3:13][CH2:12][O:11][C:9]([CH2:8][NH:7][C:5]([C:4]([NH:19][CH2:18][CH:17]([O:20][CH3:21])[O:16][CH3:15])=[O:14])=[O:6])=[O:10]
Reactant: COC(CN)OC
Reactant: CCOC(=O)CNC(=O)C(=O)OCC
Solvent: CC(C)O
Product: CCOC(=O)CNC(=O)C(=O)NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-ethoxycarbonylmethyl-oxalamic acid ethyl ester (84.0 g, 414 mmol) 2–1 in 2-propanol (500 mL) was added aminoacetaldehyde dimethyl acetal (45.7 g, 435 mmol) in one portion. After stirring overnight at room temperature, the reaction mixture was concentrated to a thick orange oil. This thick slurry was diluted with 2-propanol (300 mL) and the solid was broken up with a spatula. Filtration afforded a solid which was further rinsed with an additional portion of 2-propanol. Removal of residual 2-propanol was accomplished via high vacuum to afford a light orange solid: 1H NMR (CDCl3) δ 7.82 (br s, 1H), 7.50 (br s, 1H), 4.41 (t, 1H, 5.3 Hz), 4.24 (q, 2H, 7.1 Hz), 4.09 (d, 2H, 5.9 Hz), 3.47 (dd, 2H, 5.3, 6.2 Hz), 3.40 (s, 6H), 1.30 (t, 3H, 7.1 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])[C:15](=O)[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1.CC([O-])=O.[Na+].Cl.[NH2:31][OH:32]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[C@@H:16]([CH2:17][CH3:18])/[C:15](=[N:31]/[OH:32])/[C:14]3[NH:20][N:21]=[CH:22][C:13]=3[C@H:12]2[CH2:23][CH3:24])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC[C@@H]1c2cn[nH]c2C(=O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC[C@@H]1c2cn[nH]c2/C(=N\O)[C@H](CC)N1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of compound 62 (67 mg, 0.17 mmol) in a mixture of MeOH/H2O (5:1, 9 mL) was added NaOAc (141 mg, 1.7 mmol) followed by hydroxylamine hydrochloride (131.6 mg, 1.9 mmol). The resulting solution was stirred at room temperature for a weekend. The solvent was removed by rotary evaporation and the residue was taken up in EtOAc. The organic phase was washed with water, brine and dried (MgSO4). After removal of the solvent under reduced pressure, the crude product was purified by flash chromatography to give a white solid as the product 63 1H NMR (CDCl3) δ 10.28 (bs, 1H), 7.56 (d, J=9.0 Hz, 2H), 7.45 (s, 1H), 7.20 (d, J=9.0 Hz, 2H), 5.48 (dd, J=4.5, 10.5 Hz, 1H), 4.97 (t, J=7.5 Hz, 1H), 2.06-1.96 (m, 1H), 1.91-1.77 (m, 2H), 1.68-1.57 (m, 1H), 1.22 (t, J=6.9 Hz, 3H), 114 (t, J=7.2 Hz, 3H); MS (m/z) 383.0 (M+H)+.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH:4]1[C:9]2[C:10]3[C:21](=O)[C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[O:12][C:13](=[O:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:11](=[O:12])[C:10]=2[C:9]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:13]1=[O:14])[CH3:2]
Reactant: CCN
Reactant: O=C1c2ccccc2-c2oc(=O)c3ccccc3c21
Solvent: ClC(Cl)Cl
Product: CCn1c2c(c3ccccc3c1=O)C(=O)c1ccccc1-2
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Ethylamine (0.2 mL, 3 mmol) was added to a stirred solution of benz[d]indeno[1,2-b]pyran-5, 11-dione (2) (0.49 g, 2 mmol) in CHCl3 (10 mL). The bright orange mixture stirred overnight. To the reaction mixture CHCl3 (100 mL) was added and the mixture washed with H2O (3×25 mL) and brine (1×25 mL), dried (MgSO4), and concentrated under reduced pressure to give an orange-red solid (0.43 g, 75%): mp 188-189° C.; IR (thin film) 2986, 1690, 1656, 1611, 1549, 1503, 1430, 1320, 1197, 991 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ8.66 (d, 1H, J=8.3 Hz), 8.32 (d, 1H, J=7.9 Hz), 7.69 (dt, 1H, J=8.4, 1.4 Hz), 7.60 (dd, 1H, J=8.0, 1.4 Hz), 7.52 (d, 1H, J=6.9 Hz), 7.40 (m, 3H), 4.56 (q, 2H, J=7.2 Hz), 1.53 (t, 3H, J=7.2 Hz); CIMS, m/z (relative intensity) 276 (MH+, 100). Anal. Calcd for C18H13NO2: C, H, N.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13])=[N:5]2.C(N(CC)CC)C.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH:13][C:32]([NH:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33])=[N:5]2
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccccc1Oc1ccc2nccn2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)Nc1ccccc1Oc1ccc2nccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
To a solution of 2-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (90 mg, 0.40 mmol) and triethylamine (0.011 mL, 0.08 mmol) in tetrahydrofuran (20 mL) was added phenyl isocyanate (0.061 mL, 0.56 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol to give the title compound (99 mg, 0.29 mmol, yield 72%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](C)=[CH:8][CH2:9][CH2:10]2)=[CH:5][CH:4]=1.[Mg+2].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=O.O.[C:29]([O-:32])(O)=O.[Na+]>C(O)(C)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:29](=[O:32])[CH:10]2[CH3:9])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)CCC=C2C
Reactant: O=C([O-])O
Agent: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2c(c1)C(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dihydro-7-methoxy-4-methylnaphthalene (20.87 g) was dissolved in isopropanol (100 ml) and cooled in an ice bath. Monoperoxyphthalic acid magnesium salt (mmpp) (17 g) was added, then water (50 ml) was added and the mixture was stirred at room temperature for 2 hours. When oxidation was complete, the product mixture was hydrolyzed with aqueous NaHCO3, partially evaporated and extracted with ethylacetate. The latter extract was washed with brine and evaporated. The residue was dissolved in a mixture of ethanol (156 ml), water (121 ml) and conc. H2SO4 (24.3 ml), and heated to reflux under N2 atmosphere for 3 hours, cooled and neutralized with NaHCO3. After partial evaporation, the residue was extracted with ethylacetate, washed with brine, dried over MgSO4 and evaporated. The product was purified on a silica gel column using a mixture of hexanes and ethylacetate (100:1, 50:1, 50:1.5). The yield of the product was 16.2 g (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[C:10]([CH:11]([CH3:13])[CH3:12])[C:3]=12.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[C:20]#[N:21].O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([Cl:1])=[C:3]2[C:10]([CH:11]([CH3:13])[CH3:12])=[N:9]1)[C:20]#[N:21]
Reactant: N#Cc1ccc(F)c(Cl)c1
Reactant: CC(C)c1n[nH]c2nccc(Cl)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1nn(-c2ccc(C#N)cc2Cl)c2nccc(Cl)c12
Reaction time: 0.5 h

Procedure:
Compound (6b) (0.5 g) was dissolved in DMF (13 mL), and sodium hydride (0.145 g, a 55% dispersion in paraffin liquid) was added to the resulting solution at 0° C., followed by stirring for 30 min. Then, 3-chloro-4-fluorobenzonitrile was added to the reaction solution, followed by stirring at 60° C. for 1 hr. Water was added to the reaction solution. The precipitate was collected by filtration and washed by sprinkling water to obtain compound (99a) (0.72 g, 85′. %) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(O)[CH2:32][CH2:31]CC[CH2:28][CH2:27][CH2:26]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:32][CH2:31][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCCCCC1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.33 h

Procedure:
A mixture of 10.35 g (0.03 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1 carboxylate, 50 g of cyclooctanol and 2 g of tetraethyl orthotitanate is heated to 130° for 8 hours, a small amount of solvent being distilled off twice in vacuo. The mixture is subsequently evaporated in vacuo, the residue is taken up in chloroform and the solution is poured into about 20 percent hydrochloric acid. The mixture is stirred for 20 minutes, the chloroform phase is separated, washed successively with 1N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By chromatography on a silica gel column while eluting with ethyl acetate and subsequent crystallization from ethyl acetate/hexane there is obtained cyclooctyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 183°-184°.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14](Cl)=[CH:13][C:12]=1Br.C(=O)([O-])[O-].[K+].[K+]>[Cu].C(O)CC>[Cl:1][C:7]1[CH:6]=[CH:5][N:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:2]=[C:3]2[N:8]=1
Reactant: Nc1nccc[n+]1COc1ccc(Cl)cc1Br
Reactant: [Cl-]
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Product: ClC1=NC2=Nc3ccccc3OCN2C=C1
Yield: 73 %

Procedure:
A mixture of 14.0 g of 2-amino-1-[(2-bromo-4-chlorophenoxy)methyl]pyrimidinium chloride, 11.1 g of micronized, anhydrous potassium carbonate, 0.4 g of copper bronze, and 350 ml of anhydrous n-propanol is stirred and heated under reflux for about eight hours, filtered hot, and the deep yellow filtrate is concentrated to dryness in vacuo. Workup gives about 6.8 g of 2-chloro-6H-pyrimido[1,2-c] [1,3,5]-benzoxadiazepine.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:10]=[C:11]([NH2:17])[CH:12]=[CH:13][C:14]=2[O:15][CH3:16])=[CH:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[N:29]=[C:30]=[O:31]>C(Cl)Cl>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[NH:29][C:30]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([C:8]2[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=[CH:6][CH:7]=2)[CH:10]=1)=[O:31]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1Cl
Reactant: COc1ccc(N)cc1-c1ccnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(C(F)(F)F)cc2Cl)cc1-c1ccnn1C(C)C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of 3-(2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 2-Chloro-4-trifluoromethylphenyl isocyanate (0.106 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 48 as a colorless solid (0.109 g, 56%). LCMS m/z (%)=455 M+H+ (37Cl, 35), 453 M+H+ (35Cl, 100), 1H NMR (400 MHz, acetone-d6) δ: 8.78 (bs, 1H), 8.48 (d, J=8.97 Hz, 1H), 7.99 (bs, 1H), 7.615 (s, 1H), 7.52-7.46 (m, 1H), 7.375 (d, J=1.41 Hz, 1H), 7.337 (d, J=2.64 Hz, 1H), 6.973 (d, J=8.92 Hz, 1H), 6.027 (d, J=1.63 Hz, 1H), 4.151 (m, 1H), 3.676 (s, 3H), 1.244 (d, J=6.61 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18][OH:19])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[N+]([C:30]1C=CC(N2CCC(=O)CC2)=C(C=1)C#N)([O-])=O.COCCN>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][CH2:18][O:19][CH3:30])[CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: CC(C)(C)OC(=O)N(CCO)C1CCN(c2ccc(N)cc2C#N)CC1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(=O)CC1
Agent: COCCN
Product: COCCN(C(=O)OC(C)(C)C)C1CCN(c2ccc(N)cc2C#N)CC1

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 85(2), (3) and (4) using 5-nitro-2-(4-oxopiperidino)benzonitrile and 2-methoxyethylamine, the title compound as obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)Br
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)Oc1ccc(OCc2ccccc2)cc1

Procedure:
A solution of 4-benzyloxyphenol (4.2 g) in dimethyl formamide (50 ml) was treated with sodium hydride (840 mg) of a 60% dispersion), and the mixture stirred until evolution of gas ceased. There was then added ethyl 3-bromobutyrate (2.9 ml), and the solution stirred overnight. It was then poured into water (300 ml) and the mixture extracted with ether (3×50 ml). The combined extracts were washed with water (3×) and brine, dried (MgSO4) and evaporated to give a crude product as a brown oil (6 g). This was purified by chromatography on silica, eluting with hexane containing increasing amounts of ethyl acetate to give ethyl 3-(4-benzyloxyphenoxy)butyrate as a colourless crystalline solid (4.5 g) NMR (d6DMSO) δ 1.25(3H,t); 1.8-2.0(2H,m); 2.45(2H,t); 3.9(2H,t); 4.1(2H,q); 5.0(2H,s); 6.8-7.0(4H,m); 7.4(5H,m); m/e 314 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[N+:16]([C:19]1[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=1[OH:31])[CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])([O-:18])=[O:17]>>[C:25]([C@@H:23]([NH:24][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:22][C:21]1[CH:28]=[CH:29][C:30]([OH:31])=[C:19]([N+:16]([O-:18])=[O:17])[CH:20]=1)([OH:27])=[O:26]
Reactant: N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(O)c([N+](=O)[O-])c1)C(=O)O
Yield: 10 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-nitro-L-tyrosine to provide the title compound in 10% yield as yellow needles.
Reaction SMILES: [S:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21].[OH-].[K+]>C1COCC1>[C:19]([N:4]1[CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:1][CH2:2][CH2:3]1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C=CC(=O)Cl
Reactant: c1ccc2c(c1)CNCCS2
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CC(=O)N1CCSc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2,3,4,5-Tetrahydro-1,4-benzothiazepine (11 g) and triethylamine (13.5 g) were dissolved in THF (300 ml) and acryloyl chloride (9.5 g) was added dropwise thereto under ice cooling and agitated at room temperature for 30 minutes. A 10% potassium hydroxide aqueous solution was added thereto, agitated at room temperature and thereafter extracted with chloroform. The chloroform phase was washed with a saturated saline solution and dried on sodium sulfate and the solvent was distilled out under reduced pressure. Residue was purified by silica gel column chromatography (Wako Gel C-200, 200 g) and eluted with a mixed solvent of n-hexane (60 parts) +ethyl acetate (40 parts) to give 4-acryloyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (12.59).
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[OH:42][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:45])=[O:44].OS(C(F)(F)F)(=O)=O.[C:58]1([N:64]2[CH2:69][CH2:68][N:67]([C:70]3[N:71]=[C:72]([NH:79][CH:80]4[CH2:84][CH2:83][CH2:82][CH:81]4[NH2:85])[C:73]4[S:78][CH2:77][CH2:76][C:74]=4[N:75]=3)[CH2:66][CH2:65]2)[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1>CN(C)C=O>[OH:45][S:43]([C:46]([F:49])([F:48])[F:47])(=[O:44])=[O:42].[C:58]1([N:64]2[CH2:65][CH2:66][N:67]([C:70]3[N:71]=[C:72]([NH:79][C@H:80]4[CH2:84][CH2:83][CH2:82][C@@H:81]4[NH:85][C:6]([C:5]4[O:1][N:2]=[CH:3][CH:4]=4)=[O:8])[C:73]4[S:78][CH2:77][CH2:76][C:74]=4[N:75]=3)[CH2:68][CH2:69]2)[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1
Reactant: NC1CCCC1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: O=C(O)c1ccno1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2)c1ccno1
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
0.004 g (0.03 mmol) of isoxazole-5-carboxylic acid (IX), 0.012 g (0.03 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.017 mL (0.10 mmol) of diisopropylethylamine are placed in 1 mL of dimethylformamide, stirred for 0.1 hours at ambient temperature. Then 0.020 g (0.03 mmol) of N-[2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl]cyclopentane-1,2-diamine ditriflate (VIII) (chiral) in 1 mL of dimethylformamide are added. The mixture is shaken for 1 hour at ambient temperature. Then the reaction mixture is purified directly by HPLC through an RP column (column: XTerra, MS-C18, 5 μm, 19*100 mm, eluant: water+0.1% trifluoroacetic acid (A), acetonitrile+0.1% trifluoroacetic acid (B)).
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]1[C:9]2[CH:10]=[C:11]([S:14]([OH:17])(=O)=[O:15])[CH:12]=[CH:13][C:8]=2[N:7]=[CH:6]1.CN(C)C=O>ClC(Cl)C>[Cl:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[CH:6][S:5][C:9]=2[CH:10]=1)(=[O:17])=[O:15]
Reactant: O=S(=O)(O)c1ccc2ncsc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2ncsc2c1
Reaction time: 1.5 h

Procedure:
Thionyl chloride (4 mL) was added to a suspension of the benzothiazole-6-sulfonic acid (0.60 g, 2.79 mmol) in dichloroethane (15 mL) and the reaction mixture was heated at reflux and dimethylformamide (5 mL) was added to the reaction mixture to yield a clear solution. After 1.5 hr. at reflux, the solvent was removed in vacuo and excess HCl and thionyl chloride was chased by evaporation with dichloroethane.
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]1=[O:7].[OH-].[Na+].Cl[CH2:11][C:12]([OH:14])=[O:13].Cl>>[O:7]=[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCl
Reactant: O=c1cncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1ccncc1=O
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Pyrazin-2(1H)-one (0.333 g, 3.47 mmol) was added 5 N sodium hydroxide solution (2.1 mL) followed by chloroacetic acid (0.524 g, 5.54 mmol). The reaction mixture was heated at 100° C. for 2 h. After cooled down to ambient temperature, 2 N hydrochloric acid (3.5 mL) was added and the reaction mixture was directly purified by reverse phase HPLC (TMC Pro-Pac C18; 0-40% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to yield the title compound as a yellow solid. LC/MS 155.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].[CH3:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([C:41](=[O:43])[CH3:42])[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]OS(C)(=O)=O)=[CH:29][C:22]=2[O:21]1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CCOCC.C1(C)C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>[CH3:16][O:17][C:18]([CH:20]1[CH2:25][CH2:24][C:23]2[CH:26]=[C:27]([C:41](=[O:43])[CH3:42])[C:28]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[CH:29][C:22]=2[O:21]1)=[O:19]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: COC(=O)C1CCc2cc(C(C)=O)c(OCCCCCOS(C)(=O)=O)cc2O1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCc1c(OCCCCCOc2cc3c(cc2C(C)=O)CCC(C(=O)OC)O3)ccc2c1OCCC2=O
Yield: 90.9 %

Procedure:
A mixture of 0.8 g (3.88 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one, 1.6 g (3.88 mmol) of rac-6-acetyl-7-[[5-[(methylsulfonyl)oxy]pentyl]oxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester, 0.78 g (5.65 mmol) of anhydrous potassium carbonate, 0.082 g of tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), and 20 mL of toluene was stirred and refluxed for 6 hr. After being cooled, the reaction mixture was diluted with ether and toluene and filtered with suction. The solids were washed with more toluene and ether and then the filtrate and washes were combined and concentrated in vacuo. The residue was dissolved in 1:1 ether-dichloromethane and washed with water and brine. Completion of the usual work-up afforded a solid residue which was purified by flash chromatography, eluting with 1:1 hexane-ethyl acetate. There was obtained 1.85 g (91%) of rac-6-acetyl-7-[5-[(3,4-dihydro-4-oxo- 8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid methyl ester as a solid, mp 131°-133° C. This material was saponified using the procedure described in example 8 giving rac-6-acetyl-7-[5-[(3,4-dihydro-4-oxo-8-propyl-2H-1-benzopyran-7-yl)oxy]pentyloxy]-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid as an off-white solid, mp 148°-151° C., in 38.4% yield, after recrystallization from hexane-ethyl acetate.