Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[CH:27]([NH:29][CH2:30][C:31](O)=O)=[O:28]>>[C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:2]=[CH:3][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17]2[N:18]=[C:31]([CH2:30][NH:29][CH:27]=[O:28])[O:20][N:19]=2)=[O:8])=[CH:5][CH:6]=1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=CNCC(=O)O
Product: CON=C1C[C@@H](c2noc(CNC=O)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (formylamino)acetic acid, the title compound was obtained in 72% purity by HPLC.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:8][NH:9][CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]2[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:31][C:32]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.COC(=O)C.[Cl:49]C1C(C(F)(F)F)=CC=CC=1C=O.Cl.CCOCC>CCOCC>[ClH:49].[F:31][C:32]1[C:39]([C:40]([F:41])([F:42])[F:43])=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:9]([CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:10][CH2:11][C@@H:12]([CH3:24])[O:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1
Reactant: C[C@H](CCNCC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1Cl
Reactant: O=Cc1cccc(C(F)(F)F)c1F
Agent: Cl
Solvent: CCOCC
Solvent: COC(C)=O
Product: C[C@H](CCN(Cc1cccc(C(F)(F)F)c1F)CC(c1ccccc1)c1ccccc1)Oc1cccc(CC(=O)O)c1

Procedure:
Following the procedure of Example 7(d) except (R)-2-(3-{3-[(2,2-diphenylethyl)amino]-1-methyl-propoxy}-phenyl)acetic acid and 2-fluoro-3-(trifluoromethyl)benzaldehyde were used instead of (R)-2-(3-{3-(2,2-diphenylethyl)amino]-3-methyl-propoxy}-phenyl)acetic acid methyl ester and 2-chloro-3-trifluoromethylbenzaldehyde in step (d) the corresponding carboxylic acid was obtained. The crude product was purified by preparative HPLC (TMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile: H2O, UV detection at 254 nm) to afford the free base. The resulting amine/carboxylic acid was dissolved in Et2O (diethylether) and acidified with 1.0 M HCl/Et2O. The reaction mixture was concentrated in vacuo and dried under reduced pressure to give the title compound as a white solid, 90 mg (84%). MS (ESI) 580.6 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][NH2:6].C(N(C(C)C)C(C)C)C.[Br:20][CH:21]([CH2:25][CH2:26][Br:27])[C:22](Cl)=[O:23]>ClCCl>[Br:20][CH:21]([CH2:25][CH2:26][Br:27])[C:22]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([F:1])[CH:3]=1)=[O:23]
Reactant: O=C(Cl)C(Br)CCBr
Reactant: Cc1ccc(CN)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNC(=O)C(Br)CCBr)cc1F
Temperature: 0 °C
Yield: 87.6 %

Procedure:
To a stirring 0° C. solution of 3-fluoro-4-methylbenzyl amine (2.0 g, 14 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.5 mL, 20 mmol) in dichloromethane (30 mL) was added dropwise a solution of 2,4-dibromobutanoyl chloride (3.98 g, 15 mmol) in dichloromethane (5 mL). After completion of the addition, the reaction was stirred in the ice bath until all of the ice had melted, then it was partitioned between ethyl acetate and water. The layers were separated, the organic layer was washed with brine, and it was then dried over magnesium sulfate. The drying agent was filtered off, the solvent was evaporated, and the residue was dissolved in ethyl acetate and subjected to silica gel chromatography in 10→25→100% ethyl acetate/hexane, collecting the main component to yield 4.5 g (85%) 2,4-dibromo-N-(3-fluoro-4-methylbenzyl)butanamide. LCMS (method CZ-1): RT 1.21 min, m/z 367.9 (MH+); 1H NMR (500 MHz, chloroform-d) δ 7.17 (t, J=7.7 Hz, 1H), 7.01-6.91 (m, 2H), 6.70 (br. s., 1H), 4.59 (dd, J=9.0, 4.9 Hz, 1H), 4.51-4.37 (m, 2H), 3.64-3.51 (m, 2H), 2.71 (dddd, J=15.0, 8.5, 6.1, 4.9 Hz, 1H), 2.51 (ddt, J=15.0, 9.2, 5.5 Hz, 1H), 2.27 (d, J=1.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH2:14][CH3:15])[N:4]=[CH:3]1.S(=O)(=O)(O)[OH:18].[H][H]>O.[Pt]>[CH3:1][C:2]([CH3:16])([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH2:14][CH3:15])[NH2:4])[CH2:3][OH:18]
Reactant: O=S(=O)(O)O
Reactant: [H][H]
Reactant: CCC1CC=CCCC=CCC(C)(C)C=N1
Agent: [Pt]
Solvent: O
Product: CCC(N)CCCCCCCCC(C)(C)CO
Yield: 67.4 %

Procedure:
199 g (0.91 mol) of 3,3-dimethyl-12-ethyl-1-aza-1,5,9-cyclododecatriene is added dropwise, in the course of 15 minutes, to a solution of 150 g (1.53 mols) of sulphuric acid in one liter of water. Impurities are removed by means of subsequent steam distillation for 20 minutes. The aqueous sulphuric acid solution is then hydrogenated under normal pressure at 20°-25° C. in the presence of a platinum/charcoal catalyst (5% by weight of platinum), with absorption of 3 mols of hydrogen, to yield 2,2-dimethyl-11-ethyl-11-aminoundecanol. After removal of the catalyst by filtration, the aqueous solution is neutralised with concentrated sodium hydroxide solution; the amino alcohol separating out is extracted with toluene, and distilled to thus obtain 149 g (0.613 mol) of 2,2-dimethyl-11-ethyl-11-aminoundecanol corresponding to a yield of 67.4% of theory; b.p. 118° C./0.05 Torr; nD20 =1.4656.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[OH-].[Na+].[F:17][CH:18]([F:20])Cl>O1CCOCC1>[F:17][CH:18]([F:20])[O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13]
Reactant: FC(F)Cl
Reactant: CC(=O)c1ccc2ccccc2c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)c1ccc2ccccc2c1OC(F)F

Procedure:
10 g of 1-hydroxy-2-acetylnaphthalene are dissolved in 60 ml of dioxane, and 30 ml of 30% sodium hydroxide solution are added. At a temperature of from 70° C. to 80° C., difluorochloromethane (Freon 22) is introduced until no further absorption is observed. The dioxane phase is then decanted, the NaOH phase is washed with dioxane, the dioxane phase is decanted, and the combined dioxane solutions are largely concentrated in vacuo using a rotary evaporator. Water is added to the residue, the mixture is extracted several times with diethyl ether, and the diethyl ether solution is dried over Na2SO4, filtered and concentrated by evaporation. The residue is recrystallised from diethyl ether/hexane. Yield: 4 g, m.p. 80°-81° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[O:5].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.Cl.[CH3:42][N:43]([CH3:50])[CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([N:47]1[CH2:48][CH2:49][CH:44]([N:43]([CH3:50])[CH3:42])[CH2:45][CH2:46]1)=[O:17])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CN(C)C1CCNCC1
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(C(=O)N3CCC(N(C)C)CC3)ccc2[nH]1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 1, intermediate a), from 1H-indole-2,5-dicarboxylic acid 2-ethyl ester, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4-dimethylamino-piperidine dihydrochloride (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light yellow foam (67%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@@H:16]([O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:15]([CH2:35][O:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[O:14][C@H:10]1SCC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:45]([C@H:48]([C@H:51]([O:67][C:68](=[O:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)/[CH:52]=[CH:53]/[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:49][OH:50])=[N+]=[N-].[O:76]1[CH2:81][CH2:80]OCC1>C(Cl)Cl.C1C=CC=CC=1>[C:81]([NH:45][C@H:48]([C@H:51]([O:67][C:68](=[O:75])[C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)/[CH:52]=[CH:53]/[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH3:66])[CH2:49][O:50][C@H:10]1[O:14][C@H:15]([CH2:16][O:26][CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[C@H:35]([O:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[C@H:17]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:76])[CH2:80][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:48][CH3:49]
Reactant: C1COCCO1
Reactant: CCS[C@@H]1O[C@H](COCC(=O)OC(C)(C)C)[C@H](OCC(=O)OC(C)(C)C)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCCCCCCCCCCCC/C=C/[C@@H](OC(=O)c1ccccc1)[C@H](CO)N=[N+]=[N-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC/C=C/[C@@H](OC(=O)c1ccccc1)[C@H](CO[C@H]1O[C@H](COCC(=O)OC(C)(C)C)[C@H](OCC(=O)OC(C)(C)C)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)NC(=O)CCCCCCCCCCCCCCC
Yield: 66 %

Procedure:
Ethyl 2,3-di-O-benzyl-4,6-di-O-tert-butyloxycarbonylmethyl-1-thio-β-D-galactopyranoside (0.555 g, 0.88 mmol) and (2S,3R,4E)-2-azido-3-benzoyloxy-4-octadecenol (0.239 g, 0.55 mmol) were reacted by the general procedure as described in Example 1-D using methylene chloride/benzene (1:1) as solvents instead of dioxane and afforded the α-anomer (0.174 g, 31%) and the β-anomer (0.365 g, 66%) of the title compound as yellow oils.
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[Cl:24].C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:25][C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O-:3])=[O:2]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1cccc(Oc2ccc(Cl)c(Cl)c2)c1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 3,4-dichlorophenol (7.4 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was treated in a similar manner to the above to give oil of the captioned compound (6.6 g.)
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[CH2:13][CH2:12][CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[C:5]=1[C:14]([O:16]C)=[O:15].[OH-].[Na+]>CCO>[CH2:3]=[C:4]1[CH2:13][CH2:12][CH2:11][C:6]2([CH2:10][CH2:9][CH2:8][CH2:7]2)[CH:5]1[C:14]([OH:16])=[O:15].[CH3:3][C:4]1[CH:5]([C:14]([OH:16])=[O:15])[C:6]2([CH2:11][CH2:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)C1=C(C)CCCC12CCCC2
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=C1CCCC2(CCCC2)C1C(=O)O
Product: CC1=CCCC2(CCCC2)C1C(=O)O
Yield: 4 %
Yield: 5 %

Procedure:
A solution of KOH (47.5 g, 0.72 mol) in EtOH (200 ml) was treated with methyl 7-methylspiro[4.5]dec-6-ene-6-carboxylate (15 g, 0.072 mol, prepared as described in Example 26) and the resulting mixture was stirred at reflux for 6 h, poured into cold 2N aqueous NaOH (300 ml), and extracted twice with cyclohexane (100 ml). The combined organic phases were washed with 2N aqueous NaOH (100 ml), and the combined aqueous phases were acidified with conc. HCl, and extracted twice with MTBE (150 ml). The combined organic phases were washed with water (100 ml), with a saturated aqueous solution of NaCl (150 ml), dried (MgSO4), and concentrated. FC (90 g SiO2, hexane/MTBE 88:12) of the crude product (12.8 g) gave 7-methylenespiro[4.5]decane-6-carboxylic acid (0.7 g, 5%) and 7-methylspiro[4.5]dec-7-ene-6-carboxylic acid (0.57 g, 4%).
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:11](O)[CH2:12][OH:13]>C1(C)C=CC=CC=1>[CH2:9]([C:2]1([CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[O:13][CH2:12][CH2:11][O:1]1)[CH3:10]
Reactant: CCC(=O)CCC(=O)OC
Reactant: OCCO
Solvent: Cc1ccccc1
Product: CCC1(CCC(=O)OC)OCCO1
Yield: 94.1 %

Procedure:
To a stirring solution of 4.05 g (28 mmol) of methyl 4-oxohexanoate (16), prepared as described above in Example 16, in 200 mL of toluene and 0.53 g (2.8 mmol) of tosyl acid was added 5.59 g (90 mmol) of ethylene glycol. After refluxing for 2 hours using a Dean-Stark trap, the solvent was removed under vacuum. The resulting orange oil was dissolved in 200 mL of EtoAc. The EtoAc was then washed with 2×200 mL of H2O. The organic layer was then dried over Na2S04 anhydrous, filtered, and concentrated in vacuo to yield 4.96 g (94%) of methyl 2-ethyl-1,3-dioxolane-2-propanoate (17), which was employed immediately in Example 18 below.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]3[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:15]=3[CH:16]=1)=[O:11])[CH2:2]2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+].[CH:74]1([C:77]([CH3:79])=[O:78])[CH2:76][CH2:75]1>O1CCOCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[O:13][C:14]3[CH:20]=[C:19]([CH2:79][C:77]([CH:74]4[CH2:76][CH2:75]4)=[O:78])[CH:18]=[CH:17][C:15]=3[CH:16]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(Br)cc2o1
Reactant: CC(=O)C1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2ccc(CC(=O)C3CC3)cc2o1
Temperature: 85 °C

Procedure:
150 mg (0.43 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzofuran-2-carboxamide, 27 mg (0.04 mmol) of rac-BINAP, 45 mg (0.47 mmol) of sodium tert-butoxide and 20 mg (0.02 mmol) of tris(benzylideneacetone)dipalladium are dried under high vacuum for 1 h. Under an atmosphere of argon, 2 ml of dioxane are added. 72 mg (0.86 mmol) of methyl cyclopropyl ketone are added dropwise, and the mixture is heated at 85° C. overnight. The crude product is purified by preparative HPLC. The solvent is removed under reduced pressure. Finally, any last solvent residues are removed under high vacuum. 75 mg (50% of theory) of the title compound are isolated.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[CH:12][C:13]([OH:15])=O.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([N:22]2[C:13](=[O:15])[CH:12]=[C:3]3[C:2]([C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH2:5][CH2:4]3)=[N:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NNc1ccccc1
Reactant: O=C(O)C=C1CCc2ccccc2C1=O
Solvent: CCO
Product: O=c1cc2c(nn1-c1ccccc1)-c1ccccc1CC2
Yield: 20.6 %

Procedure:
A mixture of 5 g of 1,2,3,4-tetrahydro-1-oxo-2-naphthylideneacetic acid and 3 g of phenylhydrazine in 100 ml of ethanol is refluxed for 10 hours. The precipitated crystals are collected by filtration, washed with ethanol and dissolved in 50 ml of acetic acid. The solution is refluxed under heating for 8 hours and the acetic acid is distilled off. The residue is extracted with ethyl acetate and the extract is washed with an aqueous sodium hydrogencarbonate solution. After drying over magnesium sulfate anhydride, the solvent is distilled off and to the residue is added ethanol. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 1.4 g of 2-phenyl-5,6-dihydrobenzo[h]cinnolin-3(2H)-one as pale yellow needles, melting at 155°-157° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:21]([OH:25])[C:22](O)=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]([C:49]([CH3:52])([CH3:51])[CH3:50])[C:41](=[O:48])[C@@H:42]1[CH2:46][C@H:45]([Br:47])[CH2:44][NH:43]1)=O)(C)(C)C>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:19][C@@H:20]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C@H:21]([OH:25])[C:22]([N:43]1[CH2:44][C@@H:45]([Br:47])[CH2:46][C@H:42]1[C:41]([NH:40][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:48])=[O:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)[C@@H]1C[C@H](Br)CN1)C(C)(C)C
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)[C@H](O)C(=O)O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@H](Br)CN1C(=O)[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1

Procedure:
A procedure similar to that described in Example 1 was repeated, except that (2S,3S)-3-(N2 -benzyloxycarbonyl-L-asparaginyl)amino-2-hydroxy-4-phenylbutyric acid (prepared as described in Preparation 1) and (4S)-N-t-butoxycarbonyl-4-bromo-N-t-butyl-L-prolinamide (prepared as described in Preparation 8) were used as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound as colorless powdery crystals, melting at 100°-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][S:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[OH:28]O>FC(F)(F)C(O)C(F)(F)F>[NH3:6].[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][S:12](=[O:28])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ccc2c(c1)CSCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Reactant: OO
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: N
Product: O=S1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ccccn3)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the sulphide of example 107 (150 mg, 0.38 mmol) in 1,1,1,3,3,3-Hexafluoro-propan-2-ol (5 ml) was added a 30% aqueous solution of hydrogen peroxide (0.09 ml). The resulting reaction mixture was stirred at room temperature for 1 hour before partitioning with aqueous sodium sulfite. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The resulting residue was purified by column chromatography on silica gel using dichloromethane:Methanol:0.880 ammonia (95:5:0.5) as eluant, to afford the title compound as an off-white foam (64 mg)
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH2:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O>[Pd].CO>[NH2:12][C@H:10]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[NH2:1])[CH3:11]
Reactant: C[C@H](N)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)c1cccc(N)c1
Reaction time: 19 h
Yield: 99.9 %

Procedure:
A mixture of (1S)-1-(3-nitrophenyl)ethanamine (13.1 g, 79.4 mmol) and 10% palladium on carbon (0.75 g) in methanol (250 mL) was stirred vigorously under an atmosphere of hydrogen for 19 hours. After this time the mixture was filtered through a pad of Celite and the pad was washed with methanol (800 mL). The combined filtrates were concentrated under reduced pressure to give 3-[(1S)-1-aminoethyl]aniline as a brown solid (10.8 g, 100%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:15])=[C:9]([CH:14]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:4])=[O:3].[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[OH:15][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:20]2[CH2:21][CH2:22][N:17]([CH3:16])[CH2:18][CH2:19]2)(=[O:4])=[O:3])=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N2CCN(C)CC2)ccc1O
Reaction time: 0.5 h

Procedure:
Methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 60; 500 mg, 1.995 mmol) was added to a stirred solution of 1-methylpiperazine (200 mg, 2.00 mmol) in dichloromethane (20 ml). The mixture was stirred for 0.5 h, and then concentrated under reduced pressure to yield the title compound as a colourless oil. 430 mg.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH2:15][NH2:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].O>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH2:15][NH:16][C:28]([NH:27][CH2:25][CH3:26])=[O:29])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CCN=C=O
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)=C1CN
Solvent: ClCCl
Solvent: O
Product: CCNC(=O)NCC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 55.8 %

Procedure:
A solution of 6-nitro-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.5 g, 1.53 mmol) in dichloromethane (10 ml) was stirred with ethyl isocyanate (0.12 ml, 1.53 mmol) at room temperature for two hours. Water was added and the organic phase separated, dried and evaporated to give crude product, which was chromatographed on silica gel, eluting with dichloromethane/methanol (95/5) to give 0.34 g of 6-nitro-2,2-dimethyl-3-(N'-ethylureido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 197° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5](O)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].IC.[C:15](=O)([O-])[O-].[K+].[K+].CN(C)[CH:23]=[O:24]>>[Br:1][C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([O:24][CH3:23])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: Cc1cc(Br)cc(C(=O)O)c1O
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Agent: [K+]
Solvent: CI
Product: COC(=O)c1cc(Br)cc(C)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-Bromo-2-hydroxy-3-methylbenzoic acid (2.8 g, 12.1 mmol), iodomethane (1.97 mL, 31.6 mmol) and potassium carbonate (16.9 g, 123 mmol) were combined in dimethylformamide (30 mL). After stirring at room temperature for 16 h, the solvent was removed in vacuo and the crude product dissolved in ethyl acetate, which was washed with water (2×), then brine (2×), dried over sodium sulfate, and concentrated. Flash chromatography on silica gel (10% ethyl acetate/hexanes) gave 2.26 g (72%). 1H-NMR (CDCl3, 500 MHz) δ 7.74-7.75 (m, 1H), 7.45-7.46 (m, 1H), 3.90 (s, 3H), 3.80 (s, 3H), 2.28 (s, 3H). Mass spec.: 261.08 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[CH2:7][C:6]=2[CH:16]=1.[CH:17]1([CH2:21]Br)[CH2:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:21][CH:17]3[CH2:20][CH2:19][CH2:18]3)[C:10](=[O:12])[CH:9]3[CH2:13][CH2:14][CH2:15][N:8]3[CH2:7][C:6]=2[CH:16]=1
Reactant: BrCC1CCC1
Reactant: O=C1Nc2ccc(Cl)cc2CN2CCCC12
Product: O=C1C2CCCN2Cc2cc(Cl)ccc2N1CC1CCC1

Procedure:
If 7-chloro-1,2,3,5,10,11a-hexahydro-11H-pyrrolo- [2,1-c] [1,4]benzodiazepin-11-one is treated with cyclobutylmethylbromide by the procedure of Example 18, the above product is obtained.