Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[N:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[F:15][C:12]([F:13])([F:14])[C@H:11]([CH3:16])[O:10][C:7]1[N:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1
Reactant: C[C@H](Oc1ccc([N+](=O)[O-])cn1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@H](Oc1ccc(N)cn1)C(F)(F)F

Procedure:
5-Nitro-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine (81.9 g) and palladium on carbon (10% Pd, 0.0065 mol-eq) were added to MeOH and the mixture was hydrogenated until uptake of hydrogen was ceasing. The catalyst was removed by filtration and the filtrate was concentrated and further dried in vacuo to provide the title compound as a dark oil. MS (m/e): 207.0 (MH+).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:11])[C:3]1=2.C(N(CC)CC)C.[CH2:19]([N:21]=[C:22]=[O:23])[CH3:20]>C(Cl)Cl>[CH2:19]([NH:21][C:22]([NH:11][CH:10]1[C:3]2[S:2][CH:6]=[CH:5][C:4]=2[CH2:7][CH2:8][CH2:9]1)=[O:23])[CH3:20]
Reactant: NC1CCCc2ccsc21
Reactant: CCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCNC(=O)NC1CCCc2ccsc21

Procedure:
Equivalent amounts of 4,5,6,7-tetrahydrobenzo[b]thiophen-7-amine hydrochloride, triethylamine, and ethyl isocyanate in methylene chloride are stirred at room temperature for an hour and then heated to reflux for half an hour. The product is collected, washed well with water, and dried to afford the title compound.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][CH:3]=1.C([Mg]Br)C.CON(C)[C:15]([C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1)=[O:16]>C(Cl)Cl>[CH3:7][N:6]1[C:2]([C:15]([C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)=[O:16])=[CH:3][N:4]=[CH:5]1
Reactant: Cn1cncc1Br
Reactant: CON(C)C(=O)c1cncn1C
Agent: CC[Mg]Br
Solvent: ClCCl
Product: Cn1cncc1C(=O)c1cncn1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1-methyl-1H-imidazole (1.2 g, 7.448 mmol) in DCM (10 mL) was added ethyl magnesium bromide (2.5 mL, 7.448 mmol; 3.0 M in diethyl ether) dropwise over a 10 minute period. The resulting pale yellow solution was stirred at room temperature for 15 minutes, cooled in an ice bath to 0° C. and N-methoxy-N,1-dimethyl-1H-imidazole-5-carboxamide (1.0 g, 6.206 mmol, Intermediate 39: step a) dissolved in DCM (3 mL) was added dropwise. The cold bath was removed and the reaction mixture stirred at room temperature for 48 hours. To the resulting yellow suspension was added water followed by 6 M aqueous HCl to a neutral pH (pH=6-7). The aqueous mixture was extracted with DCM (2×). The combined DCM extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The product was precipitated with Et2O, filtered and dried to provide the title compound as a tan solid.
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:14][O:13][C:12]([CH3:16])([CH3:15])[O:11]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[CH3:15][C:12]1([CH3:16])[O:11][C@@H:10]([CH2:9][OH:8])[CH2:14][O:13]1
Reactant: CC1(C)OC[C@H](COCc2ccccc2)O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)OC[C@H](CO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
10% Palladium-carbon (2.63 g) was added to thus obtained (S)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (9.267 g, 41.69 mmol) in ethanol (250 ml) and the mixture was stirred for 3 hours at 25° C. under an atmosphere of hydrogen. After the reaction was over, palladium-carbon was filtered off and the solvent was condensed in vacuo. The crude product was distilled to give 4.68 g of (S)-2,2-dimethyl-1,3-dioxolane-4-methanol (yield 85%, b.p. 65° C. at 3 mmHg, optical purity 97.5% e.e., specific rotation [α]D20 +10.84°(c=1,MeOH))).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][C:11]([O:13]CC)=[O:12])=[N+:2]=[N-:3].S(=O)(=O)(O)O.P(=O)(O)(O)O>>[N:1]([CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: CCOC(=O)Cc1sccc1CN=[N+]=[N-]
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: [N-]=[N+]=NCc1ccsc1CC(=O)O

Procedure:
Hydrolysis of ethyl 3-azidomethyl-2-thienylacetate by the above procedure or by employing an equal volume of 6M sulfuric acid or 8M phosphoric acid in place of the 3M hydrochloric acid also affords the title compound.
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=2[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]1([C:21](=[N:28][C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH:40]=2)[C:34](N(OC)C)=[O:35])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21](=[N:28][C:29]2[CH:40]=[C:33]([C:34]([C:2]3[C:6]4[CH:7]=[N:8][CH:9]=[C:10]([F:11])[C:5]=4[N:4]([CH:12]([CH3:14])[CH3:13])[CH:3]=3)=[O:35])[CH:32]=[N:31][CH:30]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)n1cc(Br)c2cncc(F)c21
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Product: CC(C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncc(F)c21

Procedure:
Prepared according to the method described for Preparation 36 using 3-bromo-7-fluoro-1-isopropyl-1H-pyrrolo[3,2-c]pyridine (Preparation 46) and 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (Preparation 52). Taken on directly to the next step.
Reaction SMILES: Cl[C:2]1[N:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][C:8]1([CH2:21][CH:22]2[CH2:24][CH2:23]2)[CH2:13][CH2:12][CH:11]([S:14]([CH2:17][CH:18]2[CH2:20][CH2:19]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:5].[CH3:33][S-:34].[Na+].O>CC(O)C>[CH:18]1([CH2:17][S:14]([CH:11]2[CH2:12][CH2:13][C:8]([CH2:7][NH:6][C:4](=[O:5])[C:3]3[CH:25]=[CH:26][C:27]([C:29]([F:32])([F:31])[F:30])=[N:28][C:2]=3[S:34][CH3:33])([CH2:21][CH:22]3[CH2:24][CH2:23]3)[CH2:9][CH2:10]2)(=[O:16])=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1)c1ccc(C(F)(F)F)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CSc1nc(C(F)(F)F)ccc1C(=O)NCC1(CC2CC2)CCC(S(=O)(=O)CC2CC2)CC1
Yield: 97.8 %

Procedure:
A solution of 2-chloro-N-(4-cyclopropylmethanesulfonyl-1-cyclopropylmethylcyclohexylmethyl)-6-trifluoromethylnicotinamide (75 mg, 0.15 mmol) in propan-2-ol (5 ml) was treated with sodium thiomethoxide (21 mg, 0.30 mmol) and the mixture was heated under reflux for 4 hours. Water (1 ml) was added and the solvent was evaporated. The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and the layers were separated using a 5 micron PTFE frit and the filtrate was evaporated. The residue was purified by preparative plate chromatography eluting with 10% ethyl acetate in dichloromethane. Collecting the appropriate band followed by trituration of the silica with ethyl acetate, filtration and evaporation gave a pale yellow foam (74 mg, 97%). 1H NMR δ (ppm) (CDCl3): 8.00 (1H, d, J=7.8 Hz), 7.41 (1H, d, J=7.8 Hz), 6.40 (1H, s), 3.64 (2H, d, J=6.3 Hz), 2.98-2.89 (3H, m), 2.63 (3H, s), 2.09-1.90 (6H, m), 1.46-1.16 (5H, m), 0.79-0.69 (3H, m), 0.55-0.51 (2H, m), 0.45-0.40 (2H, m), 0.09-0.06 (2H, m). MS (m/e)=505.
Reaction SMILES: [N+:1](=[C:3]1[CH:12]=[CH:11][C:10]2[C:9]([S:13](Cl)(=[O:15])=[O:14])=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]1=[O:17])=[N-:2].[K].[OH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=1.Cl>O1CCOCC1.O>[N+:1](=[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]=[N+:27]=[N-:28])=[CH:22][CH:21]=2)(=[O:15])=[O:14])[C:4]1=[O:17])=[N-:2]
Reactant: [N-]=[N+]=Nc1ccc(O)cc1
Reactant: [N-]=[N+]=C1C=Cc2c(cccc2S(=O)(=O)Cl)C1=O
Agent: Cl
Agent: [K]
Solvent: C1COCCO1
Solvent: O
Product: [N-]=[N+]=Nc1ccc(OS(=O)(=O)c2cccc3c2C=CC(=[N+]=[N-])C3=O)cc1

Procedure:
1,2-Dihydro-2-diazo-1-oxo-naphthalene-5-sulfonyl chloride (2.2 grams) is dissolved in dioxane (16 mls.) and the potassium salt of 4-hydroxyphenylazide (1.6 grams) in a mixture of water (4 ml.) and dioxane (4 ml.) is added gradually over a period of 10 minutes with stirring. The mixture is then stirred at room temperature (22°C) for 30 minutes to complete the reaction and then diluted with water (60 ml.) containing 3N hydrochloric acid (8 ml.). An oil separates out which solidifies on standing. The product is then collected and dried (2.5 grams). It is dissolved in benzene treated with carbon and filtered. Addition of 60°-80° pet. ether to the filtrate yields Compound 1. (1.7 grams) m.p. 136°-7° with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[O:11][C:12]2[C:18]([F:19])=[C:17]([CH2:20][C:21]([O:23]C)=[O:22])[CH:16]=[CH:15][C:13]=2[N:14]=1.[OH-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[O:11][C:12]2[C:18]([F:19])=[C:17]([CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: COC(=O)Cc1ccc2nc(Nc3c(C)cccc3Cl)oc2c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1Nc1nc2ccc(CC(=O)O)c(F)c2o1
Temperature: 25 °C
Reaction time: 17 h
Yield: 93.4 %

Procedure:
To a solution of methyl (2-(2-chloro-6-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetate (1.45 g, 4.16 mmol) in THF/methanol (4:1, v/v 100 ml) was added 1N NaOH (40 ml). After stirring at room temperature for 17 hours, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was acidified with 1N HCl. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (2-(2-chloro-6-methylphenylamino)-7-fluoro-6-benzoxazolyl)acetic acid (1.30 g, 93%) as a colorless crystalline powder.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2)(=[O:5])=[O:4].Cl[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[N:17]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[C:11]2[C:20]1[CH:21]=[CH:16][N:17]=[C:18]([NH:22][CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[N:19]=1)(=[O:5])=[O:4]
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Reactant: CNS(=O)(=O)c1cccc2cc[nH]c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CNS(=O)(=O)c1cccc2c(-c3ccnc(NC4CC(C)(C)NC(C)(C)C4)n3)c[nH]c12

Procedure:
The title compound was prepared as described in Example 215, starting from SEM-protected 1H-indole-7-sulfonic acid methylamide and (4-chloro-pyrimidin-2-yl)(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by cleavage of the SEM-protecting groups with TBAF. Yield: 70 mg (5%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]([CH2:8][C@@H:9]2[C@H:12]([NH:13][C:14](=[O:30])/[C:15](=[N:22]\[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:16]3[N:17]=[C:18]([NH2:21])[S:19][CH:20]=3)[C:11](=[O:31])[N:10]2[S:32]([OH:35])(=[O:34])=[O:33])[N:6]=[CH:5][N:4]=1.Cl.[N:37]1([C:42](N)=[NH:43])C=CC=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:21][C:18]1[S:19][CH:20]=[C:16](/[C:15](=[N:22]/[O:23][C:24]([CH3:29])([CH3:28])[C:25]([OH:27])=[O:26])/[C:14]([NH:13][C@@H:12]2[C:11](=[O:31])[N:10]([S:32]([OH:35])(=[O:34])=[O:33])[C@@H:9]2[CH2:8][N:7]2[C:3]([CH2:2][NH:1][C:42]([NH2:43])=[NH:37])=[N:4][CH:5]=[N:6]2)=[O:30])[N:17]=1
Reactant: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CN)c1csc(N)n1)C(=O)O
Reactant: N=C(N)n1cccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1ncnc1CNC(=N)N)c1csc(N)n1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.2 %

Procedure:
To a solution 2-(((Z)-(2-(((2R,3S)-2-((5-(aminomethyl)-1H-1,2,4-triazol-1-yl)methyl)-4-oxo-1-sulfoazetidin-3-yl)amino)-1-(2-aminothiazol-4-yl)-2-oxoethylidene)amino)oxy)-2-methylpropanoic acid (25 mg, 0.047 mmol) and pyrazole-1-carboxamidine hydrochloride (10.9 mg, 0.099 mmol) in DMF (470 μL) was added DIPEA (33 μL, 0.188 mmol). After stirring at rt for 12 h the solution was concentrated in vacuo. Toluene was added and it was reconcentrated (3×). The crude residue was purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (13 mg, 42%) as a white powder. LCMS: Rt=0.29 min, m/z=574.2 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 7.96-7.78 (m, 1H), 7.41-6.96 (m, 5H), 6.80-6.71 (m, 1H), 6.55 (s, 1H), 5.42-5.32 (m, 1H), 4.75-4.63 (m, 1H), 4.62-4.42 (m, 1H), 4.39-4.28 (m, 1H), 1.38 (s, 3H) 1.34 (s, 3H).
Reaction SMILES: O(P(O[C:18]1[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21][O:20][CH:19]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35]>>[CH3:32][O:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([C:18]2[N:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:23][CH2:22][CH2:21][O:20][CH:19]=2)=[CH:38][CH:37]=1)=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(C2=COCCCN2C(=O)OC(C)(C)C)cc1
Yield: 41 %

Procedure:
This compound was prepared from tert-butyl 3-((diphenoxyphosphoryl)oxy)-6,7-dihydro-1,4-oxazepine-4(5H)-carboxylate and (4-methoxycarbonylphenyl)boronic acid according to the procedure described above in Example 2 (Step 3). The product was isolated as a white solid (41% yield); 1H-NMR (CDCl3) 1.11 (7H, s), 1.61 (2H, s), 2.16-2.18 (2H, m), 3.93-4.22 (7H, m), 6.32 (1H, s), 7.29-7.32 (2H, m), 7.97 (2H, d); MS ES(+) 278.1 (M+-tBu).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[NH2:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:14][C:4]1[N:3]=[C:2]([NH:15][C:16]2[CH:21]=[C:20]([CH:19]=[CH:18][N:17]=2)[C:22]#[N:23])[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: Clc1cc(C2CCOCC2)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccnc(Nc2cc(C3CCOCC3)cc(Cl)n2)c1
Temperature: 80 °C
Yield: 54.5 %

Procedure:
To a 25 mL round-bottomed flask charged with 2,6-dichloro-4-(tetrahydro-2H-pyran-4-yl)pyridine (1.20 g, 5.20 mmol, 1.00 equiv), 2-aminopyridine-4-carbonitrile (620 mg, 5.20 mmol, 1.00 equiv), cesium carbonate (2.40 g, 7.20 mmol, 1.40 equiv), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (170 mg, 0.260 mmol, 0.0500 equiv), and tris(dibenzylidineacetone)dipalladium(0) (120 mg 0.130 mmol, 0.0250 equiv) was added 1,4-dioxane (10 mL) under nitrogen atmosphere. The reaction was then heated to 80° C. for 16 h after which the mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water (2×15 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (40:60 ethyl acetate/heptane) afforded the desired product as a yellow solid (892 mg, 51% yield). 1H NMR (400 MHz, DMSO-d6), δ: 10.38 (s, 1H), 8.49 (d, J=5.3 Hz, 1H), 7.94 (s, 1H), 7.63 (s, 1H), 7.34-7.23 (dd, J=4.0, 2.0 Hz, 1H), 6.98 (d, J=1.1 Hz, 1H), 3.95 (dd, J=11.9, 4.0 Hz, 2H), 3.44 (td, J=11.9, 2.4 Hz, 2H), 2.82 (tt, J=12.0, 3.6 Hz, 1H), 1.77-1.70 (m, 2H), 1.69-1.61 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([OH:23])=[O:22])=[C:15]([CH:18]=[CH:19][CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH:39](Br)[CH3:40])(=[O:37])[CH3:36]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:26]/[O:27][CH3:28])/[C:8]([NH:10][CH:11]2[C:24](=[O:25])[N:13]3[C:14]([C:21]([O:23][CH:39]([O:38][C:35](=[O:37])[CH3:36])[CH3:40])=[O:22])=[C:15](/[CH:18]=[CH:19]\[CH3:20])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Reactant: CC(=O)OC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C/C=C\C1=C(C(=O)OC(C)OC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 45 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-propenyl)-3-cephem-4-carboxylic acid (190 mg, 0.45 mmole) and potassium carbonate (75 mg, 0.54 mmole) in DMF (5 ml) was added at 5° C. 1-bromoethyl acetate** (90 mg, 0.54 mmole). The mixture was stirred at 5° C. for 1.5 hours and diluted with ethyl acetate (20 ml). The dilute was washed successively with water and a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in chloroform and chromatographed on a silica gel column (5 g) with 1% methanol in chloroform. The desired fractions were combined and concentrated. The residue was dissolved in dioxane and lyophilized to yield 103 mg (45%) of the title compound as its dioxane solvate. Mp. 105°-110° C. Estimated purity 85% (by HPLC).
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.[C:16]1([C:22]2[N:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]=[CH:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:14]1[C:15]2[C:10](=[CH:9][C:8]3[C:3]([C:2]=2[C:18]2[CH:17]=[C:16]([C:22]4[N:23]=[C:24]([C:2]5[CH:3]=[CH:8][CH:9]=[CH:10][CH:15]=5)[N:25]=[C:26]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:27]=4)[CH:21]=[C:20]([C:2]4[C:15]5[C:10]([CH:9]=[C:8]6[C:3]=4[CH:4]=[CH:5][CH:6]=[CH:7]6)=[CH:11][CH:12]=[CH:13][CH:14]=5)[CH:19]=2)=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(-c2ncnc(-c3ccccc3)n2)cc1
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4c5ccccc5cc5ccccc45)cc(-c4c5ccccc5cc5ccccc45)c3)n2)cc1
Temperature: 25 °C
Yield: 54 %

Procedure:
In a stream of argon, 0.62 g (2.13 mmol) of 9-bromoanthracene, 0.50 g (0.89 mmol) of 2-(3,5-bis(4,4,5,5-tetramethyl)-1,3,2-dioxabororan-2-yl)phenyl]-4,6-diphenyl-1,3,5-triazine and 18.7 mg (0.027 mmol) of dichlorobis-(triphenylphosphine)palladium were suspended in 40 mL of tetrahydrofuran, and the temperature of the obtained suspension was elevated to 70° C. 1.34 mL (5.34 mmol) of an aqueous 4N NaOH solution was gradually added dropwise to the suspension, and the obtained mixture was distilled under reflux for 3 hours. The resultant reaction mixture was cooled to room temperature, and then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The thus-obtained crude product was purified by silica gel column chromatography using a hexane/chloroform (5:1-2:1) mixed solvent as an eluent to give 0.32 g of the target 2-[3,5-di(9-anthryl)phenyl]-4,6-diphenyl-1,3,5-triazine as white solid (yield: 54%).
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][OH:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C.O>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([CH2:16][O:17][CH3:27])=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:2]=1
Reactant: CI
Reactant: OCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc2c(c1)ncn2-c1cccc(-c2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of 1--(3-biphenylyl)-5-hydroxymethylbenzimidazole (61a) (0.16 g, 0.5 mmol) in dry DMF (1.5 ml) under nitrogen, was added a 80% sodium hydride suspension (20 mg, 0.7 mmol) and then iodomethane (33.5 μl, 0.5 mmol). The reaction mixture was stirred overnight and then poured in water. Neutralization with 4M aqueous HCl was followed by extraction with ethyl acetate. The extract was evaporated to dryness and purified by chromatography. The product was dissolved in dry ether and precipitated as the hydrochloride. Yield: 130 mg, 0.4 mmol, 80%. mp 70°-72° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:17]4[CH:18]=[C:19]([CH2:21][OH:22])[N:20]=[C:16]4[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[H-].[Na+].Cl[C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=1.O>CN(C=O)C>[NH:1]1[C:5]([C:6]2[N:11]=[CH:10][C:9]([C:12]3[N:17]4[CH:18]=[C:19]([CH2:21][O:22][C:32]5[CH:41]=[CH:40][C:39]6[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=6)[N:33]=5)[N:20]=[C:16]4[C:15]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[N:14][CH:13]=3)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1
Reactant: OCc1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1
Reactant: Clc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2nc(OCc3cn4c(-c5ccc(-c6nnn[nH]6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of compound 1h (187 mg, 0.510 mmol) in DMF (2 mL) was added sodium hydride (49.0 mg, 2.04 mmol) in portions at 0° C. The mixture was stirred for 15 min before the addition of 2-chloroquinoline (125 mg, 0.765 mmol). The reaction mixture was stirred at 70° C. overnight. Water was added, and the resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel with EtOAc/petroleum ether (1:3 v/v) to obtain the title compound 97 as a yellow solid (27.6 mg, 11% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 8.23-8.28 (m, 1H), 8.25 (d, J=8.7 Hz, 1H), 8.23-8.15 (m, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.68 (t, J=7.2 Hz, 1H), 7.63-7.55 (m, 1H), 7.44 (t, J=7.2 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 7.03-7.00 (m, 1H), 5.59 (s, 2H), 4.35-4.20 (m, 4H), 3.85-3.69 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H22N10O2: 507.2 (M+H). Found 507.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])[CH:29]=[CH2:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:33])[C:28]([F:32])([F:31])/[CH:29]=[CH:30]/[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: C=CC(F)(F)C(O)c1c(C)noc1-c1ccc(-c2ccc(C3(C(=O)OCC)CC3)cc2)cc1
Reactant: Ic1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C(F)(F)/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 168, Step 1, using 1-{4′-[4-(2,2-difluoro-1-hydroxy-but-3-enyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and iodobenzene.