Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]1C=CC=CC=1)C=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:24]I>ClCCl.S([O-])([O-])(=O)=S.[Na+].[Na+]>[CH2:1]([O:8][CH2:9][CH:10]1[CH:16]([CH2:17][I:24])[O:15][C:14](=[O:23])[NH:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: II
Reactant: C=CC(COCc1ccccc1)NC(=O)OCc1ccccc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C1NC(COCc2ccccc2)C(CI)O1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of benzyl [1-(benzyloxy)but-3-en-2-yl]carbamate (3.0 g, 9.6 mmol) and iodine (4.9 g, 19 mmol) in dichloromethane (200 mL) was stirred at 20° C. for 16 hours. The reaction mixture was diluted with aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product residue. The crude product residue was purified by silica gel chromatography (ethyl acetate/petroleum ether) to give 4-[(benzyloxy)methyl]-5-(iodomethyl)-1,3-oxazolidin-2-one. MS ESI calc'd. for C12H15INO3 [M+H]+ 348. found 348. 1H NMR (300 MHz, CDCl3) δ 7.40-7.27 (m, 5H), 5.53 (s, 1H), 4.57 (s, 2H), 4.37-4.34 (m, 1H), 3.82-3.80 (m, 1H), 3.67-3.51 (m, 2H), 3.38-3.32 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[N:5][C:6]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:7]([Cl:18])[N:8]=2)[N:3]=1.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[Cl:18][C:7]1[N:8]=[C:9]2[C:4](=[N:5][C:6]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:3]=[C:2]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[N:11]=[C:10]2[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCOCC2)c2nc(Cl)c(N3CCOCC3)nc2n1
Solvent: C1COCCO1
Product: Clc1nc2c(N3CCOCC3)nc(N3CCNCC3)nc2nc1N1CCOCC1

Procedure:
9.3 g (0.025 mol) of 2,6-dichloro-4,7-dimorpholino-pteridine were refluxed for one hour with 8.6 g (0.1 mol) of anhydrous piperazine in 200 ml of dioxane. The solvent was substantially distilled off, and the residue was digested with about 100 ml of water. After the aqueous mixture stood for a short time, it was suction-filtered, and the filter cake was washed with water and dried at about 70° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[NH:7][N:6]=1.[O-:22][C:23]#[N:24].[K+].C(O)C.C(O)(=O)C>O>[Cl:21][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:23]([NH2:24])=[O:22])[C:13]=23)[CH:20]=[CH:19][CH:18]=1
Reactant: NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: NC(=O)NCCNc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 200 mg (0.655 mmol) of 3-(2-amino-ethylamino)-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine (water content: 0.48%), 72 mg (0.887 mmol) of potassium cyanate, 1.2 ml of ethanol, 1.2 ml of water and 46.8 ml (0.819 mmol) of acetic acid is stirred at RT for 15 hours. 2 ml of water are added to the resulting suspension and the mixture is filtered. Washing the filter residue with water and a small amount of ethanol and drying in vacuo (about 100 mbar, 8 hours, 1 00C) yield the title compound having a water content of 5.54%; m.p. 212-214° C.; ESI-MS: (M+H)+=347
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:11][S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([CH3:27])[CH:4]=1)#[N:2].[OH-:28].[Na+].OO>CS(C)=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:11][S:12][C:13]=2[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)=[C:5]([CH3:27])[CH:4]=1)(=[O:28])[NH2:2]
Reactant: [OH-]
Reactant: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C#N)cc2C)cc1
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(-c2scc(CCC(=O)O)c2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
To a solution of 3-(4-(4-cyano-2-methylphenyl)-5-(4-methoxyphenyl)thiophen-3-yl)propanoic acid (30 mg, 0.08 mmol) in DMSO (5 mL) was added NaOH (6 mg, 0.16 mmol), and 30% H2O2 (9 mg, 0.08 mmol). The mixture was stirred at room temperature for 2 h, and purified by preparative HPLC to give 16 mg of the title compound, Example 14 (Scheme III, 17, X1=4-carbamoyl-2-methylphenyl, X2=4-methoxyphenyl) (yield 52%) as a white solid. 1H NMR (CD3OD 400 MHz TMS): δ7.72 (s, 2H), 7.26 (d, J=8.4 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J=8.8 Hz, 2H), 6.70 (d, J=8.4 Hz, 2H), 3.70 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.38 (t, J=8.0 Hz, 2H), 1.96 (s, 3H); MS (ESI): m/z 317.9 [M+23]+.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH2:12][C:13]([OH:15])=O)[CH:10]=[N:11][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH3:29])([CH3:28])[C:26]#[N:27])=[C:21]([Cl:30])[CH:20]=1)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN(C=O)C.CO>[Cl:30][C:21]1[CH:20]=[C:19]([CH:17]([NH:16][C:13](=[O:15])[CH2:12][N:9]2[C:8]3[C:3]([C:1]#[N:2])=[CH:4][CH:5]=[CH:6][C:7]=3[N:11]=[CH:10]2)[CH3:18])[CH:24]=[CH:23][C:22]=1[C:25]([C:26]#[N:27])([CH3:29])[CH3:28]
Reactant: CC(N)c1ccc(C(C)(C)C#N)c(Cl)c1
Reactant: N#Cc1cccc2ncn(CC(=O)O)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: CC(NC(=O)Cn1cnc2cccc(C#N)c21)c1ccc(C(C)(C)C#N)c(Cl)c1
Yield: 52.9 %

Procedure:
To a solution of (7-cyano-1H-benzimidazol-1-yl)acetic acid (271 mg, 1.35 mmol) prepared according to scheme 3, 2-[4-(1-aminoethyl)-2-chlorophenyl]-2-methylpropanenitrile (300 mg 1.35 mmol) prepared according to scheme 17 and DMAP (325 mg, 2.69 mmol) stirred in anhydrous DMF (3.0 mL) is added HATU (511 mg, 1.35 mmol) after 18 hours of stirring, the mixture is diluted with Methanol (200 μL) the solution is purified directly on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (0.1% TFA), B=MeCN using a short 40 to 60% B 10 min. gradient method. The pure fractions are combined the TFA neutralized with a 4N NaOH solution and then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product (+) and (−)-N-{1-[3-chloro-4-(1-cyano-1-methylethyl)phenyl]ethyl}-2-(7-cyano-1H-benzimidazol-1-yl)acetamide (290 mg, 53%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) δ ppm 1.50 (d, J=7.03 Hz, 3H) 1.83 (s, 6 H) 5.02 (q, J=7.03 Hz, 1H) 5.14 (s, 2H) 7.17 (ddd, J=11.33, 8.98, 7.42 Hz, 1H) 7.33 (dd, J=8.20, 1.95 Hz, 1H) 7.43 (ddd, J=8.89, 3.81, 1.37 Hz, 1H) 7.47 (d, J=2.34 Hz, 1H) 7.51 (d, J=8.20 Hz, 1H) 8.13 (s, 1H), MS [M+H], calcd: 417.1. found: 417.3.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1>[O:15]1[CH2:16][CH2:17][N:12]([CH2:2][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[CH2:13][CH2:14]1
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2CCOCC2)cc1
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a stirred solution of 4-bromomethyl-benzoic acid (239, 1.5 g, 6.78 mmol) in THF (15 mL) was added morpholine (0.61 mL, 6.78 mmol). The reaction mixture was allowed to stir for 10 minutes before the resulting white precipitate was filtered off and discarded. The filtrate was evaporated under reduced pressure and the remaining solid was dried under vacuum to afford the title compound 240 as a white solid (1.15 g, 75% yield). 1H NMR: (DMSO) δ 7.89-7.86 (m, 2H), 7.52 (d. J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 4.12 (s, 2H), 3.75-3.72 (m, 1H), 3.56-3.58 (m, 4H), 3.10-3.07 (m, 1H), 2.45-2.35 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1([CH2:7][O:8][CH3:9])[CH2:6]O1.[S-:10]C#N.[K+]>O>[CH3:1][O:2][CH2:3][C:4]1([CH2:7][O:8][CH3:9])[CH2:6][S:10]1
Reactant: COCC1(COC)CO1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Product: COCC1(COC)CS1
Reaction time: 6 h
Yield: 89.2 %

Procedure:
2,2-Bis(methoxymethyl)oxirane (13 g) was stirred with a solution of potassium thiocyanate (9.7 g) in water (40 cm3) for 18 h at room temperature. The aqueous layer was then replaced with a fresh solution of potassium thiocyanate (9.7 g) in water (40 cm3) and the mixture stirred for a further 6 h. The bulk of the thiirane was then separated from the aqueous layer which was then extracted with diethyl ether. These extracts were combined with the bulk of the thiirane, the solution dried and the solvent removed (40° C. at 15 mmHg) to give the thiirane (13 g, 90%) as a colourless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]=[C:12]=[S:13].[N-:14]=[N+:15]=[N-:16].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[C:12]([SH:13])=[N:16][N:15]=[N:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(OC)c(N=C=S)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(OC)c(-n2nnnc2S)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.1 %

Procedure:
2,5-Dimethoxyphenylisothiocyanate (39 g, 0.22 mol) and sodium azide (14.3 g, 0.22 mol) were added to a mixture of water (150 ml) and ethanol (60 ml) and the mixture was heated on a steam bath to about 80° C. to 90° C. with stirring for 3 hours. The reaction mixture was cooled to room temperature and a 2N HCl solution (100 ml) was added. The raw crystals formed were collected by filtration and recrystallized from isopropanol to obtain 1-(2,5-dimethoxyphenyl)-5-mercaptotetrazole (35.7 g, yield 75%). The melting point was 151° to 152° C.
Reaction SMILES: [N:1]([CH:4]1[C:29](=[O:30])[N:6]2[C:7]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@:5]12[O:31][CH3:32])=[N+]=[N-].CCN(CC)CC>C(Cl)(Cl)Cl>[NH2:1][C@@H:4]1[C:29](=[O:30])[N:6]2[C:7]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=3)=[O:17])=[C:8]([CH2:11][O:12][C:13](=[O:15])[CH3:14])[CH2:9][S:10][C@:5]12[O:31][CH3:32]
Reactant: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)C2N=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CO[C@]12SCC(COC(C)=O)=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N1C(=O)[C@H]2N
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
A solution of p-nitrobenzyl 7-azido-6-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate (249 mg., 0.54 mMol) in CHCl3 (5 ml.) is cooled in an ice-bath and treated with Et3N (150 μl, 1.08 mMol). H2S is bubbled through the cold solution for 2-3 mins., followed by N2 for 10 mins. The resulting solution is diluted with cold CH2Cl2 (5 ml.), washed with cold dilute HCl to pH 6, cold H2O (3x) and brine, dried with MgSO4, filtered, and evaporated in vacuo to provide a mixture (245 mg.) of p-nitrobenzyl 7β-amino-6α-methoxy-3-acetoxymethyl-ceph-3-em-4-carboxylate and the corresponding 7α-amino-derivative as a yellow foam.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1(=[O:27])[N:17]([CH2:18][C:19]([OH:21])=O)[C:16](=[O:22])[C:15]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:14]12.[C:28](=[N:32]O)([NH2:31])[CH2:29][CH3:30]>C1COCC1>[CH2:29]([C:28]1[N:32]=[C:19]([CH2:18][N:17]2[C:13](=[O:27])[C:14]3=[CH:26][CH:25]=[CH:24][CH:23]=[C:15]3[C:16]2=[O:22])[O:21][N:31]=1)[CH3:30]
Reactant: CCC(N)=NO
Reactant: O=C(O)CN1C(=O)c2ccccc2C1=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCc1noc(CN2C(=O)c3ccccc3C2=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At 40° C., a suspension of 26.0 g of carbonyldiimidazole in 250 ml of THF is added to a solution of 65.7 g of phthalimidoacetic acid in 500 ml of THF (absolute). After about one hour, no release of gas can be observed any longer. At this point in time, a solution of 28.2 g of propionamidoxime in 50 ml of THF is added, and the mixture is stirred at room temperature for 24 hours. After the precipitate has been filtered off, the filtrate is concentrated under vacuum and, after addition of 500 ml of dry xylene, is heated under reflux for 6 hours on a water trap. The still hot solution is separated from the oily residue and concentrated under vacuum. Crystallization from EtOH yields 31.5 g (76.5%, based on carbonyldiimidazole) of oxadiazole having a melting point of 106°-107° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:11]=[C:10]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[Si]([N:35]1[C:43]2[C:38](=[C:39](B3OC(C)(C)C(C)(C)O3)[C:40]([F:44])=[CH:41][CH:42]=2)[CH:37]=[CH:36]1)(C(C)(C)C)(C)C>>[F:44][C:40]1[C:39]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[N:11]=[C:10]([CH2:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19](=[O:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[C:38]2[C:43](=[CH:42][CH:41]=1)[NH:35][CH:36]=[CH:37]2
Reactant: CC(=O)N1CCC(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: CC1(C)OB(c2c(F)ccc3c2ccn3[Si](C)(C)C(C)(C)C)OC1(C)C
Product: CC(=O)N1CCC(Cc2ccc3nc(-c4c(F)ccc5[nH]ccc45)nc(N4CCOCC4)c3n2)CC1

Procedure:
1-(4-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-1-yl)ethanone (30 mg) was reacted with 1-(tert-butyldimethylsilyl)-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole via General Procedure A to produce 13.7 mg of 148 following reverse phase HPLC purification. MS (Q1) 489.2 (M)+
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH2:8][N:9]2[CH2:15][CH2:14][C:13]3[CH:16]=[CH:17][C:18]([N+:20]([O-])=O)=[CH:19][C:12]=3[CH2:11][CH2:10]2)=[CH:4][C:3]=1[CH3:25].C(OCC)(=O)C>[Pd].CO>[NH2:20][C:18]1[CH:17]=[CH:16][C:13]2[CH2:14][CH2:15][N:9]([CH2:8][CH2:7][O:6][C:5]3[CH:23]=[CH:24][C:2]([NH2:1])=[C:3]([CH3:25])[CH:4]=3)[CH2:10][CH2:11][C:12]=2[CH:19]=1
Reactant: Cc1cc(OCCN2CCc3ccc([N+](=O)[O-])cc3CC2)ccc1N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(OCCN2CCc3ccc(N)cc3CC2)ccc1N

Procedure:
3-[2-(4-Amino-3-methylphenoxy)ethyl]-7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.5 g) was stirred at room temperature under a hydrogen atmosphere [344.7 kPa (50 p.s.i.)]in ethyl acetate (20 ml) and methanol (20 ml) containing 5% Pd/C (0.075 g) for 3 hours. The catalyst was then removed by filtration and the filtrate was evaporated in vacuo to give the title compound as an oil, yield 0.385 g, which was used directly without further purification.
Reaction SMILES: [CH2:1]([O:6][C@@H:7]1[C@H:11]([OH:12])[C@@H:10]([CH2:13][OH:14])[O:9][C@H:8]1[N:15]1[C:25]2[N:24]=[C:22]([NH2:23])[NH:21][C:19](=[O:20])[C:18]=2[N:17]=[CH:16]1)[CH2:2][CH2:3][CH2:4][CH3:5].C[Si](Cl)(C)C.[C:31](Cl)(=[O:35])[CH:32]([CH3:34])[CH3:33]>N1C=CC=CC=1>[C:31]([NH:23][C:22]1[NH:21][C:19](=[O:20])[C:18]2[N:17]=[CH:16][N:15]([C:25]=2[N:24]=1)[C@@H:8]1[O:9][C@H:10]([CH2:13][OH:14])[C@@H:11]([OH:12])[C@H:7]1[O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])(=[O:35])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)C(=O)Cl
Reactant: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21
Agent: C[Si](C)(C)Cl
Solvent: c1ccncc1
Product: CCCCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21

Procedure:
2′-O-pentylguanosine (2.3 g) in pyridine (35 ml) was treated with trimethylsilyl chloride (4.15 ml, 5 eq) and isobutyryl chloride (3.4 ml, 5 eq) as per the procedure of Example 4 to yield the product as a foam (2.3 g). An analytical sample was crystallized from EtOAc/Hex. m.p. 178-180° C. 1H NMR (DMSO-d6) δ 0.75 (t, 3, CH3), 1.1 [m, 10, 2×CH2, CH(CH3)2], 1.4 (m, 2, CH2), 2.74 [m, 1, CH(CH3)2], 3.56 (m, 4, OCH2, H-5′), 3.93 (m, 1, H-4′), 4.25 (m, 1), 4.34 (m, 1), 5.05 (t, 1, 5′-OH), 5.17 (d, 1, 3′-OH), 5.88 (d, 1, H-1′), 8.27 (s, 1, H-8), 11.65 (br s, 1, NH) and 12.05 (br s, 1, NH). Anal. Calcd. for C19H29N5O6: C, 53.89; H, 6.90; N, 16.54. Found: 53.75; H, 6.92; N, 16.40
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Br.O>CN(C)C=O.C(OCC)(=O)C>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]2[O:1][CH2:18][CH:20]([CH2:21][OH:22])[O:11][C:3]=2[CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)c(O)c1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(c1)OC(CO)CO2
Temperature: 100 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
1,2-Dihydroxy-4-nitrobenzene (5.00 g, 0.032 mol), potassium carbonate (9.67 g, 0.07 mol) and epibromohydrin (5.30 g. 0.039 mol) were dissolved in dimethylformamide (100 ml), which was stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and extraction was conducted using ethyl acetate. The organic layer was washed with water, and concentrated. The residue was purified by alumina column chromatography (development solvent: ethyl acetate). The eluent was washed with a mixed solution of ethyl acetate-n-hexane (1:1), to give (7-nitro-2,3-dihydro-1,4-benzodioxin-2-yl)methanol (3.31 g) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:38]([O:40]C)=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([NH:8][CH:9]([C:38]([OH:40])=[O:39])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:34](=[O:37])[CH:35]=[O:36])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:33])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3cccs3)C2=O)cc1)C(=O)O
Reaction time: 7 h
Yield: 74.7 %

Procedure:
2-[3-{4-(3-tert-butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(2-thienyl)acetic acid (0.480 g.) was dissolved in methanol (3 ml.), and to the solution, there was added 1 N aqueous sodium hydroxide (2 ml.) under ice-cooling. The mixture was stirred at the same temperature for 7 hours while adjusting to pH 9.0 to 9.5 with 1 N aqueous sodium hydroxide. After the reaction, the reaction mixture was adjusted to pH 7.0 with dilute hydrochloric acid and evaporated to dryness under reduced pressure on a water bath. The resultant residue was dissolved in a small amount of water, and the aqueous solution was adjusted to pH 5.5 with dilute hydrochloric acid and then washed with ethyl acetate. The aqueous solution was adjusted to pH 4.0 to 4.5 with dilute hydrochloric acid and then extracted with ethyl acetate. This extract was evaporated to dryness under reduced pressure to give 2-[3-{4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2-oxo- 1-azetidinyl]-2-(2-thienyl)acetic acid (0.350 g.).
Reaction SMILES: C([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25]([OH:27])=O)=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:40][NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:40][N:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)[C:25]([C:18]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:24]=2[C:15]([OH:14])=[C:16]2[C:30](=[O:31])[N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH2:28][C:17]=12)=[O:27]
Reactant: CNc1ccccn1
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1c2c(c(O)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2)c1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.8 %

Procedure:
9-Benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid 213 (0.02 g, 0.0386 mmol) was dissolved in 0.3 mL of dimethylformamide. To this was added 2-methylaminopyridine (0.0079 mL, 0.0772 mmol), diisopropylethylamine (0.027 mL, 0.1544 mmol), O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.03 g, 0.0772 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Purified by reverse phase HPLC (0.1% TFA, H2O/ACN) to give 7-(4-fluoro-benzyl)-9-hydroxy-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carboxylic acid methyl-pyridin-2-yl-amide 318 (0.0017 g, 0.003 mmol, 8%.) 1H NMR (CDCl3) δ 9.02 (dd, 1H), 8.50 (d, 1H), 8.18 (d, 1H), 7.65 (dd, 1H), 7.38 (m, 5H), 7.08 (dd, 2H), 4.94 (dd, J=15 Hz, 11Hz, 2H), 4.49 (d, J=17 Hz, 1H), 4.19 (d, J=17 Hz, 1H), 3.61 (s, 3H.) MS: 443 (M+1).
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[CH2:3][C:4]([O:6]CC)=O.[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:24](=[N:26]O)[NH2:25]>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[C:24]1[N:26]=[C:4]([CH2:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[O:1])[O:6][N:25]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1C
Reactant: NC(=NO)c1cc(F)ccc1F
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)Cc1nc(-c2cc(F)ccc2F)no1

Procedure:
A solution of ethyl 3-oxo-3-o-tolylpropanoate (0.44 mL; 2.5 mmol) and 2,5-difluoro-N′-hydroxybenzenecarboximidamide (JRD-Fluorochemical, 215 mg; 1.25 mmol) in toluene (1.5 mL) was heated to 120° C. 18 hours. The solvent was removed in vacuo and the residue purified by flash chromatography on a Biotage 25+M column, eluting with petrol containing increasing amounts of EtOAc. The residue was triturated with petrol to give the title compound as an off-white solid which was used directly without any further purification. 1H NMR (CDCl3, 400 MHz) δ 11.62‡ (1H, br s), 7.82-7.74 (1H, m), 7.55-7.12 (6H, m), 5.95‡ (1H, s), 4.68* (2H, s), [2.58, 2.55 and 2.47] (3H, s) (compound isolated as a mixture of keto and enol forms and as a mixture of rotamers, *=keto form, ‡=enol form). LC/MS: 315 (M+H)+. HPLC (Method D) Rt=4.28 min (Purity: 98.4%).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[C:8]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]>>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[CH:16]=[C:20]([C:21]([O:23][CH3:24])=[O:22])[S:19][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CS
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Product: COC(=O)c1cc2c3ccccc3n(-c3ccccc3)c2s1
Yield: 79.6 %

Procedure:
Prepared from 1-Phenyl-2-chloroindole-3-carbaldehyde (0.90 g), K2 CO3 (1.38 g) and methyl 2-mercaptoacetate (0.55 ml) yielding (51) 0.86 g (79.6%). M.p. 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[C:9](F)=[CH:10][C:11]#N)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C([O:28]CC)C>CCCCCC.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:15])([CH3:14])[CH:9]=[CH:10][CH:11]=[O:28])=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: CC(C)(C(F)=CC#N)c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C=CC=O)c1ccc(Cl)cc1
Temperature: -40 °C
Reaction time: 0.58 h
Yield: 97 %

Procedure:
A solution of 4-(p-chlorophenyl)-3-fluoro-4-methyl-2-pentenenitrile, (Z)- (15.6 g, 69.7 mmol) in diethyl ether is treated dropwise with diisobutylaluminum hydride (83.6 mmol, 83.6 mL of a 1M solution in hexane) over 90 minutes at -45° C. under nitrogen, stirred at -40° C. for 35 minutes, and diluted sequentially with water and 2N hydrochloric acid at -10° C. The resultant aqueous mixture is stirred at room temperature for one hour and extracted with diethyl ether. The organic extracts are combined, washed sequentially with water, 2N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a brown oil (15.34 g, 97% yield).