Azzindani/Open_Reaction_Data huggingface dataset:
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[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:31]=[CH:32][C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:34][CH:35]=1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-methoxy-5-pyridineboronic acid in General Procedure A. Purification on silica yielded 227. NMR (CDCl3): 2.67-2.69 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.29-3.31 (m, 4H, 2×CH2), 3.86-3.89 (m, 6H, 3×CH2), 4.01-4.05 (m, 7H, 2×CH2+CH3), 6.80 (d, H, ArH, J=8.56 Hz), 7.30 (s, H, ArH), 8.57 (dd, H, ArH, J=8.64 Hz, 2.31 Hz), 9.23 (d, H, ArH, J=2.22 Hz). MS: (ESI+): MH+ 505.15
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([S:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.O.ON1C2C=CC=CC=2N=N1.[NH2:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[N:44]1([CH2:43][CH2:42][NH:41][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][S:22][C:11]2[NH:10][C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:13]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=3)[N:12]=2)[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1
Reactant: NCCN1CCOCC1
Reactant: COc1ccc(-c2nc(SCCCCC(=O)O)[nH]c2-c2ccc(OC)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(SCCCCC(=O)NCCN3CCOCC3)[nH]c2-c2ccc(OC)cc2)cc1
Reaction time: 0.33 h

Procedure:
A solution of 5-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]pentanoic acid (1.91 g, 4.63 mmol) and 1-hydroxy-1H-benzotriazole hydrate (890 rag, 6.59 mmol) in tetrahydrofuran (20 mL) was cooled to 0° C., and treated with 2-aminoethylmorpholine (1.0 mL, 7.62 mmol). After 20 minutes, dicyclohexylcarbodiimide (1.42 g, 6.88 mmol) was added in small portions over 20 minutes. This mixture was allowed to stir an additional 48 hours, then poured into ethyl acetate (250 mL), filtered, and washed with water (200 mL). The phases were separated, and the aqueous phase was saturated with sodium chloride and reextracted with methylene chloride (200 mL). The organic phases were combined, dried over anhydrous sodium sulfate and evaporated. The mixture was separated by flash chromatography to afford the product, N-(2-morpholinyl-ethyl)-5-[4,5-bis(4-methoxyphenyl)-1H-imidazol-2-ylthio]-pentanamide, as an oil (1.77 g, 3.37 mmol, 73%). 1H NMR (CDCl3): 7.42 (4H, br d, J=9 Hz); 6.82 (4H, d, J=9 Hz); 6.22 (1H, br t, J=4 Hz); 3.80 (6H, s); 3.65-3.60 (4H, m); 3.15 (2H, q, J=6 Hz); 2.98 (2H, t, J=7 Hz); 2.38-2.24 (8H, m); 1.96-1.85 (2H, m); 1.70-1.60 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH2:31][C:30](=[O:32])[NH:29][N:28]=2)=[CH:23][CH:22]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[N:5]=[CH:4][N:3]=[C:2]2[O:32][C:30]1[CH:31]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[NH:28][N:29]=1
Reactant: COc1ccc(C2=NNC(=O)C2)cc1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc2ncnc(Oc3cc(-c4ccc(OC)cc4)[nH]n3)c2cc1OC
Yield: 59.2 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (134 mg, 0.5 mmol), (prepared as described for the starting material in Example 4), was reacted with 3-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-5-one (190 mg, 1 mmol) in the presence of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(2-methoxyethoxy)-4-(5-(4-methoxyphenyl)pyrazol-3-yloxy)quinazoline (125 mg, 59%).
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Reactant: NCCO
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)NCCO)on1
Yield: 81.7 %

Procedure:
As described for example 14e, 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (100 mg, 0.32 mmol) was converted, using ethanolamine (23 mg, 0.38 mmol) instead of isopropyl amine, to the title compound (90 mg, 82%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=345.2 [M+H]+.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[C:10]([CH3:12])[CH3:11])(=O)=O.CN(P(N(C)C)(N(C)C)=O)C.[Br-:31].[K+].O>C1COCC1.C1OCCOCCOCCOCCOCCOC1>[CH3:11][C:10]([CH3:12])=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][Br:31]
Reactant: [Br-]
Reactant: CC(C)=CCCCCOS(=O)(=O)c1ccc(C)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCCCCBr
Yield: 76.6 %

Procedure:
A solution of 11 g of 6-methyl-5-heptenyl tosylate in 100 ml of THF were added 10 ml of HMPA, 50 g of potassium bromide and 300 mg of 18-crown-6, and the resulting mixture was refluxed for 5 hours. After cooling, water was added, and the mixture was concentrated, the residue was extracted with pentane 3 times, the combined organic layers were washed with a saturated aqueous solution of sodium hydrogen carbonate water and saturated brine, dried and concentrated to give 8 g of an oily substance. This oily substance was distilled (bp 70° C./5 mm Hg) to yield 5.7 g of a pure bromide.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[C:3]([OH:21])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)c1ccc(C#CCO)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.2 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid methyl ester (1.55 g, 5.41 mmol) in methanol (30 mL) and water (30 mL) was treated with lithium hydroxide (2.60 g, 61.9 mmol). The reaction mixture was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in water (100 mL) which was then acidified to pH=2 with concentrated hydrochloric acid. This solution was extracted with ethyl acetate (2×120 mL). The combined organic extracts were then washed with a half-saturated aqueous sodium chloride solution (1×40 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(3-hydroxy-prop-1-ynyl)-phenyl]-propionic acid (1.27 g, 86%) as an off-white solid.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([CH2:7]O)=[CH:3][CH:4]=[CH:5][CH:6]=1.S(=O)(=O)(O)O.[BrH:20]>>[Br:20][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1-c1ccccc1
Reactant: Br
Agent: O=S(=O)(O)O
Product: BrCc1ccccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A stirred solution of 58.9 g (0.319 mole) of 2-biphenylmethanol and 6 ml of concentrated sulfuric acid in 67 ml of aqueous 48% hydrobromic acid was heated under reflux for 5 hours. The reaction mixture was cooled to ambient temperature, poured into ice-water, and the resulting mixture extracted with three portions of 100 ml each of diethyl ether. The combined extracts were washed with 50 ml of a saturated aqueous solution of sodium bicarbonate, then with 50 ml of water. The organic layer was dried with magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to give 76.8 g of 2-(bromomethyl)biphenyl as a residual oil. The nmr and ir spectra were consistent with the proposed structure.
Reaction SMILES: Br[CH:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.C1CCN2C(=NCCC2)CC1>CC(C)=O>[F:16][C:12]1[N:11]=[C:10]([O:9][CH:2]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)C(=O)C(Br)Oc1cccc(F)n1
Reactant: c1c[nH]cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)C(Oc1cccc(F)n1)n1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 45.4 %

Procedure:
To a stirred solution of 14.5 g (0.05 mole) of 1-bromo-1-(6-fluoro-2-pyridinyloxy)-3,3-dimethyl-2-butanone in 75 ml acetone cooled to -10° C. was added 3.4 g (0.05 mole) imidazole. Then, 7.61 g (0.05 mole) of 1,5-diaza(5.4.0)undec-5-ene was added dropwise. After the addition was complete, the mixture was stirred for 30 minutes at 0° C. and the solvent evaporated. Water was added to the residue and the mixture extracted with diethyl ether. The ether extract was dried using magnesium sulfate and the solvent evaporated. Chromatography on silica gel (8:2 hexane:acetone) gave 6.3 g (55% yield) of 1-(6-fluoro-2-pyridinyloxy)-3,3-dimethyl-1-(imidazol-1-yl)-2-butanone. Recrystallization from hexane gave product melting at 90°-93° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:41])[O:13][CH2:14][C@@H:15]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][P:21]([O:25]C)([O:23]C)=[O:22])[N:2]=1.[Si](I)(C)(C)C>C(#N)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:41])[O:13][CH2:14][C@@H:15]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=2[F:39])=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][O:20][P:21]([OH:25])([OH:23])=[O:22])[N:2]=1
Reactant: COP(=O)(OC)OCCCC[C@@H](COC(=O)Nc1cc2ccccc2cn1)N(C)C(=O)NCc1cccc(F)c1F
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CN(C(=O)NCc1cccc(F)c1F)[C@@H](CCCCOP(=O)(O)O)COC(=O)Nc1cc2ccccc2cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.1 %

Procedure:
To a solution of (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-6-(dimethoxyphosphoryloxy)hexyl isoquinolin-3-ylcarbamate (0.28 g, 0.47 mmol, 1.0 equiv.) in acetonitrile (25 mL) was added TMSI (0.28 mL, 1.88 mmol, 4.0 equiv.) at RT After stirred at RT for 15 min, the reaction was quenched with MeOH. The solvent was concentrated. The resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with 0.1% TFA. The fractions containing the product were combined and concentrated. The resulting residue was suspended in EtOAc, 5 drops of HCl (4 M in 1,4-dioxane) were added, and the organic solvent was removed. This procedure was repeated to give (S)-2-(3-(2,3-difluorobenzyl)-1-methylureido)-6-(phosphonooxy)hexyl isoquinolin-3-ylcarbamate (0.16 g, 57%) as a HCl salt. LRMS (M+H+) m/z 567.2.
Reaction SMILES: [CH3:1][C@@H:2]1[O:4][C@@H:3]1[P:5]([O-:8])([O-:7])=[O:6].[Na+].[Na+].Cl.[CH2:12]1[C@@H:17]([NH2:18])[C@H:16]([O:19][C@H:20]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([NH2:29])[C@H:21]2[OH:30])[C@@H:15]([OH:31])[C@H:14]([O:32][C@H:33]2[O:38][C@H:37]([CH2:39][NH2:40])[C@@H:36]([OH:41])[CH2:35][C@H:34]2[NH2:42])[C@H:13]1[NH2:43]>O>[CH3:1][C@@H:2]1[O:4][C@@H:3]1[P:5]([OH:8])([OH:7])=[O:6].[CH2:12]1[C@@H:17]([NH2:18])[C@H:16]([O:19][C@H:20]2[O:25][C@H:24]([CH2:26][OH:27])[C@@H:23]([OH:28])[C@H:22]([NH2:29])[C@H:21]2[OH:30])[C@@H:15]([OH:31])[C@H:14]([O:32][C@H:33]2[O:38][C@H:37]([CH2:39][NH2:40])[C@@H:36]([OH:41])[CH2:35][C@H:34]2[NH2:42])[C@H:13]1[NH2:43]
Reactant: C[C@@H]1O[C@@H]1P(=O)([O-])[O-]
Agent: Cl
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](N)C[C@@H]1O
Agent: [Na+]
Solvent: O
Product: C[C@@H]1O[C@@H]1P(=O)(O)O

Procedure:
Fosfomycin disodium (18.057 g, 13.99 g free acid) was dissolved in 250 mL of water and the pH was adjusted to 7.41 by the dropwise addition of 1.53 mL of 4.5 N HCl. To the resulting solution was added 1.56 g of 97.5% tobramycin base. The pH of the solution was adjusted to 7.60 by the addition of 2.45 mL of 4.5 N HCl. The solution was diluted to 500 mL with water and filtered through a 0.2 μm Nalge Nunc 167-0020 membrane filter. The final pH was 7.76, the osmolality was 537 mOsmol/kg, the fosfomycin/tobramycin ratio was calculated to be 9:1, and the chloride concentration was 35.8 mM.
Reaction SMILES: [OH:1]O.[Br:3][C:4]1[C:12]([O:13][CH3:14])=[C:11]2[C:7]([C:8](=[O:16])C(=O)[NH:10]2)=[CH:6][CH:5]=1.[OH-].[Na+]>O>[NH2:10][C:11]1[C:12]([O:13][CH3:14])=[C:4]([Br:3])[CH:5]=[CH:6][C:7]=1[C:8]([OH:16])=[O:1]
Reactant: OO
Reactant: COc1c(Br)ccc2c1NC(=O)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(Br)ccc(C(=O)O)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
H2O2 (37%, 7.7 mL, 0.075 mol) in H2O (70 mL) is slowly added to the solution of 6-Bromo-7-methoxy-1H-indole-2,3-dione (8.0 g, 0.0312 mol), NaOH (8.8 g, 0.219 mol) in H2O (200 mL) then stirred at room temperature for 1 hour. After reaction, the mixture is filtered and the solid is dried under vacuum to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:31]>C(OCC)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][C:3]=1[CH2:4][Br:31]
Reactant: OCc1cc(Cl)ccc1F
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Fc1ccc(Cl)cc1CBr
Yield: 112.3 %

Procedure:
A solution of 2-fluoro-5-chlorobenzyl alcohol (1.28 g, 7.97 mmol) in diethyl ether (26 ml) was treated with triphenylphosphine (2.72 g, 10.36 mmol), followed by carbon tetrabromide (3.44 g, 10.36 mmol). The resultant suspension was stirred for 3.5 hours, then filtered, washing with diethyl ether. The filtrate was concentrated, then passed through a plug of silica to remove triphenylphosphate. The residue was then purified by liquid chromatography affording 2.0 grams of a clear oil.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.C(OC(=O)C)C>CCCCCC>[C:4]1(=[O:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6][NH:5]1
Reactant: CCOC(=O)NCCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1NCCc2ccccc21
Temperature: 120 °C
Reaction time: 2 h
Yield: 1.3 %

Procedure:
Phenethyl-carbamic acid ethyl ester (I-23a: 9 g, 46.875 mmol) and poly phosphoric acid (187.5 g) were taken in a flask and the flask was heated to 120° C. for 4 hours. The reaction was monitored by TLC (30% ethylacetate in hexane). The reaction mixture was partitioned between chilled water and ethylacetate. The resulting mixture was stirred at 115° C. for 2 hours to afford the crude product. Purification by column chromatography on silica gel (60% ethylacetate in hexane) afforded 0.090 g of the product (9.1% yield).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[NH:43]1[CH:46]([C@@H:47]2[CH2:51][C@H:50]([SH:52])[CH2:49][N:48]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:45][C:44]1=[O:66].C(NC(C)C)(C)C.C(OCC)(=O)C>C(#N)C>[NH:43]1[CH:46]([C@@H:47]2[CH2:51][C@H:50]([S:52][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=3)=[O:24])[CH2:49][N:48]2[C:53]([O:55][CH2:56][C:57]2[CH:62]=[CH:61][C:60]([N+:63]([O-:65])=[O:64])=[CH:59][CH:58]=2)=[O:54])[CH2:45][C:44]1=[O:66]
Reactant: O=C1CC([C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)N1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Solvent: CC#N
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C4CC(=O)N4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Temperature: 4 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
To a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (110 mg, 0,195 mmol) in acetonitrile (5 ml) was added in a nitrogen stream at -10° C. a solution of (2S,4S)-2-(2-azetidinon-4-yl)-4-mercapto-N-(p-nitrobenzyloxycarbonyl)pyrrolidine diastereomer B (67 mg, 0.191 mmol, compound of Reference Example 3) in acetonitrile (5 ml), and then N,N-diisopropylamine (34 μl, 0.21 mmol) was dropwise added thereto. The mixture was stirred overnight at 4° C. Then, ethyl acetate (50 ml) was added to the reaction solution. This mixture was washed with water and a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (Wakogel™ C-300, 3% methanol-chloroform) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-2-(2-azetidinon-4-yl)-N-(p-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate diastereomer B (88.5 mg, yield: 68.2%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[C:21]([F:23])[C:7]([CH2:8][N:9]2[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)=[C:6]([F:24])[CH:5]=1)[CH3:2].IC.[C:27](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([F:24])[C:7]([CH2:8][N:9]2[C:13]([O:14][CH3:27])=[C:12]([CH3:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:10]2)=[C:21]([F:23])[CH:22]=1)[CH3:2]
Reactant: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(O)c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CCOC(=O)c1nn(Cc2c(F)cc(OCC)cc2F)c(OC)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.95 g of ethyl 1-(4-ethoxy-2,6-difluorobenzyl)-5-hydroxy-4-methyl-1H-pyrazole-3-carboxylate 1-1-1 (11.6 mmol, 1.0 eq.) were dissolved in 50 mL of acetone. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) and 5.78 g (41.8 mmol, 3.6 eq.) of potassium carbonate were added and stirred over for 24 hours at rt. 1.45 mL of iodomethane (23.2 mmol, 2.0 eq.) were added and the mixture was stirred for further 24 hours at rt. The suspension was filtered off over sea sand and the filtrate was concentrated in vacuo. The residue was extracted by DCM and water. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to give 2.29 g (6.46 mmol, 55.7%) of analytically pure target compound.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1[S:28][CH:29]=[CH:30][C:31]=1[CH3:32]>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2[S:28][CH:29]=[CH:30][C:31]=2[CH3:32])[CH:23]=1
Reactant: Cc1ccsc1CO
Reactant: O=c1ncc(Cl)c[nH]1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1Cn1cc(Cl)cnc1=O
Temperature: 90 °C
Yield: 28.9 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (2.70 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (783 mg) and 2-hydroxymethyl-3-methylthiophene (1.077 g) in dry N,N-dimethylformamide (15 ml) under nitrogen. The resulting solution was then heated at 90° C. under nitrogen. After 0.5 h the reaction mixture was evaporated to a dark brown crystalline solid (1.812 g). The solid was subjected to column chromatography on silica (70-230 mesh) (180 g) developing with chloroform-ethanol, 29:1. The resulting light brown crystalline solid (694 mg) was crystallised twice from acetone to give buff needles of the title thiophene (417 mg), m.p. 135°-145° C., λmax 230 nm (ε 16,420), 335 nm (ε 3,830), λinf 250 nm (ε 5,800).
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(=O)([O-])[O-].[K+].[K+].O.[CH3:28][O:29][C:30]1[C:35](B(O)O)=[CH:34][CH:33]=[CH:32][N:31]=1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][C:3]2[C:2]([C:35]3[C:30]([O:29][CH3:28])=[N:31][CH:32]=[CH:33][CH:34]=3)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([F:12])[CH:4]=2)=[CH:15][CH:16]=1
Reactant: COc1ncccc1B(O)O
Reactant: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1cc(-c2cccnc2OC)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 50 °C
Yield: 179.6 %

Procedure:
To a stirred solution of methyl 5-bromo-4-(4-chlorophenoxy)-2-fluorobenzoate (Preparation 32, 199 mg, 0.55 mmol) in dioxane (10 mL) and water (0.5 mL) was added potassium carbonate (158 mg, 1.14 mmol) and 2-methoxypyridin-3-ylboronic acid mono hydrate (147 mg, 0.86 mmol). The reaction was degassed three times followed by the addition of tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 0.012 mmol). The reaction was degassed three times and heated at 50° C. overnight under a nitrogen atmosphere. The reaction was cooled to room temperature, concentrated in vacuo to afford a brown residue. The residue was partitioned between EtOAc (25 mL) and water (25 mL). The aqueous phase was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with water (25 mL), brine (25 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford brown oil (383 mg). The oil was then purified by flash column chromatography using the Biotage System™ (50 g silica column, eluting with DCM). Fractions containing product were combined and concentrated in vacuo to afford the title compound as a grey oil (194 mg, 91%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH2:15])([CH3:4])([CH3:3])[CH3:2].C([O:21][C:22](=O)[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:22](=[O:21])[CH2:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-phenyl)-carbamic acid tert-butyl ester (Example J4) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) according to the general procedure M. Obtained as a light brown solid (227 mg).