Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:24]=[C:23]([CH3:25])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[OH:16])=[C:9]([CH3:26])[CH:8]=2)=[N:3]1.Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[S:29]>C(#N)C.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:8]=[C:9]([CH3:26])[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH:15]([C:17]3[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=3)[O:16][C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[S:29])=[C:23]([CH3:25])[CH:24]=2)=[N:3]1
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(O)c1nccn1C
Reactant: S=C(Cl)Oc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCC(OC(=S)Oc1ccccc1)c1nccn1C
Yield: 78.5 %

Procedure:
To a solution of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-hydroxy-butyl]-1-methylimidazole (690 mg, 1.94 mmol) in 30 ml of acetonitrile was added at 20° C. 473 mg (3.88 mmol) of DMAP and 403 mg (2.33 mmol) of phenyl chlorothioformate, and the mixture was stirred at 20° C. for 3 h. The solvent was concentrated in vacuo and the residue was partitioned between methylene chloride and an aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (20 cm column, ethyl acetate/hexane, 1/1-4/1) to afford 750 mg (78%) of 2-[4-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxy]-1-phenoxythiocarbonyloxy-butyl]-1-methylimidazole, as a yellow oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:32])[CH:24]=1>ClCCl>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[C:25]([Cl:32])[CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Br)cc1Cl)N1Cc2cccn2Cc2ccccc21
Reaction time: 22 h
Yield: 96.2 %

Procedure:
To a mixture of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]-benzodiazepine (1,44 g) and triethylamine (0.95 g) in dichloromethane (40 ml), cooled in an ice bath, was added dropwise a solution of 4-bromo-2-chlorobenzoyl chloride (2.42 g) in dichloromethane (20 ml). The cooling bath was removed and after stirring for 22 hours, the reaction mixture was washed sequentially with water, saturated aqueous sodium bicarbonate, 0.5 N hydrochloric acid and water. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered, then evaporated in vacuo to dryness to yield an off-white foam. Purification by flash chromatography on silica gel eluting with hexane-ethyl acetate (2:1) resulted in a white foam (3.02 g), m.p. 77-80° C., MS m/z: 400 (M)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[F:14])[CH3:2]>CO.[Pt](=O)=O>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[F:14])[CH3:2]
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Agent: O=[Pt]=O
Solvent: CO
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
A solution of 2-fluoro-4-nitrobenzoic acid ethyl ester (770 mg, 3.62 mmol) in methyl alcohol (15 mL) was treated with platinum (IV) oxide (75 mg) at 40 psi of H2. After 0.5 h the reaction mixture was filtered through celite and concentrated in vacuo to give 700 mg (Y: 99%) of the title product; 1H-NMR (CDCl3): δ7.76 (t, J=8.3 Hz, 1H), 6.42 (d, J=8.5 Hz, 1H), 6.35 (d, J=12.9 Hz, 1H), 4.33 (q, J=7.1 Hz, 2H), 4.20 (bs, 2H), 1.36 (t, J=7.1 Hz, 3H); MS (DCI) m/e: 184 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:16][CH:17]([N:19]=[C:20]=[O:21])[CH3:18]>CN(C)C=O>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20]([NH:19][CH:17]([CH3:18])[CH3:16])=[O:21])=[CH:3][N:4]=1
Reactant: CC(C)N=C=O
Reactant: Nc1ccnnc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccnnc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
To a stirred solution of 2.3 grams (0.024 mole) of 4-aminopyridazine (prepared as in Example 1, Step A) and 0.5 gram (0.004 mole) of 1,4-diazabicyclo[2.2.2]octane in 20 ml of dimethylformamide is added dropwise 3.3 ml (0.033 mole) of (1-methylethyl) isocyanate. Upon completion of addition the reaction mixture is stirred at ambient temperature for two days. The reaction mixture is concentrated under reduced pressure and the solid residue dried at 60°-70° C. The solid is stirred with ethanol and collected by filtration to yield 1.9 grams of N-(4-pyridazinyl)-N'-(1-methylethyl)urea; m.p. 206°-209° C. then 266°-269° C. The nmr spectrum is cnsistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][NH:15][C:14]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:38]1[CH:43]=[N:42][CH:41]=[CH:40][N:39]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[C@@H:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:25])[F:27])[CH:19]=4)[CH2:16][N:15]([C:38]4[CH:43]=[N:42][CH:41]=[CH:40][N:39]=4)[C:14]3=[O:28])=[CH:11][CH:12]=2)=[CH:29][CH:30]=1
Reactant: Clc1cnccn1
Reactant: O=C1NC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(c2cnccn2)C[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
To a solution of (S)-1-(4-(4-chlorophenoxy)phenyl)-5-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (20.0 mg, 0.046 mmol) in DMF (0.5 mL) are added Cs2CO3 (30.1 mg, 0.092 mmol) and chloropyrazine (8.25 μL, 0.092 mmol). The reaction mixture is heated at 100° C. overnight, and additional Cs2CO3 (30.1 mg, 0.092 mmol) and chloropyrazine (8.25 μL, 0.092 mmol) are added. After heating at 100° C. for another 8 h, the reaction mixture is quenched with H2O (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layer is evaporated under vacuo and purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C26H18ClF3N4O2 (M+H+) 511.1, found 511.1.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([O:15]C(=O)C)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([NH:4][C:5]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cccc(OC(C)=O)c1NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)c1cccc(O)c1NC(C)=O
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
To a solution of methyl 2-acetamido-3-acetoxybenzoate (1.72 g) in methanol (9 ml) was added powdered potassium carbonate (1.4 g), and the mixture was stirred for 20 minutes. The resulting solid was removed by filtration and washed with methanol. The filtrate was evaporated in vacuo, and the residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with a mixture of isopropyl ether and hexane to give methyl 2-acetamido-3-hydroxybenzoate (1.21 g) as solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:5][C:6](=O)[C:7]=1[CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10].P(Cl)(Cl)([Cl:25])=O.CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:25][C:6]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:2]([CH3:1])[N:3]=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:5]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1Cl
Yield: 73 %

Procedure:
To a suspension of methyl 2-(4-methyl-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-yl)pentanoate (0.900 g; 3 mmol) in dry toluene (6 mL) under a nitrogen atmosphere were carefully added phosphorus oxychloride (3 mL), dimethylaniline (0.3 mL) and the reaction mixture was heated to reflux for 3 h. The volatiles were removed under reduced pressure, the residue was cooled down in an ice-bath and quenched by adding crushed-ice and a saturated solution of sodium hydrogencarbonate until neutralization. The product was extracted with ethyl acetate, the combined organics were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-40%) in heptane furnished 0.701 g (73%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.Cl([O-])(=O)(=O)=O.[Li+].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C@@:29]1([CH2:33][N:34]2[CH:38]=[N:37][CH:36]=[N:35]2)[C@@H:31]([CH3:32])[O:30]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C@H:31]([CH3:32])[C@:29]([C:23]3[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=3[F:21])([OH:30])[CH2:33][N:34]3[CH:38]=[N:37][CH:36]=[N:35]3)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(NC2CCNCC2)cc1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CC#N
Product: C[C@@H](N1CCC(Nc2ccc(Cl)cc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 31 %

Procedure:
To a solution of the N-(4-chlorophenyl)piperidine-4-amine (400.0 mg, 1.9 mmol) obtained in step 2 in acetonitrile were added lithium perchlorate (134.1 mg, 1.3 mmol) and 1-(((2R,3R)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazole (158.9 mg, 0.6 mmol), followed by irradiating microwaves onto the solution at 150° C. for 30 min. After removal of the solvent, the reaction mixture was diluted in ethyl acetate and washed with distilled water and saline to separate an organic solvent layer. The organic solvent layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum. Isolation and purification of the concentrate through silica gel chromatography afforded the title compound (yield 31%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:19][C:20](=[CH2:24])[C:21](Cl)=[O:22]>C(OCC)C>[F:19][C:20](=[CH2:24])[C:21]([O:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][CH:7]=1)=[O:22]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: C=C(F)C(=O)Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=C(F)C(=O)Oc1ccc(C(F)(F)F)cc1
Yield: 83.3 %

Procedure:
16.2 g (0.1 mol) of 4-trifluoromethylphenol were dissolved in 80 ml of anhydrous diethyl ether, and 10.1 g (0.1 mol) of triethylamine were added in portions to the solution; 12 g (0.11 mol) of α-fluoroacryloyl chloride (obtained in accordance with example 1c) were then added dropwise, at a temperature of 10° C., with stirring, and in the course of 20 minutes, and the reaction mixture was stirred for a further 60 minutes at the same temperature. The solid formed was filtered off and washed with 20 ml of diethyl ether. The mixture of filtrate and wash solution was distilled, after adding 0.005 g of hydroquinone monomethyl ether. 19.5 g (83% of theory) of 4-trifluoromethylphenyl α-fluoroacrylate were obtained, boiling point 69° to 70° C. (under 3 mbar).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)[NH:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: Oc1ccc(/C=C/c2cc(-c3ccc(Cl)cc3)n[nH]2)cc1
Reactant: CN1CCNCC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1CCN(c2ccc(-c3cc(/C=C/c4ccc(O)cc4)[nH]n3)cc2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 8.4 %

Procedure:
N-Methylpiperazine (50 μL, 0.49 mmol) was added to a suspension of 4-{(E)-2-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol (0.097 g, 0.33 mmol), NaOtBu (0.110 g, 1.14 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium (0.015 g, 33 μmol, 10 mol %) in anhydrous toluene (1.5 mL) and heated to 80° C. After 24 hours, the reaction was cooled to room temperature, diluted with methanol and filtered though a celite pad. The filtrate was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title compound (10 mg, 9% yield) as an off-white solid: 1H NMR (400 MHz, CD3OD): δ 7.71 (m, 2H), 7.40 (m, 2H), 7.20 (d, J=16.4 Hz, 1H), 7.10 (m, 2H), 6.87 (d, J=16.4 Hz, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 3.95 (bd, J=14.4 Hz, 2H), 3.63 (bd, J=11.2 Hz, 2H), 2.28 (m, 2H), 3.10 (bt, J=13.2 Hz, 2H), 2.99 (s, 3H); MS (EI) for C22H24N4O: 361.2 (MH+).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].OS(O)(=O)=O.[CH2:18](O)[CH3:19]>>[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[C:3]([O:5][CH2:18][CH3:19])=[O:4]
Reactant: NC(C(=O)O)c1ccc(F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(N)c1ccc(F)cc1
Yield: 65 %

Procedure:
To a cooled solution of 2-amino-2-(4-fluorophenyl)acetic acid (1.0 g, 6.17 mmol) in ethanol was added con. H2SO4 (1 mL) over a period of 1 min. The reaction mixture was heated at reflux for 5 h. The solvent was evaporated under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The organic solution was washed with aqueous saturated NaHCO3 (15 mL×2), water (20 mL), brine solution (10 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give ethyl 2-amino-2-(4-fluorophenyl)acetate (0.75 g, 65%) as crude compound (oily liquid). The crude compound was taken to the next step without further purification. LC-MS (M+H2O)+=198.0. 1H NMR (400 MHz, DMSO-d6): δ 7.44-7.40 (2H, m), 7.18-7.13 (2H, m), 4.51 (1H, s), 4.12-4.01 (2H, m), 2.26 (2H, s), 1.12 (3H, t, J=8.0 Hz).
Reaction SMILES: [C:1]([O:5][C:6]1[C:13]([F:14])=[CH:12][C:9]([C:10]#[N:11])=[C:8](F)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Na].[CH3:17][O:18][C:19](=[O:28])[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].O1CCOCC1>CCOCC>[CH3:17][O:18][C:19](=[O:28])[CH:20]([C:8]1[C:9]([C:10]#[N:11])=[CH:12][C:13]([F:14])=[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[N:7]=1)[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22]
Reactant: COC(=O)CC(=O)OC(C)(C)C
Reactant: CC(C)(C)Oc1nc(F)c(C#N)cc1F
Agent: [Na]
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)C(C(=O)OC(C)(C)C)c1nc(OC(C)(C)C)c(F)cc1C#N
Temperature: 95 °C
Reaction time: 14 h

Procedure:
A thick mixture of 6-tert-butoxy-2,5-difluoro-nicotinonitrile (18.22 g, 85.9 mmol), as prepared in Example 1b, malonic acid tert-butyl ester methyl ester sodium salt (34.49 g, 176 mmol), as prepared in the previous step, and dioxane (110 mL) was stirred under argon at 95° C. (oil bath) for 14 h. The resulting homogeneous dark amber solution was allowed to cool to rt, diluted with ether (150 mL), and washed with a solution of 1.0 M NaH2PO4 (200 mL) containing 2.0 M citric acid (40 mL). The aqueous layer was back-extracted with ether (1×100 mL), the organic layers were combined, washed with 4 M NaCl (1×100 mL), dried (Na2SO4), and concentrated under reduced pressure. Malonic acid tert-butyl ester methyl ester was largely removed from the residue by high vacuum at 95° C. for 1 h to afford the title compound as a clear, dark brown viscous oil (32.37 g, approx. 100% crude yield). 1H-NMR (300 MHz, CDCl3) δ 7.48 (d, 1H), 5.06 (s, 1H), 3.80 (s, 3H), 1.62 (s, 9H), 1.47 (s, 9H).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)=[N+]=[N-].[C:21]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[CH:22]=O>C(O)(=O)C.C(Cl)Cl.[Zn]>[CH2:26]([O:25][C:21](=[O:24])[CH:22]=[N:1][CH2:4][C@H:5]1[C@@H:8]([NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:20])[NH:6]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [N-]=[N+]=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Reactant: O=CC(=O)OCc1ccccc1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(C=NC[C@@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OCc1ccccc1

Procedure:
cis-2-Azidomethyl-3-benzyloxycarbonylamino-4-oxoazetidine is treated with zinc dust in 50% aqueous acetic acid as described in Preparation 7. Reaction of the crude reduction product with benzyl glyoxalate in methylene dichloride as described in the procedure of Example 1 gives N-(cis-3-benzyloxycarbonylamino-4-oxo-2-azetidinyl-methyl)iminoacetic acid benzyl ester which, when treated with acetyl chloride according to the procedure of Example 1, gives 3-acetyl-6β-benzyloxycarbonylamino-7-oxo-1,3-diazabicyclo[3.2.0]heptane-2-carboxylic acid benzyl ester.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[O:15]1[CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]12.[OH-].[K+]>CCOCC.CCCCCC>[O:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[OH:15])=[CH:10][CH:9]=1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: C1CC2OC2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1CCCC1Oc1ccc(Oc2ccccc2)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
A mixture of 52 g of 4-hydroxydiphenyl ether and 23.5 g of 1,2-epoxycyclopentane is heated to 150° C. To this melt are added in the course of 25 minutes 6.7 g of 90% potassium hydroxide powder and the mixture is stirred for one hour at 130° C. After cooling, the reaction mixture is taken up in ether/hexane (1:1) and the organic solution is washed 4 times with 10% potassium hydroxide solution and 3 times with saturated sodium chloride solution. The organic phase is dried over sodium sulphate and concentrated by rotary evaporation under reduced pressure. Distillation of the crude product yields 2-(4-phenoxyphenoxy)-cyclopentan-1-ol as a colourless oil with a boiling point of 181°-185° C./0.001 torr and a refractive index of nD20 =1.5812.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=O)[O:20][CH2:21][CH2:22]/1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[C:18]1/[C:19](=[S:33])[O:20][CH2:21][CH2:22]/1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\CCOC2=O)c1Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)c(Nc2ccccc2/C=C2\CCOC2=S)c1Cl
Yield: 75.9 %

Procedure:
A solution of (E)-3-[[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]methylene]-4,5-dihydro-2(3H)-furanone (386 mg, 1.11 mmol) and Lawesson's Reagent (273 mg, 0.68 mmol) in 15 mL of toluene is heated at reflux for 1.5 hours. The solution is concentrated in vacuo and purified by flash chromatography eluting with hexane:ethyl acetate (3:1) to provide 188 mg (47%) of (E)-3-[[2-[(2,6-dichloro-3-methylphenyl)amino]-phenyl]methylene]-4,5-dihydro-2(3H) - furanthione; mp = 163°-165° C. dec.
Reaction SMILES: O[C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(O)c(C(=O)O)nn(C)c1=O
Product: Cc1c(Cl)c(C(=O)O)nn(C)c1=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (876 mg, 4.76 mmol) and POCl3 (4.5 mL) was heated for 24 hours at 85° C. POCl3 was removed under reduced pressure. The crude material was quenched with ice. The reaction mixture was stirred for 1 hour at room temperature. After removing solids by filtration, the aqueous filtrate was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give. The recovered material was combined with the solids previously isolated and triturated with ether to afford 577 mg (60%) of the desired product.
Reaction SMILES: [H-].[Na+].[SH:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[C:13](F)[CH:12]=1>CS(C)=O>[CH2:8]([O:7][C:5]([C:4]1[S:3][C:13]2[CH:12]=[C:11]([Br:10])[CH:18]=[CH:17][C:14]=2[CH:15]=1)=[O:6])[CH3:9]
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
Sodium hydride (1.41 g, 35.32 mmol) is added to a round bottom flask and washed with hexanes (10 mL) twice. To the flask is added dimethyl sulfoxide (30 mL) and ethyl 2-mercaptoacetate (3.54 g, 29.43 mmol). The mixture is stirred for 10 minutes and 4-bromo-2-fluoro-benzaldehyde (4.78 g; 23.55 mmol) is added. The reaction mixture is stirred for 15 minutes and quenched with ice-water (100 g). The mixture is extracted with CH2Cl2 (50 mL×2). The combined organic layers are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified via flash chromatography eluting with 10% EtOAc/Hexanes. The appropriate fractions are combined and concentrated under reduced pressure to afford the title compound (5.75 g, 86%). 1H NMR (400 MHz, CDCl3): δ 8.00 (s, 1H), 7.99 (s, 1H), 7.75 (d, 1H), 7.48 (d, 1H), 4.38 (q, 2H), 1.39 (t, 3H).