Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1.[CH:36]1([NH2:39])[CH2:38][CH2:37]1.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:39][CH:36]4[CH2:38][CH2:37]4)=[O:26])[CH:11]3[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:34])[C:5]2=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: Cc1ccccc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1ccccc1C1N(CC(=O)NC2CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 30.9 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(fluorocarbonyl)-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.12 g, 0.23 mmol) prepared in example 34a was reacted with cyclopropylamine (0.1 g, 1.8 mmol) (Aldrich), N-methylmorpholine (48 mg, 0.47 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(cyclopropylamino)-carbonyl-methyl]-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.039 g, 30%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[CH2:15]1[CH2:19][O:18][CH2:17][CH2:16]1.[C:20](O)(=O)[CH2:21][CH2:22][CH3:23].[NH4+].[OH-]>O.[Ni].CO>[O:18]=[C:17]([NH:12][C:5]1[C:6]([CH3:11])=[C:7]2[NH:8][C:20]([CH2:21][CH2:22][CH3:23])=[N:1][C:2]2=[N:3][CH:4]=1)[CH2:16][CH2:15][CH3:19]
Reactant: Cc1c([N+](=O)[O-])cnc(N)c1[N+](=O)[O-]
Reactant: C1CCOC1
Reactant: CCCC(=O)O
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCC(=O)Nc1cnc2nc(CCC)[nH]c2c1C
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A mixture of 2-amino-3,5-dinitro-4-methylpyridine (3.1 g, 15.6 mmol), THF (100 mL), methanol (100 mL) and Raney-nickel (6 mL of a 1:1 suspension in H2O) was stirred under H2 (1 atm.) for 6 h. The mixture was quickly filtered into a receiving flask containing 3 mL of conc. aqueous HCl, and the solvent was removed in vacuo at r.t. To the resulting crude 2,3,5-triamino-3-methylpyridine.HCl complex was added butyric acid (4.3 mL, 46.9 mmol) and polyphosphoric acid (100 mL) and this mixture was heated to 85° C. for 10 h. The warmed mixture was poured into stirred ice-H2O (200 mL) and this mixture was cooled and neutralized (to pH 3) by the addition of conc. NH4OH. Extraction with CH2Cl2 (3×50 mL), drying (Na2SO4), and concentration gave the title compound as a solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]1([NH2:10])[CH2:9][CH2:8]1.Br[CH:12]1[CH2:17][CH2:16][O:15][C:13]1=[O:14].O>C(#N)C>[CH:7]1([NH:10][CH:12]2[CH2:17][CH2:16][O:15][C:13]2=[O:14])[CH2:9][CH2:8]1
Reactant: O=C1OCCC1Br
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1OCCC1NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
After potassium carbonate (18.24 g, 132.0 mmol) was added to a solution of cyclopropylamine (5.50 ml, 80.0 mmol) and (±)-α-bromo-γ-butyrolactone (3.32 ml, 42.0 mmol) in acetonitrile (80 ml), the mixture was stirred at room temperature for 8 hours. To the reaction mixture, water was added and then this was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1 as the eluant to give (±)-α-cyclopropylamino-γ-butyrolactone (4.10 g, yield 73%) as a yellow oil.
Reaction SMILES: [F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:26])[CH2:8][C:9]2[CH:25]=[CH:24][C:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])[O:15][C:11]=3[CH:10]=2)[C@H:4]([CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36]C)=[O:35])[CH2:3]1.[OH-].[Na+:39].C(O)C.CCOCC>C1COCC1>[F:1][C@@H:2]1[CH2:6][N:5]([C:7](=[O:26])[CH2:8][C:9]2[CH:25]=[CH:24][C:12]3[N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH3:23])[O:15][C:11]=3[CH:10]=2)[C@H:4]([CH2:27][O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=[O:35])[CH2:3]1.[Na+:39]
Reactant: COC(=O)CCCCCOC[C@@H]1C[C@H](F)CN1C(=O)Cc1ccc2nc(Nc3ccccc3C)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)N3C[C@@H](F)C[C@H]3COCCCCCC(=O)[O-])cc2o1
Reaction time: 24 h

Procedure:
Methyl 6-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)hexanoate (330 mg, 0.645 mmol) was dissolved in THF (30 ml). At room temperature, 0.25N NaOH (30 ml) was added and the mixture was stirred for 24 hours. The reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl, followed by extraction with a chloroform/methanol (10/1) mixture. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by thin-layer silica gel chromatography, followed by separation by using chloroform/methanol (20/1), whereby the title compound (238 mg, 74%) was obtained as a yellow oil. Ethanol (10 ml) and 1N NaOH (0.478 ml, 0.478 mmol) were added to the resulting carboxylic acid derivative (238 mg, 0.478 mmol). After stirring for 10 minutes, ether was added to crystallize the residue, which had been obtained by distilling off the solvent under reduced pressure, whereby sodium 6-((2S,4S)-4-fluoro-1-(2-(2-methylphenylamino)-6-benzoxazolylacetyl)-2-pyrrolidinylmethoxy)hexanoate (199 mg) was obtained.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: O=C=Nc1ccccc1Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1Cl)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-chlorophenyl isocyanate (0.147 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 167 mg (51.5%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][C:20]([CH2:29][CH2:30][OH:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH2:18]2)=[O:16])[C:12]([Cl:32])=[CH:11][C:10]=1[F:33])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][C:20]([CH2:29][CH:30]=[O:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH2:18]2)=[O:16])[C:12]([Cl:32])=[CH:11][C:10]=1[F:33])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cc(C(=O)N2CCC(CCO)(c3ccccc3)OC2)c(Cl)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cc(C(=O)N2CCC(CC=O)(c3ccccc3)OC2)c(Cl)cc1F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of N-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide (25.2 mg, 0.05 mmol) in dimethyl sulfoxide (71 μL, 1 mmol), diisopropylethylamine (53 μL, 0.30 mmol) and 1 mL CH2Cl2 was added SO3.pyr in one portion. The reaction mixture was stirred for 2 h at 0° C., saturated aqueous NaHCO3 was added, and the aqueous layer was extracted with CHCl3. After evaporation, the resultant crude N-(tert-butyl)-4-chloro-2-fluoro-5-{[6-(2-oxoethyl)-6-phenyl-1,3-oxazinan-3-yl]carbonyl}benzenesulfonamide was obtained and used in the next step without further purification.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][OH:21])[O:16]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C1C=CN=CC=1.C(#N)C>[CH:1]1([CH2:4][NH:5][C:6]2[N:14]=[CH:13][N:12]=[C:11]3[C:7]=2[N:8]=[CH:9][N:10]3[C@H:15]2[CH2:19][CH2:18][C@@H:17]([CH2:20][O:21][C:29](=[O:34])[CH2:30][CH2:31][CH2:32][CH3:33])[O:16]2)[CH2:2][CH2:3]1
Reactant: OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Reactant: CCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCC(=O)OC[C@@H]1CC[C@H](n2cnc3c(NCC4CC4)ncnc32)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 59 %

Procedure:
6-(Cyclopropylmethylamino)-9-[(2R,5S)-tetrahydro-5-(hydroxymethyl)-2-furyl]-9H-purine (0.624 g, 2.1 mmoles), 4-dimethylaminopyridine (27 mg, 0.2 mmoles, Aldrich Chemical Co., Madison, Wis.), and triethylamine (2.0 mL, 14 mmoles, Aldrich Chemical Co., Madison, Wis.) were dissolved in 100 mL acetonitrile. Valeryl chloride (1.08 mL, 8.9 mmoles, Aldrich Chemical Co., Madison, Wis.) was added and the reaction was stirred at room temperature for 6 hours. The reaction was quenched with methanol and solvents were evaporated in vacuo. The residue was dissolved in acetone and passed over a silica gel column (4.8×13 cm). After evaporation of the solvent, the product was further purified on a Chromatotron (4 mm silica gel plate) with a mixture of hexane:acetone (85:15). The product containing fractions were combined, concentrated, and loaded onto preparative silica gel plates (20×20×0.2 cm). The plates were developed in a mixture of chloroform-acetone (80:20). The product was scraped from the preparative plate and eluted from the silica gel with ethanol. The product was then flash chromatographed on a silica gel column (2.5×40 cm) with a mixture of chloroform:acetone (95:5). Lyophilization afforded 0.463 g of 6-(cyclopropylmethylamino)-9-((2R,5S)-5-((pentanoyloxy)methyl)-tetrahydro-2-furyl)-9H-purine as an oil (58% yield).
Reaction SMILES: [Al:1].[CH:2]([OH:5])([CH3:4])[CH3:3]>Cl[Hg]Cl>[CH3:3][CH:2]([O-:5])[CH3:4].[CH3:3][CH:2]([O-:5])[CH3:4].[CH3:3][CH:2]([O-:5])[CH3:4].[Al+3:1]
Reactant: CC(C)O
Reactant: [Al]
Agent: Cl[Hg]Cl
Product: CC(C)[O-]
Product: [Al+3]

Procedure:
Aluminum isopropylate is prepared by reacting in a dry 2 liter flask swept with nitrogen, 231 ml. of isopropyl alcohol and 14 g. of aluminum in presence of a small amount of HgCl2. The reaction starts immediately and is maintained by heating under reflux. After 1 hour the isopropyl alcohol in excess is eliminated. After that, the aluminum isopropylate is distilled under 6 mm. of Hg at about 150° C. The distillate crystallizes very slowly. It contains 133 g. of aluminum per kg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4]([CH2:10][CH3:11])[C:3]=1[CH:12]=[O:13].C([C:16](CC)([C:20]([O-:22])=O)[C:17]([O-:19])=[O:18])C.[CH2:25](O)[CH3:26]>N1CCCCC1>[CH2:10]([C:4]1[N:5]=[C:6]([CH2:8][CH3:9])[CH:7]=[C:2]2[C:3]=1[C:12]([OH:13])=[C:16]([C:17]([O:19][CH2:25][CH3:26])=[O:18])[C:20](=[O:22])[NH:1]2)[CH3:11]
Reactant: CCc1cc(N)c(C=O)c(CC)n1
Reactant: CCO
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(O)c2c(CC)nc(CC)cc2[nH]c1=O

Procedure:
4-amino-2,6-diethylpyridine-3-carbaldehyde (1.78 g), diethylmalonate (1.92 g), ethanol (15 ml) and piperidine (4 drops) were heated at reflux for 16 hours. Volatile material was removed by evaporation and the residue was recrystallised from ethyl acetate/petroleum ether to give ethyl 5,7-diethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-carboxylate (B) (1.4 g), m.p. 159°-160° C. NMR (CDCl3) 1.34(t, 3H), 1.38(t, 3H), 1.47(t, 3H), 2.87(q, 2H), 3.14(q, 2H), 4.47(q, 2H), 7.03(s, 1H), 8.78(s, 1H), 12.2(s, 1H); mass spectrum (CI, ammonia): 275 (M+H)+ ; microanalysis, found: C, 65.8; H, 6.8; N, 10.4%; C15H18N2O3 requires: C, 65.7; H, 6.6; N, 10.2%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1O.[H-].[Na+].C([O-])([O-])=[O:15].[Cs+].[Cs+].Br[C:21]([CH3:26])([CH3:25])[C:22]([NH2:24])=[O:23]>O1CCOCC1.CN1C(=O)N(C)CCC1.CN1C(=O)CCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:24][C:22](=[O:23])[C:21]([OH:15])([CH3:26])[CH3:25]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(Br)C(N)=O
Agent: [Cs+]
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN1CCCN(C)C1=O
Solvent: CN1CCCC1=O
Product: CC(C)(O)C(=O)Nc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
To a solution of 2-naphthol (533 mg, 3.70 mmol) in dioxane (20 mL) was added NaH (Aldrich, dry, 300 mg, 12.2 mmol) and Cs2CO3 (4.00 g, 12.2 mmol). The resulting mixture was stirred at room temperature for about 30 minutes, then 2-bromo-2-methyl-propanamide (2.03 g, 12.2 mmol) was added and the resulting mixture was stirred at reflux for 16 h. After the reflux period, NMP (20 mL), DMPU (2 mL), and NaH (Aldrich, dry, 100 mg, 4.07 mmol) were added. The resulting mixture was stirred at 150° C. for 72 h. The reaction was cooled to room temp., and partitioned between water (50 mL) and EtOAc (100 mL). The aqueous layer was extracted with EtOAc (100 mL) and the combined organics washed with water (2×50 mL), dried (Na2SO4), and concentrated to about 3 g of material. The brown oil was chromatographed on silica (200 mL, 4 cm diam. column), eluting with 3:7 EtOAc/hexane to obtain N-(2-naphthyl)-2-hydroxy-2-methylpropionamide as a white solid (607 mg, 2.65 mmol, 71.6% yield).: mp 155-157° C. 1H NMR (300 MHz, DMSO) δ 9.74 (br s, 1H, N--H), 8.41 (d, 1H, C1 --H, J =2.20 Hz), 7.86-7.76(om's, 4H), 7.49-7.37 (om's, 2H), 5.80 (br s, 1H, O--H), 1.40 (s, 6H, C(CH3)2); 13C NMR (75 MHz, DMSO) δ 175.7, 136.2, 133.3, 129.8, 128.1, 127.4, 127.3, 126.3, 124.6, 120.6, 115.6, 72.5, 27.7; IR (KBr pellet) 1607, 1634, 1655 (amide C=O stretches), 3289 (NH/OH stretch); MS (CI/NH3) 247;
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=O.CCOC(C)=O>CN(C=O)C>[BrH:8].[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([C:10]2[N:1]=[C:2]3[N:7]=[CH:6][CH:5]=[CH:4][N:3]3[CH:9]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncccn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Br
Product: O=[N+]([O-])c1ccc(-c2cn3cccnc3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-aminopyrimidine (0.40 g, 4.22 mmol) and 2-bromo-4′-nitroacetophenone (1.03 g, 4.22 mmol) in DMF (8 ml) was stirred at rt for 16 h. EtOAc (15 ml) was added to the resulting yellow, viscous mixture and the precipitate collected by filtration and washed with EtOAc (50 ml). After drying under high vacuum, a yellow solid was obtained (0.67 g, 51%).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([SH:30])[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[CH3:48][O:49][C:50]1[CH:60]=[CH:59][C:53]([O:54][CH2:55]C(Cl)=O)=[CH:52][CH:51]=1>ClCCl.CN(C)C1C=CN=CC=1.[Ag]>[CH2:1]([O:4][C:5](=[O:41])[C:6]([N:26]1[C@H:29]([S:30][CH2:48][O:49][C:50]2[CH:60]=[CH:59][C:53]([O:54][CH3:55])=[CH:52][CH:51]=2)[C@@H:28]([C@H:31]([O:33][C:34]([O:36][CH2:37][CH:38]=[CH2:39])=[O:35])[CH3:32])[C:27]1=[O:40])=[P:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1S
Reactant: COc1ccc(OCC(=O)Cl)cc1
Agent: [Ag]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(C(=O)OCC=C)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SCOc1ccc(OC)cc1

Procedure:
The starting material is prepared as follows: A solution of 2.43 g of the silver salt of 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-mercapto-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester in 40 ml of absolute dichloromethane is treated successively with 0.56 ml of pyridine, 20 mg of 4-dimethylaminopyridine and 1.12 g of 4-methoxyphenoxyacetylchloride. The work-up procedure described above gives the desired 2-[(3S,4R)-3-[(1R)-1-allyloxycarbonyloxyethyl]-4-[4-methoxyphenoxymethylthio)-2-oxo-azetidin-1-yl]-2-triphenylphosphoranylideneacetic acid allyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1CC=O.C(=[O:31])CC.[C:32]1([CH3:38])[CH:37]=CC=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[C:4]=1[CH2:34][CH:33]=[C:32]([CH3:38])[CH:37]=[O:31]
Reactant: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC=O)C(=O)OC2
Reactant: CCC=O
Reactant: Cc1ccccc1
Product: COc1c(C)c2c(c(OS(=O)(=O)c3ccc(C)cc3)c1CC=C(C)C=O)C(=O)OC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy-5-isobenzofuranyl)acetaldehyde (10.0 g) and 2-triphenylphosphoranylidine propionaldehyde (10.3 g) in toluene (150 mL) was heated under nitrogen atmosphere using an oil bath at 80° C. After allowing the reaction to proceed for 16 hours, the mixture was cooled to ambient temperature and subjected to flash chromatography three times (7/2/1 hexanes/methylene chloride/methanol; 6/3/1 hexanes/methylene chloride/methanol; 1/1/1 hexanes/methylene chloride/ether). The residual solid (5.56 g) was recrystallized from ethyl acetate (200 mL) to afford 4-(1,3-dihydro-6-methoxy-7-methyl-3-oxo-4-p-toluenesulfonyloxy -5-isobenzofuranyl)2-methylbut-2-enaldehyde (2.65 g), m.p. 168.3°-173.2° C., impure with the starting aldehyde.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CO.CCO.[Cl:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=[CH:35][CH:34]=1>O>[ClH:32].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:33]4[C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=[CH:35][CH:34]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)cc2)nc(N)n1

Procedure:
To solution of amine E5 (267 mg, 0.720 mmol) in ˜1:1:1 MeOH:EtOH:H2O were sequentially added 4-chloroquinoline (1.06 g, 6.48 mmol) and 3 drops of CHCl, and the resulting mixture was refluxed for ˜24 h. After this time, solvent was removed under reduced pressure, and the resulting residue dried via two MeOH-azeotrope cycles. The residue was re-precipitated from MeOH/EtOAc, and then further purified by preparative HPLC, to afford Cpd. E as an amorphous yellow solid (16 mg, 4%). 1H NMR [(CD3)2SO]: 1.91 [s, 3H, ArCH3], 6.11 [s, 1H, ArH], 7.02 [d, J=6.77 Hz, 1H, ArH], 7.65 [d, J=8.55 Hz, 2H, ArH], 7.71 [br s, 2H, ArNH2], 7.84 [m, 4H, ArH], 8.04 [m, 2H, ArH], 8.15 [d, J=8.55 Hz, 2H, ArH], 8.63 [d, J=6.77 Hz, 1H, ArH], 8.70 [d, J=8.50 Hz, 1H, ArH], 10.38 [s, 2H, ArNHAr & ArH], 10.77 [br s, 1H, ArNHAr], 13.10 [v v br s, 2H, ArC(O)NHAr & quinoline-N+H]. LCMS (APCl+): 463 (100%). HPLC: 95.7%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[C:6]([CH2:8][C:9]#N)[CH:7]=1.S(=O)(=O)(O)[OH:23].[OH2:27]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=2[CH3:21])=[C:6]([CH2:8][C:9]([OH:23])=[O:27])[CH:7]=1
Reactant: O
Reactant: COc1cccc(CCc2ccc(Br)cc2CC#N)c1C
Reactant: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cccc(CCc2ccc(Br)cc2CC(=O)O)c1C
Temperature: 115 °C
Yield: 55 %

Procedure:
A stirred mixture of 5-bromo-2-[2-(3-methoxy-2-methyl-phenyl)-ethyl]-phenylacetonitrile 10 (8.57 g; 24.9 mmol) in water and acetic acid was treated drop-wise with concentrated sulfuric acid (8.5 mL), heated at 115° C. for 5 hours, cooled to ambient temperature, diluted with water and extracted with chloroform. The extracts were combined, dried over Na2SO4, and evaporated. The resultant residue was purified on a silica gel column (hexane and ethyl acetate (7:3) as eluent) to give compound 11, 5.0 g, 55% yield.
Reaction SMILES: [F:1][C:2]1[C:15]([N+:16]([O-])=O)=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.O>C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:16][C:15]1[C:2]([F:1])=[CH:3][C:4]2[O:9][CH2:8][C:7](=[O:10])[N:6]([CH2:11][C:12]#[CH:13])[C:5]=2[CH:14]=1
Reactant: C#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C#CCN1C(=O)COc2cc(F)c(N)cc21
Temperature: 80 °C
Yield: 74.9 %

Procedure:
Iron powder (1.05 g) was suspended in 5% aqueous acetic acid (2.0 ml) and heated to 80° C. To the suspension, a solution of 7-fluoro-6-nitro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.47 g) in acetic acid (1.9 ml) and ethyl acetate (1.9 ml) was dropwise added, and the resultant mixture was heated under reflux at 60° to 80° C. for 3 hours. After being allowed to cool, water and ethyl acetate were added to the mixture. The residue was removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with water and aqueous sodium bicarbonate solution, dried and concentrated to give 6-amino-7-fluoro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.31 g). m.p., 183°-185° C.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10](O)=[O:11])=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:44]1([CH2:50][C@H:51]([C:53]([OH:55])=[O:54])[NH2:52])[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[NH2:8][CH2:9][C:10]([NH:52][C@@H:51]([C:53]([OH:55])=[O:54])[CH2:50][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
N-(tert-butoxycarbonyl)glycine (2.0 g, 11.4 mmol) and DIPEA (4.0 g, 31 mmol) were dissolved in methylene chloride (25 ml). TBTU (4.1 g, 12.8 mmol) was added and the mixture was stirred for 15 min at room temperature. 3-cyclohexyl-D-alanine (2.1 g, 12.2 mmol) was added and the reaction mixture was stirred over night at room temperature. The reaction mixture was transferred to a separation funnel and was then extracted with a water/acetic acid solution (100 ml 5% acetic acid). The organic layer was separated and evaporated under reduced pressure. The residue was dissolved in formic acid (20 ml) and the mixture was stirred over night at 40° C. The formic acid was removed under reduced pressure. The residue was washed with water (50 ml) and then stirred in aceton (25 ml) for 1 h at room temperature. The solid material was filtered off and washed with aceton (20 ml). The title compound was obtained.