Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:28]=[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:21](O)=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:28][C:22]=2[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)c1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.5 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (10.2 g), ethyl 5-nitrosalicylate (10.7 g) and triphenylphosphine (17.3 g) in dichloromethane (200 ml) was added dropwise diethyl azodicarboxylate (10.4 ml) in an ice bath and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1 as an eluant to afford a yellow solid. A suspension of the solid in hexane was filtered to give the desired compound (12.3 g, yield 61%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=1)#[CH:2].Br[C:10]1[C:11]([NH2:17])=[N:12][CH:13]=[C:14]([Br:16])[N:15]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Br:16][C:14]1[N:15]=[C:10]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=2)[C:11]([NH2:17])=[N:12][CH:13]=1
Reactant: C#Cc1cnn(C)c1
Reactant: Nc1ncc(Br)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: Cn1cc(C#Cc2nc(Br)cnc2N)cn1
Temperature: 70 °C
Yield: 82.3 %

Procedure:
To a round bottom flask was added 4-ethynyl-1-methyl-1H-pyrazole (8.5 g, 80 mmol, Preparation #Q.1), 3,5-dibromopyrazin-2-amine (16.8 g, 66.4 mmol), THF (166 mL), PdCl2(PPh3)2 (2.33 g, 3.32 mmol), copper(I) iodide (0.633 g, 3.32 mmol) and TEA (27.8 mL, 199 mmol). The mixture was heated to about 70° C. for about 1 h. The mixture was cooled to rt. The solids were filtered away and rinsed with THF (50 mL). The filtrate was partitioned with water (300 mL) and the mixture was extracted with EtOAc (400 mL). The organic layer was dried with anhydrous MgSO4, filtered and concentrated in vacuo. The residue was triturated with EtOH (100 mL) and the solid material was collected by filtration. The mother liquor was purified by flash chromatography (300 g silica gel column, heptane/EtOAc 10:1 to 0:1) to give 5-bromo-3-((1-methyl-1H-pyrazol-4-yl)ethynyl)pyrazin-2-amine (15.2 g, 82%): LC/MS (Table 2, Method c) Rt=1.40 min; MS m/z 278 (M+H)+.
Reaction SMILES: [Li][CH3:2].[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH:23]=[CH:22][CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:12]=1)=[O:7])[CH3:4]>CCOCC.C1COCC1.[Cu]I>[CH2:3]([O:5][C:6]([C:8]1[C:9]2[C:24](=[O:25])[CH2:23][CH:22]([CH3:2])[CH2:21][CH2:20][C:10]=2[N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH:12]=1)=[O:7])[CH3:4]
Reactant: [Li]C
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C=CCC2
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)CC(C)CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
MeLi (1.4M in ether, 2 ml) is added dropwise to a stirred suspension of CuI (268 mg, 1.40 mmol) in Et2O at 0° C. The reaction mixture is kept at 0° C. for 15 min. 4-oxo-7,8-dihydro-4H-cyclohepta[b]pyrrole-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (300 mg, 0.94 mmol) in THF is added slowly to the solution at 0° C., the reaction mixture is allowed to warm up to room temperature over a period of 30 min and then quenched with saturated NH4Cl(aq., 30 ml). 50 ml Et2O is added and stirring is continued for 5 min. The layers are separated; the organic layer is washed with water (20 ml), dried (Na2SO4), and evaporated. Flash chromatography (30% EtOAc/hexanes) provides the title compound as white powder. 1H NMR (400 MHz, CDCl3) δ 1.02 (3H, d), 1.28 (3H, t), 1.56 (9H+1H, s+m), 1.92 (1H, m), 2.15 (1H, m), 2.48 (1H, q), 2.80 (1H, q), 3.15-3.25 (2H, m), 4.24 (2H, q), 7.57 (1H, s). MS (ES+) 336 (M+1) Step 2: 6-Methyl-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta[b]pyrrole-3-carboxylic acid ethyl ester
Reaction SMILES: [CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([C:16]([CH3:18])=[CH2:17])=[CH:8][C@H:9]2[CH2:14][OH:15])[CH:2]=[CH2:3].[CH3:19]I.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:4][N:5]1[C:11](=[O:12])[N:10]2[CH2:13][C@H:6]1[C:7]([C:16]([CH3:18])=[CH2:17])=[CH:8][C@H:9]2[CH2:14][O:15][CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCON1C(=O)N2C[C@H]1C(C(=C)C)=C[C@H]2CO
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCON1C(=O)N2C[C@H]1C(C(=C)C)=C[C@H]2COC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
To a solution of (2S,5R)-6-(allyloxy)-2-(hydroxymethyl)-4-(prop-1-en-2-yl)-1,6-diazabicyclo[3.2.1]oct-3-en-7-one (Intermediate 58, 0.289 g, 1.15 mmol) in DMF (10 mL) at 0° C. was added methyl iodide (0.435 mL, 6.93 mmol) followed by sodium hydride (60% in mineral oil) (0.051 g, 1.27 mmol). The reaction was stirred for 1.5 hours at 0° C. The reaction mixture was diluted with ethyl acetate and washed twice with water. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-50% ethyl acetate/hexanes) afforded the desired product as a pale yellow oil (233 mg, 76%).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][C@H:14]3[C@@H:16](O)[CH2:17][CH2:18][N:13]3[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCN(S(F)(F)[F:27])CC>ClCCl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH2:15][CH:14]3[C@H:16]([F:27])[CH2:17][CH2:18][N:13]3[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C[C@H]3[C@@H](O)CCN3C2=O)ccc(C#N)c1Cl
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: Cc1c(N2CC3[C@H](F)CCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.9 %

Procedure:
A solution of (7S,7aS)-2-chloro-4-(7-hydroxy-3-oxotetrahydropyrrolo[1,2-c]imidazol-2-yl)-3-methylbenzonitrile (WO 03/096980) (30 mg, 0.103 mmol) in dry dichloromethane (1.0 mL) was cooled to −65° C., treated with DAST (26 μL, 0.21 mmol) and stirred for 17 h, allowing the temperature to warm to rt. The reaction mixture was then cooled to 0° C., quenched with 10% sodium carbonate (0.5 mL) and extracted with CH2Cl2 (2×10 mL). The organic phase was washed with H2O (0.5 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The syrup was combined with a previous batch (5.4 mg) and chromatographed 3× (silica gel; EtOAc/hexane gradient then CH3OH/CH2Cl2 gradient) to yield the title compound (14.5 mg, 47.9%). HPLC: 99.1% at 2.04 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3C—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm). Chiral HPLC: retention time=20.8 min (100%); Conditions: OD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 60 min at 1 mL/min. MS (ES+): m/z 294 [M+H]+.
Reaction SMILES: [OH:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl.CO>[CH2:10]([NH:17][CH:5]1[CH2:6][CH2:7][C:2]([CH3:9])([OH:1])[CH2:3][CH2:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CC1(O)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CO
Solvent: CC(=O)O
Product: CC1(O)CCC(NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 107.8 %

Procedure:
4-hydroxy-4-methylcyclohexanone (270 mg, 1.48 mmol) was dissolved in 1,2-dichloroethane (8.3 ml), followed by sequential addition of benzylamine (0.2 ml, 1.83 mmol), NaBH(OAc)3 (560 mg, 2.66 mmol), and acetic acid (0.1 ml, 1.66 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 72 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 5% MeOH/MC (50 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (10% MeOH/MC), to obtain 350 mg of yellow solid (96%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1S(C)(=O)=O)#[N:2].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[C:1]([C:3]1[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[C:5]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[S:6][C:7]=1[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)#[N:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1sc(S(C)(=O)=O)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Yield: 63.3 %

Procedure:
A solution of ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-(methylsulfonyl)thiophene-2-carboxylate (1.77 g, 4.38 mmol) and morpholine (1.91 mL, 21.9 mmol) in THF (40 mL) was stirred at rt under an atmosphere of argon for 3 days. A precipitate had formed and was filtered to give ethyl 4-cyano-3-(3,4-dichlorophenyl)-5-morpholin-4-ylthiophene-2-carboxylate (1.14 g, 63%). 1H NMR (400 MHz, d6-DMSO) δ: 7.67-7.74 (m, 2H), 7.37 (dd, 1H), 4.06 (q, 2H), 3.74-3.78 (m, 4H), 3.59-3.63 (m, 4H) and 1.06 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:17]([O:19][CH2:20][CH3:21])=[CH2:18])CCC>CN(C=O)C.[F-].[K+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([O:19][C:17]([C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:11])[CH3:10])[CH:5]=[N:6][CH:7]=1)=[CH2:18])[CH3:21]
Reactant: CC(=O)Nc1cncc(Br)c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(OCC)c1cncc(NC(C)=O)c1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of N-(5-bromopyridin-3-yl)acetamide (2.7 mmol) and Pd(PPh3)2Cl2 (0.13 mmol) in DMF (5 mL) under an atmosphere of nitrogen was added tributyl(1-ethoxyvinyl)stannane (2.97 mmol). The reaction was allowed to stir at 80° C. until for approximately 24 hrs. The reaction mixture was allowed to cool to rt and then diluted with aq KF solution (10 mL) and allowed to stir for 30 min. A thick white precipitate formed and was filtered. The filter cake was washed with water and Et2O. The filtrate was diluted with water and extracted with Et2O. The organic solutions were combined, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give N-[5-(1-ethoxyvinyl)pyridin-3-yl]acetamide in quantitative yield. LCMS: (FA) ES+ 205.2.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N[C:26]1SC2CC(C)CCC=2C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:26][CH:17]1[CH2:16][C:14]2[S:15][C:11]([NH:10][S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:9])=[O:8])=[C:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]=2[CH2:19][CH2:18]1
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Reactant: CCOC(=O)c1c(N)sc2c1CCC(C)C2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCC(C)C2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-6-methyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (prepared according to Pinkerton et al., Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569) and benzenesulphonyl chloride.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[C:26]4[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=4[O:24][N:23]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].C([O-])(O)=O.[Na+]>ClCCl>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[F:31][C:28]1[CH:29]=[CH:30][C:25]2[O:24][N:23]=[C:22]([CH:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][C@H:11]4[CH2:12][CH2:13][C@H:8]([NH2:7])[CH2:9][CH2:10]4)[CH2:17][CH2:18]3)[C:26]=2[CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CCN2CCC(c3noc4ccc(F)cc34)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.3 g (5 mmol) of trans(4-{2-[4-(5-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-ethyl}-cyclohexyl)-carbamic acid tert-butyl ester is solved in dichloromethane (15 mL) and trifluoroacetic acid is added at 0° C. (10.7 mL, 46 mmol) and the mixture is stirred at room temperature overnight. NaHCO3 is slowly added until pH 9 and the mixture extracted 3 times with dichloromethane and ethyl acetate. The solvent was evaporated to yield 1.86 g (5.3 mmol, 100%) of a white solid that was used without purification on the next steps. MS (m/e): 346.3 (M+H+).
Reaction SMILES: N1C=CC(=O)NC1=O.[O:9]=[CH:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17](CO)[OH:18])[OH:16])[OH:14])[OH:12]>>[CH2:10]([OH:9])[C@@H:11]([C@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=c1cc[nH]c(=O)[nH]1
Product: OC[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 30 °C
Reaction time: 48 h

Procedure:
The expression cassette PGtrpfs2-CoAraA constructed above was introduced into Candida parapsilosis in which URA3 was inactivated, which was smeared on the uracil-free solid selection medium (yeast nitrogen base 6.7 g/L, glucose 20 g/L, and agarose powder 15 g/L), followed by incubation for 2 days at 30° C. The colonies formed on the solid medium were the strains introduced with the cassette. The colonies were inoculated in 4 ml of YM medium (glucose 20 g/L, yeast extract 3 g/L, malt extract 3 g/L, and peptone 5 g/L), followed by shaking-culture at 150 rpm for 12 hours at 30° C. Then, the culture solution was smeared on 5-FOA solid medium (yeast nitrogen base 6.7 g/L, glucose 20 g/L, 5-FOA 0.8 g/L, uracil 0.1 g/L, and agarose powder 15 g/L), followed by incubation for 2 days at 30° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[CH2:14][NH:13][C:12]2=[O:15])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[H-].[Na+].C(OCC)(=O)C>CN(C)C=O>[CH2:21]([O:20][C:18]([CH:17]([N:13]1[CH2:14][CH:11]([NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:12]1=[O:15])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OCc1ccccc1)C(Br)c1ccccc1
Reactant: O=C(Cc1ccccc1)NC1CNC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1CN(C(C(=O)OCc2ccccc2)c2ccccc2)C1=O

Procedure:
3-(2-Phenylacetamido)-2-azetidinone (816 mg.) and benzyl 2-bromo-2-phenylacetate (1.22 g.) were dissolved in N,N-dimethylformamide (20 ml.), and to the solution was added sodium hydride (50% oily) (210 mg.) in nitrogen atmosphere under ice-cooling while stirring, and then the reaction mixture was stirred for an hour at the same temperature. Ethyl acetate (150 ml.) was added to the reaction mixture, and the solution was washed with water, a sodium bicarbonate-saturated-aqueous solution and water respectively, and then dried over anhydrous magnesium sulfate. The solution was evaporated to dryness under reduced pressure to give the yellow oily material (1.7 g.). The material was subjected to column chromatography using silica-gel (developer: chloroform) to give two isomers of 1-(α-benzyloxycarbonylbenzyl)-3-(2-phenyl)acetamido-2-azetidinone. Yield of the isomer A is 26 mg. and it of the isomer B is 65 mg.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:6][CH:5]([C@H:7]2[N:11]([O:12][CH3:13])[C@:10]3([CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])[C:14]4[C:19]([C:20](=[O:22])[CH:21]=[C:9]3[O:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:4][O:3]1>C(OCC)(=O)C.O=[Pt]=O>[CH3:1][C:2]1([CH3:28])[O:6][CH:5]([C@H:7]2[N:11]([O:12][CH3:13])[C@:10]3([CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])[C:14]4[C:19]([C:20](=[O:22])[CH:21]=[C:9]3[O:8]2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:4][O:3]1
Reactant: CON1[C@H](C2COC(C)(C)O2)OC2=CC(=O)c3ccccc3[C@]21CC=C(C)C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CON1[C@H](C2COC(C)(C)O2)OC2=CC(=O)c3ccccc3[C@]21CCC(C)C
Yield: 77.4 %

Procedure:
The product from Example 22B (82 mg, 0.21 mmol) and PtO2 (Adam's catalyst, 5 mg) in ethyl acetate (2 mL) was stirred at rt under 1 atm H2 for 90 min. The catalyst was filtered off, the solvent was evaporated and the crude product was purified by column chromatography on silica gel using a solvent gradient of 10-25% ethyl acetate in hexanes to provide the title compound as a colorless gum (63 mg, 77%): 1H NMR (300 MHz, DMSO-d6) δ ppm 7.95 (d, J=7.4 Hz, 1H), 7.63-7.79 (m, 2H), 7.42-7.56 (m, 1H), 5.91 (d, J=5.5 Hz, 1H), 5.84 (s, 1H), 4.53-4.67 (m, 1H), 4.09-4.22 (m, 1H), 3.98-4.09 (m, 1H), 3.49 (s, 3H), 1.80-1.97 (m, 2H), 1.45 (s, 3H), 1.36 (s, 3H), 1.21-1.34 (m, 1H), 0.82-1.01 (m, 1H), 0.57-0.74 (m, 6H), 0.32-0.52 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[I:17]Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][C:7]=1[I:17]
Reactant: ClI
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3ccccc3o2)cc1I
Yield: 65.8 %

Procedure:
2-(4'-Aminophenyl)benzoxazole (0.14 g, 1.9 mmol) was treated with iodine monochloride (0.37 g, 2.23 mmol) in acetic acid according to the above-described general procedure for iodination. Crude product was purified by flash chromatography on silica gel using ethyl acetate-hexane (1:2) as eluent to give a brown powder (0.42 g, 65.7%), m.p. 188.0-191.2° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=1>O>[N:1]1([C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: NC(=O)c1ccc(F)cc1
Solvent: O
Product: NC(=O)c1ccc(N2CCNCC2)cc1
Yield: 90 %

Procedure:
A mixture of piperazine (7.56 g) and 4-fluorobenzamide (2.44 g) in water (10 mL) is heated at reflux for 27 h. The mixture is then allowed to cool slightly and the solid is collected and washed with water and dichloromethane, followed by drying to give 3.24 g of 4-(piperazin-1-yl)benzamide; mp 238-243° C.; ms m/z 205; IR (mineral oil) 1609, 1255, 1665, 1389, 3149 cm-1. 1H NMR (DMSOd6) δ2.59, 2.80, 3.14, 6.90, 7.02, 7.72, 7.73.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[N:20]=[N:19][NH:18][C:13]3=2)[N:8]=1>S(=O)(=O)(O)O>[OH:6][C:7]1[C:16]([OH:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([N+:1]([O-:4])=[O:2])=[C:12]3[N:20]=[N:19][NH:18][C:13]3=2)[N:8]=1
Reactant: Oc1nc2ccc3nn[nH]c3c2nc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2[nH]nnc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Finely powdered potassium nitrate (3.1 q, 30.7 mmol) was added to a stirred solution of 7,8-dihydroxy-1H-1,2,3-triazolo[4,5-f]quinoxaline (6.1 g, 30 mmol) in 50 ml of conc. sulfuric acid at 0° C. (ice bath). The mixture was stirred over night at room temperature. Then a further amount of potassium nitrate (3 g) was added with cooling on an ice bath, and stirring was continued for 5 h at room temperature. The mixture was poured into 700 ml of ice/water, and the yellow precipitate was isolated, washed with water, and recrystallized from ethanol giving 5.2 g (70%) of the title compound; m.p.>300° C.; IR (KBr): 3300-2200, 1700 cm-1 ; 1H-NMR (DMSO-d6): 8.13 (s, 1H, ArH), 11-16 (broad, 3H, NH+2OH).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][CH:9]([OH:12])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:16]=3)[CH:5]=[CH:4][C:3]1=2.C(NCC)(C)C.[CH3:33][O:34][CH2:35]Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][C:2]1([CH3:1])[CH2:11][CH2:10][CH:9]([O:12][CH2:33][O:34][CH3:35])[C:8]2[CH:7]=[C:6]([N:13]=[N:14][C:15]3[CH:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][CH:25]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COCCl
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(O)CCC3(C)C)cc1
Agent: CCNC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OCOC)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of (+/−) ethyl 4-[(5,5-dimethyl-8-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)azo]benzoate (Compound D5, 49.7 mg, 0.141 mmol) in 4 ml of dry CH2Cl2 at 0° C. was added isopropyl ethyl amine (0.152 ml, 0.847 mmol) followed by chloromethyl methyl ether (0.0323 ml, 0.423 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvent was removed-under reduced pressure, the residue was dissolved in ethyl acetate and the solution was washed with NaHCO3 (sat.), and brine. The organic layer was dried (MgSO4). The solvent was removed under reduced pressure, the residue was purfied by flash chromatography (silica, ethyl acetate:hexane, 1:3) to afford the title compound as a red oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][CH2:10][C:11]1([CH2:14]Cl)[CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][CH2:10][C:11]1([CH2:14][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:13][O:12]1
Reactant: Oc1ccc(Cl)cc1
Reactant: ClCC1(CCl)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCC1(COc2ccc(Cl)cc2)CO1
Yield: 32.6 %

Procedure:
12.85 g (0.1 mol) of 4-chlorophenol in 50 ml of acetone are added dropwise to a mixture of 14.1 g (0.1 mol) of 2,2-di(chloromethyl)-oxirane and 13.8 g (0.1 mol) of potassium carbonate in 200 ml of acetone. The mixture is heated under reflux for 18 hours, left to cool and filtered. The filtrate is concentrated in vacuo, the residue is dissolved in chloroform and the solution is washed with water, dried over sodium sulphate and concentrated. Purification of the residue by distillation gives 7.6 g (32.5% of theory) of 2-chloromethyl-2-(4-chlorophenoxymethyl)-oxirane of boiling point 150° C./0.5 mbar.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[C:4]([CH3:10])[CH:3]=1.[C-:11]#[N:12].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([CH3:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Cc1cc(Br)ccc1CCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Br)ccc1CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
4-Bromo-1-chloromethyl-2-methyl-benzene (63 g, 287 mmol) was dissolved in DMF (180 mL). NaCN (15.5 g, 316 mmol, 1.1 eq.) was added in 1 portion, and the reaction was stirred at room temperature overnight under a N2 atmosphere. The mixture was concentrated under reduced pressure, and the residue was taken into a mixture of sat. aq. NH4Cl (300 mL) and EtOAc (300 mL). The bi-phase solution was diluted with H2O (200 mL). The EtOAc layer was separated, and the aqueous layer was re-extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine (3×300 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure, yielding the title compound (58.8 g, 280 mmol, 98%) with acceptable purity as a brown oil, which solidified to a brown solid on standing. 1H-NMR (CDCl3, 300 MHz) δ ppm 2.34 (s, 3H); 3.63 (s, 2H); 7.26 (t, 1H); 7.38 (d, 2H).