Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH:2]1[CH2:38][C@@H:37]([CH3:39])[CH2:36][O:35][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:34])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[O:27]C(=O)C(Cl)(Cl)Cl.[OH-].[Na+]>O.C(O)C>[Br:1][CH:2]1[CH2:38][C@@H:37]([CH3:39])[CH2:36][O:35][C@@:3]21[C@@H:7]([CH3:8])[C@@H:6]1[C@:9]3([CH3:34])[C@@H:22]([CH2:23][C@@H:5]1[O:4]2)[C@H:21]1[C@@H:12]([C@:13]2([CH3:25])[C@@H:18]([CH2:19][CH2:20]1)[CH2:17][C@@H:16]([OH:24])[CH2:15][CH2:14]2)[C@@H:11]([OH:26])[C@@H:10]3[OH:27]
Reactant: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](OC(=O)C(Cl)(Cl)Cl)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H]1CO[C@@]2(O[C@H]3C[C@H]4[C@@H]5CC[C@H]6C[C@@H](O)CC[C@]6(C)[C@H]5[C@@H](O)[C@H](O)[C@]4(C)[C@H]3[C@@H]2C)C(Br)C1

Procedure:
Using the procedure described in J. Chem. Soc., 1956, 4330, (3β,5α,11β,12α,25R)-23-bromo-12-(trichloroacetoxy)spirostan-3,11-diol was saponifled with sodium hydroxide in water and ethanol to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([S:16][C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[CH:15]=2)[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:25]([O-])([O-])=O.[K+].[K+].IC.CN(C=O)C>CCOCC>[CH3:25][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([S:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[CH:15]=[C:7]([O:6][C:5]2[CH:23]=[CH:24][C:2]([I:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Cn1ccnc1Sc1cc(Oc2ccc(I)cc2)cc(C(=O)O)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CI
Product: COC(=O)c1cc(Oc2ccc(I)cc2)cc(Sc2nccn2C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 3-(4-iodo-phenoxy)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzoic acid (1.4 g, 3.1 mmol), K2CO3 (856 mg, 6.2 mmol), iodomethane (0.29 mL, 4.65 mmol) and 16 mL of DMF were stirred for 2 h at rt. Then the mixture was diluted with ether and washed with water, brine, dried (MgSO4) and evaporated. The residue was adsorbed to SiO2 from CH2Cl2 and subjected to MPLC on a 40 g column of SiO2 eluting with % EtOAc in hexanes (time): 33% (10 min), 35-50% (20 min ramp) which provided 1.32 g (91%) of the title compound: 1H NMR (500 MHz, DMSO-d6): δ 3.63 (s, 3H), 3.79 (s, 3H), 6.91 (d, 21-1, J=8 Hz), 6.96 (dd, 1H, J=2, 1 Hz), 7.14 (d, 1H, J=1 Hz), 7.23 (dd, 1H, J=2, 1 Hz), 7.32 (t, 1H, J=1 Hz), 7.51 (d, 1H, J=1 Hz), 7.75 (d, 2H, J=8 Hz); LCMS (m/z): 467.4 [C18H15IN2O3S+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:33]=[CH:32][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:16]([CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:15]3)=[CH:11][CH:10]=2)[N:6]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:13][N:14]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:16]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:15]3)=[CH:32][CH:33]=2)[N:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(C)n3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1nc(COc2ccc(Cn3cc(CCC(=O)O)c(-c4ccccc4)c3)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
A mixture of ethyl 3-[1-[4-(2-methyl-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionate (368 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml), and ethanol (4 ml) was stirred at room temperature for 4 hours, and 1N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[1-[4-(2-methyl-4-thiazolylmethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (251 mg, yield: 73%). This was recrystallized from ethanol-hexane. Melting point: 113–114° C.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]2[O:8][C:9]3[CH:19]=[CH:18][CH:17]=[CH:16][C:10]=3[CH2:11][N:12]([C:13]([OH:15])=O)[C:6]=2[CH:5]=1.[C:22]1(=[O:28])[O:27][C:25](=[O:26])[CH:24]=[CH:23]1>C1C=CC=CC=1.C(Cl)Cl>[C:22]([CH:23]=[CH:24][C:25]([NH:1][NH:2][C:13]([N:12]1[CH2:11][C:10]2[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=2[O:8][C:7]2[CH:20]=[CH:21][C:4]([Cl:3])=[CH:5][C:6]1=2)=[O:15])=[O:26])([OH:27])=[O:28]
Reactant: NN
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: c1ccccc1
Product: O=C(O)C=CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazine dissolved in 50 parts by volume of 1:1 benzene-methylene chloride solution, is added in one portion 0.344 part of maleic anhydride.The reaction mixture is stirred at room temperature for 24 hours, and the solvent is evaporated to yield an oil which is crystallized from benzene-ethyl acetate solution. Recrystallization from ethyl acetate-cyclohexane-ethanol solution yields 1-(3-carboxypropenoyl)-2-(8-chloro-10,11-dihydrodibenz[b,f]-[1,4]oxazepine-10-carbonyl)hydrazine, melting at about 171°- 172°. This compound can be represented by the following structural formula ##SPC2##
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:23])[NH:7][N:8]=[C:9]2[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([F:22])=[C:17]([CH:21]=2)[C:18]([OH:20])=O)=[CH:4][CH:3]=1.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.C(OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[C:6](=[O:23])[NH:7][N:8]=[C:9]2[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:22])=[C:17]([C:18]([N:29]2[CH2:30][CH2:31][CH:26]([O:25][CH3:24])[CH2:27][CH2:28]2)=[O:20])[CH:21]=1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccc(Br)cc23)ccc1F
Reactant: COC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccc(Br)cc34)ccc2F)CC1
Reaction time: 1 h
Yield: 5.3 %

Procedure:
5-((7-bromo-4-oxo-3,4-dihydrophthalazin-1-yl)methyl)-2-fluorobenzoic acid (97) (1.0 g, 2.65 mmol), 4-methoxypiperidine (0.336 g, 2.92 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (0.936 g, 2.92 mmol) were dissolved in DMF (40 mL), to this was added DIPEA (0.509 mL, 2.92 mmol) and the reaction was stirred for 1 hour. The DMF was evaporated and the crude gum was quenched with 2M NaOH (75 mL), extracted with EtOAc (3×75 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford a brown gum. The gum was passed through a plug of silica eluting with ethyl acetate to afford a white solid, most of which was used without further purification. A sample (100 mg) was purified via preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired material as a white solid (66 mg); 1H NMR (400.132 MHz, CDCl3) δ 1.62-1.48 (1H, m), 1.85-1.68 (2H, m), 1.94-1.89 (1H, m), 3.18-3.07 (1H, m), 3.35 (3H, s), 3.47-3.40 (2H, m), 3.67-3.53 (1H, m), 4.06-3.89 (1H, m), 4.23 (2H, s), 7.04 (1H, t), 7.31-7.26 (2H, m), 7.86-7.84 (2H, m), 8.33-8.31 (1H, m), 10.55 (1H, s); m/z (LC-MS, ESI+), RT=1.94 (M+H 476).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH2:59])=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1>C1COCC1.C(Cl)(Cl)Cl>[O:44]1[CH2:49][CH2:48][O:47][CH2:46][CH:45]1[C:50]1[C:58]2[S:57][C:56]([NH:59][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:55][C:54]=2[C:53]([O:60][CH3:61])=[CH:52][CH:51]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(C2COCCO2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-ethyldiisopropylamine in THF, then treatment with (+)-7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-ylamine. [α]D20=+22.7° (c=1.04, CHCl3), ES-MS m/e (%): 385 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[N:5]=[C:4](OC(Cl)(Cl)Cl)[N:3]=1.[Sb](F)(F)F.[Sb](Cl)(Cl)(Cl)(Cl)[Cl:19].FC1N=C(F)N=C([O:32][C:33]([F:36])(F)[F:34])N=1>>[Cl:19][C:4]1[N:5]([O:32][CH:33]([F:36])[F:34])[CH:6]([F:8])[N:7]=[C:2]([F:1])[N:3]=1
Reactant: Fc1nc(F)nc(OC(F)(F)F)n1
Reactant: Fc1nc(F)nc(OC(Cl)(Cl)Cl)n1
Reactant: Cl[Sb](Cl)(Cl)(Cl)Cl
Agent: F[Sb](F)F
Product: FC1=NC(F)N(OC(F)F)C(Cl)=N1
Temperature: 110 °C

Procedure:
210 g (0.838 mol) of 2,4-difluoro-6-trichloromethoxy-1,3,5-triazine were added within 10 minutes to 110 g (0.614 mol) of antimony trifluoride while stirring at 110° C. After addition of 3/4 of 9.38 g (0.0313 mol) of antimony pentachloride, the mixture was heated to 145° C. and stirred for 1 hour. The remaining catalyst was added, and the mixture was stirred for a further 2 hours while a fraction boiling at 95°-105° C. was obtained through a 30 cm packed column: 20 g (11.8% of theory) of 2,4-difluoro-6-trifluoromethoxy-1,3,5-triazine. The residue was distilled without a column to yield 94.8 g (52% of theory) of the title compound of boiling point 125°-130° C.; nD24 =1.4042.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1)(=[O:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([C:23](=[O:25])[CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccc(C(C)=O)cc2)CC1
Yield: 71 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(4-acetylphenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>>[ClH:19].[C:1]1([CH:7]([N:9]2[C:13]([C:14]([Cl:19])=[O:16])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)n1cncc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(c1ccccc1)n1cncc1C(=O)Cl
Product: Cl
Yield: 94 %

Procedure:
A mixture of 25.5 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid and 280 parts of sulfinyl chloride is stirred and refluxed for 2 hours. The reaction mixture is cooled in an ice-bath. The product crystallizes upon the addition of 2,2'-oxybispropane. It is filtered off, washed with 2,2'-oxybispropane and dried, yielding 94% of (-)-1-(1-phenylethyl)-1H-imidazole-5-carbonyl chloride hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=1)[CH3:6])[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O)[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:30]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[CH2:20][CH2:21]2)[CH:9]=1)([CH3:23])[CH3:6])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3ccc(OC)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[3-(piperidin-4-ylcarbamoyl)-phenoxy]-propionic acid ethyl ester (example 50i) was reacted with 3-ethoxy-4-methoxybenzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 499.2 (MH+).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH2:12][CH2:11]2)=[N:2]1.O.NN.Cl>CO>[NH2:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]1[CH2:14][CH2:15][N:10]([C:3]2[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1][N:2]=2)[CH2:11][CH2:12]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NCCCCN1CCN(c2nsc3ccccc23)CC1

Procedure:
A mixture of N-[4-{4-(1,2-benzisothiazol-3-yl)-1-piperazinyl}butyl]phthalimide (1 g; 2.38 mmol), hydrazine hydrate (0.2 g; 3.57 mmol) and methanol (10 ml) was refluxed for 2.5 hours. After cooling, the reaction mixture was combined with a 10% aqueous hydrochloric acid solution (20 ml) and stirred. The precipitated crystals were removed by filtration, and the filtrate was neutralized with a 10% sodium hydroxide solution and extracted with chloroform. The organic layer was washed with a saturated sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give the objective compound as an oily substance. IR νmaxfilm (cm-1): 3360, 3280, 3070, 1590, 1560, 1490.
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[N:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])C=CC=CC=1.[O:28]=[CH:29][C:30]([Cl:33])([Cl:32])[Cl:31].C(=O)([O-])[O-].[K+].[K+].OOS([O-])=O.[K+]>C1(C)C=CC=CC=1.CCCCCC>[Cl:31][C:30]([Cl:33])([Cl:32])[CH:29]1[O:28][N:8]1[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1OC1C(Cl)(Cl)Cl
Temperature: 120 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
20.0 g (53.0 mol) of triphenyl(t-butoxycarbonylimino)phosphorane was suspended in 80 mL of toluene, mixed with 8.84 g (60.0 mmol) of anhydrous chloral and heated at 120° C. for 4 hours under reflux. After cooling to room temperature, 300 mL of hexane was added, and the resulting white solid was separated by filtration. The filtrate was concentrated under reduced pressure. The resulting brown liquid was dissolved in 200 mL of chloroform, and simultaneous addition of 3.74 g (50.0 mmol) of potassium carbonate in 20 mL of ice-cold water and 4.94 g (15 mmol) of OXONE (2 KHSC5.KHSC4.K2SC4, supplied from Du Pont) in 40 mL of ice-cold water and 1 hour of stirring under cooling with ice were repeated three times. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE (2 KHSC5.KHSC4.K2SC4, supplied from Du Pont) and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, simultaneous addition of aqueous potassium carbonate and aqueous OXONE and 1 hour of stirring under cooling with ice were repeated three times, similarly. After removal of the aqueous layer, 11.2 g (150 mmol) of potassium carbonate in 60 mL of ice-cold water and 14.8 g (45 mmol) of OXONE in 120 mL of ice-cold water were added simultaneously, and the reaction solution was stirred for 1 hour of stirring under cooling with ice. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, aqueous potassium carbonate and aqueous OXONE were simultaneously added, the reaction solution was stirred for 1 hour of stirring under cooling with ice, similarly. After removal of the aqueous layer, the chloroform layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate {100:0 (volume ratio, hereinafter the same applies) to 80:20} as the eluent to give 10.3 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH:1]([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[CH:11]=1)(=[O:9])=[O:8])=[O:5])([CH3:3])[CH3:2]>C(O)C.[Pd].O>[CH:1]([C:4]([NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[CH:11]=1)(=[O:9])=[O:8])=[O:5])([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)NS(=O)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C)C(=O)NS(=O)(=O)c1cccc(N)c1
Reaction time: 0.17 h
Yield: 76.3 %

Procedure:
To a suspension of 1-(isopropylcarbonylaminosulphonyl)-3-nitrobenzene (5 g, 18.4 mmol) in ethanol (100 ml) was added 10% palladium on carbon (0.5 g, 10% (w/w)) in water (5 ml). The mixture was hydrogenated at 40 psi for 10 min then the catalyst was filtered off and washed with ethanol. The solvents were evaporated in vacuo to give the title compound (3.4 g, 76%) as a yellow solid. mp 110°-112° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.95 (6H, d, J=6.9 Hz), 2.45 (1H, septet, J=6.9 Hz), 5.63 (2H, br s), 6.79 (1H, ddd, J=8.0, 2.3 and 0.8 Hz), 6.96 (1H, ddd, J=7.6, 1.7 and 0.8 Hz), 7.09 (1H, dd, J=2.0 and 2.0 Hz), 7.20 (1 H, dd, J=7.9 and 7.9 Hz), 11.79 (1H, brs).
Reaction SMILES: BrCCOC1C=C(S(C)(=O)=O)C=C(Cl)C=1.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18].[F:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:34]=1)[O:25][CH2:26][CH2:27]NCCC>C(O)C>[F:21][C:22]1[CH:23]=[C:24]([CH:32]=[C:33]([S:35]([CH3:38])(=[O:37])=[O:36])[CH:34]=1)[O:25][CH2:26][CH2:27][NH:20][CH2:16][CH:17]([CH3:19])[CH3:18]
Reactant: CC(C)CN
Reactant: CCCNCCOc1cc(F)cc(S(C)(=O)=O)c1
Agent: CS(=O)(=O)c1cc(Cl)cc(OCCBr)c1
Solvent: CCO
Product: CC(C)CNCCOc1cc(F)cc(S(C)(=O)=O)c1

Procedure:
Preparation according to Example 1 but performed in one portion: 1-(2-bromoethoxy)-3-chloro-5-methylsulfonyl-benzene (0.05 g, 0.16 mmol) and isobutylamine (0.2 ml, 1.3 mmol) in ethanol (5 ml). MS m/z (relative intensity, 70 eV) 289 (M+, 1), 246 (bp), 138 (2), 86 (70), 56 (17).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[CH:15]=1.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35]Cl)[CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:29][CH2:30][N:31]([CH2:34][CH2:35][N:10]2[C:9](=[O:14])[NH:8][C:7]3[CH:15]=[C:3]([O:2][CH3:1])[C:4]([O:16][CH3:17])=[CH:5][C:6]=3[S:11]2(=[O:13])=[O:12])[CH2:32][CH2:33]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: COc1cc2c(cc1OC)S(=O)(=O)NC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)S(=O)(=O)N(CCN1CCN(c3ccccc3OC)CC1)C(=O)N2
Temperature: 80 °C
Reaction time: 5 h
Yield: 36 %

Procedure:
One gram and a half of 6,7-dimethoxy-3,4-dihydro-1,2,4-benzothiadiazine-3-one 1,1-dioxide was dissolved in 10 ml of dimethylformamide. After adding 280 mg of sodium hydride in 50% oil, the mixture was heated to 80° C. Then, a solution of 1.5 g of 2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl chloride in 5 ml of dimethylformamide was added dropwise to the resultant reaction liquid. After the addition was finished, the stirring was continued for 5 hours while heating at 80° C. to react. The resultant reaction mixture was poured into water to precipitate crystals. The produced crystals were filtered off followed by recrystallizing from methanol to obtain 1.0 g of the titled compound (yield: 36%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([S:19]([NH2:22])(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:9])[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25].[C:26]12([N:36]=[C:37]=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:26]12([NH:36][C:37]([NH:22][S:19]([N:16]3[CH2:17][CH2:18][CH:13]([CH2:12][CH2:11][NH:10][C:8]([C:6]4[C:5](=[O:23])[N:4]([CH3:24])[C:3](=[O:25])[N:2]([CH3:1])[CH:7]=4)=[O:9])[CH2:14][CH2:15]3)(=[O:21])=[O:20])=[O:38])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Reactant: Cn1cc(C(=O)NCCC2CCN(S(N)(=O)=O)CC2)c(=O)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1cc(C(=O)NCCC2CCN(S(=O)(=O)NC(=O)NC34CC5CC(CC(C5)C3)C4)CC2)c(=O)n(C)c1=O
Yield: 40 %

Procedure:
A mixture of 380 mg. (0.001 mole) of 4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonamide, 220 mg. (0.001 mole) of 1-adamantyl isocyanate and 310 mg. (0.002 mole) of anhydrous potassium carbonate in 30 ml. of acetone was refluxed for a period of 20 hours. At the end of this time, the spent reaction mixture was cooled and the excess potassium carbonate subsequently removed therefrom by means of suction filtration. The resulting filtrate was then slowly acidified with 1N aqueous hydrochloric acid causing a white precipitate to form. The latter material was subsequently recovered by suction filtration and thereafter recrystallized from acetonitrile-methanol to afford 220 mg (38%) of pure 1-(1-adamantyl)3-{4-[2-(1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione-5-carboxamido)ethyl]-1-piperidinesulfonyl}urea, m.p. 224°-226° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClCCl.[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:29][C@@H:28]3[O:30][C@:27]3(C)[C@@H:13]2[C@H:14]([O:17][C:18](OC2C=CC=CC=2)=[O:19])[O:15][CH:16]=1)=[O:10]>CCCCCC.C(OCC)(=O)C>[CH3:7][O:8][C:9]([C:11]1[C@H:12]2[CH2:29][C@@H:28]3[O:30][C@@H:27]3[C@@H:13]2[C@H:14]([O:17][C:18](=[O:19])[N:2]([CH3:3])[CH3:1])[O:15][CH:16]=1)=[O:10]
Reactant: CNC
Reactant: COC(=O)C1=CO[C@@H](OC(=O)Oc2ccccc2)[C@@H]2[C@@H]1C[C@@H]1O[C@]21C
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C1=CO[C@@H](OC(=O)N(C)C)[C@H]2[C@H]3O[C@H]3C[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
5 ml of a 50% aqueous dimethylamine solution were added to a dichloromethane solution containing 198 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(phenoxycarbonyloxy)cyclopenta[c]pyrane-4-carboxylic acid methylester described in Example 10 followed by stirring for 10 minutes at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the hexane-ethyl acetate eluate in the form of (1S,4aS,6S,7R,7aR)-1-(dimethylcarbamoyloxy)-6,7-epoxy-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyrane-4-carboxylic acid methylester (140 mg, yield: 83%). The physicochemical properties of this compound are described in Table 7, Compound No. 31.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:5]=1[CH:6]=O)([OH:3])=[O:2]>CCO>[CH3:13][O:12][C:10]1[CH:11]=[C:4]2[C:5]([CH:6]=[C:4]([C:1]([OH:3])=[O:2])[O:3][C:1]2=[O:2])=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)c(C(=O)O)c1
Solvent: CCO
Product: COc1ccc2cc(C(=O)O)oc(=O)c2c1

Procedure:
7- Methoxyisocoumarin -3- carboxylic acid, mp. (EtOH) 280°-3°, (Found: C, 60.11; H, 3.93. C11H8O5 requires C, 60.00; H, 3.66) was prepared from 2- carboxy -4- methoxybenzaldehyde by an analogous procedure to that described in Example 1.