Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][NH:2][C:3](=[O:32])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]([CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:6]1=[O:31].C1COCC1.[OH-].[Li+].Cl>C(OCC)(=O)C.O>[OH:1][NH:2][C:3](=[O:32])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[CH:13]=[CH:14][C:9]=2[S:8][CH:7]([CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[C:6]1=[O:31]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)NO)C(=O)C(CCCc1ccc(OC)cc1)S2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CCCC2Sc3ccc(C(=O)O)cc3N(CC(=O)NO)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.9 %

Procedure:
To the compound of Example 1 (0.51 g) were added THF (10 ml) and water (10 ml). After the resulting mixture was ice-cooled, a 0.5N aqueous lithium hydroxide solution (4.4 ml) was slowly added dropwise thereto. The resulting mixture was slowly warmed up to room temperature and stirred overnight. Ice-cooled 1N aqueous hydrochloric acid solution and ethyl acetate were added thereto to effect extraction. The oil layer was washed twice with a 1N aqueous hydrochloric acid solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Chloroform was added to the residue, and after standing for 4 days, the solid precipitated was collected by filtration and dried under reduced pressure. 4-[2-(Hydroxyamino)-2-oxoethyl]-2-[3-(4-methoxyphenyl)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylic acid (325 mg) was obtained as a white solid.
Reaction SMILES: C([O:8][C:9](=[O:23])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[CH:17][C:18]([O:20][CH3:21])=[O:19])=[C:12]([CH3:22])[CH:11]=1)C1C=CC=CC=1.[H][H]>C1COCC1.CO.[Pd]>[CH3:21][O:20][C:18]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:23])=[O:8])=[CH:11][C:12]=1[CH3:22])=[O:19]
Reactant: [H][H]
Reactant: COC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1C
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc(C(=O)O)cc1C
Yield: 99.9 %

Procedure:
A mixture of 4-(2-methoxycarbonyl-vinyl)-3-methyl-benzoic acid benzyl ester (11.6 g, 37.4 mmol) and Pd/C (5%, 1.5 g) in THF (300 mL) and methanol (100 mL) is stirred under 60 psi of hydrogen overnight. Catalyst is filtered off, filtrate is concentrated giving the title compound (8.3 g, 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1.C(OCC)(=O)C.CCCCCC>ClCCl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=4[S:2][CH3:1])=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: CSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CSc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reaction time: 2.5 h
Yield: 32.3 %

Procedure:
As described for Example 9, a mixture of 0.242 g of 2-(methylthio)benzoyl chloride (m.p. 61°-64° C.), 0.134 g of triethylamine and 0.314 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 10 ml of dichloromethane is stirred for 2.5 hours and worked up to give a solid. Trituration with ethyl acetate-hexane gives 0.150 g of crystals, m.p. 222°-225° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[CH2:7][OH:8])([O-:3])=[O:2].[F:15][C:16]([F:42])([F:41])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36](O)=[O:37])=[CH:30][CH:29]=2)=[O:26])=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[F:15][C:16]([F:41])([F:42])[CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([O:27][C:28]2[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]([O:8][CH2:7][C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=3)=[O:37])=[CH:30][CH:29]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Reactant: O=C(O)/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(OC(=O)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.2 %

Procedure:
1.00 g (51.0 mmol) of 3,5-dinitrobenzylalcohol, 2.00 g (51.0 mmol) of (2E)-3-(4-{[4-(4,4,4-trifluorobutoxy)benzoyl]oxy}phenyl)acrylic acid, 62 mg (0.51 mmol) of 4-Dimethylaminopyridine are dissolved in 10 ml of dichloromethane. 1.07 g (56.0 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0° C. The solution is stirred for 1 h at 0° C. and allowed to stir at room temperature overnight. After 22 hours at room temperature the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulphate, filtered and concentrated by rotary evaporation to yield 3,5-dinitrobenzyl (2E)3-{4-[(4-(4,4,4-trifluorobutoxy)benzoyl)oxy]phenyl}acrylate 2.1 g as colorless crystals.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:13][CH2:12][N:11](S(C)(=O)=O)[CH2:10][CH2:9][N:8]([CH2:18][C:19]([OH:21])=[O:20])[CH2:7][CH2:6]1)([OH:3])=[O:2].O>S(=O)(=O)(O)O>[C:1]([CH2:4][N:5]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][N:8]([CH2:18][C:19]([OH:21])=[O:20])[CH2:7][CH2:6]1)([OH:3])=[O:2]
Reactant: CS(=O)(=O)N1CCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CN1CCNCCN(CC(=O)O)CC1
Reaction time: 24 h

Procedure:
A mixture of 1,4-bis-(carboxymethyl)-7-methanesulfonyl-1,4,7-triazacyclononane (15.0 g, 0.05 mol) in 15 mL of concentrated sulfuric acid is stirred at 25 C. for 24 hours. The reaction mixture is cooled in an ice bath and 50 mL of water is slowly added. Then the pH of the solution is adjusted to 7 and the solvent is evaporated under reduced pressure. The residue is triturated with methanol several times and the combined methanol solutions are evaporated to give 1,4-bis-(carboxymethyl)-1,4,7-triazacyclononane.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])[CH2:7][C@@H:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O>[OH:27][CH2:28][C:29]1[CH:34]=[C:33]([C:2]2[N:11]=[CH:10][C:9]3[N:8]([CH2:12][C:13]([NH:15][CH2:16][CH:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:14])[CH2:7][C@@H:6]4[CH2:23][O:24][CH2:25][CH2:26][N:5]4[C:4]=3[N:3]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)NCC1CCOCC1
Reactant: OCc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(-c3cccc(CO)c3)ncc21)NCC1CCOCC1
Temperature: 120 °C
Yield: 79.4 %

Procedure:
A mixture of (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide (PREPARATION x26, 50 mg, 0.131 mmol), 3-(hydroxymethyl)phenylboronic acid (29.8 mg, 0.196 mmol), tetrakis(triphenylphospine)palladium(0) (15.13 mg, 0.013 mmol) and sodium carbonate (27.8 mg, 0.262 mmol) in 1,4-dioxane (0.5 mL) and H2O (0.25 mL) was heated to 120° C. in a microwave for 1 hour. After cooling to room temperature, the reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (amine-functionalized silica, 0-10% MeOH gradient in CHCl3) to afford the title compound as an off-white solid (47.2 mg, 0.104 mmol, 79%). 1H NMR (400 MHz, DMSO-d6) δ 1.06-1.24 (m, 2H), 1.47-1.71 (m, 3H), 2.92-3.03 (m, 3H), 3.12-3.37 (m, 5H), 3.50-3.67 (m, 2H), 3.73-3.93 (m, 4H), 3.98-4.07 (m, 2H), 4.50-4.60 (m, 3H), 5.21 (t, J=5.81 Hz, 1H), 7.26-7.38 (m, 2H), 7.50 (s, 1H), 8.06-8.11 (m, 2H), 8.18 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C24H31N5O4, 453.24. found 454.4.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.N1C=CN=C1.[Si:23](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][O:12][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)[Si](OC[C@@H](O)COCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.03 h
Yield: 90 %

Procedure:
To a solution of (R)-3-benzyloxypropane-1,2-diol (prepared from (S)-4-benzylymethyl-2,2-dimethyl-1,3-dioxolane (commercially available from FLUKA) by acid hydrolysis using 80% aqueous acetic acid), (8.3 g, 47.2 mmol) in dry THF (70 ml) was added imidazole (6.42 g, 94.4 mmol). After 2 minutes, t-butyldiphenylsilyl chloride (12.28 ml, 47.2 mmol) was added. A white precipitate formed immediately. After 2 hours, the reaction mixture was filtered and the filtrate evaporated. The residue was partitioned between ethyl acetate and water, the organic layer separated, washed with saturated brine, dried (MgSO4), filtered and evaporated to give a colourless oil. Chromatography of the oil on silica gel (dichloromethane as eluant) afforded the title compound as a colourless oil (17.72 g, 90%).
Reaction SMILES: [OH-].[Na+].[CH:3]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:8][C@H:9]([NH:13][C:14]([CH2:16][CH2:17][NH2:18])=[O:15])[C:10]([OH:12])=[O:11].C([O-])(=O)C.[Zn+2:23].C([O-])(=O)C>CO>[CH:3]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:8][CH:9]([N:13]=[C:14]([O-:15])[CH2:16][CH2:17][NH-:18])[C:10]([O-:12])=[O:11].[Zn+2:23]
Reactant: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: [NH-]CCC([O-])=NC(Cc1cnc[nH]1)C(=O)[O-]
Reaction time: 8 h
Yield: 97.6 %

Procedure:
In 100 ml of methanol, 3.51 g of sodium hydroxide was dissolved, and 9.96 g of L-carnosine was added to obtain a homogeneous solution. To this solution, a solution obtained by dissolving 9.67 g of zinc acetate.2H2O into 145 ml of methanol was dropped over 30 minutes, while the solution was stirred, to gradually produce white precipitate therein. After finishing of the dropping, the solution was stirred for 2 hours and then left it overnight as was. The solution was filtered, and the precipitation was washed by 140 ml of water and then air-dried at 80° C. for 5 hours to obtain 12.4 g of white powdery crystals. The results of an analysis of the obtained material are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[F:23].[OH:24][C@H:25]([CH3:43])[CH2:26][N:27]1[C:31]([CH3:32])=[C:30]([C:33](O)=[O:34])[C:29](=[O:36])[N:28]1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:33]([C:30]2[C:29](=[O:36])[N:28]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:27]([CH2:26][C@H:25]([OH:24])[CH3:43])[C:31]=2[CH3:32])=[O:34])=[CH:18][C:17]=1[F:23]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@@H](C)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (5.0 g, 0.016 mol) and (R)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (6.2 g, 0.022 mol) in CH2Cl2 (100 mL) at 0° C. was added TEA (5.5 g, 0.054 mol), followed by HATU (10.3 g, 0.027 mol) in portions. The reaction mixture was stirred at 0° C. for 2 h, warmed up to rt and continued to stir overnight. The reaction mixture was washed with water (30 mL×3). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was crystallized in a mixture of EtOAc/n-hexane (50 mL, v/v=5:1) to give the title compound as a pale yellow solid (7.8 g, 85.2%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of N-cyclopentyl-3-[2-(cyclopentylamino)-4-pyrimidinyl]-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (1.16 g, 2.48 mmol) in dichloromethane (50 mL) at −78° C. was added boron tribromide (9.92 mL, 1.0 M in dichloromethane, 9.92 mmol) dropwise. The resulting solution was allowed to warm to room temperature. After stirring for 15 hours at room temperature, the mixture was cooled to 0° C. and quenched by the addition of water. The mixture was extracted with ethyl acetate. The organic phase was dried (magnesium sulfate), filtered and concentrated to give a solid residue which was purified by flash chromatography (95:5 chloroform-methanol). 4-{7-(Cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol was obtained as a yellow solid (0.80 g, 71%). 1H NMR (CDCl3): δ 7.91 (d, 1H), 7.70 (d, 1H), 7.46 (d, 2H), 7.26 (t, 1H), 6.86 (d, 2H), 6.27 (d, 1H), 6.00–5.97 (m, 2H), 5.06 (d, 1H), 4.33 (m, 1H), 3.96 (m, 1H), 2.10–2.03 (m, 4H), 1.78–1.47 (m, 12H); MS m/z 455 (M+1). U157430-190
Reaction SMILES: [C:1]12([C:11](=[O:28])[CH:12](Cl)[C:13]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[O:25][CH3:26])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:29][C:30]1([CH3:37])[O:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[C:1]12([C:11](=[O:28])[CH:12]([N:32]3[C:31](=[O:36])[C:30]([CH3:37])([CH3:29])[O:34][C:33]3=[O:35])[C:13]([NH:15][C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[O:25][CH3:26])=[O:14])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC1(C)OC(=O)NC1=O
Reactant: COc1ccc([N+](=O)[O-])cc1NC(=O)C(Cl)C(=O)C12CC3CC(CC(C3)C1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1NC(=O)C(C(=O)C12CC3CC(CC(C3)C1)C2)N1C(=O)OC(C)(C)C1=O
Yield: 79.7 %

Procedure:
A suspension of 16.28 g (0.04 mol) of [4], 5.17 g (0.04 mol) of 5,5-dimethyloxazolidine-2,4-dione, and 16.58 g (0.12) mol of anhydrous potassium carbonate in 380 mL of dried acetone was refluxed for 3 hours. Thin layer chromatographic analysis indicated that the reaction was complete. The reaction mixture was concentrated in vacuo to yield an orange-colored solid. It was dissolved in ethyl acetate and the organic layer was washed with HCl (10%) and brine until neutrality. The organic layer was dried, filtered, and concentrated to yield an oil which solidified upon standing. It was triturated in ligroin. The final dried product (15.92 g, 79.8%) gave one spot on TLC. All analytical data confirmed the assigned structure.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.CCN(C(C)C)C(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:31]([NH:21][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:34])[CH2:32][CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2CN)CC1
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCC(=O)NCc1ccccc1N1CCNCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.9 %

Procedure:
1-Boc-4-(2-aminomethyl-phenyl)-piperazine (0.75 g, 2.6 mmol) was dissolved in methylene chloride (20 mL), treated with DIPEA (2.3 mL, 13 mmol), and cooled to about 0° C. Propionyl chloride (0.20 mL, 2.34 mmol) was added and the mixture was stirred for about 1 hour at 0° C. and subsequently stirred overnight at r.t. The mixture is diluted with ethyl acetate (400 mL), washed with water (45 mL), saturated aqueous sodium bicarbonate (45 mL) and brine (45 mL), and then dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by silica gel chromatography (50% ethyl acetate in hexanes) gave an oil, which was dissolved in methylene chloride (10 mL). The mixture was stirred with TFA (10 mL) for about 1.5 hours. The mixture was concentrated under reduced pressure, and the residue taken up in water (25 mL). Sodium hydroxide (1.0 g, 25 mmol) and ethyl acetate (25 mL) were added and the mixture was stirred for about 45 minutes. The organic phase was collected and the aqueous phase was extracted with ethyl acetate (45 mL). The combined organic fractions were washed with water (20 mL) and brine (20 mL) and then dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to yield the title compound (0.26 g, 40%) as a clear oil.
Reaction SMILES: [OH:1][CH:2]([CH3:17])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][CH:5]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH2:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH2:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:8][CH:9]=1)[C:2]([CH3:17])=[O:1]
Reactant: CC(O)Cc1ccc(C2=NNC(=O)CC2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)Cc1ccc(C2=NNC(=O)CC2)cc1
Reaction time: 18 h

Procedure:
A mixture of 4,5-dihydro-6-[4-(2-hydroxypropyl)-phenyl]-3(2H)-pyridazinone (0.23 g) and pyridiniumchlorochromate (0.21 g) in dichloromethane (20 ml) was stirred at ambient tempeature for 18 hr., filtered and evaporated to a gum which was chromatographed on slice gel. Elution with 4% MeOH in CHCl3 gave 4,5-dihydro-6-[(4-acetonyl)phenyl]-3(2H)-pyridazinone as a crystalline solid.
Reaction SMILES: [H-].[Na+].N1C=NC=N1.Br[CH2:9][CH2:10][N:11]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].O>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:11]([CH:10]=[CH2:9])[S:22]([C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Agent: c1nc[nH]n1
Solvent: CN(C)C=O
Solvent: O
Product: C=CN(c1ccc(Cl)cc1[N+](=O)[O-])S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 18.2 %

Procedure:
To a suspension of sodium hydride (60%, 0.04 g (1.00 mmol)) in DMF (5.0 ml), 1,2,4-triazole (0.08 g (1.16 mmol)) was added with stirring at room temperature. To the resulting mixture, after 15 minutes' stirring at room temperature, N-(2-bromoethyl)-4′-chloro-2′-nitro-p-toluenesulfonanilide (0.35 g (0.81 mmol)) was added and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.052 g (18%) of the title compound as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:12]([Si:15](Cl)([CH:19]([CH3:21])[CH3:20])[CH:16]([CH3:18])[CH3:17])([CH3:14])[CH3:13].N1C=CN=C1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][Si:15]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc([N+](=O)[O-])c(F)c1)(C(C)C)C(C)C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
A mixture of 3-fluoro-4-nitro-phenol (4.94 g, 31.4 mmol), triisopropylsilyl chloride (6.40 mL, 29.9 mmol), and imidazole (4.85 g, 70.7 mmol) in 70 mL of dichloromethane is stirred for 1.5 hours. Dichloromethane (100 mL) is added and the mixture is washed with water and brine, dried (MgSO4), and concentrated under reduced pressure. The residue is purified on silica gel (120 g) eluting with a gradient of ethyl acetate in heptane (0 to 80%) to provide the title compound (8.55 g, 87%) as an oil. ES/MS m/e 314.3.0 (M+1).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+].CO>>[C:12]([C:10]1[N:11]=[C:6]([C:4]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:5])[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)[C:9]=12)#[N:13]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2cccc(OC)c2)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc(Cn2ccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c32)c1

Procedure:
Prepared in analogy to that of Example 1(e) from 7-cyano-1-(3-methoxy-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 381 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])[C:14]=2[CH:32]=1>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])[C:14]=2[CH:32]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1ccc(C(=O)OC)cc1OC)CCO2
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Hexanoyl chloride (0.084 g.) was added to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (0.2 g.) in dichloromethane (20 ml.), under an atmosphere of nitrogen. The mixture was stirred for one hour and then diluted with dichloromethane (40 ml.). This mixture was washed with water, dried (MgSO4) and evaporated. The residual oil was dissolved in 3:7 v/v ethyl acetate:hexane, and the solution obtained was allowed to filter through a short column of silica gel, washing with one column volume of the same solvent mixture. Evaporation of the column eluate gave the title compound (0.212 g., 82%), as a foam: NMR (250 MHz, CDCl3) 0.9(t,3H, CH2CH3), 1.3(m,4H, CH3.CH2.CH2), 1.6(m,2H, CH2.CH2.CON), 2.2(t,2H, CH2.CON), 3.35(t,2H, OCH2.CH2N), 3.9(br s,6H, OCH3 + CO.OCH3), 4.2(t,2H, OCH2.CH2N), 4.5(s,2H, CH2 --Ar), 6.8(m,3H), 6.9(br s,1H, NH), 7.2(m,1H), 7.5(m, 2H).