Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:9]([O:10][CH3:11])=[C:8]([OH:12])[C:7]([CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4]=1[OH:5].[C:44]([Si:48](Cl)([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:47])([CH3:46])[CH3:45].N1C=CN=C1>ClCCl>[Si:48]([O:12][C:8]1[C:7]([CH3:13])=[C:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:4]([OH:5])=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])([C:44]([CH3:47])([CH3:46])[CH3:45])([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1
Reactant: COc1c(O)c(C)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(O)c1OC
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COc1c(O)c(CCCCCCCCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1OC
Temperature: 40 °C
Reaction time: 21 h

Procedure:
2,3-Dimethoxy-5-methyl-6-(10-trityloxydecyl)-hydroquinone (80.4 g) was dissolved in dichloromethane (250 ml). tert-Butylchlorodiphenylsilane (26 ml) and imidazole (6.8 g) were added, and the mixture was stirred at 40° C. for 21 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel and eluted with hexane/ethyl acetate (9:1) to obtain the desired compound (40 g).
Reaction SMILES: [C:1]1([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].[OH-].[Na+].Cl>C1COCC1.CO>[OH:24][NH:23][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][NH:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NO)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
To a solution of crude methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate (0.5 mmol) in a 1:1 mixture of THF/methanol (20 ml) was added 50 wt. % aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml) adjusting the pH between 10-11. The reaction mixture was stirred for 14 h, neutralized to pH=7-8 with 6 M aqueous HCl and concentrated in vacuo. The precipitate was collected and purified by HPLC providing the title compound as a white solid. 1H NMR (DMSO-d6): δ 8.69 (t, J=5.8 Hz, 1H), 7.83 (d, J=7.5 Hz, 2H), 7.69 (d, J=9.1 Hz, 2H), 7.46 (m, 3H), 6.99 (d, J=9.1 Hz, 2H), 4.16 (t, J=5.8 Hz, 2H), 3.63 (q, J=5.8 Hz, 2H). EM (calc.): 300.1; MS (ESI) m/e: 301.1 (M−1)+, 299.0 (M+1)−.
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)[S:13][N:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].C([O-])(=O)C.[Na+].Cl.[NH:36]1[CH2:39][CH:38]([C:40]([O:42]C)=[O:41])[CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH2:1]([C:3]1[C:10]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)[S:13][N:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:36]1[CH2:37][CH:38]([C:40]([OH:42])=[O:41])[CH2:39]1)[CH3:2]
Reactant: CCc1c(C=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Reactant: COC(=O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1nsc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
To a solution of 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}benzaldehyde (D47) (100 mg) in dichloromethane (DCM) (5 mL) and methanol (5.00 mL) was added sodium acetate (39.0 mg) and hydrogen chloride-methyl 3-azetidinecarboxylate (1:1) (72.1 mg). The reaction solution was stirred at room temperature for overnight. Sodium triacetoxyborohydride (101 mg) was added and the resulting solution was stirred at ambient temperature for 2 h. The solvent was removed in vacuo and the residue was dissolved in isopropanol/water (1:1, 5 mL), sodium hydroxide (2.378 mL) was added and the resulting solution was heated to 90° C. for 2 h. Isopropanol was removed in vacuo and the residue was acidified to pH=3-4, extracted with ethyl acetate (2*20 mL), the combined organic phases were dried over sodium sulphate and concentrated, the residue was purified by Mass Directed AutoPrep to afford 1-[(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,2,4-thiadiazol-3-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E19) (44 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.27 (6H, d), 2.87 (2H, q), 3.16 (4H, m), 3.34 (1H, m), 3.60 (2H, s), 4.89 (1H, m), 7.23 (1H, t), 7.38 (1H, dd), 7.45 (1H, d), 7.65 (1H, dd), 8.18 (1H, d), 8.25 (1H, dd). δF (DMSO-d6, 376 MHz): −61.4. MS (ES): C26H26F3N3O3S requires 505. found 506.1 (M+H+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:19]1[CH:45]=[CH:44][C:22]([C:23]([C:25]2[CH:43]=[CH:42][C:28]([C:29]([O:31][CH2:32][CH:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:34])=[O:30])=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1)=O)(=[O:4])[CH:2]=[CH2:3].N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:25]2[CH:43]=[CH:42][C:28]([C:29]([O:31][CH2:32][CH:33]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH3:34])=[O:30])=[CH:27][CH:26]=2)=[O:24])=[CH:44][CH:45]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OCCCCCCCCCCC(=O)Oc1ccc(C(=O)c2ccc(C(=O)OCC(C)OCCCCCC)cc2)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: Cc1ccccc1
Product: C=CC(=O)OCCCCCCCCCCCOc1ccc(C(=O)c2ccc(C(=O)OCC(C)OCCCCCC)cc2)cc1
Yield: 65.5 %

Procedure:
0.500 g of 2-hexyloxypropyl 4-[4'-(11-acryloyloxyundecanoyloxy)benzoyl]benzoate and 3 mol % of azobisisobutyronitrile were added to 5 ml of dry toluene and degassed under freezing, followed by polymerization for 24 hours at 60° C. The product was repeatedly re-precipitated from methanol to obtain 0.32 g (yield: 64%) of the objective polymer, which showed the following physical properties.
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2)[CH2:2][CH3:3].C1C(=O)NC(=O)N([C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]2[OH:30])C=1.[C@@H]1(N2C=CC(=O)NC2=O)O[C@H](CO)[C@@H](O)[C@H]1O>P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(O)CC>[C@@H:22]1([N:9]2[CH:8]=[N:7][C:6]3[C:10]2=[N:11][CH:12]=[N:13][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[O:26][C@H:25]([CH2:27][OH:28])[C@@H:24]([OH:29])[C@@H:23]1[OH:30]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]1
Reactant: CCCOc1ncnc2nc[nH]c12
Agent: O=P([O-])([O-])[O-]
Agent: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: [K+]
Solvent: CCCO
Product: CCCOc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Temperature: 35 °C
Reaction time: 20 h
Yield: 43.6 %

Procedure:
6-n-Propoxypurine (5.6 mmoles, 1 g, Sigma Chemicals, St. Louis Mo.) was combined with 545 ml of a uracil arabinoside solution (10.1 mmoles)in 10 mM potassium phosphate and 7% n-propanol (v/v). Purified uridine phosphorylase (680 I.U.) and purine nucleoside phosphorylase (12000 I.U.) were added and the reaction stirred at 35° C. The reaction was filtered after 58 days and the filtrate stored at 3° C. for 20 hours. The resulting precipitate was collected by centrifugation, dissolved in 30% n-propanol/water (v/v), and chromatographed on a column of Dowex-1-formate resin (2.5×5 cm) after adjusting the pH to 10.5 with concentrated ammonium hydroxide. The column was eluted with 30% n-propanol/water (v/v) and fractions containing product were combined and solvent removed in vacuo. The residue was dissolved in n-propanol and chromatographed on a column containing BioRad P-2 (5×90 cm). The column was eluted with 30% npropanol/water (v/v). Product-containing fractions were combined and after removing the solvent under vacuum the residue was dissolved in water and chromatographed on a column containing BioRad P-2 (5×90 cm). The column was eluted with water. Product containing fractions were combined and after lyophilization, yielded 0.758 g of 9-β-D-arabinofuranosyl-6-n-propoxy-9 H-purine that analyzed as a monohydrate. NMR and mass spectrometry were consistent with the structure.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:15](=[O:17])[CH3:16])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(N)ccc1O
Solvent: O
Product: CCOC(=O)c1cc(NC(C)=O)ccc1O
Temperature: 100 °C
Yield: 65 %

Procedure:
Ethyl 2-hydroxy-5-aminobenzoate (33.0 g, 0.182 mole) was dissolved in acetic anhydride (33 ml) and heated to 100° C. for 10 minutes. The mixture was cooled to room temperature, water (33 ml) was added and the mixture was evaporated to dryness. The remaining material was recrystallized from water-ethanol (1:1) to give the title compound (26.4 g, 65%), m.p. 135°-136° C. Found (Calc. for C11H13NO4) C 59.12 (59.19), H 5.93 (5.83), N 6.30 (6.28).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2].[Cl:17]N1C(=O)CCC1=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[C:5]([Cl:17])=[N:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)C=NNc1ccc(OC)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cl)=NNc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Method A. A solution of [(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (33, 4.0 g, 18.0 mmol) in anhydrous THF (40 mL) was treated with N-chlorosuccinimide (NCS, 2.52 g, 18.9 mmol, 1.05 equiv) at 0–5° C. under N2, and the resulting reaction mixture was stirred at 0–5° C. for an additional 30 min before being gradually warmed to 25° C. for 12 h. When HPLC and TLC showed the reaction was deemed complete, the solvent was removed in vacuo. The residue was directly purified by column chromatography (SiO2, 0–25% EtOAc/hexane gradient elution) to afford the desired chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (34, 3.51 g, 4.62 g theoretical, 76%) as pale-yellow solids, which was found to be essentially pure to do the following reaction without further purification. For 34, CIMS m/z 255/257 (M+−H, C11H13ClN2O3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[C:22](=[O:25])[CH2:23]Cl)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>C(O)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])([OH:11])[CH2:9][CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(c1cccc(Cl)c1)c1ccccc1O
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCO
Product: CCN(CC)C(=O)COc1ccccc1C(O)(CC)c1cccc(Cl)c1

Procedure:
5.3 g. of 1-(3-chlorophenyl)-1-(2-hydroxyphenyl)-propan-1-ol and 3.3 g. of monochloroacetic acid diethyl amide are dissolved in 36 ml. of n-propanol, and the reaction mixture is boiled for 4 hours, with stirring in the presence of 3 g. of anhydrous potassium carbonate. After cooling the solvent is distilled off under reduced pressure. To the residue water is added and it is extracted with ether. The ethereal solution is washed with water, a 5% aqueous sodium hydroxide solution and again with water until neutral. After drying over anhydrous magnesium sulfate, the solvent is distilled off in vacuo. The residue is crystallized from a mixture of n-hexane and ethyl acetate to yield 5.8 g. of the named compound, melting at 93°-94° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:14]([O:21][C:22]1[CH:49]=[CH:48][C:47](Br)=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>[CH2:14]([O:21][C:22]1[CH:49]=[CH:48][C:47]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:46][C:23]=1[C:24]([NH:26][C:27]1[CH:39]=[C:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:37]=[CH:36][C:28]=1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Br)ccc1OCc1ccccc1
Reactant: CN1CCNCC1
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C

Procedure:
1-Methylpiperazine (0.089 mL), cesium carbonate (0.35 g), tris(dibenzylideneacetone)dipalladium(0) (4.9 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (13 mg), and palladium(II) acetate (2.4 mg) were added to a toluene (4.5 mL) solution of tert-butyl 2-(2-(benzyloxy)-5-bromobenzamido)-4-phenylbenzoate (0.30 g), followed by heating to reflux under a nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, and then 1-methylpiperazine (0.060 mL), cesium carbonate (0.18 g), tris(dibenzylideneacetone)dipalladium(0) (4.9 mg), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (13 mg), and palladium(II) acetate (2.4 mg) were added thereto, followed by heating to reflux under a nitrogen atmosphere for 3 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and water and chloroform were added to the residue. The insoluble substance was removed by filtration. The organic layer was separated, washed with a 1 mol/L aqueous solution of sodium hydroxide and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-90% chloroform/methanol] to obtain 0.26 g of tert-butyl 2-(2-(benzyloxy)-5-(4-methylpiperazin-1-yl)benzamido)-4-phenylbenzoate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH:6]([C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7].CN(C)[CH:22]=[O:23]>>[CH:6]([C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH:22]=[O:23])=[CH:15][C:14]([O:18][CH3:19])=[CH:13][CH:12]=2)([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: COc1ccc2[nH]c(C(C)C)cc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2[nH]c(C(C)C)c(C=O)c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Dimethylformamide (2 mL) was cooled to 0° C. Phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirred for 10 minutes. A solution of 2-isopropyl-5-methoxyindole (200 mg, 1.05 mmol) in dimethylformamide (3 mL) was added to the reaction mixture dropwise over 10 minutes. The solution was stirred for an additional 40 minutes. The reaction mixture was added to ice cold 1 N NaOH (50 mL) and stirred for 10 minutes. The precipitate was collected and dried overnight in an oil driven vacuum pump equipped to a vacuum desiccator set at 40° C. yielding a light brown solid (318 mg, 86%): TLC Rf 0.71 in 4:1 ethyl acetate/hexanes. Melting point=181-183° C. 1H NMR (600 MHz, CDCl3) δ 10.22 (s, 1H), 8.63 (s, 1H), 7.79 (d, 1H, J=2.46 Hz), 7.26-7.24 (d, 1H, J=8.94 Hz), 6.89-6.87 (dd, 1H, J1=2.52 Hz, J2=8.76 Hz), 3.87 (s, 3H), 3.79-3.74 (m, 1H), 1.46-1.45 (d, 6H, J=7.02 Hz); 13C NMR (150 MHz, CDCl3) δ 184.1, 156.52, 156.51, 129.4, 126.9, 113.5, 113.2, 111.6, 103.0, 55.8, 25.8, 22.7. Elemental analysis calculated for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.59; H, 6.98; N, 6.39.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][O:11]2)=[CH:6][CH:5]=1)(O)=[O:2].CN(C)C=O.S(Cl)([Cl:32])=O>>[CH2:16]([CH:13]1[CH2:14][O:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([Cl:32])=[O:2])=[CH:5][CH:6]=2)[O:11][CH2:12]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCC1COC(c2ccc(C(=O)O)cc2)OC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCCCCCCCCC1COC(c2ccc(C(=O)Cl)cc2)OC1

Procedure:
A solution of 2-(4-carboxyphenyl)-5-n-nonyl-1,3-dioxane (2.00 g) in thionyl chloride (10 g) was heated under refluxing for 4 hours with a small amount of N,N-dimethylformamide. Excessive amount of thionyl chloride was distilled to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:23])[CH2:22][NH:21][CH2:20]1.[CH3:24]C(O)=O.C([BH3-])#N.[Na+]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]3[C:11]([CH2:12][O:13]2)=[N:10][NH:9][C:8](=[O:16])[C@H:7]3[CH3:17])=[CH:4][C:3]=1[NH:18][C:19]1([CH3:23])[CH2:20][N:21]([CH3:24])[CH2:22]1
Reactant: CC(=O)O
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CNC4)cc3N21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(Br)c(NC4(C)CN(C)C4)cc3N21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
A mixture of (R)-7-bromo-4-methyl-6-(3-methyl-azetidin-3-ylamino)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (4.0 g, 10.4 mmol) and polyformaldehyde (0.78 g, 26 mmol) in MeOH (10 mL) was stirred at ambient temperature for 10 min followed by the addition of AcOH (0.5 mL). The mixture was stirred at ambient temperature for 30 min before the addition of sodium cyanoborohydride (1.4 g, 22.8 mmol). The mixture was stirred at 40° C. overnight. The mixture was cooled to ambient temperature and concentrated in vacuo to give the residue, which was purified by chromatography on silica gel (eluting with 1% methanol in dichloromethane) to give (R)-7-bromo-6-(1,3-dimethyl-azetidin-3-ylamino)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (2.8 g, 62%). 1H NMR (400 MHz, CDCl3) δ=8.77 (s, 1H), 7.14 (s, 1H), 6.01 (s, 1H), 4.63 (q, J=6.8 Hz, 1H), 4.56 (d, J=12.8, 2H), 4.46 (s, 1H), 3.87 (m, 2H), 3.46 (m, 2H), 2.57 (s, 3H), 1.65 (s, 3H), 1.55 (d, J=6.8 Hz, 3H). LC/MS (Table 1, Method 25) Rt=0.659 min.; MS m/z: 394 [M+H]+ and 396 [M+H+2]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:9][S:8]C2[N:4](C(=O)C2NC(=O)CC2C=CC=CC=2)[C:3]=1[C:21]([O:23][CH3:24])=[O:22].C1C(=O)N(Cl)C(=O)C1>ClCCl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[C:3]([C:21]([O:23][CH3:24])=[O:22])=[N:4][S:8][CH:9]=1
Reactant: COC(=O)C1=C(C)CSC2C(NC(=O)Cc3ccccc3)C(=O)N12
Agent: O=C1CCC(=O)N1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nscc1C
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Methyl 3-methyl-8-oxo-7-[(phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (I127) (971 mg, 2.80 mmol) was dissolved in dry dichloromethane (DCM) (37 mL), treated with NCS (749 mg, 5.61 mmol) before adding 2 drops of TFA (0.05 mL, 0.649 mmol) and stirring at RT for 80 mins. LCMS as run and the desired product seen. Reaction left to stand for 16 hours before work up by diluting with DCM (20 ml), washing with saturated sodium bicarbonate solution (50 ml), then water (40 ml), dried over Na2SO4 before filtering and evaporating to afford an oil. Purified on a 100 g SNAP cartridge eluting with chloroform over 10 CV. 2 spots were isolated, desired product identified and solvent evaporated to afford an orange yellow gum of desired material in 57 mg.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:21][OH:22])[NH2:20])[C:3]=1[S:23]([C:25]([F:28])([F:27])[F:26])=[O:24].N1C=CC=CC=1.[C:35](Cl)(=[O:37])[CH3:36]>ClC(Cl)C>[C:35]([O:22][NH:21][C:19]([C:4]1[C:3]([S:23]([C:25]([F:27])([F:28])[F:26])=[O:24])=[C:2]([NH2:1])[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][C:12]=2[Cl:13])[N:5]=1)=[NH:20])(=[O:37])[CH3:36]
Reactant: NC(=NO)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: CC(=O)ONC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
5-Amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinyl-3-pyrazolecarboxamide oxime (0.50 g, 1.06 mmol) was dissolved in 8 ml of dichloroethane, and then pyridine (0.10 ml, 1.2 mmol) was added and acetyl chloride (99 mg, 1.26 mmol) dissolved in 2 ml of dichloroethane was added dropwise at room temperature. After the completion of adding dropwise, the mixture was stirred at room temperature for 2 hours and the solvent was distilled off. To the resulting mixture, 50 ml of ethyl acetate was added, then 15 ml of water and 15 ml of an aqueous saturated sodium chloride solution was added. The ethyl acetate layer was taken and washed once with 30 ml of 0.5 N hydrochloric acid, then washed three times with 30 ml of an aqueous saturated sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain 0.54 g (1.06 mmol) of the title compound as a colorless amorphous. Yield 99%.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([CH:9]2[CH2:13][CH2:12][CH:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:25][C:26]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27]1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][CH2:12][C@@H:11]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:28]4[CH2:29][CH2:30][C:26]([F:31])([F:25])[CH2:27]4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: FC1(F)CCNC1
Reactant: N#CC1(NC(=O)C2CCC(S(=O)(=O)c3ccc(F)cc3Cl)C2)CC1
Product: N#CC1(NC(=O)[C@@H]2CC[C@@H](S(=O)(=O)c3ccc(N4CCC(F)(F)C4)cc3Cl)C2)CC1

Procedure:
The title compound was synthesized in analogy to Example 80, from rac-(1S,35)-3-(2-chloro-4-fluoro-benzenesulfonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide and 3,3-difluoro-pyrrolidine to afford the desired product as a light yellow oil. MS (EI): 458.2 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH:21]([CH2:23][O:24]S(C)(=O)=O)[O:20]C2=O)=[CH:14][CH:13]=1)=[NH:11])(=[O:8])C1C=CC=CC=1.[O:30]=C1ON=C(C2C=CC(N)=CC=2)N1.O1CC1CO>>[O:30]=[C:1]1[O:8][N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][CH2:22][CH:21]([OH:20])[CH2:23][OH:24])=[CH:14][CH:13]=2)[NH:9]1
Reactant: Nc1ccc(-c2noc(=O)[nH]2)cc1
Reactant: CS(=O)(=O)OCC1CN(c2ccc(C(=N)NC(=O)c3ccccc3)cc2)C(=O)O1
Agent: OCC1CO1
Product: O=c1[nH]c(-c2ccc(NCC(O)CO)cc2)no1

Procedure:
3.0 g of 3-[4-(N-benzoylamidino)phenyl]-5-methanesulfonyloxymethyl-2-oxazolidinone [obtainable by reacting 4-(5-oxo-1,2,4-oxadiazolin-3-yl)aniline with 2,3-epoxypropan-1-ol to give N-[4-(5-oxo-1,2,4-oxadiazolin-3-yl)phenyl]-2,3-dihydroxypropylamine, reacting with diethyl carbonate in the presence of tert-butoxide to give 3-[4-(5-oxo-1,2,4-oxazolin-3-yl)phenyl]-5-hydroxymethyl-2-oxazolidinone, reductive cleavage of the 5-oxo-1,2,4-oxadiazoline group, reacting with benzoyl chloride and subsequently esterifying with methanesulfonyl chloride) dissolved in 10 ml of DMF, are added to a solution of 1.2 g of 4-ethoxycarbonylmethylpiperazine (“A”) in 20 ml of DMF, and the mixture is stirred at room temperature for 60 min. Removal of the solvent and the usual working up result in 3-[4-(N-benzoylamidino)phenyl]-5-(4-ethoxycarbonylmethylpiperazinomethyl)-2-oxazolidinone, m.p. 114°.