Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>C(O)(C)(C)C>[CH2:17]([NH:21][C:3]([NH:2][CH3:1])=[N:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[CH2:18][CH2:19][CH3:20]
Reactant: CN=C=Nc1ccccc1N1CCOCC1
Reactant: CCCCN
Solvent: CC(C)(C)O
Product: CCCCNC(=Nc1ccccc1N1CCOCC1)NC

Procedure:
A mixture of N-methyl-N'-(2-morpholinophenyl)carbodiimide (1 g), n-butylamine (0.5 g) and t-butanol (5 ml) was heated at 90°-95° C. for four hours. The solvent was removed by evaporation and the residue dissolved in dichloromethane (100 ml) and the resulting solution was washed with water, dried and filtered. Removal of the solvent gave 1-(n-butyl)-2-(2-morpholinophenyl)-3-methylguanidine which was converted into its monofumarate salt (m.p. 178°-179° C.).
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]2[CH2:39][C@@:38](O)([CH3:40])[CH2:37][C@@H:36]3[N:31]2[C:32](=[O:42])[CH2:33][CH2:34][CH2:35]3)=[CH:26][CH:25]=1.O>C1COCC1.C(OCC)(=O)C>[Si:8]([O:15][C@:38]1([CH3:40])[CH2:37][C@@H:36]2[N:31]([C:32](=[O:42])[CH2:33][CH2:34][CH2:35]2)[C@H:30]([C:27]2[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=2)[CH2:39]1)([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: C[C@@]1(O)C[C@H]2CCCC(=O)N2[C@H](c2ccc(F)cc2)C1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)O[C@]1(C)C[C@H]2CCCC(=O)N2[C@H](c2ccc(F)cc2)C1
Reaction time: 0.83 h
Yield: 82.2 %

Procedure:
Triethylamine (201 μL) and TBSOTf (286 mg) were added to a solution of (6S*,8R*,9aR*)-6-(4-fluorophenyl)-8-hydroxy-8-methyloctahydroquinolizin-4-one (100 mg) in THF (1.0 mL) under ice-cooling, and the reaction solution was stirred for one hour and 50 minutes. Water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 116 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1=[C:3]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:4](=[O:43])[O:5]/[C:6]/1=[CH:7]/[C:8]1[CH2:9][S:10][C@@H:11]2[C@H:31]([NH:32]C(=O)CC3C=CC=CC=3)[C:30](=[O:42])[N:12]2[C:13]=1[C:14]([O:16][CH:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].CO.O>ClCCl>[NH2:32][C@@H:31]1[C:30](=[O:42])[N:12]2[C:13]([C:14]([O:16][CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:15])=[C:8](/[CH:7]=[C:6]3\[C:2]([CH3:1])=[C:3]([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[C:4](=[O:43])[O:5]\3)[CH2:9][S:10][C@H:11]12
Reactant: CC1=C(c2ccccc2)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC1=C(c2ccccc2)C(=O)O/C1=C/C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Diphenylmethyl 3-(E-2,5-dihydro-4-methyl-2-oxo-3-phenylfuran-5-ylidenemethyl)-7β-phenylacetamidoceph-3-em-4-carboxylate (0.6 g) in dichloromethane (5 mls) under argon, was cooled to -20° C. N-methylmorpholine phosphorous pentachloride (0.253 g) in dichloromethane (6.075 mls). The solution was maintained at -20° C. for 30-40mins. I.r. analysis showed no starting material present Dry methanol (5 mls) was added rapidly, in one portion. The reaction mixture was allowed to warm to room temperature over 30mins. Water (10 mls) was then added and the solution vigorously stirred for 30 mins. The organic phase was separated, washed with brine and then dried. After removal of solvent the residue was purified by flash chromatography on silica gel, eluting with 70% ethyl acetate/hexane. The title compound was obtained as a yellow foam, (0.453 g, 92%), νmax (CH2Cl2) 1780 (shoulder), 1760, 1720(w) and 1615(vw)cm-1 ; δH (CDCl 3) 2.06 (3H,s), 3.47 (2H,ABq,J18.6Hz), 4.87 (1H,d,J5.1Hz), 5.00 (1H,d,J5.1Hz), 6.33 (1H,s), 7.00 (1H,s) and 7.1-7.5 (15H,m); [mass spectrum: +ve ion (3-NOBA, Na+) MNa+, 573].
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][C:10]2[N:9]=[C:8]([CH3:12])[C:7]3[NH:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=4[C:6]=3[C:5]=2[C:4](=[O:20])[CH2:3]1.[H-].[Na+].I[CH2:25][CH3:26]>CN(C)C=O.O.[Cl-].[Na+].O>[CH2:25]([N:13]1[C:7]2[C:8]([CH3:12])=[N:9][C:10]3[CH2:11][C:2]([CH3:21])([CH3:1])[CH2:3][C:4](=[O:20])[C:5]=3[C:6]=2[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]1=2)[CH3:26]
Reactant: CCI
Reactant: Cc1nc2c(c3c1[nH]c1ccccc13)C(=O)CC(C)(C)C2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2c3c(nc(C)c21)CC(C)(C)CC3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3,3,6-trimethyl-2,3,4,7-tetrahydroindolo[2,3-c]quinolin-1-one of Example 4 (0.28 g, 1 mmol) in anhydrous N,N-dimethylformamide (4 mL) was added dropwise at room temperature under stirring to a suspension of sodium hydride (60% dispersion in mineral oil, 0.051 g, 1.3 mmol) in anhydrous N,N-dimethylformamide (4 mL). The reaction mixture was stirred for 2 h at room temperature, and then 1-iodoethane (0.19 g, 1.2 mmol) was added dropwise. The mixture was stirred at room temperature until the reaction was completed (4 h, thin layer chromatography control). The reaction mixture was diluted with water (25 mL) and brine (10 mL), and then extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over anhydrous sodium sulfate, and ethyl acetate was distilled off in vacuum to give the crude product (0.18 g, 60%). Crystallization from hexanes yielded the pure product as light orange crystals; m.p. 174-177° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(N(C(C)C)CC)(C)C.[NH2:17][C:18]1[N:23]=[C:22]([NH:24][C@@H:25]([CH2:29][CH2:30][CH3:31])CCO)[C:21]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])=[CH:35][C:34]=2[O:51][CH3:52])=[C:20]([CH3:53])[N:19]=1>CN(C)C1C=CN=CC=1.C1COCC1.O.C(OC([O-])=O)(O)=O.[Na+]>[C:5]([O:4][CH2:1][CH2:2][C@@H:25]([NH:24][C:22]1[C:21]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][CH2:41][CH2:42][O:43][Si:44]([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:46])[CH3:45])=[CH:35][C:34]=2[O:51][CH3:52])=[C:20]([CH3:53])[N:19]=[C:18]([NH2:17])[N:23]=1)[CH2:29][CH2:30][CH3:31])(=[O:7])[CH3:6]
Reactant: CCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])OC(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](CCOC(C)=O)Nc1nc(N)nc(C)c1Cc1ccc(OCCCO[Si](C)(C)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
4-Dimethylaminopyridine (cat. amount) was added to the mixture of acetic anhydride (0.162 mL), diisopropylethylamine (0.697 mL) and the product from step (ii) (760 mg) in THF (10 mL). After the mixture was stirred at RT for 3.5 h, the reaction mixture was diluted with water and sat. sodium hydrogen dicarbonate and extracted with EtOAc. The combined organic layer was washed with water and brine, dried and concentrated under reduced pressure to afford the crude product as pale yellow oil, which was used for next reaction without further purification; 1H NMR (CDCl3); 6.81 (1H, d), 6.44 (1H, d), 6.38 (1H, dd), 4.79 (2H, br s), 4.25-4.15 (1H, m), 3.99 (2H, t), 3.96-3.88 (2H, m), 3.85 (3H, s), 3.76 (2H, t), 3.58 (2H, s), 2.33 (3H, s), 1.97 (3H, s), 2.00-1.88 (2H, m), 1.86-1.71 (1H, m), 1.64-1.50 (1H, m), 1.48-1.32 (1H, m), 1.30-0.95 (3H, m), 0.86 (9H, s), 0.76 (3H, t), 0.02 (6H, s); LC-MS: m/z 576.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[NH:7][CH:6]([CH3:23])[CH2:5]1.C=O.[C:26]([BH3-])#N.[Na+].C(O)(=O)C>C(#N)C>[OH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][C:10]([CH2:15][CH2:16][CH2:17][S:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:12]=2[OH:14])[N:7]([CH3:26])[CH:6]([CH3:23])[CH2:5]1
Reactant: CCCCSCCCc1cc(O)c2c(c1)NC(C)CC2CCO
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCCSCCCc1cc(O)c2c(c1)N(C)C(C)CC2CCO

Procedure:
To a stirred solution of dl-4-(2-hydroxyethyl)-5-hydroxy-2-methyl-7-(4-thiaoctyl)-1,2,3,4-tetrahydroquinoline (337 mg, 1.0 mmole) in 5 ml acetonitrile cooled to 15° C. is added 0.5 ml aqueous formaldehyde and 100 mg sodium cyanoborohydride. Acetic acid is added to maintain a neutral pH until the reaction is complete. The reaction mixture is partitioned between water and ethyl ether, the organic phase dried (MgSO4) and evaporated to afford the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[N+:12]([O-])=O)[CH2:3][CH2:2]1>CCOC(C)=O.[Pd]>[CH:1]1([NH:4][C:5]2[C:6]([NH2:12])=[CH:7][CH:8]=[C:9]([F:11])[CH:10]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)cc1NC1CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(F)cc1NC1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.1 %

Procedure:
To a solution of cyclopropyl-(5-fluoro-2-nitrophenyl)amine (6.3 mmol) in EtOAc (60 mL) was added 10% Pd/C (150 mg) and the reaction mixture was stirred at RT under a hydrogen atmosphere for 5 h. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as a brown oil (1.1 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.76 (1H, dd, J=10.85, 2.76 Hz), 6.60 (1H, dd, J=8.38, 5.56 Hz), 6.34 (1H, td, J=8.45, 2.82 Hz), 4.15 (1H, br s), 3.03 (2H, br s), 2.45-2.36 (1H, m), 0.80-0.72 (2H, m), 0.56-0.49 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Cl:16])=[C:14]([Cl:17])[N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10](Cl)[N:11]=1)=[O:5])[CH3:2].C[C:28]([N:30](C)C)=O>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[C:15]([Cl:16])=[C:14]([Cl:17])[N:13]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[C:10]([C:28]#[N:30])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Cl)c2c(c1O)c(Cl)c(Cl)n2CCc1ccccc1
Reactant: CC(=O)N(C)C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Cl)c(Cl)n2CCc1ccccc1

Procedure:
Prepared in analogy to that of Example 111(a) from 2,3,7-trichloro-4-hydroxy-1-phenethyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, Zn(CN)2, Zn dust, Pd2(dba)3, and dppf in DMA. The title compound, ESI MS (m/z): 404 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:7]([N:11]2C(=O)C3=CC=CC=C3C2=O)[CH:8]=[CH:9][CH:10]=1)=[O:5].CN>CN(C=O)C.O>[NH2:11][N:7]1[CH:8]=[CH:9][CH:10]=[C:6]1[C:4](=[O:5])[C:3]1[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=1[F:1]
Reactant: O=C(c1ccccc1F)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: Nn1cccc1C(=O)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
To a suspension of 2-(2-fluorobenzoyl)-1-phthalimidopyrrole (12.5 g, 27 mmole) in 40 ml DMF was added 40 ml methylamine (40% solution in water). After stirring one hour at ambient temperature, the reaction mixture was diluted with water and extracted with ether. The organic extract was washed with water and with saturated NaCl solution, dried over anhydrous MgSO4, filtered and evaporated to 9 g oil, half of which was purified by Kugelrohr distallation (120°-130° at 0.2 mm Hg) to give 3.5 g (93%) solid, m.p. 44°-47°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH2:9])[CH:3]=1.[CH:10]([N:13]=[C:14]=[O:15])([CH3:12])[CH3:11]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][NH:9][C:14]([NH:13][CH:10]([CH3:12])[CH3:11])=[O:15])[CH:3]=1
Reactant: NNc1cc(Br)ccn1
Reactant: CC(C)N=C=O
Solvent: ClCCl
Product: CC(C)NC(=O)NNc1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-bromopyridin-2-yl) hydrazine (0.376 g, 2.00 mmol) in 10 mL of DCM at 0° C. was added isopropyl isocyanate (0.216 mL, 2.20 mmol). The heterogeneous mixture was allowed to warm up to RT and stir. A white precipitate appeared and after 1 h the solid was collected by filtration and washed with DCM to afford 1-(4-bromopyridin-2-yl)-4-isopropylsemicarbazide as a white solid. MS (ESI, pos. ion) m/z: 273.2 (M+1).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:6]=1[C:7]#[N:8]>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:1][C:10]1[C:9]([CH3:13])=[C:6]([C:5]([O:4][CH3:3])=[CH:12][CH:11]=1)[C:7]#[N:8]
Reactant: BrBr
Reactant: COc1cccc(C)c1C#N
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(C)c1C#N
Temperature: 0 °C

Procedure:
A solution of Br2 (261 mg, 1.63 mmol) in CCl4 (1 mL) was added over 15 min to a solution of 2-methoxy-6-methylbenzonitrile in CCl4 (3 mL) at −10° C. containing 4 mg of Fe powder. After 45 min the reaction was poured into ice water (10 mL). The organic layer was washed with Na2SO3 (aq.) solution (10 mL*2), brine (20 mL) and dried over Na2SO4, concentrated in vacuo to give 3-bromo-6-methoxy-2-methylbenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:35]1[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]1)=[O:19])=[N:5]2
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4cc(Cl)ccc4nc3OC)CC2)cc(OC)c1OC
Yield: 84 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 84%). 1H NMR (300 MHz, CDCl3): 3.17-3.25 (m, 4H), 3.81-3.86 (m, 12H), 4.09-4.16 (m, 4H), 6.21 (s, 2H), 7.21-7.30 (m, 1H), 7.33-7.54 (m, 1H), 7.58-7.69 (m, 1H), 7.81 (s, 1H).
Reaction SMILES: I[C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19])([CH3:16])[CH3:15]>>[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])([CH3:16])[CH3:15]
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Reactant: CC(C)c1ccccc1N
Product: CC(C)c1ccccc1Nc1c(C(=O)O)cccc1C(=O)O
Yield: 38 %

Procedure:
Similar reaction of 2-iodoisophthalic acid and 2-isopropylaniline gave 2-[(2-isopropyl)phenylamino]-isophthalic acid (38%), mp (EtOAc/petroleum ether) 217-219° C. 1H NMR [(CD3)2SO] δ 1.25 (d, J=6.8 Hz, 6 H, 2×CH3), 3.22-3.29 (m, 1 H, CH), 6.81 (dd, J=7.4, 1.8 Hz, 1 H, H-3' or H-6'), 6.93 (t, J=7.7 Hz, 1 H, H-2), 6.92-7.02 (m, 2 H, H-4' and H-5'), 7.26 (dd, J=7.1, 2.2 Hz, 1 H, H-6' or H-3'), 7.90 (d, J=7.7 Hz, 2 H, H-4 and H-6), 9.69 (s, 1 H, NH), 12.93 (br s, 2 H, 2×COOH). Anal. (C17H17NO4) C, H, N.
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[I:14]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O>[I:14][C:6]1[C:7]([C:10]([O:12][CH3:13])=[O:11])=[N:8][O:9][C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc(CC(C)C)on1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1noc(CC(C)C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
A mixture of methyl 5-isobutylisoxazole-3-carboxylate (Preparation 5A, 0.923 g, 5.04 mmol) and N-iodosuccinimide (1.247 g, 5.54 mmol) in TFA (25 mL) was stirred at room temperature overnight. The TFA was removed under reduced pressure, and the residue was diluted with dichloromethane (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (2×25 mL), 2.5% aqueous solution of sodium bisulfate (25 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane afforded methyl 4-iodo-5-isobutylisoxazole-3-carboxylate (1.21 g, 3.91 mmol, 78% yield) as a pale yellow oil. The product had an HPLC ret. time=2.40 min. (condition A); LC/MS M+1=310.1.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([OH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH3:12])=[C:8]([O:13][CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][O:16][CH2:14][CH3:15])=[CH:26][CH:25]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(O)cnn(C(C)(C)C)c1=O
Reactant: CCOCOc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOCOc1ccc(COc2cnn(C(C)(C)C)c(=O)c2C)cc1
Yield: 57.9 %

Procedure:
By using 1.0 g of 2-t-butyl-5-hydroxy-4-methyl-3(2H)-pyridazinone, 1.1 g of 4-ethoxymethoxybenzyl chloride and 1.0 g of anhydrous potassium carbonate and similarly to the procedures in Preparation Example 2, 1.1 g of the aimed product was obtained as an oil.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1C(=O)N(C)CCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:42][C:43]1[C:50]([CH3:51])=[C:49]([O:52][CH3:53])[CH:48]=[CH:47][C:44]=1[CH2:45]I.C(O)(=O)CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C(OCC)(=O)C.O>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:45][C:44]2[CH:47]=[CH:48][C:49]([O:52][CH3:53])=[C:50]([CH3:51])[C:43]=2[CH3:42])[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CI)c(C)c1C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCC(=O)O
Solvent: CN1CCCN(C)C1=O
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccccc3)NC(=O)OC(C)(C)C)OC2=O)c(C)c1C
Reaction time: 0.25 h

Procedure:
A solution of 1.248 g (4.087 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one (Example 2b)) in 5 ml of abs. THF and 0.823 ml (6.825 mmol) of DMPU is cooled down to -75° C., under argon, and treated dropwise, at an internal temperature of below -70° C. and over the space of approximately 17 min, with 8 ml of a 1M solution of lithium bis(trimethylsilyl)amide in THF (Aldrich). After a further 15 min, a solution of 1.128 g (4.087 mmol) of 2,3-dimethyl-4-methoxybenzyl iodide in 3 ml of abs. THF is added dropwise to this mixture within the space of 10 min, and the whole is allowed to react at -75° C. for a further 2 h. For the working-up, the reaction mixture is treated with 1.5 ml of propionic acid and 1.5 ml of water and the temperature is allowed to rise to 0° C. The mixture is poured onto 35 ml of (cold) 10% citric acid solution, and approximately 70 ml of (cold) ethyl acetate is added to this mixture. After stirring for a further 5 min, the phases are separated. The organic phase is washed, in succession, with saline, sat. sodium bicarbonate solution and with saline once again, dried over Na2SO4 and concentrated. The residue which remains after removing the solvent is chromatographed on silica gel (hexane:ethyl acetate, 2:1). The title compound is obtained as a colourless foam. TLC Rf (hexane:ethyl acetate 2:1)=0.37. HPLC tRet= 17.83 min (gradient II). FAB-MS (M+H)+- 453. IR(CH2Cl2)=inter alia 3428, 1769, 1712 and 1495 cm-1. 1H-NMR(CDCl3)=inter alia 7.38-7,08 (m, 5H); 6.86 and 6.62 (each d, each 1H); 3.78 (3H); 3.21 and 2.16 (each d×d, each 1H); 2.19 and 2.13 (each s, each 3H); and 1.35 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1.C(=O)C1C=CC=CC=1.FC1C=CC(C=O)=CC=1>>[CH3:1][O:2][C:3](=[O:15])[C:4](=[O:14])[CH:5]([Cl:13])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Agent: O=Cc1ccc(F)cc1
Solvent: O=Cc1ccccc1
Product: COC(=O)C(=O)C(Cl)c1ccccc1

Procedure:
This compound was synthesised as 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester but using benzaldehyde instead 4-fluorobenzaldehyde.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].I[CH2:11][CH2:12][CH3:13].OCC(CO)O.[OH-].[K+]>>[C:1]([N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:11][CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CNC(C)(C)C
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Product: CCCN(CC(C)C)C(C)(C)C

Procedure:
A mixture of tert-butylisobutylamine (19.39 g, 0.15 mol), 1-iodopropane (20.40 g, 0.12 mol) and glycerol (5.53 g, 60 mmol) was refluxed for 40 h. Aqueous 8 M potassium hydroxide (30 ml, 0.24 mol) was added, the organic layer was separated and the aqueous layer was extracted with n-pentane (50 ml). The organic solutions were combined, dried over anhydrous magnesium sulfate and the product was isolated by distillation to yield 12.52 g, (61%), bp 72-73° C./18 mm Hg; 1H NMR (CDCl3) δ0.80 (t, J=6.2 Hz, 3H, CH3), 0.84 (d, J=6.6 Hz, 6H, CH3), 1.01 (s, 9H, CH3), 1.40 (sextet, J=6.2 Hz, 2H, CH2), 159 (nonet, J=6.6 Hz, 1H, CH), 2.16 (d, J=6.6 Hz, 2H, CH2), 2.34 (m, 2H, CH2).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>>[CH:13]1([CH:11]([CH:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[OH:12])[CH2:15][CH2:14]1
Reactant: O=CC1CCC2(CC1)OCCO2
Reactant: Br[Mg]C1CC1
Product: OC(C1CC1)C1CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (1.135 g, 6.668 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292) cooled to −78° C. under argon was added a cyclopropylmagnesium bromide (40 mL, 20 mmol, 0.5 M in THF) dropwise. After the complete addition, the reaction mixture was allowed to reach room temperature overnight. It was then re-cooled to −78° C. and quenched with saturated NaHCO3 solution and warmed to room temperature. After extraction with ether, the organic layer was concentrated in vacuo and the residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to afford the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:6]=1[C:7]([O:9]C)=[O:8].C>[OH-].[Na+].C(O)C>[NH2:1][C:2]1[S:3][C:4]([CH:11]([CH3:13])[CH3:12])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C(C)C)sc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(C(=O)O)c(N)s1
Yield: 70.2 %

Procedure:
Methyl 2-amino-5-isopropylthiophene-3-carboxylate (59.8 g, 0.3 mol) was dissolved in 210 ml of 50% aqueous ethanol containing 24.6 g (0.6 mol) of sodium hydroxide and refluxed overnight. The ethanol was evaporated in vacuo, and the aqueous solution was extracted twice with chloroform. The aqueous phase was acidified by adjusting the pH to 4.5 with hydrochloric acid. The precipitate was isolated, dissolved in 150 ml of ethanol, and treated with 4 g of charcoal (Norit SU18). The mixture was filtered and concentrated to 100 ml. Water (500 ml) was added and the precipitate was filtered off to yield 39 g (70%) of 2-amino-5-isopropylthiophene-3-carboxylic acid melting with decomposition at 115° C. 1H-NMR (CDCl3, δ) : 1.2 (d, 6H), 2.9 (m, 1H), 5.8 (broad, 2H), 6.65 (s, 1H).