Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1.[CH2:18]([S:20][C:21]1[C:22]([C:27](O)=[O:28])=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[F:17][C:2]([F:1])([F:16])[CH2:3][NH:4][C:5]1[C:10]([NH:11][C:27]([C:22]2[C:21]([S:20][CH2:18][CH3:19])=[CH:26][CH:25]=[CH:24][N:23]=2)=[O:28])=[CH:9][C:8]([C:12]([F:13])([F:14])[F:15])=[CH:7][N:6]=1
Reactant: Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Reactant: CCSc1cccnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCSc1cccnc1C(=O)Nc1cc(C(F)(F)F)cnc1NCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.1 %

Procedure:
A mixture of N2-(2,2,2-trifluoroethyl)-5-trifluoromethylpyridin-2,3-diamine (0.52 g), 3-ethylsulfanylpyridin-2-carboxylic acid (0.37 g), WSC (0.46 g), HOBt (27 mg) and pyridine (2 ml) was stirred at room temperature for 3 hours. To the reaction mixture was poured aqueous 10% citric acid solution, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to give 3-ethylsulfanyl pyridin-2-carboxylic acid [2-(2,2,2-trifluoroethyl)amino-5-trifluoromethylpyridin-3-yl]amide (0.75 g), which is hereinafter referred to as “intermediate compound (M3-43)”.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)[CH3:6])[CH3:2].[Li+].[CH3:26]C([N-]C(C)C)C.CI>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[C:5]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH:9]=[CH:8]1)([CH3:26])[CH3:6])[CH3:2]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-benzyloxy-indol-1-yl)-propionic acid ethyl ester (20 g, 61.5 mmol) in THF (180 mL) is added LDA (2.0 M toluene, 37 mL) dropwise at −78° C. After the addition of LDA, the mixture is stirred for 30 min, then methyl iodide (8.77 g, 122.6 mmol) is added. The reaction mixture is allowed to warm to room temperature, after stirred for 2 hrs, quenched by water, extracted with ethyl acetate, dried over sodium sulfate. Concentration yields the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:8]=1)(=O)=O.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:44].[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47]([NH:53][C:54]([C:56]1[S:57][C:58]3[C:64](Br)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[ClH:44].[N:45]12[CH2:50][CH2:49][CH:48]([CH2:51][CH2:52]1)[C@@H:47]([NH:53][C:54]([C:56]1[S:57][C:58]3[C:64]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[CH:8]=4)=[CH:63][CH:62]=[CH:61][C:59]=3[CH:60]=1)=[O:55])[CH2:46]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: O=S(=O)(Oc1cccc(N2CCOCC2)c1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(N4CCOCC4)c3)c2s1

Procedure:
151.1 mg (0.49 mmol) of 3-(4-morpholinyl)phenyl trifluoromethanesulphonate (Example 17A), 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2 ml of DMF are reacted by general method D. Drying under high vacuum results in 125.3 mg (68% of theory) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]>C(O)(=O)C.[C].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C=CC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CCC(=O)O)cc1
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 4-methoxycarbonylcinnamic acid (4.64 g) in acetic acid (300 ml) is added 10% palladium-carbon (0.5 g), and the mixture is subjected to hydrogenation at 70° C. under atmospheric pressure for two hours. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure. To the residue is added water, and the precipitated white powder is collected by filtration to give 3-(4-methoxycarbonylphenyl)propionic acid (3.87 g).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[S:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]2[CH2:13][CH2:14][CH2:15][C:3]1=2.[OH-].[Na+].C([O-])([O-])=O.[Na+].[Na+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(O)=O>O.C(O)(C)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:8][C:6]2[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]3[CH2:13][CH2:14][CH2:15][C:3]=3[C:2](=[O:1])[N:7]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)Cn1c2c(c(=O)[nH]c1=S)CCC2
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CC(C)O
Product: O=C(O)Cn1c(SCc2ccc(F)cc2)nc(=O)c2c1CCC2
Temperature: 40 °C
Yield: 96.8 %

Procedure:
(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid (20.0 g, 1.0 eq) was slurried in a mixture of water (112 mL) and isopropyl alcohol (20 mL). NaOH solution (50.9% aqueous, 13.82 g, 1.99 eq) was added followed by a water line wash (10 mL) resulting in a solution. Then Na2CO3 (1.50 g, 0.16 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (13.4 g, 1.05 eq) was added, followed by a line wash of isopropyl alcohol (12 mL) and the reaction mixture was stirred at 40±3° C. until the reaction was deemed complete (˜2.5 hours). The reaction mixture was cooled to 20±3° C. and formic acid (2.4 g, 0.6 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (6.9 g, 1.7 eq) was added over 1 hour and the slurry was stirred at 20±3° C. for at least one hour. The slurry was filtered to isolate the product, which was washed twice with a mixture of water (32 mL) and isopropyl alcohol (8 mL), then with isopropyl alcohol (40 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (28.6 g, 97% th). 1H NMR (d6 DMSO) δ 1.95 (2H, m), 2.57 (2H, t), 2.85 (2H, t), 4.4 (2H, s), 4.7 (2H, s), 7.15 (2H, dd), 7.45 (2H, dd), ˜13.6 (1H, vbrs).
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[Br:17][CH2:18][C:19](O)=[O:20].[OH-].[Na+].Cl.C(N=C=NCCCN(C)C)C.Cl>O.C(OCC)(=O)C>[Br:17][CH2:18][C:19]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:20]
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)S[C@@H]2C(NC(=O)CBr)C(=O)N2C1c1nnn[nH]1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 70.9 %

Procedure:
To a stirred suspension of 3.0 g (0.0125 mole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam in 15 ml of water is added 1.74 g (0.0125 mole) of bromoacetic acid dissolved in 5 ml of water. The pH of the mixture is adjusted to 6.0 using 20% sodium hydroxide solution. The resulting clear solution is cooled to 0° C., and then 2.4 g (0.0125 mole) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride is added. The solution is stirred at 0° C. for a further 2.5 hr, during which time the pH is maintained between 6 and 7 by the addition of 6 N hydrochloric acid. At this point, the pH is adjusted to 7.0 and the reaction mixture is extraced with ethyl acetate. The extract is discarded. The pH of the reaction mixture is then lowered to 2.0 (6 N hydrochloric acid), and the product is extracted into ethyl acetate. The ethyl acetate is washed with water, dried, and evaporated to give 3.2 g (72% yield) of 6-(2-bromoacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as a white foam. The infrared spectrum (KBr disc) of the product shows absorption bands at 1795 cm-1 (β-lactam), 1670 cm-1 (amide I) and 1530 cm-1 (amide II). The NMR spectrum (CDCl3) shows absorption bands at 10.6-9.6 ppm (broad singlet, tetrazole hydrogen), 8.8 ppm (doublet, amide hydrogen), 5.8-5.4 ppm (multiplet, C-5 and C-6 hydrogens), 5.35 ppm (singlet, C-3 hydrogen), 4.0 ppm (singlet, methylene hydrogen), 1.90 ppm (singlet, C-2 methyl hydrogens) and 1.15 ppm (singlet, C-2 methyl hydrogens).
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:4]=[CH:3]1.[F:11][C:12]1[CH:43]=[CH:42][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@H:26]3[NH:30][CH2:29][C@H:28]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[NH:4]1[C:5]([CH2:7][C:8]([N:30]2[C@H:26]([C:24](=[O:25])[NH:23][C:20]3[CH:21]=[CH:22][C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([F:11])=[CH:43][CH:42]=4)=[CH:18][CH:19]=3)[CH2:27][C@@H:28]([NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:29]2)=[O:10])=[CH:6][N:2]=[CH:3]1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: O=C(N[C@H]1CN[C@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)C1)OCc1ccccc1
Agent: Cl
Product: O=C(N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1)OCc1ccccc1
Yield: 67 %

Procedure:
Proceeding as in Example 1, but substituting 4-imidazoleacetic acid hydrochloride and benzyl (3R,5S)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate gave Compound 253, benzyl (3R,5S)-1-(2-(1H-imidazol-5-yl)acetyl)-5-(4-(4-fluorophenoxy)phenylcarbamoyl)pyrrolidin-3-ylcarbamate (1.01 g, 1.80 mmol, 67% yield). 1H-NMR (400 MHz, DMSO-d6): 11.92 (s, 1H), 10.06 (s, 1H), 7.92-7.42 (m, 4H), 7.40-7.28 (m, 5H), 7.23-7.17 (m, 2H), 7.06-6.94 (m, 5H), 5.02 (s, 2H), 4.50 (m, 1H), 4.28-4.13 (m, 1H), 3.85-3.41 (m, 4H), 2.38-2.02 (m, 2H). MS (EI) for C30H28FN5O5. found 557.9 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH:10]([O:14][CH2:15][CH3:16])[C:11]([OH:13])=[O:12].[CH3:17][CH2:18]O>Cl>[CH2:17]([O:12][C:11](=[O:13])[CH:10]([C:3]1[C:4]([F:9])=[CH:5][CH:6]=[C:7]([OH:8])[C:2]=1[F:1])[O:14][CH2:15][CH3:16])[CH3:18]
Reactant: CCO
Reactant: CCOC(C(=O)O)c1c(F)ccc(O)c1F
Agent: Cl
Product: CCOC(=O)C(OCC)c1c(F)ccc(O)c1F
Yield: 93 %

Procedure:
A solution of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid (14.8 g) in EtOH (200 ml) and 1.25 N HCl in EtOH (60 ml) was stirred over night at rt. The solvent was evaporated and the residue was purified by CC (AcOEt/Hept 1:1) to obtain 15.5 g (93%) of (RS)-(2,6-difluoro-3-hydroxy-phenyl)-ethoxy-acetic acid ethyl ester. Off-white solid. MS 258.9 ([M−H]−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([OH:10])=O)[CH:2]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH:25]([NH:28][CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:25]([N:28]([CH:29]([CH3:31])[CH3:30])[C:8](=[O:10])[CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:27])[CH3:26]
Reactant: O=C(O)Cc1cccnc1
Reactant: CC(C)NC(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)N(C(=O)Cc1cccnc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-ylacetic acid (1.0 g, 7.292 mmol), EDC (2.796 g, 14.584 mmol) and HOAt (992 mg, 7.292 mmol) in 10 mL DMF were added diisopropyl amine (1.476 g, 14.584 mmol) and Hunig's base (1.885 g, 14.584 mmol). The reaction mixture was stirred at room temperature overnight and then partitioned between ether and half-saturated aq NaHCO3. The aqueous layer was extracted with CH2Cl2 (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by flash chromatography using a linear gradient of 0% to 6% MeOH—NH3 (90:10 v/v) in CH2Cl2 to give a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=O.O.[NH2:20][NH2:21].Cl>C(O)C>[OH:18][N:16]1[C:3]2[CH:4]=[C:5]([CH:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[OH:9])[CH:6]=[CH:7][C:2]=2[N:21]=[N:20]1
Reactant: NN
Reactant: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1F
Agent: Cl
Solvent: O
Solvent: CCO
Product: OC(c1ccccc1)c1ccc2nnn(O)c2c1
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
A mixture of 25 parts of 4-fluoro-3-nitro-α-phenylbenzenemethanol, 20 parts of hydrazine monohydrate and 80 parts of ethanol was stirred for 1.5 hours at reflux temperature. After cooling, 20 parts of a hydrochloric acid solution 10N were added. After concentration, the residue was washed twice with 50 parts of water and dissolved in a solution of 300 parts methanol (10%) in trichloromethane. The organic layer was dried, filtered and concentrated, yielding 23.8 parts (98.6%) of 1-hydroxy-α-phenyl-1H-benzotriazole-6-methanol as a residue (int. 64).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].F[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 86.6 %

Procedure:
3-Hydroxybenzaldehyde (1.15 g, 9.4 mmol), 1-fluoro-4-nitrobenzene (1.0 mL, 9.4 mmol) and K2CO3 (2.61 g, 19 mmol) were combined in DMF (20 mL) and heated at 80° C. After 6 hours, the reaction mixture was cooled to room temperature and partitioned between water and diethyl ether. The separated aqueous phase was extracted with diethyl ether. The organic layers were combined, washed with 1N NaOH, brine, dried (MgSO4), filtered and the filtrate concentrated under reduced pressure to provide the title compound as a yellow solid (1.98 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([CH2:35][CH2:36][CH3:37])[C:9]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])=[CH:10][CH:11]=2)[O:6]1)([O:3]C)=[O:2].[Li+].[OH-]>CO>[CH2:32]([C:23]1[C:24]([OH:31])=[C:25]([C:28](=[O:30])[CH3:29])[CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:9]1[C:8]([CH2:35][CH2:36][CH3:37])=[C:7]2[C:12]([CH2:13][CH2:14][CH:5]([C:1]([OH:3])=[O:2])[O:6]2)=[CH:11][CH:10]=1)[CH2:33][CH3:34]
Reactant: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)OC)CC3)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCCCCOc2ccc3c(c2CCC)OC(C(=O)O)CC3)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
5 g (9.8 mmole) of the methyl ester from Example 6 was placed in a 250 ml round bottom flask and warmed in 100 ml of methyl alcohol to effect dissolution. After cooling to room temperature, 7.5 ml of 2M LiOH was added and the reaction mixture stirred for 3 hours. Solvent was stripped on the rotary evaporator and water added. The solution was acidified to pH 2 with hydrochloric acid, and the resultant gummy mass was extracted with ethyl acetate-ether, washed once with water then with brine, and dried over Na2SO4. After filtration, the solvent was removed on the rotary evaporator under vacuum at room temperature. Recrystalization form ethyl alcohol gave 3.84 g (79% yield), mp 66°-68° C., of the title compound. Calc: C, 69.86; H, 7.76; Found: C, 70.05; H, 7.68.
Reaction SMILES: [CH:1]1[C:2]2[CH:19]=[CH:18][C:17]3[C:16]4[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=4[CH:10]=[CH:9][C:8]=3[C:3]=2[O:4][C:5]=1[CH2:6][OH:7].[Mn]([O-])([O-])(=O)=O.[Ba+2]>C(Cl)Cl>[O:4]1[C:3]2[CH:8]=[CH:9][C:10]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=4[CH:17]=[CH:18][C:19]=3[C:2]=2[CH:1]=[C:5]1[CH:6]=[O:7]
Reactant: OCc1cc2ccc3c4ccccc4ccc3c2o1
Agent: O=[Mn](=O)([O-])[O-]
Agent: [Ba+2]
Solvent: ClCCl
Product: O=Cc1cc2c(ccc3c4ccccc4ccc23)o1
Yield: 89.3 %

Procedure:
To a RB flask equipped with magnetic stirring bar, reflux condenser, N2 inlet line with bubbler was added phenanthro[1,2-b]furan-2-methanol (14A, 5.84 g, 23.5 mmol), barium manganate (Aldrich, 12.06 g, 47 mmol) and dry CH2Cl2 (400 mL). The mixture was refluxed for 6 h, filtered and the resulting dark yellow solution filtered through a small plus of SiO2 to remove inorganic salts and polar baseline material. The solvent was then removed by rotary evaporation and the crude material recrystallized using CH2Cl2 /hexane to give after drying 5.17 g (91% yield) of phenanthro[1,2-d]furan-2-carbaldehyde, mp 169°, (C, H).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([CH:7]([C:13](OCC)=[O:14])[C:8](OCC)=[O:9])=[CH:3][CH:2]=1.C[O-].[Na+].Cl.[CH:23]([NH2:25])=[NH:24]>CO>[OH:14][C:13]1[C:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=2)=[C:8]([OH:9])[N:25]=[CH:23][N:24]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2c(O)ncnc2O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.6 %

Procedure:
At 0° C. a solution of diethyl 2-(p-tolyl)-malonate (14.2 g) in methanol (50 ml) was slowly added to a solution of sodium methylate (9.4 g) in methanol (300 ml). Upon completion of the addition the reaction mixture was allowed to warm up and formamidine hydrochloride (5.4 g) was added. The mixture was stirred at r.t. for 16 h. The solvent was removed under reduced pressure and the remaining residue was treated with 2 N hydrochloric acid (150 ml). The suspension was stirred for 0.5 h. At 0–5° C., the pH was carefully adjusted to 4 using 10 N sodium hydroxide solution. The precipitate was collected, washed with cold water, isopropanol, and diethyl ether and dried under high vacuum at 65° C. to give 4,6-dihydroxy-5-(p-tolyl)-pyrimidine (11.2 g) (or a tautomer) as a white powder.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][O:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.P(Cl)(Cl)(Cl)=O.[CH:37]([NH:39][C:40]1[S:41][C:42]([Br:52])=[C:43]([C:45](=[N:49][O:50][CH3:51])[C:46](O)=[O:47])[N:44]=1)=[O:38]>C(OCC)(=O)C.CN(C)C=O>[CH:37]([NH:39][C:40]1[S:41][C:42]([Br:52])=[C:43]([C:45](=[N:49][O:50][CH3:51])[C:46]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:19]([OH:21])=[O:20])=[C:6]([CH2:9][O:10][C:11](=[O:18])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:7][S:8][C@H:3]23)=[O:47])[N:44]=1)=[O:38]
Reactant: CON=C(C(=O)O)c1nc(NC=O)sc1Br
Reactant: NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(=O)c3ccccc3)CS[C@H]12)c1nc(NC=O)sc1Br
Yield: 34.4 %

Procedure:
A solution of 7-amino-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (0.67 g.) and trimethylsilylacetamide (2.1 g.) in dry ethyl acetate (20 ml.) and a solution of dimethylformamide (0.2 ml.), phosphoryl chloride (0.24 ml.) and 2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 0.62 g.) in dry ethyl acetate (1 ml.) were treated in a similar manner to that of Example 1-(1) to give 7-[2-(2-formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-benzoyloxymethyl-3-cephem-4-carboxylic acid (syn isomer, 430 mg.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[CH:7]=[C:8]([C:12]3[N:13]=[CH:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:9]2)=[CH:4][CH:3]=1.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25]>CO>[C:24]([O:28][N:29]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=2)[O:9][C:8]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Yield: 76.6 %

Procedure:
7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime was prepared using the method D (step 1) illustrated in example 1B. 7-bromo-2-isoquinolin-3-yl-chromen-4-one (682 mg, 1.94 mmol) was treated with O-tert-butyl-hydroxylamine hydrochloride (486 mg, 3.87 mmol) in methanol (9 ml) under microwave irradiation to yield 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (629 mg, 77%) as a yellow solid after purification by flash chromatography over silica gel (cyclohexane/ethyl acetate: 50/50).
Reaction SMILES: [I-].[CH2:2]([N+:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]2[C:18]([CH3:21])=[CH:19][S:20][C:10]=12)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:22][O-:23].[Na+]>CO>[CH2:2]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11](/[C:18](/[CH3:21])=[CH:19]\[S:20][CH3:10])[C:22]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: C[O-]
Reactant: CCCCCCC[n+]1c2ccccc2n2c(C)csc21
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCn1c(=O)n(/C(C)=C\SC)c2ccccc21
Temperature: 25 °C
Yield: 83.1 %

Procedure:
257 mg of 9-heptyl-3-methyl[1,3]thiazolo[3,2-a]benzimidazol-9-ium iodide (0.620 mmol) were solubilised in methanol (40 mL), then 268 mg (8 eq) of NaOMe were added and the solution stirred at room temperature. After 48 h the solvent was evaporated, water was added (20 mL) and the mixture extracted with CH2Cl2 (3×20 mL). The organic layer was dried with MgSO4 and evaporated under reduced pressure to afford 1-heptyl-3-[(1Z)-1-(methylsulfanyl)prop-1-en-2-yl]-1,3-dihydro-2H-benzimidazol-2-one as a pale green oil (164 mg, 83%). Rf=0.65 (CH2Cl2/AcOEt 8:2); 1H NMR (300 MHz, CDCl3) δ=0.82-0.87 (3H, m, CH3), 1.14-1.44 (8H, m, 4-CH2), 1.75 (2H, quint, J=7.1, CH2), 2.12 (3H, d, J=1.2, CH3), 2.21 (3H, s, SCH3), 3.86 (2H, t, J=7.3, CH2), 6.21 (1H, q, J=1.2, H5), 6.80-7.14 (4H, m, Ar). 13C NMR (75 MHz, CDCl3) δ=13.86, 16.67, 20.20, 22.34, 26.52, 28.07, 28.70, 31.49, 40.91, 107.64, 108.80, 120.69, 121.15, 126.53, 127.23, 127.39, 129.52, 151.96; HRMS m/z C18H27N2OS [M+H]+ calcd: 319.1839, found: 319.1838.